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20- One Hundred Syndromes
Terms in this set (140)
22q11 DELETION SYNDROME
(DiGeorge, Velocardiofacial syndrome, Shprintzen syndrome)
Responsible genes: ?UFDIL, TBX1?
Cytogenetic locus: 22q11.2
Inheritance: AD; 93% de novo
Clinical Features and Diagnostic Criteria: congenital heart disease (74%) (TOF, IAA B, conotruncal defects), immune dysfunction, palate abnormalities (69%), feeding problems, developmental delay, learning problems (70-90%), hypocalcemia (50%), renal anomalies (37%), psychiatric disorders, medial deviation of the internal carotids
Clinical Tests:serum Ca, PTH, T/B Cell subsets, Ig's, post vaccine Ab's, renal US, video laryngoscopy
Molecular Tests: FISH or MLPA for DGCR deletion (95%). 3-Mb
deletion most common; no clear genotype-phenotype relationship to del size. (A small % with S/Sx 22q11 del without a DGCR deletion have 10p13-p14 deletion)
Disease Mechanism: Abnormal development of the pharyngeal
arches somehow related (at least in part) to TBX1 dosage
Treatment/Prognosis: Standard Tx for CHD, palate repair, pharyngeal flap, Ca replacement, no live vaccines if immunodeficient
Responsible genes: JAG1, NOTCH2
Proteins: Jagged 1, Neurogenic locus notch homolog protein 2
Cytogenetic locus (loci): 20p12, 1p13-p11
Inheritance: AD, 50-70% de novo
Clinical Features and Diagnostic Criteria: Dx: Bile duct paucity on liver bx + any three of: cardiac defects (most often PA disease, TOF), cholestasis, skeletal abnormalities (butterfly vertebrae), eye (posterior embryotoxin), or characteristic facial features. Also developmental delay, growth failure
Clinical Tests: Bile duct paucity on liver bx
Molecular Tests: seq JAG1 (88%), JAG1 20p12 del FISH (~7%),
NOTCH2 seq (<1%)
Disease Mechanism: JAG1:Truncated protein product rendering it unable to bind to the cell membrane resulting in functional haploinsufficiency
Treatment/Prognosis: Liver transplant, cardiac and renal anomalies treated in standard manner, evaluate head injuries and CNS symptoms for vascular accidents, fat soluble vitamins, monitor growth and development
Deep‐set eyes with moderate hypertelorism
Saddle or straight nose with a bulbous tip
Responsible gene: SCN5A
Protein: Sodium channel protein type 5 subunit alpha
Cytogenetic locus: 3p21
Clinical Features and Diagnostic Criteria: Syncope or nocturnal agonal respiration. ST-segment abnormalities in leads V1-V3 on the ECG and a high risk of ventricular arrhythmias and sudden death. Manifests primarily during adulthood (range 2 days to 85 yrs). Mean age of sudden death: 40 yrs. May present as SIDS or the sudden unexpected nocturnal death
syndrome (a typical presentation in individuals from Southeast Asia). May have FH sudden cardiac death.
Clinical Tests: ECG
Molecular Tests: SCN5A scanning/seq (20-25%)
Disease Mechanism: Gene mutations cause lack of expression of or acceleration in the inactivation of cardiac sodium channels.
Treatment/Prognosis: Implantable defibrillators, isoproterenol, avoid inducing medication (vagotonic agents, alpha adrenergic antagonists, beta adrenergic antagonists, TCA, first generation antihistamines, cocaine, class 1C antiarrhythmic drugs, class 1A agents (procainamide, disopyramide)
CARDIO-FACIO-CUTANEOUS SYNDROME (CFC)
Responsible genes: BRAF, MEK1, MEK2, KRAS
Proteins: B-Raf proto-oncogene serine/threonine-protein-kinase, Dual specificity mitogen-activated protein kinase 1 and 2, GTPase KRas
Cytogenetic loci: 7q34, 15q22.31,19p13.3, 12p12.1
Inheritance: AD (majority de novo)
Clinical Features and Diagnostic Criteria: Cardiac abnormalities
(pulmonic stenosis, septal defects, hypertrophic cardiomyopathy, arrhythmia), distinctive facial features, and cutaneous abnormalities (xerosis, hyperkeratosis, ichthyosis, eczema, ulerythema ophyrogenes), mild-moderate intellectual disability
Clinical Tests: echocardiogram, renal ultrasound, cognitive testing
Molecular Tests: gene sequencing
Disease Mechanism: sustained activation of the Ras MAPK pathway downstream effectors: MEK and/or ERK
Treatment/Prognosis: Standard cardiac care, dermatology
consultation, early intervention and individualized education plans
CARDIO-FACIO-CUTANEOUS SYNDROME (CFC) face
High forehead with bitemporal constriction
Posteriorly rotated ears with thick helices
Hypertelorism with down slanting palpebral fissures
Epicanthal folds and ptosis
Depressed nasal bridge with anteverted nares
Highly arched palate
Cupid's Bow Lips
More coarse features and more dolichocephaly than Noonan syndrome
Responsible genes: HRAS
Proteins: GTPase HRas
Cytogenetic loci: 11p15.5
Inheritance: AD (majority de novo)
Clinical Features and Diagnostic Criteria: feeding issues,
developmental delay, intellectual disability, coarse facial features, loose, soft skin, hypertrophic cardiomyopathy, pulmonary stenosis, arrhythmia
Clinical Tests: echocardiogram, neurocognitive testing
Molecular Tests: gene sequencing
Disease Mechanism: Missense mutations lead to constitutive
activation of the abnormal protein product resulting in increased
signaling through the Ras MAP Kinase pathway
Treatment/Prognosis: Standard cardiac care, dermatology
consultation, early intervention and individualized education plans, may require assisted feeding (nasogastric or gastric tube)
HEREDITARY HEMORRHAGIC TELANGIECTASIA
Responsible genes: ACVRL1, ENG
Proteins: Serine/threonine-protein kinase receptor R3
Cytogenetic loci: 12q11-q14, 9q34.1
Clinical Features and Diagnostic Criteria: nosebleeds, mucocutaneous telangiectases (lips, oral cavity, fingers, and nose), visceral AV malformation (pulmonary, cerebral, hepatic, spinal, gastrointestinal). Hemorrhage is often the presenting symptom of cerebral AVM. Most visceral AVM's present as a result of blood shunting through the abnormal vessel and bypassing the capillary beds.
Clinical Tests: Stool for occult blood, CBC (anemia or polycythemia), contrast echo to find pulmonary AVM, Head MRI for cerebral AVM, US for hepatic AVM
Molecular Tests: Sequence analysis ACVRL1, ENG (60-80%),
duplication/deletion analysis (10%)
Disease Mechanism: HHT is assumed to be the result of haploinsifficiency
Treatment/Prognosis: Transcatherter embolization of pulmonary AVM >3.0mm. OCP can decrease/eliminate bleeding. Liver transplant if hepatic AVM is causing heart failure.
Responsible gene: TBX5
Protein: T-box transcription factor TBX5
Cytogenetic loci: 12q24.1
Inheritance: AD (85% de novo)
Clinical Features and Diagnostic Criteria: Malformation of the carpal bone(s) and, variably, the radial and/or thenar bones (left often more severe than right). 100% have carpal bone abnormality. 75% have CHD, most often multiple ASD or VSD, arrhythmia (even if no CHD)
Clinical Tests: hand xray
Molecular Tests: TBX5 sequencing (>70%), Del/Dupl analysis (<1%). Rarely due to SALL4 mutations.
Disease Mechanism: The TBX5 protein product is a transcription
factor with an important role in both cardiogenesis and limb
development. TBX5 mutations lead to mutant TBX5 mRNAs that are rapidly degraded or to transcripts with diminished DNA binding- both of which result in decreased gene dosage.
Treatment/Prognosis: Pacemaker if severe heart block, standard cardiac surgery, pollicization may be indicated if thumb
aplasia/hypoplasia. Annual ECG, annual Holter if h/o abnormal ECG
Noonan syndrome with Multiple Lentigines (NS-ML) formerly known as LEOPARD Syndrome
Responsible gene: PTPN11, RAF1
Protein: SHP2 , RAF proto-oncogene serine/threonine-protein kinase
Cytogenetic locus: 12q24, 3p25
Clinical Features and Diagnostic Criteria: Lentigines, Electrocardiographic conduction abnormalities, Ocular
hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, sensorineural Deafness.
Hypertrophic cardiomyopathy in majority
Clinical Tests: Audiogram, ECG, echocardiogram
Molecular Tests: PTPN11 sequencing (80%), RAF1 (3%)
Disease Mechanism: Loss of function PTPN11 mutations
(Noonan syndrome mutations are gain of function)
Treatment/Prognosis: Treat cardiac defects, deafness
Down slanting palpebral fissures
Low set ears
Responsible genes: PTPN11, SOS1, KRAS, RAF1, NRAS, CBL, SHOC2, BRAF
Proteins: SHP2, Son of sevenless homolog 1, GTPase KRAS, RAF protooncogene serine/threonine-protein kinase, NRAS, CBL, SHOC2, B-raf protooncogene serine/threonine-protein kinase
Cytogenetic loci: 12q24.1, 2p22-p21, 12p12.1, 3p25, 1p13.2, 11q23.3, 10q25,7q35
Clinical Features and Diagnostic Criteria: Characteristic facial features, short stature, feeding problems, pulmonary valve stenosis, hypertrophic cardiomyopathy, cryptorchidism, renal malformation, lymphedema, bleeding disoders, myeloproliferative disorder, inc risk of leukemia and learning
Clinical Tests: Echocardiogram, renal ultrasound, bleeding studies
Molecular Tests: PTPN11 sequencing (50%), SOS1 sequencing (10%), RAF1 (10%), SHOC2 (2%), KRAS (1%), RAS/CBL/BRAF (<1% each)
Disease Mechanism: Gain of function mutations that lead to constitutive activation of the Ras MAP Kinase pathway
Treatment/Prognosis: Standard cardiac care, orchiopexy, early intervention, GH replacement
Responsible gene: Contiguous gene deletion syndrome, ELN in the critical region
Protein: Elastin Cytogenetic locus: 7q11.23
Inheritance: AD, majority of cases de novo
Clinical Features and Diagnostic Criteria: CV any artery may be
narrowed, supravalvar aortic stenosis (SVAS) most common (75%). Distinctive facial features. CT: hoarse voice, hernia, rectal prolapse, joint limitation or laxity. ID. Overfriendly, anxiety d/o, ADD. Endo: hypercalcemia, hypercalciuria, hypothyroidism, FTT infancy
Clinical Tests: Serum and urine calcium and creatinine, TFTs, hearing and vision evaluation, renal US, echocardiogram
Molecular Tests: FISH or MLPA for 7q11.23 critical region (~99%). Point mutations in ELN cause AD isolated SVAS
Disease Mechanism: Elastin deletion causes the CV and CT
problems, LIMK1 has been linked to the visuospatial construction cognitive deficit
Treatment/Prognosis: PT, OT, ST. Monitor adults who are at risk for MVP, AI, arterial stenosis, SNHL, hypothyroidism, DM. Monitor for hypercalciuria. Aggressive management of constipation
stellate/lacy iris pattern
full nasal tip
Responsible gene: ATM
Protein: Serine-protein kinase ATM
Cytogenetic locus: 11q22.3
Inheritance: AR (carriers may be at risk cancer)
Clinical Features and Diagnostic Criteria: Progressive cerebellar
ataxia (onset age 1-4y), oculomotor apraxia, conjunctival
telangiectasia, immunodef, choreoathetosis, ionizing radiation
sensitivity, risk cancer (lymphoma and leukemia)
Clinical Tests: AFP, decreased ATM kinase activity, 7;14
translocation (5-15% of lymphocytes after PHA stimulation)
Molecular Tests: ATM sequencing (>95%). Amish founder mutation
Disease Mechanism: Most mutations are null leading to no protein product. The normal protein finds double strand dsDNA breaks and coordinates cell cycle checkpoints prior to repair
Treatment/Prognosis: IVIG if immunodeficient, PT to reduce
contractures, wheelchair usually by age 10, supportive therapy for drooling, choreoathetosis, and ataxia. Avoid ionizing radiation. Regular medical visits to monitor for S/Sx of malignancy
Responsible gene: BLM
Protein: Bloom syndrome protein
Cytogenetic locus: 15q26.1
Inheritance: AR (1/100 carrier freq in Ashkenazi Jewish)
Clinical Features and Diagnostic Criteria: IUGR, hyper and
hypopigmentation, butterfly distribution sun sensitive
telangiectasia, microcephaly, high pitched voice, normal
intelligence, immunodeficiency, azoospermia, POF, increased risk of cancer (wide distribution of type and site (colon most common), often multiple primary tumors).
Clinical Tests: Chromatid/chromosome breaks; triradial and
Molecular Tests: BLM 2881 del6ins7 (97% mutant allele in AJ)
Disease Mechanism: Abnormal DNA replication and repair
leading to genomic instability.
Treatment/Prognosis: Increased cancer surveillance, decrease
exposure to UV light and x-ray, BMT, colon cancer surveillance
Responsible genes (Protein and Cytogenetic locus): FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG (Fanconi anemia group A, B, C, D2, E, F, and G protein; 16q24.3, Xp22.3, 9q22.3, 3p25.3, 6p22-21, 11p15, and 9p13); BRCA2
(Breast cancer type 2 susceptibility protein, 13q12.3); BRIP1 (Fanconi anemia group J protein, 17q22); FANCL (E3 ubiquitin-protein ligase FANCL).
Clinical Features and Diagnostic Criteria: Short stature; abnl pigmentation; radial, GU, ear, heart, GI, or CNS malformation; hearing loss, hypogonadism, developmental delay. Progressive bone marrow failure, aplastic anemia, myelodysplastic syndrome, AML, solid tumor of head, neck, esophagus, cervix,
vulva, or liver at unusually young age.
Clinical Tests: Chromosome breakage, macrocytic rbcs, immunoblot assay of FANCD2 monoubiquitination, increased % of cells in G2 arrest by cell sorting.
Molecular Tests: Seq and Del/Dup analysis FANCA (66%), Seq analysis FANCB (0.8%), FANCC (9.6%), FANCD1, FANCD2, FANCE, FANCF (~3% each), FANCG (8.8%), FANCL (0.4%) and BRCA2
Disease Mechanism: At least 5 of the FA proteins are assembled in a nuclear complex. In response to DNA damage, this complex activates monoubiquitination of FANCD2 protein and is targeted to BRCA1 repair foci.
Treatment/Prognosis: Androgens, blood transfusions, growth hormone, BMT, cancer prevention (avoid toxic agents and sun exposure), cancer surveillance
CONGENITAL CONTRACTURAL ARACHNODACTYLY (Beals Syndrome)
Responsible gene: FBN2
Cytogenetic locus: 5q23-q31
Clinical Features and Diagnostic Criteria: Marfanoid appearance, long slender fingers and toes, crumpled ears, major joint contracture, muscle hypoplasia, kyphosis/scoliosis, Severe/lethal: aortic dilation, ASD, VSD, IAA, duodenal or esophageal atresia, malrotation
Clinical Tests: x-ray, echocardiogram, UGI with SBFT
Molecular Tests: FBN2 sequencing (75%)
Disease Mechanism: Fibrillin 2 is a glycoprotein of the extracellular matrix microfibrils, it is co-distributed with fibrillin 1 in many tissues. The precise function is not known.
Treatment/Prognosis: PT for joint contracture, contracture surgical release, bracing and/or surgical correction of kyphoscoliosis. Echo every 2 years until it is clear the aorta is not involved. Annual exam for scoliosis/kyphosis.
EHLERS-DANLOS SYNDROME CLASSIC TYPE (Type I and Type II)
Responsible genes: COL5A1 and COL5A2
Proteins: Collagen alpha-1 and alpha-2 (V) chain
Cytogenetic loci: 9334.2-q34.3 and 2q31
Clinical Features and Diagnostic Criteria: skin hyperextensibility,
widened atrophic scars, joint hypermobility, smooth velvety skin, molluscoid pseudotumors (heaped up scar-like lesions over pressure points), subcutaneous spheroids (cyst-like lesions, feel like grains of rice, over bony prominences of legs and arms, they are fibrosed and calcified fat globules), joint sprains/dislocations/subluxations, hypotonia, easy bruising, hernia, chronic pain, aortic root dilation
Clinical Tests: Ultrastructural studies by EM suggest disturbed collagen fibrillogenesis ("cauliflower" deformity is characteristic).
Molecular Tests: COL5A1 "null" allele testing on cultured fibroblasts (30%), COL5A1 and COL5A2 sequencing (50%)
Disease Mechanism: Dominant negative activity of abnormal Collagen alpha-1 or alpha-2 (V) chains (interfere with the utilization of normal protein from the normal allele)
Treatment/Prognosis: PT, non-weight-bearing muscular exercise, dermal wounds repaired with two layer closure without tension, if possible avoid joint surgery, baseline echo for aortic root assessment
EHLERS-DANLOS SYNDROME, HYPERMOBILITY TYPE (Type III)
Responsible gene: TNXB
Cytogenetic locus: 6p21.3
Clinical Features and Diagnostic Criteria: Joint hypermobility, soft or velvety skin with normal or slightly increased elasticity, absence of skin or soft tissue fragility, recurrent joint dislocation/subluxation, chronic joint or limb pain, easy bruising, high narrow palate, dental crowding, and low bone density. Kids less than age 5 are often very flexible and therefore are hard to assess. Reported instances of aortic root dilation and MVP.
Clinical Tests: The biochemical etiology is unknown in most cases. Serum tenascin X protein testing is available on a research basis.
Molecular Tests: Not done
Disease Mechanism: Abnormal dermal elastic fibers
Treatment/Prognosis: Improve joint stability with low-resistance
exercise to inc muscle tone, avoid joint hyperextension, avoid high impact sports, wide writing utensils to avoid strain on finger and hand joints, joint bracing, pain management specialist, delay joint surgery in favor of PT and bracing. Baseline echocardiogram
EHLERS-DANLOS SYNDROME, VASCULAR TYPE (Type IV)
Responsible gene: COL3A1
Protein: Collagen alpha-1 (III) chain
Cytogenetic locus: 2q31
Clinical Features and Diagnostic Criteria: Major criteria: arterial
rupture, intestinal rupture, uterine rupture during pregnancy, FH of Vascular EDS. Minor criteria: thin, translucent skin, easy bruising, thin lips and philtrum, small chin, thin nose, large eyes, aged appearance of hands, small joint hypermobility, tendon/muscle rupture, varicose veins, AV carotidcavernous
sinus fistula, pneumothorax, CHD, clubfoot, gum recession
Clinical Tests: Cultured dermal fibroblasts: amount of type III procollagen synthesized, the quantity secreted into the medium, and the electrophoretic mobility are assessed (95% of cases of vascular EDS)
Molecular Tests: cDNA or genomic DNA COL3A1 sequence analysis (98-99%)
Disease Mechanism: Abnormalities of type III procollagen production, intracellular retention, reduced secretion, and/or altered mobility
Treatment/Prognosis: Minimization of surgical exploration and
intervention, prompt surgery for bowel rupture, distal colectomy if recurrent bowel rupture, high risk obstetrical care. Minimize lifting and weight training, no contact sports, no arteriograms
EDS VASCULAR TYPE face
EHLERS-DANLOS SYNDROME, KYPHOSCOLIOTIC TYPE (Type VI)
Responsible gene: PLOD1
Protein: Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1
Cytogenetic locus: 1p36.3-p36.2
Clinical Features and Diagnostic Criteria: Major features: friable,
hyperextensible skin, thin scars, easy bruising, generalized joint laxity, severe muscle hypotonia, progressive scoliosis, scleral fragility and rupture of the globe. Minor features: widened atrophic scars, marfanoid habitus, rupture of medium sized arteries, mild to moderate delay of attainment of gross motor milestones
Clinical Tests: Crosslinked telopeptides are excreted in urine as a byproduct of increased collagen turnover. Inc ratio of deoxypyridinoline to pyridinoline by urine HPLC is highly sensitive and specific. Enzyme activity in cultured fibroblasts (<25% activity is abnormal)
Molecular Tests: PLOD1 seq research only, unknown frequency
Disease Mechanism: Enzyme deficiency leads to deficiency in
hydroxylysine-based pyridinoline crosslinks in types I and III collagen.
Treatment/Prognosis: Surgical correction of scoliosis is not
contraindicated), PT, echocardiogram and standard treatment for MVP or aortic root dilation, aggressive control of BP, routine eye exams
LOEYS DIETZ SYNDROME
Responsible gene: TGFBR1, TGFBR2, SMAD3, TGFB2
Protein:TGF‐beta recepor type‐1 and type‐2, Mothers against decapentaplegic homolog 3, Transforming growth factor beta‐2
Cytogenetic locus: 9q22.33, 3p24.1, 15q22.33, 1q41
Clinical Features and Diagnostic Criteria: vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections) and skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). 75% have LDS type I with craniofacial manifestations (ocular hypertelorism, bifid uvula/cleft palate, craniosynostosis); 25% have LDS type II with cutaneous manifestations (velvety and translucent skin; easy bruising; widened, atrophic scars).
Clinical Tests: Echocardiogram, MRA or CT scan for arterial aneurysm/tortuosity, spinal xrays
Molecular Tests:gene sequencing and del/dup testing
Disease Mechanism:data demonstrate increased TGFβ signaling in the vasculature of persons with LDS
Treatment/Prognosis: Regular surveillance imaging of the vasculature, Beta blockers/Losartan for aortic root dilation, bracing/surgery for scoliosis
Responsible gene: FBN1
Protein: Fibrillin 1
Cytogenetic locus: 15q21.1
Clinical Features and Diagnostic Criteria: Major involvement of 2 body systems and minor involvement of a 3rd. Major Criteria CV: Dilation or dissection of the ascending aorta Skeletal: pectus carinatum or excavatum, reduced upper:lower segment or arm span:ht, scoliosis, pes planus, high palate, reduced elbow extension, protrusio acetabulae, Eye: ectopia lentis,
Dura: lumbosacral dural ectasia, FH: pathogenic FBN1 mutation, 1st degree relative with Marfan syndrome. Minor Criteria CV: MV, MR, dilation of main PA, mitral annulus calcification, dilation or dissection of the descending thoracic or
abdominal aorta age <50yrs, Skeletal: moderate pectus excavatum, joint hypermobility, high palate with crowding of teeth, typical facial features Eye: flat cornea, increased length of globe, decreased pupillary meiosis, Lung: pneumothorax, apical lung blebs, Skin: skin striae, hernia
Clinical Tests: CXR: apical blebs, Echocardiogram: MVP, aortic
measurements, CT or MRI: dural ectasia
Molecular Tests: FBN1 seqencing (70-90%)
Disease Mechanism: Dominant negative effect of mutant forms of fibrillin
Treatment/Prognosis: Beta blockers/Losartan for aortic root dilation, bracing/surgery for scoliosis, annual dilated eye exam, glasses for myopia
HIDROTIC ECTODERMAL DYSPLASIA
Responsible gene: GJB6
Protein: Gap junction beta-6 protein (Connexin 30)
Cytogenetic locus: 13q12
Clinical Features and Diagnostic Criteria: malformed,
thickened, small nails; hypotrichosis (partial or total alopecia),
palmoplantar hyperkeratosis, normal sweating and teeth.
Clinical Tests: None
Molecular Tests: Three GJB6 mutations (G11R, A88V, V37E)
account for 100% of indentified mutant alleles
Disease Mechanism: Helps form a gap junction channel
which mediates ion diffusion. Mutations are thought to affect
trafficking of the protein and thus the formation of the gap
Treatment/Prognosis: No specific treatment. Skin emollients
HYPOHIDROTIC ECTODERMAL DYSPLASIA (HED)
Responsible genes: EDA, EDAR, EDARADD
Proteins: Ectodysplasin-A, Tumor necrosis factor receptor superfamily member EDAR, ectodysplasin A receptor-associated adapter protein
Cytogenetic loci: Xq12-q13.1, 2q11-q13, 1q42.2-q43
Inheritance: XL (95%), AD or AR (5%)
Clinical Features and Diagnostic Criteria: At birth: peeling skin and perioral hyperpigmentation. Hypotrichosis (sparse scalp and body hair), hypohidrosis (inability to sweat in response to heat leads to hyperthermia), hypodontia (usually only 5-7 teeth develop, teeth are smaller with conical crowns. Carriers of XL HED show mosaic pattern of sweat pore function and some degree of hypodontia.
Clinical Tests: dental xray.
Molecular Tests: EDA sequencing (~95% XL HED), EDAR and EDARADD sequencing
Disease Mechanism: Defective ectodysplasin A cannot be activated to mediate the cell-to-cell signaling that regulates morphogenesis of ectodermal appendages. Defective EDAR cannot bind ectodysplasin. The protein encoded by EDARADD is co-expressed with EDAR.
Treatment/Prognosis: During hot weather maintain hydration and keep down body temp with A/C, "cooling vests", and/or spray bottle of water. Tooth restoration, orthodontics, and/or dentures may be necessary
Responsible gene: IKBKG (aka NEMO)
Protein: NF-kappaB essential modulator
Cytogenetic locus: Xq28
Inheritance: XLD (most male fetuses miscarry)
Clinical Features and Diagnostic Criteria: Major: Four stages of
skin changes: erythema->blister->hyperpigmented streaks->atrophic skin patches. Minor: hypo/andontia, small or malformed teeth, alopecia, woolly hair, nail ridging or pitting, retinal neovascularization causing retinal detachment. ID is rare.
Clinical Tests: Free melanin granules if hyperpigmented streak
Molecular Tests: Southern blot: Exon 4-10 deletion (80%). Skewed X inactivation in females (not diagnostic).
Disease Mechanism: Lack of NF-kappa beta activation leads to
cells that are sensitive to proapoptotic signals and apopose easily.
Treatment/Prognosis: Regular retinal exams in first 1-2 yrs.
Cosmetic dentistry. Normal life expectancy.
Responsible genes: TYR and OCA2
Proteins: Tyrosinase protein, P protein
Cytogenetic loci: 11q14-q21, 15q11.2-q12 (in PWS/Angelman
Clinical Features and Diagnostic Criteria: OCA1A (no melanin
synthesis) nystagmus, dec iris pigment, foveal hypoplasia, dec visual acuity, strabismus, white hair and skin, translucent iris. OCA1B (some melanin synthesis) milder eye and skin manifestation than OCA1. OCA2 ocular problems same as OCA1 but better vision, range of skin and eye pigmentation from minimal to near normal
Clinical Tests: Skin and eye exam, VEP
Molecular Tests: TYR sequencing (OCA1A: 2 mutations 83%;
OCA1B: 2 mutations 37%). 2kb OCA2 deletion testing (most of Sub-Saharin African heritage)
Disease Mechanism: Lack of melanin production
Treatment/Prognosis: Yearly eye exam, sun screen and monitoring for skin cancer.
X-LINKED ADRENAL HYPOPLASIA CONGENITA
Responsible gene: NROB1
Protein: Nuclear receptor 0B1
Cytogenetic locus: Xp21.3-p21.2
Clinical Features and Diagnostic Criteria: acute onset adrenal
insufficiency (hyperkalemia, acidosis, hypoglycemia, shock),
cryptorchidism, delayed puberty. Carrier females: may have adrenal insufficiency or hypogonadotropic hypogonadism
1/3 contiguous gene deletion with glycerol kinase, DMD del
2/3 isolated CAH (half are de novo)
Clinical Tests: Dec Na+, Inc K+, acidosis, inc ACTH with low cortisol, dec 17 hydroxyprogesterone. If GKD: serum triglyceride, urine glycerol. If DMD: elevated CK
Molecular Tests: NROB1 FISH deletion (100%)
Disease Mechanism: OB1 is a negative regulator of nuclear receptor pathways
Treatment/Prognosis: Treat adrenal crisis, replacement steroids and stress dosing, HRT for hypogonadism
Responsible gene: CYP21A2
Protein: Cytochrome P450 XXI
Cytogenetic locus: 6p21.3
Clinical Features and Diagnostic Criteria: virilized female, precocious puberty or adrenarche, childhood virilization in males, infant with Na+ losing crisis at birth. Nonclassic form: moderate enzyme deficiency with variable postnatal virilization, no salt wasting, but rare cortisol def.
Clinical Tests: Elevated serum 17-OHD at baseline or after ACTH stim, elevated testosterone and adrenal androgen precursors in females and prepubertal males. Part of NBS (17-OHD level)
Molecular Tests: CYP21A2 common mutation and deletion panel detects 80-98%
Disease Mechanism: cortisol production pathway is blocked->
accumulation of 17-OHP->shunted into the intact androgen pathway->17,20-lyase enzyme converts the 17-OHP to -androstenedione->converted into androgens. The mineralocorticoid pathway requires minimal 21-hydroxylase activity->salt wasting
Treatment/Prognosis: Hydrocortisone (monitor closely: too little will have excess androgen, too much causes Cushing's, skeletal maturation), stress dose steroids
ANDROGEN INSENSITIVITY SYNDROME (Testicular Feminization)
Responsible gene: AR
Protein: Androgen receptor
Cytogenetic locus: Xq11-q12
Clinical Features and Diagnostic Criteria: Evidence of feminization (i.e., undermasculinization) of the ext. genitalia, abnl secondary sexual development, and infertility in those with a 46,XY karyotype. Spectrum: complete androgen insens. syndrome (CAIS), with typical female genitalia; partial androgen insens. syndrome (PAIS) with predominantly female, predominantly male, or ambiguous genitalia; and mild androgen insens. syndrome (MAIS) with nl male genitalia.
Clinical Tests: impaired spermatogenesis, absent or rudimentary müllerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, normal or increased LH, and deficient
or defective androgen-binding activity of genital skin fibroblasts
Molecular Tests: AR sequence analysis (>95% CAIS, <50% PAIS, unknown %MAIS)
Disease Mechanism: Impaired androgen binding
Treatment/Prognosis: To prevent testicular malignancy, treatment of CAIS includes either removal of the testes after puberty when feminization is complete or prepubertal gonadectomy accompanied by estrogen replacement therapy.
Systematic disclosure of the diagnosis of AIS in an empathic environment
KALLMAN SYNDROME TYPE 1 and 2
Responsible genes: KAL, FGFR1
Proteins: Anosmin 1, fibroblast growth factor receptor 1
Cytogenetic loci: Xp22.3, 8p11.1-11.2
Inheritance: XLR, AD
Clinical Features and Diagnostic Criteria: Type 1and 2:
hypogonadotropic hypogonadism and anosmia. Usually present
with delayed pubertal development. Type 1 can also include mirror hand movements, ataxia, GU anomaly, high palate, pes cavus. Type 2 ID, CL/P, cryptorchidism, choanal atresia, CHD, SNHL.
Clinical Tests: Low FSH and LH; low testosterone in males; low
estradiol in females. MRI: hypo/aplasia olfactory bulbs and tracts.
Molecular Tests: Sequencing KAL (5-10%), FGFR1 (8-16%)
Disease Mechanism: Lack of anosmin stops olfactory axons from interecting with their target. It is thought that FGFR1 may play a role in olfactory bulb formation and possibly interacts with anosmin
Treatment/Prognosis: Normalize gonadal steroid levels.
Clinical Features and Diagnostic Criteria: Tall stature,
slightly delayed motor and language skills, inc learning probs,
testosterone plateaus age 14, small fibrosed testes, azoospermia and infertility, gynecomastia, inc cholesterol,
slightly inc risk of autoimmune disorders and mediastinal
germ cell tumors (1% risk)
Clinical Tests: karyotype, at least one extra chromosome
to a 46,XY Karyotype
Disease Mechanism: 1st or 2nd meiotic division
nondisjunction of either parent. Maternal>paternal origin.
Treatment/Prognosis: Testosterone in mid-late adolescence
for bone density, secondary sex characteristic development,
muscle mass, cholesterol, increase libido, improved energy.
Can do testicular biopsy and use any retrieved sperm for ICSI
(inc risk sex chrom abnormality so follow with PGD
Responsible gene: GNAS
Protein: Guanine nucleotide-binding protein G(s), alpha subunit
Cytogenetic locus: 20q13.2
Clinical Features and Diagnostic Criteria: polyostotic fibrous
dysplasia, pathologic fracture, cranial foramina thickening->deafness and blindness, large irregular café au lait ("coast of Maine"), precocious puberty, hyperthyoidism, inc GH, PRL, or PTH, ovarian cysts
Clinical Tests: x-ray, pelvic US, vision and hearing testing, pituitary hormone analysis
Molecular Tests: Targeted mutation analysis
Disease Mechanism: Activating mutations (a stimulatory G-protein) leads to persistently high cAMP (de-activating mutations cause Albright Heredity Osteodystrophy)
Treatment/Prognosis: Aromatase inhibitor to block testosterone,
bisphosphonate for fibrous dysplasia, anti-thyroid meds, octreotide (somatostatin analog) and bromocriptine (dopamine receptor agonist)
TRANSIENT NEONATAL DIABETES MELLITUS
Responsible genes: HYMAI, PLAGL1
Proteins: unknown (HYMAI), zinc finger protein PLAG1
Cytogenetic loci: 6q24 (HYMAi and PLAG1)
Inheritance: UPD isodisomy chromosome 6, paternal 6q24
duplication, or 6q24 methylation defect
Clinical Features and Diagnostic Criteria: DM in the first six weeks of life, resolves by 18 months, severe IUGR, dehydration,
hyperglycemia. Occassional macroglossia and umbilical hernia.
Clinical Tests: High serum glucose and low plasma insulin, no islet cell antibodies, no ketoacidosis. 2% have a visible 6q24 duplication
Molecular Tests: UPD6 (35%), 6q24 duplication (35%), imprinting mutation (20%)
Disease Mechanism: PLAGL1 and HYMAI are normally only
expressed on the paternal allele, unclear why overexpression causes DM. HYMAI may regulate PLAGL1 expression
Treatment/Prognosis: Rehydration, IV insulin and then
subcutaneous insulin within two weeks, close blood glucose
monitoring. Inc risk to later develop type II DM during illness, puberty or during pregnancy
Responsible genes: X genes that escape inactivation, SHOX
Proteins: SHOX: Short stature homeobox protein
Cytogenetic locus: SHOX: Xpter-p22.32
Clinical Features and Diagnostic Criteria: congenital lymphedema, growth failure, normal intelligence (10% sig delays), coarctation of the aorta, bicuspid aortic valve, HLHS, hyperlipidemia, gonadal dysgenesis (10% 45,X go into puberty), hypothyroidism, diabetes, strabismus, recurrent OM, SNHL, Crohns, renal malformation, osteoporosis.
Clinical Tests: echo, renal US, TFTs, GH testing, FISH SRY
Molecular Tests: Karyotype
Disease Mechanism: SHOX: thought to act as a transcription regulator with many down-stream targets that modify growth and stature. SHOX protein has been id'ed in the growth plate from 12 weeks GA to late childhood.
Treatment/Prognosis: GH, HRT, gonadectomy if Y chromosome
mosaicism (risk for gonadoblastoma). Need lifelong cardiac follow-up, at risk for aortic dilation and dissection with bicuspid aortic valve.
BLEPHAROPHIMOSIS, PTOSIS, and EPICANTHUS INVERSUS (BPES)
Responsible gene: FOXL2
Protein: Forkhead Box Protein L2
Cytogenetic locus: 3q23
Inheritance: AD (50% de novo)
Clinical Features and Diagnostic Criteria: blepharophimosis,
ptosis, epicanthus inversus, and telecanthus. BPES type I includes the four major features and premature ovarian failure (POF); BPES type II includes only the four major features. Can also see: lacrimal duct anomalies, amblyopia, strabismus, and refractive errors. Minor features: broad nasal bridge, low-set ears, and a short philtrum.
Molecular Tests: Combination of seq analysis and deletion testing
Disease Mechanism: FOXL2 is a transcriptional repressor of
granulosa cell differentiation; mutations cause accelerated
differentiation of granulosa cells and secondary depletion of the
primordial follicle pool
Treatment/Prognosis: Surgical correction of eye anomalies, ovum donation if POF
CONGENITAL HEARING LOSS
Connexin 26 and 30
Responsible genes: GJB2 (Cx26), GJB6 (Cx30)
Proteins: Gap junction proteins 2 and 6
Cytogenetic loci: 13q11-12
Clinical Features and Diagnostic Criteria: Congenital mild-profound SNHL. Rare patients can have AD Cx26 HL which can include skin findings: palmarplanter keratoderma, KID syndrome
Clinical Tests: Newborn hearing screen, ABR diagnostic, monitor with standard audiometry.
Molecular Tests: GJB2: sequencing of exon 2 and exon 1 for splice site mutation (4th most common mutation). 35delG common in caucasians, 235delC in Asians, 167delT, del35Gand Cx30 gene deletion in Ashkenazi Jewish. GJB6-D13S1830 deletion: deletion that includes Cx30, causes HL if homozygous or combined with single Cn26 mutation.
Disease Mechanism: Loss of gap junction prevents recycling of toxic ions and metabolites away from hair cells leading to their death
Treatment/Prognosis: Some have progressive HL. Habilitation with hearing aids or cochlear implants.
Responsible gene (protein, cytogenetic locus): HPS1 (10q23.1, HPS 1 protein), AP3B1 (5q14.1, AP-3 complex subunit beta), HPS3,4,5,6,7and 8 (3q24, 22q11.2-q12.2, 11p15-p13, 10q24.3, 6p22.3, 19q13, HPS 3,4,5,and 6 proteins, dysbindin, and biogenesis of lysosome-related organelles complex -
Clinical Features and Diagnostic Criteria: Findings of oculocutaneous albanism and a bleeding diathesis: hypopigmentation of the skin and the hair, nystagmus, reduced iris pigment, reduced retinal pigment, foveal hypoplasia,
increased crossing of optic nerve fibers. Can develop skin cancer, pulmonary fibrosis, colitis
Clinical Tests: Absent platelet dense bodies (sine qua non) on platelet EM. Prolonged bleeding time.
Molecular Tests: Del/Dup analysis HPS1 (~75% Puerto Rican HPS), HPS3 (~25% Puerto Rican HPS). Targeted mutation analysis HPS3 (~5% non Puerto Rican HPS)
Disease Mechanism: The HPS genes protein products have unknown fxn
Treatment/Prognosis: DDAVP prior to dental work, thrombin-soaked gel foam for minor cuts, skin protection, annual eye exam, skin exam, and in adulthood PFT's.
JERVELL and LANGE-NIELSEN SYNDROME
Responsible gene: KCNQ1 and KCNE1
Protein: Voltage-gated K+ channel protein KvLQT1; K+ voltage-gated channel subfamily E member 1
Cytogenetic loci: 11p15.5, 21q22.1-q22.2
Inheritance: AR (Heterozygotes at risk for AD long QT a.k.a. Romano Ward syndrome)
Clinical Features and Diagnostic Criteria: Congenital severe- profound bilateral SNHL and prolonged QT interval. At risk for
arrhythmia, syncope, and sudden death
Clinical Tests: Hearing tests (ABR, audiogram)
Molecular Tests: KCNQ1 sequencing (90%), KCNE1 (10%)
Disease Mechanism: In cardiac cells: abnormal repolarization of the ventricular action potential. In cochlear cells: abnormal depolarization of the auditory nerve
Treatment/Prognosis: Cochlear implants for HL, beta blockers,
cardiac pacemakers, and/or implantable defibrillators. Avoid QT
prolonging drugs (http://www.arizonacert.org/). If left untreated, over ½ of children with JLNS die prior to age 15 yrs
LEBER HEREDITARY OPTIC NEUROPATHY
Responsible genes: MTND1, MTND4, MTND5, MTND6'
Proteins: Complex I subunits of the mitochondrial respiratory chain
Cytogenetic loci: Mitochondrial
Clinical Features and Diagnostic Criteria: Blurred or clouded vision progressing to degeneration of the retinal nerve and then optic atrophy. Fundus: vascular tortuosity of central retinal vessels, circumpapillary telangiectatic macroangiopathy, and swelling of the retinal nerve fibers
Clinical Tests: Visual field assessments, ERG, VEP
Molecular Tests: Targeted mutation analysis: G11778A
(70% cases), G3460A, T14484C (15%)
Disease Mechanism: Focal degeneration of the retinal
ganglion cell layer and optic nerve
Treatment/Prognosis: No treatment available, worsened
by smoking or EtOH
Responsible gene: SLC26A4 (PDS)
Protein: solute carrier 26A4
Cytogenetic locus: 7q31
Clinical Features and Diagnostic Criteria: bilateral severe SNHL,
temporal bone abnormalities, vestibular abnormalities, goiter in 75% though only 10% have abnormal thyroid function.
Clinical Tests: Hearing test. CT/MRI: dilation of the vestibular
aqueduct with or without cochlear hypoplasia (Mondini
Molecular Tests: l236P, T416P, H723R, IVS8+G>A represent 50% of all mutations. SLC26A4 sequencing available.
Disease Mechanism: SLC26A4 is a chloride/iodide exchanger in
the inner ear and thyroid, mutation leads to inner ear malformation and abnormal iodide processing in the thyroid
Treatment/Prognosis: Hearing aids, cochlear implant, monitor
Responsible genes: 11 genes, majority of cases due to MYO7A, USH2A
Proteins: Myosin-VIIa, Usherin
Cytogenetic loci: 11q13.5, 1q41 Inheritance: AR
Clinical Features and Diagnostic Criteria: Type I congenital profound HL, congenital balance problems, retinitis pigmentosa (RP) onset prepuberty. Type II congenital mild-severe HL, normal balance, RP onset in teens-20's, Type III progressive later onset HL, progressive balance problems, variable onset RP.
Clinical Tests: hearing tests, ERG, eye exam for pigment changes
Molecular Tests: Type I MYO7A sequence analysis (40-50%) Type II USH2A sequencing (65%)
Disease Mechanism: RP is caused by degeneration of rod and cone functions of the retina. For at least some gene, inner hair cell function and structure are affected in the ear.
Treatment/Prognosis: RP is progressive, bilateral, and symmetric resulting in progressively constricted visual fields though not complete blindness. Vitamin A may slow progression. HL is complete in Usher Type I and progressive in types II and III. Cochlear implants and hearing aids for HL
Responsible gene: PAX3
Protein: Paired box protein Pax-3
Cytogenetic locus: 2q35
Clinical Features and Diagnostic Criteria: WS1: SNHL, heterochromic irides, white forelock, early graying, leukoderma, dystopia canthorum, neural tube defect. WS2: WS1 without dystopia canthorum WS3: WS1 features and limb hypoplasia or contracture, carpal bone fusion, or syndactyly WS4: WS1 with Hirschprung disease
Clinical Tests: ABR, audiogram, calculation of W-index to identify dystopia canthorum
Molecular Tests: PAX3 gene sequencing (90% WS1)
Disease Mechanism: Haploinsufficiency. PAX3 is a homeobox
transcription factor involved in melanocyte development.
Treatment/Prognosis: Hearing aids or cochlear implants. Folic acid supplementation of pregnancies at risk for WS1 related neural tube defect
ACUTE INTERMITTENT PORPHYRIA
Responsible gene: HMBS
Protein: Porphobilinogen deaminase
Cytogenetic locus: 11q23.3
Clinical Features and Diagnostic Criteria: Onset after puberty,
acute attacks, abdominal pain, muscle weakness, neuropathy,
hysteria, anxiety, hepatocellular carcinoma, NO CUTANEOUS
Clinical Tests: inc urine delta-amonolevulinic acid (ALA) and
porphobilinogen (PBG) during acute attack
Molecular Tests: HMBS gene sequencing (>98%)
Disease Mechanism: ?direct neurotoxicity of PBG, ?generation of reactive oxygen species or inhibition of GABA release at central synapses by ALA, ?loss of heme in the CNS
Treatment: Stop or treat precipitant (medication, infection, EtOH,
dehydration, smoking, poor caloric intake); intubate if bulbar
paralysis; IV dextrose; IV hemin (repress ALAS-N enzyme activity); pain control
Responsible genes: HBA1, HBA2
Protein names: Hemoglobin subunit alpha 1 and 2
Cytogenetic locus (loci): 16pter-p13.3
Inheritance: AR; if parents Alpha Thal trait, risk for HbH disease if one parent's mutations are in cis, at risk for HB Bart if both parents in cis
Clinical Features and Diagnostic Criteria: HB Bart: loss or dysfunction of all 4 alpha thal alleles, hydrops fetalis, severe hypochromic anemia, death in neonatal period; HbH: loss or dysfunction of 3 of 4 alpha thal alleles, microcytic hypochromic
hemolytic anemia, HSM, jaundice Alpha Trait: loss or dysfunction of 2 alpha thal alleles, low MCV, low MCH, nl levels Hgb A2 and F; Alpha "silent" carrier: loss or dysfunction of one alpha thal allele, none or mild thalassemia-like effect
Clinical Tests: MCV, MCH, peripheral smear, reticulocyte count, hemoglobin electrophoresis. Prenatal screen at risk populations!
Molecular Tests: Targeted mutation analysis for common deletions (90%); gene sequencing (10%)
Disease Mechanism: Inability to form normal Hb A (normally composed of two alpha and two beta chains)
Treatment/Prognosis: No tx for HB Bart, rec termination due to maternal complications with hydrops. Hb H: prbc transfusions during hemolytic crisis, anemia causing cardiac sx, or severe bony changes; splenectomy with abx prophylaxis (if <5y) for splenomegaly
Responsible gene: HBB
Protein: Hemoglobin subunit beta
Cytogenetic locus: 11p15.5
Clinical Features and Diagnostic Criteria: severe anemia and HSM. Without Tx: severe FTT and shortened life expectancy. Thal. intermedia: present later, milder anemia, only rarely requires transfusion; at risk for iron overload due to inc intestinal absorption of iron. The clinical severity of the beta-thal syndromes depends on the extent of globin alpha chain/non-globin alpha chain imbalance. At risk pop's: Mediterranean, middle eastern, Indian, Thai, Chinese, African, African American.
Clinical Tests: microcytic hypochromic anemia, an abnl peripheral blood smear with nucleated RBCs, and reduced amounts of hemoglobin A (HbA) on hemoglobin analysis.
Carriers: reduced MCV, MCH, and RBC morphologic changes that are less severe than in affected individuals.
Molecular Tests: Mutation scanning/sequencing. In each at-risk population, 4-10 mutations account for the large majority of HBB disease. Compound heterozygosity for a mild/silent mutation and a severe mutation produces a variable phenotype, ranging from thalassemia intermedia to thalassemia major.
Disease Mechanism: Absence of globin beta chains. The non-assembled globin alpha chains that result from unbalanced globin alpha chain/non-globin alpha chain synthesis
precipitate in the form of inclusions which damage the erythroid precursors in the bone marrow and spleen, causing ineffective erythropoiesis.
Treatment/Prognosis: Treat with a regular transfusion program and chelation therapy (to reduce transfusion iron overload), allows for normal growth and development and extends life expectancy into the third to fifth decade.
FACTOR V LEIDEN THROMBOPHILIA
Responsible gene: F5
Protein: Coagulation factor V
Cytogenetic locus: 1q23
Inheritance: AD (moderately inc. risk VTE), AR (significantly inc .risk VTE)
Clinical Features and Diagnostic Criteria: inc. risk venous thromboembolism (VTE), most commonly deep venous thrombosis (DVT). Heterozygous: at most modest inc. in VTE recurrence risk, 2-3x inc RR pregnancy loss. Homozygous: Inc.
chance VTE recurrence. Arterial thrombosis, MI, and stroke not associated with factor V Leiden.
Clinical Tests: APC resistance assay, sensitivity and specificity for factor V Leiden approaches 100%
Molecular Tests: F5 G to A substitution at nt 1691 (100%)
Disease Mechanism: The G>A substitution affects an APC cleavage site and the mutant factor V Leiden is inactivated 10x more slowly and persists longer in circulation-> inc. thrombin generation
Treatment/Prognosis: Risk of VTE compounded by coexisting thromboembolic d/o, malignancy, travel, central venous catheters, pregnancy, OCP, HRT, advancing age, surgery, organ transplant. Heterozygotes with first VTE with no id'ed risk factor or a persistent risk factor require longer course of anticoagulation than those with a transient risk factor (eg surgery). Long term anticoagulation with LMW Heparin or
Warfarin if recurrent VTE, multiple thrombophilic d/o, coexistent circumstantial risk factors, and factor V Leiden homozygotes
Responsible gene: F8
Protein: Coagulation Factor VIII
Cytogenetic locus: Xq28 Inheritance: XLR
Clinical Features and Diagnostic Criteria: hemarthrosis or intracranial bleed with mild or no trauma; deep muscle hematomas; prolonged or renewed bleeding after trauma, surgery, tooth extraction, nose bleeds, mouth injury, or circumcision, excessive bruising.
Clinical Tests: Prolonged PTT, severe hemophilia: <1%, moderate: 1-5%, and mild hemophilia 6-35% Factor VIII activity. 10% of carrier females have Factor VIII activity <35%.
Molecular Tests: Severe: F8 intron 22-A gene inversion (45%), F8 intron 1 gene inversion (3%), F8 gene del or rearrangement, frameshift, splice junction, or nonsense mutations (40%), missense mutation (10%). Mild-moderate:
missense mutation (97%)
Disease Mechanism: Normal Factor VIII circulates as an inactivated clotting cofactor activated by thrombin. Severe mutations lead to absent protein, mild-mod mutations to abnormal protein.
Treatment/Prognosis: IV Factor VIII prophylactically 3x/wk in severe cases and after trauma, avoid IM injection. Consider HIV, Hep A, B, and C testing if history of receiving blood products.
Responsible gene: F9
Protein: Coagulation factor IX
Cytogenetic locus: Xq27.1-q27.2
Clinical Features and Diagnostic Criteria: hemarthrosis or intracranial bleed with mild or no trauma; deep muscle hematomas; prolonged or renewed bleeding after trauma, surgery, tooth extraction, nose bleeds, mouth injury, or circumcision, excessive bruising.
Clinical Tests: Prolonged PTT, severe hemophilia: <1%, moderate: 1-5%, and mild hemophilia 6-30% Factor IX activity. 10% of carrier females have Factor VIII activity <30%.
Molecular Tests: F9 sequence analysis (99%). Large gene deletions, nonsense mutations, and most frameshift mutations cause severe disease.
Disease Mechanism: Factor IX activates Factor X which is a critical early step that can regulate the overall rate of thrombin generation in coagulation.
Treatment/Prognosis: Recombinant factor IX concentrate 2-3x/wk for severe deficiency and within one hour of trauma. Avoid IM injection. Consider HIV, Hep A, B, and C testing if history of receiving blood products.
HFE-ASSOCIATED HEREDITARY HEMOCHROMATOSIS (HFE-HHC)
Responsible gene: HFE
Protein: Hereditary hemochromatosis protein
Cytogenetic locus: 6p21.3 Inheritance: AR (penetrance is low, a large fraction of homozygotes never develop symptoms.
Clinical Features and Diagnostic Criteria: Inappropriately high iron absorption by the GI mucosa leads to excessive iron storage in the liver, skin, pancreas, heart, joints, and testes. Early Sx: abdominal pain, weakness, lethargy, and weight loss.
Clinical Tests: Inc. fasting transferrin-iron saturation (men >60%, women >50%; some use >45% as cutoff for both men and women) on at least 2 occasions, inc. serum ferritin concentration (nonspecific for HHC), quantitative phlebotomy to determine iron quantity., liver biopsy, hepatic MRI
Molecular Tests: Targeted mutation testing (60-90%C282Y/C282Y; 3-8% C282Y/H63D.
Disease Mechanism: HFE protein binds transferrin receptor 1 and is thought to reduce cellular iron uptake- mutation leads to inc. iron uptake
Treatment/Prognosis: If untreated: hepatic fibrosis or cirrhosis, increased skin pigmentation, DM, CHF and/or arrhythmias, cardiomyopathy, arthritis, or hypogonadism. Treat with phlebotomy if symptomatic, aim for ferritin <50, transferrin-iron saturation <50%
Responsible gene: BTK
Cytogenetic locus: Xq21.3-q22
Clinical Features and Diagnostic Criteria: recurrent OM,
pneumonia, sinusitis <5yrs; sepsis, meningitis, or cellulitis,
paucity of lymphoid tissue
Clinical Tests: Low but measureable IgG, <1% B Cells CD19)
Molecular Tests: 90% BTK sequence variant, 10% del/dupl/inv
Disease Mechanism: Immune deficiency; BTK protein expressed in myeloid cells, platelets, B lineage cells
Treatment/Prognosis: Monthly IV or weekly SC gammaglobulin
FAMILIAL MEDITERRANEAN FEVER
Responsible gene: MEFV
Cytogenetic locus: 16p13
Clinical Features and Diagnostic Criteria: Type 1 recurrent febrile episodes with peritonitis, synovitis, or pleuritis, recurrent erysipelas-like erythema, AA type amyloidosis, favorable response to continuous colchicine treatment, at risk ethnic group (Armenian, Turkish, Arab, North African Jewish, Iraqi Jewish, Ashkenazi Jewish). Type 2 amyloidosis as first clinical presentation
Clinical Tests: Inc ESR, leukocytosis, inc serum fibrinogen, proteinuria
Molecular Tests: MEFV targeted mutation analysis (70-90% depending on panel and ethnicity), MEFV sequencing (90% all ethnic groups)
Disease Mechanism: Mutations result in less IL-1beta activation and as a result inc IL-1 responsiveness-> inc inflammatory attacks
Treatment/Prognosis: M694V homozygotes or compound
heterozygotes with another FMF allele treated with daily colchicine for life. Colchicine decreases inflammatory attacks and deposition of amyloid.
Responsible gene: FGD1
Protein: Rho/Rac guanine nucleotide exchange factor
Cytogenetic locus: Xp11.22
Inheritance: XLR (some AR, AD cases reported)
Clinical Features and Diagnostic Criteria: hypertelorism,
shawl scrotum, brachydactyly, short stature, cryptorchidism,
cervical vertebral abnormalities, ID (30%), milder manifestations in females
Clinical Tests: xray
Molecular Tests: FGD1 sequencing (7-20%)
Disease Mechanism: unclear, FGD1/Rho GTPase Cdc42
implicated in cytoskeletal organization, and potentially in
skeletal formation and morphogenesis
Treatment/Prognosis: orchiopexy, growth hormone trials
have not been successful
Responsible gene: POR
Protein: NADPH-cytochrome P450 reductase
Cytogenetic locus: 7q11.2
Clinical Features and Diagnostic Criteria: Ambiguous genitalia,
enlarged cystic ovaries, poor masculinization in males, maternal virilization during pregnancy with an affected fetus. craniosynostosis, choanal stenosis or atresia, stenotic external auditory canals, hydrocephalus. Neonatal fractures, bowing of the long bones, joint contractures, renal malformations
Clinical Tests: Sterol or or steroid abnormalities using GC-MS, increased urinary pregnenolone and progesterone metabolites
Molecular Tests: POR sequence variants
Disease Mechanism: Disorder of steroid and cholesterol synthesis due to cytochrome P450 reductase deficiency
Treatment/Prognosis: Airway management, hydrocortisone replacement, stress dose steroids, surgical correction of genital abnormalities, VP shunt for significant hydrocephalus, PT to minimize joint contracture
Responsible genes: BBS1, BBS10 (11 additional genes id'ed)
Proteins: BBS1 protein, BBS10 protein Cytogenetic loci: 11q13,
Inheritance: AR (though 10% BBS thought to be tri-allelic)
Clinical Features and Diagnostic Criteria: cone-rod dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal dysfunction. Night blindness by age 7-8 yrs, legally blind by age 15.5 yrs. A
majority have significant learning difficulties, only a minority have severe impairment. Renal disease is a major cause of morbidity and mortality.
Clinical Tests: atypical pigmentary retinal dystrophy with early macular involvement, renal anomalies on US
Molecular Tests: Targeted mutation analysis: p.M390R BBS1 (18%-32% of BBS) and C91fsX95 BBS10 (10% of BBS).
Disease Mechanism: Defects in cilia or intraflagellar transport (IFT)
Treatment/Prognosis: visual aids and educational programs for the visually impaired; diet, exercise, and behavioral therapies for obesity; surgery to remove accessory digits; surgical repair of hydrocolpos, vaginal atresia, or hypospadias; HRT for hypogonadism.
BRANCHIOOTORENAL SYNDROME (BOR)
Responsible gene: EYA1, SIX1
Proteins: Eyes absent homolog 1, Homobox protein SIX1
Cytogenetic loci: 8q13.3, 14q23
Clinical Features and Diagnostic Criteria: malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment; branchial fistulae and cysts; renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis
Clinical Tests: Temporal bone CT, hearing test, renal US
Molecular Tests: Mutation scanning (30%), Dupl/del testing (10%)
Disease Mechanism: EYA1 encodes products important for inner-ear, kidney, and branchial-arch development. Some mutations encode proteins that are rapidly degraded. Expression of SIX1 is necessary for normal development of the inner ear, nose, thymus, kidney, and skeletal muscle
Treatment/Prognosis: excision of branchial cleft cysts/fistulae, fitting with appropriate aural habilitation, hearing impaired education programs. Endstage renal disease may require dialysis or renal transplantation. Surveillance includes semiannual examination for hearing impairment and
annual audiometry to assess stability of hearing loss and
semiannual/annual examination by a nephrologist if indicated
Responsible gene: CHD7
Protein: Chromodomain-helicase-DNA-binding protein 7
Cytogenetic locus: 8q12.1
Clinical Features and Diagnostic Criteria: 4/7: eye coloboma, heart anomaly (conotruncal defects, arch abnormalities), choanal atresia, growth and mental retardation, genitourinary malformations (microphallus), ear anomalies (ossicular malformations, Mondini defect of the cochlea) and/or deafness. Facial palsy, cleft palate, TE fistula, and dysphagia are commonly associated. 20-25% mortality in the first year
Clinical Tests: echocardiogram, audiology evaluation, temporal bone CT, renal ultrasound
Molecular Tests: CHD7 sequencing (60-65%)
Disease Mechanism: Haploinsufficiency. This class of proteins is
thought to have pivotal roles in early embryonic development by
affecting chromatin structure and gene expression
Treatment/Prognosis: Assess for airway compromise, swallowing
problems, typical surgical correction of heart and GI malformations
Responsible gene: RPS6KA3
Protein: Ribosomal protein S6 kinase alpha-3
Cytogenetic locus: Xp22.2-p22.1
Clinical Features and Diagnostic Criteria: severe to profound ID in males, short, soft fleshy hands, tapering fingers with small terminal phalanges, males <3% in height, microcephaly, stimulus induced drop episodes, kyphoscoliosis, characteristic facial features in older males, normal to profound ID in females.
Clinical Tests: x-ray: thickened skull, anterior vertebrae beaking,
Molecular Tests: RPS6KA3 sequencing (35-40%)
Disease Mechanism: unclear, RPS6KA3 is a member of the Ras
signaling cascade and participates in cellular events such as
proliferation and differentiation
Treatment/Prognosis: Medication for drop episodes, Rispieridone for self-injurious behavior, annual cardiac exam with echo every 5-10 years.
COFFIN-LOWRY SYNDROME face
Prominent forehead and eyebrows
Full supraorbital ridges
Marked ocular hypertelorism with downslanting palpebrae
Low nasal bridge, blunt tip, and thick alae nasi and septum
Large mouth, usually held open
Patulous lips with everted lower lip
CORNELIA DE LANGE SYNDROME
Responsible gene: NIPBL, SMC1L1, SMC3
Protein: Nipped-B-like protein, Structural maintenance of
chromosomes protein 1A and 3
Cytogenetic loci: 5p13.1, Xp11.22-p11.21, 10q25.2
Inheritance: AD (NIPBL and SMC3), XLR (SMC1L1)
Clinical Features and Diagnostic Criteria: pre/postnatal growth retardation, low anterior hairline and synophrys, diaphragmatic hernia, upper limb anomalies (hypoplastic middle phalanx of the index finger, hypoplastic thenar eminence), ptosis, nystagmus, mod-severe ID, pulmonary valve stenosis and/or VSD
Molecular Tests: NIPBL sequencing (~50%), SMC1L1 sequencing (4%), SMC3 (<1%)
Disease Mechanism: Unknown, the majority of mutations are
truncating, likely leading to protein haploinsufficiency
Treatment/Prognosis: Treat individual medical and
CORNELIA DE LANGE SYNDROME face
Synophrys, arched eyebrows
Long, thick eyelashes
Low‐set posteriorly rotated and/or hirsute ears with thickened helices
Depressed or broad nasal bridge, upturned nasal tip with anteverted nares, and prominence of the lateral aspects
Long smooth philtrum, thin vermillion border of the upper lip with a midline "drip" appearance, downturned corners of the mouth
High and arched palate with clefts
Small widely‐spaced teeth
CRI DU CHAT (5p MINUS SYNDROME)
Responsible gene(s): RPS14?, microRNA 145 and 146a?
Cytogenetic locus: 5p15.2
Inheritance: 12% due to unequal segregation of a translocation or recombination involving a pericentric inversion in one of the parents, 85% sporadic de novo deletions (80% are on the paternal chromosome)
Clinical Features and Diagnostic Criteria: Cat-like cry (abnormal laryngeal development), slow growth, microcephaly, ID, hypotonia, strabismus, characteristic facial features. Cat-like cry only when deletion limited to band 5p15.32
Molecular Tests: Most are visible, a few are submicroscopic and diagnosed by FISH for the critical region.
Disease Mechanism: A study of 50 patients with deletions ranging from 5p15.2 to 5p13 and found no correlation with size of deletion and degree of mental impairment
Treatment/Prognosis: Supportive care
CRI DU CHAT (5p MINUS SYNDROME) face
Responsible gene(s), Protein(s), Cytogenetic locus (loci): unknown
Clinical Features and Diagnostic Criteria: LGA, coarse face, CL/CP, diaphragmatic defect, distal digital hypoplasia, ID in survivors, agenesis of the CC, optic and olfactory tract hypoplasia, encephalocele, GU malformation
Disease Mechanism: unknown
Treatment/Prognosis: The majority are stillborn or die in early neonatal period, 14% survive
GREIG CEPHALOPOLYSYNDACTYLY (GCPS)
Responsible gene: GLI3
Protein: Zinc finger protein GLI3
Cytogenetic locus: 7p13
Clinical Features and Diagnostic Criteria: Major findings:
macrocephaly, ocular hypertelorism, preaxial polydactyly, cutaneous syndactyly. Developmental delay, ID, or seizures (<10%)- more common in those with large (>300 kb) deletions including GLI3. Allelic with Pallister-Hall syndrome (caused by GLI3 frame shifting mutations).
Clinical Tests: 500-600 band karyotype 7p13 translocation or interstitial deletion (5-10%)
Molecular Tests: GLI3 sequence analysis (70%)
Disease Mechanism: GLI proteins regulate genes distal to Sonic
Hedgehog in the SHH pathway. Pathogenesis of GCPS is
Treatment/Prognosis: Surgical correction of polydactyly and syndactyly as indicated. CNS imaging if HC increasing faster than normal to r/o hydrocephalus
Responsible genes: NPHP1, AHI1, CEP290, TMEM67
Proteins: Nephrocystin-1, Jouberin, Centrosomal protein Cep290, Meckelin
Cytogenetic loci: 2q13, 6q23.3, 12q21.32, 8q21.1-q22.1
Clinical Features and Diagnostic Criteria: Hypotonia in infancy leading to ataxia later, DD/ID, alternating tachypnea and/or apnea), pigmentary retinopathy, oculomotor apraxia or difficulty in smooth visual pursuits and jerkiness in gaze tracking. M:F, 2:1. Renal disease seen in those with retinal involvement. Rarely hepatic fibrosis.
Clinical Tests: Molar tooth sign (cerebellar vermis hypoplasia) on MRI, ERG, renal US, LFT's
Molecular Tests: NPHP1 FISH or deletion analysis (1-2%), Sequencing AHI1 (11%), CEP290 (10%), TMEM67 (10%)
Disease Mechanism: The CEP290 protein product modulates ATF4, a transcription factor implicated in renal cyst formation. Meckelin localizes to the primary cilium and plasma membrane of renal and biliary epithelial cells and other ciliated cells
Treatment/Prognosis: apnea monitoring, ST, G tube if severe dysphagia, surgery as needed for eye disease, dialysis for nephronophthisis
Responsible genes: MLL2 (66%), KDM6A
Proteins: MLL2, Lysine-specific demethylase 6A
Cytogenetic loci: 12q12-q14, Xp11.3
Inheritance: AD, XLD
Clinical Features and Diagnostic Criteria: unique facial features, fetal finger pads, IQ<80, joint laxity, high palate, hypotonia, short stature, CHD, CL/P, scoliosis, renal anomalies, hearing loss, speech delay
Clinical Tests: echocardiogram, renal ultrasound, eye exam,
Molecular Tests: MLL2 gene sequencing, KDM6A gene sequencing and deletion testing
Disease Mechanism: MLL2 encodes a protein that is part of the SET family of proteins, important to the epigenetic control of active chromatin states. Mutations are predicted to truncate the polypeptide chain before translation of the SET domain. H3K4 methylation by MLL2 is linked to the demethylation of H3K27 by KDM6A.
Treatment/Prognosis: Individual medical problems are treated as in the general population. GH for short stature if deficient. At risk for immunodeficiency.
KABUKI SYNDROME face
Elongated palpebral fissures
Eversion of the lateral third of the lower eyelid
Arched and broad eyebrows
Short columella with depressed nasal tip
Large, prominent, or cupped ears
Responsible genes, Proteins: unknown
Cytogenetic locus: 1p36
Clinical Features and Diagnostic Criteria: The most common terminal deletion syndrome. Hypotonia, developmental delay, growth retardation, obesity, microcephaly, orofacial clefting, typical facial features. Also minor cardiac malformations, cardiomyopathy, seizures, ventricular dilation, SNHL
Clinical Tests: Brain CT/MRI
Molecular Tests: The deletion can be detected by HR karyotype, confirmatory FISH required in most cases. The
majority are maternally derived.
Disease Mechanism: contiguous gene deletion syndrome
Treatment/Prognosis: symptomatic treatment
MONOSOMY 1p36 face
Broad and flat nasal root/bridge
Posteriorly rotated, low‐set, abnormal ears.
Responsible genes: Paternally expressed genes within
imprinted locus on 15q11-13 (SNURF-SNRPN, MKRN3,
MAGEL2, and NDN)
Cytogenetic locus: 15q11-13
Inheritance: autosomal, expressed from paternal Ch 15
Clinical Features and Diagnostic Criteria: Hypothalamic
insufficiency, neonatal hypotonia, developmental delay,
hyperphagia leading to obesity, short stature, small hands
and feet, hypogonadism, ID
Molecular Tests: 3-5 Mb deletion of 15q11.2-q13 (~70%), matUPD (15%), PWS imprinting center defect (1-2%)
Disease Mechanism: unknown
Treatment/Prognosis: Monitor for feeding problems in infancy, obesity, OCD, psychosis, scoliosis, obstructive sleep apnea, diabetes, osteopenia
Responsible gene: CREBBP, EP300
Protein: CREB-binding protein, histone acetyltransferase-p300
Cytogenetic locus: 16p13.3, 22q13
Inheritance: AD though only a few cases of affected parent and child
Clinical Features and Diagnostic Criteria: microcephaly, beaked nose, broad thumbs and toes, cryptorchidism, growth delay, severe ID (35-50), congenital heart defect, strabismus, ptosis, sleep apnea, tumors (meningioma, pilomatrixoma, leukemia), behavior problems
Clinical Tests: ERG, echocardiogram, deletion or translocation
occasionally seen on karyotype
Molecular Tests: FISH CREBBP (~10%), direct sequencing CREBBP (40-60%), EP300 (~3%)
Disease Mechanism: Some CREBBP mutations lead to abnormal
acetylation of histones, an important step in transcription activation
Treatment/Prognosis: Standard care for vision, hearing loss, heart defects, feeding problems. Some require thumb/toe surgery, behavior modification programs
Responsible gene: RAI1
Protein: Retinoic acid-induced protein 1
Cytogenetic locus: 17p11.2
Inheritance: AD (sporadic unless secondary to a parental balanced translocation)
Clinical Features and Diagnostic Criteria: mild-moderate infantile hypotonia, feeding problems and FTT, short stature, brachydactyly, ophthalmologic and ENT abnormalities, early speech delay with or without hearing loss, peripheral
neuropathy, sleep problems, and stereotypic maladaptive behaviors (self-injurious behaviors, inattention(+-)hyperactivity, impulsivity, disobedience, "self-hug" and "lick and flip" page turning motion), mild-mod ID, coarsening face over time
Clinical Tests: Renal US, echo, spine x-ray, FISH for 17p11.2 deletion (~90%)
Molecular Tests: RAI1 sequencing (5-10%)
Disease Mechanism: The RAI1 gene product is thought to function in transcriptional regulation
Treatment/Prognosis: ST, sensory integration, psychotropic meds for attention issues, behavioral therapies, melatonin may help with sleep, monitoring for hypercholesterolemia. Annual team eval, TFTs, fasting lipid profile, UA, scoliosis check, eye exam
SMITH-MAGENIS SYNDROME face
Relative prognathism with age
Broad, square‐shaped face
Everted, "tented" vermilion of the upper lip
Deep‐set, close‐spaced eyes
Cytogenetic abnormality: 69,XXY>69,XXX (69,XYY very rare)
Inheritance: Sporadic without inc risk of recurrence
Clinical Features and Diagnostic Criteria: >99% lost in first trimester, accounts for 6-10% of all SAb's and 16-20% of all chromosomally abnormal SAb's. Dysplastic calvaria with large posterior fontanelle, ¾ finger syndactyly, ASD, VSD, hydrocephalus, holoprosencephaly.
Parent of origin effect: If Maternal: small placenta, severe asymmetric IUGR with a large head. If Paternal: hydropic large placenta, well grown to mod symmetric IUGR, nl or microcephalic head
Clinical Tests: Prenatal US, maternal serum hCG low
Molecular Tests: Karyotype
Disease Mechanism: Gynogenic triploidy (digyny): NDJ producing diploid oocyte, fertilization of ovulated primary oocyte, or polar body retention. Androgenic triploidy (Diandry) NDJ producing a diplod sperm or dispermy (most common)
Treatment/Prognosis: Very poor prognosis, may be better if triploid mosaic
TRISOMY 13, PATAU SYNDROME
Inheritance: 20% due to translocation
Clinical Features and Diagnostic Criteria: The LEAST common
of live born trisomy disorders. HPE,
POLYDACTYLY, seizures, HL, microcephaly, midline CL/P,
omphalocele, cardiac and renal anomalies, ID, CUTIS APLASIA.
Mosaic Tri 13: very broad phenotype from typical features of full trisomy to more mild ID and physical features and longer survival.
Clinical Tests: Brain MRI, EEG, audiogram, echo, renal US
Molecular Tests: Karyotype is diagnostic
Disease Mechanism: 75% due to maternal nondysjunction,
20% to translocation, and 5% to mosaicism. Defect in fusion
of midline prechordial mesoderm in first three weeks of
gestation cause major midline dysmorphic features.
Treatment/Prognosis: 44% die in first month, >70% die
within one year. Severe ID exists in all survivors.
TRISOMY 18, EDWARDS SYNDROME
Inheritance: Less than 1% due to translocation
Clinical Features and Diagnostic Criteria: TRISOMIC HAND-- fingers 2/5 overlap 3/4, IUGR, ROCKER BOTTOM FEET,
micrognathia, prominent occiput, MICROPHTHALMIA, VSD,
ASD, PDA, generalized muscle spasm, renal anomalies, ID.
Mosaic Tri 18 has variable but usually somewhat milder expression.
Clinical Tests: Echo, abdominal US. Maternal serum screen: low AFP, hCG, and UE3.
Molecular Tests: karytype is diagnostic
Disease Mechanism: Maternal nondysjunction (90%), mosaicism (10%)
Treatment/Prognosis: 50% die in first week, 90% die by one year
TRISOMY 21, DOWN SYNDROME
Cytogenetic locus (loci): (21.22.1-22.2 has been called DS critical region though there have been cases of duplication outside of this region who manifest DS
Inheritance: 95% de novo, 5% due to Robertsonian Translocation or isochromosome 21
Clinical Features and Diagnostic Criteria: mild-mod ID, hypotonia, growth delay, strabismus, adult cataracts, myopia, conductive HL, macroglossia, hypodontia, joint hyperflexibility, hypogenitalism, congenital heart defect, duodenal atresia, hirschprung, thyroid disease, early onset Alzheimers, transient myeloproliferation, ALL
Clinical Tests: prenatal US abnormalities detected in 50%, maternal serum screen: high free beta HCG, low PAPP-A
Molecular Tests: maternal fetal free DNA testing, karyotype is diagnostic
Disease Mechanism: 90% due to maternal meiosis nondisjunction (¾ MI error, ¼ MII error)
Treatment/Prognosis: Supportive care, overall life expectancy is
VACTERL (VATER) ASSOCIATION
Responsible genes: unknown (HOXD13 21 bp deletions: 1 case report)
Proteins, Cytogenetic locus: unknown
Clinical Features and Diagnostic Criteria: Vertebral anomalies, Anal atresia, Cardiac malformations (VSD, PDA, TOF, TOV),
Treacheoesophageal fistula, Esophageal atresia, Renal anomalies, and Limb anomalies (polydactyly, humeral hypoplasia, radial aplasia, proximally placed thumb).
Diagnosis requires 3 of 7 features and it is diagnosis of exclusion. A variant is VACTERL with hydrocephalus which
can be AR or XL.
Clinical Tests: echo, spinal x-ray, limb x-ray, and renal US
Molecular Tests: There isn't a molecular test but rule out aneuploidy with karyotype, Fanconi anemia with DEB testing, and consider SALL1 sequencing to rule out Townes-Brocks syndrome.
Disease Mechanism: unknown
Treatment/Prognosis: Severe cardiac malformation, anal atresia, TE fistula, and EA require surgical repair in neonatal period
WOLF-HIRSCHORN SYNDROME (4p minus, Monosomy 4p)
Responsible genes: 4p deletion, critical region includes 2 genes, WHSC1 and WHSC2 of unknown significance
Cytogenetic locus: 4p; critical region: 165-kb region between markers D4S166 and D4S3327
Inheritance: 87% de novo, 13% due to unbalanced translocation from a balanced parent
Clinical Features and Diagnostic Criteria: "greek warrior helmet
appearance", microcephaly, pre and postnatal growth deficiency, ID of variable degree, seizures, facial asymmetry, ptosis, IgA deficiency, structural brain anomalies, CL/P, CHD (ASD>PVS>VSD>PDA>AI>TOF), renal US
Clinical Tests: Distinctive EEG, Brain MRI, echo, plasma IgA level
Molecular Tests: HR karyotype for 4p16.3 deletion (60-70%), FISH/array CGH for critical region deletion (>95%)
Disease Mechanism: The function of WHSC1, WHSC2, and LETM1 in normal development and in WHS patients is not known
Treatment/Prognosis: 2/3 develop valproate responsive atypical absence seizures, standard treatment of other medical problems
WOLF-HIRSCHORN SYNDROME (4p minus, Monosomy 4p) face
"Greek warrior helmet appearance" of nose (broad bridge of nose continuing to forehead)
High forehead with prominent glabella
Highly arched eyebrows
Poorly formed ears with pits/tags
Responsible gene: ABCD1
Protein: ATP-binding cassette sub-family D member 1
Cytogenetic locus: Xq28
Clinical Features and Diagnostic Criteria:
a. Childhood cerebral: ADHD->total disability within 2 yrs
b. Adrenomyeloneuropathy: late 20's progressive paraparesis,
sphincter disturbance, adrenocortical dysfunction
c. Adrenocortical insufficiency (only); majority by age 7.5 (seen in 20% carrier females
Clinical Tests: Brain MRI, VLCFA (not reliably abnl in carrier
Molecular Tests: ABCD1 seq (92%); ABCD1 del/dup (6%)
Disease Mechanism: Peroxisomal disorder, accumulation of
Treatment/Prognosis: Corticosteroid replacement, BMT if
diagnosed after changes visible on brain MRI but before
significant neuropsych problems develop (Lorenzo's Oil)
EARLY ONSET FAMILIAL ALZHEIMER DISEASE (EOFAD)
Responsible genes: PSEN1, APP, PSEN2
Proteins: Presenelin-1, Amyloid beta A4, Presenilin-2
Cytogenetic loci: 14q24.3, 21q21, 1q31-q42
Clinical Features and Diagnostic Criteria: Dimentia, confusion, poor judgment, language disturbance, agitation, withdrawal, and
hallucinations. Early onset: <age 60
Clinical Tests: Gross cerebral cortical atrophy. Post mortem neuropath: A beta-amyloid neuritic plaques, intraneuronal neurofibrillary tangles, and amyloid angiopathy
Molecular Tests: Seq.: PSEN1 (20-70%), APP (10-15%), PSEN2 (rare)
Disease Mechanism: ?chromosomal instability and breakage at
nonrandom sites? Triple dose of APP may explain Alzheimer's in Tri 21.
Treatment/Prognosis: Death from general aninition, malnutrition, and pneumonia. Clinical duration 8-10 yrs (range 1-25 yrs)
EOFAD 1-6% OF ALL Alzheimer's, 60% of which is familial, and 13% inherited in an AD manner. (<2% of all Alzheimer's)
LOFAD: Appears to be an assoc with APOE e4 but not sensitive or specific- supports the dx. APOE e2 may be protective.
Responsible gene: UBE3A
Protein: Ubiquitin protein ligase E3A
Cytogenetic locus: 15q11-q13
Inheritance: loss of the maternally imprinted contribution in the 15q11.2-q13 (AS/PWS) region
Clinical Features and Diagnostic Criteria: severe developmental delay or ID, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability, microcephaly and seizures
Clinical Tests: acquired microcephaly by age two years,
Seizures before age three, abnl EEG: large amp. slow-spike waves
Molecular Tests: 4-6 Mb del (65-75%), UBE3A mutation (11%),
imprinting defect (2.5%), unbal chrom transloc (<1%), Pat UPD 15 (<1%), del of imprinting center (0.5%)
Disease Mechanism: Disruption of E6AP ultimately causes an
abnormality in the ubiquitin protein degradation pathway, but no clear AS-causing target protein yet identified
Treatment/Prognosis: Typical care for medical issues, PT, OT, ST, and individualized education and behavior program.
ANGELMAN SYNDROME face
Widely spaced teeth
Light hair and eye color
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)
Responsible gene: NOTCH3
Protein: Neurogenic locus notch homolog protein 3
Cytogenetic locus: 19p13.2-p13.1
Clinical Features and Diagnostic Criteria: Stroke-like episodes before age 60, cognitive disturbance, behavioral abnormalities, migraine with aura
Clinical Tests: Skin Bx EM: e- dense granules in media of arterioles.
Brain MRI: T2 signal abnormalities in the WM of the temporal pole and external capsule, subcortical lacunar lesions (groups of rounded lesions at the junction of GM and WM. WM changes seen as early as age 21 yrs.
Molecular Tests: NOTCH3 sequencing (>90%)
Disease Mechanism: NOTCH genes encode transmembrane receptors involved in cell fate specification during development. The functional consequences of NOTCH3 mutations in the abnormal protein are not known.
Treatment/Prognosis: supportive care, angiography and anticoagulants may precipitate CVA, smoking increases risk of stroke. Mean age to walk with asst.: 60yrs, bedridden by 64yrs, med. age of death 68 yrs.
Responsible gene: ASPA
Cytogenetic locus: 17pter-p13
Clinical Features and Diagnostic Criteria: Macrocephaly, lack of head control, developmental delays by age 3-5 mos, severe hypotonia, never sit, walk, or speak. Hypotonia evolves to spasticity.
Clinical Tests: High urine N-acetyl aspartic acid (NAA)
Molecular Tests: 3 common mutations account for 99% of disease-causing alleles in Ash. Jewish, 50-55% in non-jewish.
Disease Mechanism: Absence of aspartoacylase leads to build up of NAA in the brain leading to demyelination
Treatment/Prognosis: Supportive care: nutrition, hydration, managing infectious disease, protecting airway. Life expectancy to the teens.
Responsible gene: IKBKAP
Protein: IkappaB kinase complex-associated protein
Cytogenetic locus: 9q31
Clinical Features and Diagnostic Criteria: Progressive, GI
dysfunction, vomiting crises, recurrent pneumonia, altered sensitivity to pain and temperature, CV instability, autonomic crises, hypotonia, broad based ataxic gate deteriorates, decreased life expectancy. Dec taste and absence of fungiform papillae of the tongue, dec or absent DTR's, absence of overflow tears with crying
Clinical Tests: Pupillary hypersensitivity to parasympathetic agents, absence of axon flare response after intradermal histamine injection
Molecular Tests: IVS20 (+6T>C); R696P in IKBKAP (>99%
Ashkenazi Jewish population)
Disease Mechanism: Abnormal development and survival of
sensory, sympathetic and parasympathetic neurons
Treatment/Prognosis: Aspiration precautions, hydration and elastic stockings for orthostatic hypotension, protect cornea with artificial tears, PT for contracture
Responsible gene: FMR-1
Protein: FMRP (Fragile X Mental Retardation Protein)
Cytogenetic locus: Xq27.3
Inheritance: X-linked triplet repeat
Clinical Features and Diagnostic Criteria: Delayed motor and verbal development, ID (mod-severe in boys, milder in girls), prominent jaw and forehead, high activity, autistic features. Carrier females: anxiety, OCD, depression, 20% have POF. Carrier Males: (>30% of males >50y), progressive intention tremor, ataxia, parkinsonism, and autonomic dysfunction.
Two other loci: FraXE: only ID, FraXF: no phenotype
Clinical Tests: None
Molecular Tests: CGG triplet repeat detection. Southern Blot: good for small or large expansions, doesn't give repeat #. PCR: Better quantification of repeat number, subject to allele dropout with large expansions. NL: 5-44 repeats, Intermediate: 45-58 repeats (gray zone), Pre-mutation: 59-200 repeats, Mutation: >200 repeats
Disease Mechanism: >200 repeats leads to silencing by methylation. POF and ataxia thought to be due to toxic gain of function.
Treatment/Prognosis: No specific treatment.
FRAGILE X face
Responsible gene: HD
Cytogenetic locus: 4p16.3
Clinical Features and Diagnostic Criteria: progressive motor disability involving both involuntary and voluntary movement (chorea, dysarthria, dysphagia progress to bradykinesia, rigidity, and dystonia) , cognitive decline (problems with planning or organization), psychiatric disturbances (personality change, affective psychosis, or schizophrenic psychosis. Mean
age of onset 35-44 yrs (juvenile onset <20yrs ~10%).
Clinical Tests: CT or MRI: characteristic atrophy of caudate and putamen. PET scan: dec uptake and metab. of glucose in the caudate nucleus (often abnl before MRI or CT).
Molecular Tests: Targeted mut. analysis: trinucleotide CAG repeat expansion >36. 27-35: no symptoms but, if male, risk of expansion in children (6-10% risk of expansion with 35 repeats). 36-39: reduced penetrance, may never develop symptoms. >40: fully penetrant. >60 repeats: juvenile onset.
Disease Mechanism: Unknown
Treatment/Prognosis: Tx is symptomatic: neurolepetics, benzo's,
psychotropics, Median survival time: 15-18 yrs after onset, average age of death is 55 yrs. Suicide in 12%.
Responsible gene: GALC
Cytogenetic locus: 14q31
Clinical Features and Diagnostic Criteria: Infantile form: irritability to sensory stimuli, muscle hypertonicity, progressive neurologic deterioration, peripheral neuropathy, white matter disease, elevated CSF protein. Later onset (6 mos to 5th decade): weakness, vision loss, intellectual regression.
Clinical Tests: CT: nonspecific- diffuse cerebral atrophy of grey and white matter. MRI: demyelination of the brainstem and cerebellum. Dec GALC enzyme activity (0-5% of normal activity). Abnl EEG, low nerve conduction velocity
Molecular Tests: GALC targeted mutation analysis: GALC 30-kb deletion (45% of Europeans, 35% of Mexicans); 809G>A mutation (50% of late onset Krabbe). GALC sequencing (virtually 100%)
Disease Mechanism: Missense mutations result in unstable protein that is rapidly degraded
Treatment/Prognosis: Hematopoietic stem cell transplant decreases morbidity and mortality when given to infants before they show symptoms. Supportive care to control irritability and spasticity if diagnosed when symptomatic. Infantile form: average age of death is 13 mos due to infections or resp failure.
NEUROFIBROMATOSIS TYPE I
Responsible gene: NF1
Cytogenetic locus: 17q11
Clinical Features and Diagnostic Criteria: 2 or more of: 6x5mm
(prepubertal) or 6x15mm (postpubertal) café au lait, 2 or more
neurofibromas, one plexiform neurofibroma, axillary or inguinal
freckling, optic glioma, 2 or more Lisch nodules, sphenoid
dysplasia or thinned long bone cortex, 1st degree relative with
Clinical Tests: x-ray, eye exam, brain MRI
Molecular Tests: >500 mutations reported, usually unique to a
Disease Mechanism: Loss of function mutations impair ras
GTPase mediated cellular proliferation and tumor suppression
Treatment/Prognosis: The majority live normal lifespan.
Surgery for bone malformations or painful or disfiguring tumors
Responsible gene: Multiple, main gene PARK2
Cytogenetic locus: 6q25.2-q27
Inheritance: AD, AR, multifactorial
Clinical Features and Diagnostic Criteria: bradykinesia, rigidity, and tremor, asymmetric limb involvement. Juvenile Onset AR PARK2 mutations, typical features, onset 20-40yrs.
Clinical Tests: Good response to L-Dopa
Molecular Tests: PARK2 sequencing
Disease Mechanism: Unclear but thought to be due to loss of function by absent protein or protein inactivation
Treatment/Prognosis: Dopamine therapy, PT, OT, ST. Some patients may benefit from palliodotomy or deep brain stimulation of the subthalamic nucleus.
Responsible genes: MECP2
Cytogenetic loci: Xq28
Clinical Features and Diagnostic Criteria: ID, developmental
regression (especially language and hand use), acquired
microcephaly, stereotypical wringing hand movements,
hyperventilation, bruxism, paroxysmal laughing, prolonged QT,
Clinical Tests: EEG (nonspecific for Rett), ECG
Molecular Tests: MECP2 sequencing (>80%), Need to test parents if a novel variant found. MECP2 MLPA or quantitative PCR testing for deletion (~16%).
Disease Mechanism: Decreased function of loss-of-function of MECP2. Normally MECP2 binds methylated CpG islands.
Treatment/Prognosis: Seizures are often difficult to manage, SSRI's for agitation, monitor for scoliosis, periodic ECG to monitor for long QT. Small subset have CDKL5 mutations and present atypically with early onset seizures
Responsible gene: ATP7B
Protein: Copper-transporting ATPase 2
Cytogenetic locus: 13q14.3-q21.1
Clinical Features and Diagnostic Criteria: Can present age 3-50 yrs. Liver disease: jaundice, self-limited hepatitis-like illness, autoimmune hepatitis, hepatic failure, chronic liver disease. Neurologic presentation: movement disorder, disorganization of personality
Clinical Tests: Kayser-Fleisher rings on corneal exam, low serum Cu and ceruloplasmin, inc urinary copper excretion. Liver bx: inc copper storage.
Molecular Tests: ATP7B sequencing (98%). H1069Q (35-45%
Europeans), R779L (57% Asians), H714Q and delC2337 (40%
Disease Mechanism: Loss of ATP7b function impairs
holoceruloplasmin biosynthesis and biliary copper excretion with
resultant copper-mediated oxidative damage, activation of cell death pathways, leakage of copper into plasma and eventual tissue copper overload.
Treatment/Prognosis: Chelating agents, liver transplant
AMYOTROPHIC LATERAL SCLEROSIS (Lou Gehrig Disease)
Responsible genes: SOD1 (rare: SETX, VAPB, BSCL2, VCP, ALS2, SPG20)
Protein: Superoxide dismutase
Cytogenetic locus: 21q22
Inheritance: AD (AR ALS2 and SPG20)
Clinical Features and Diagnostic Criteria: UMN: hyperreflexia, extensor plantar response, inc muscle tone, and weakness. LMN: weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Frontotemporal dementia
Clinical Tests: EMG; Path: (1) degeneration and loss of the motor neurons in the anterior horns and in the motor nuclei of cranial nerves VII, X, and XI and most commonly the hypoglossal nucleus; and (2) axonal loss with decreased
myelin staining in the lateral and anterior corticospinal tracts
Molecular Tests: SOD1 mutation (20% familial, 3% sporadic ALS- 50% have the A4V Exon 1 mutation)
Disease Mechanism: Toxic gain of function, not enzyme deficiency (SOD1 prevents oxidative damage to cells)
Treatment/Prognosis: Primarily palliative, Riluzole (glutamate inhibitor)-the only FDA-approved drug. Mean age of onset: 46 yrs if familial, 56 yrs if sporadic. Death usually caused by resp. muscle compromise.
CHARCOT MARIE TOOTH DISEASE
CMT1: Abnormal myelin, AD, 50% of all CMT, PMP22 (17p11.2), MPZ (1q22), LITAF (16p13.1-p12.3), EGR2 (10q21.1-q22.1), NEFL (8p21)
CMT2: Axonopathy, AD, 20-40% of all CMT, KIF1B and MFN2 (1p36.2), RAB7 (3q21), LMNA (1q21.2), GARS (7p15), NEFL (8p21), HSPB1 (7q), MPZ (1q22), GDAP1 (8q12-q21.1)
CMT Intermediate Form: Combination of myelinopathy and axonopathy, AD, rare cause of CMT, DNM2 (19p12-p13.2), YARS (1p34-p35)
CMT 4: Either myelinopathy or axonopathy, AR, rare cause of CMT, GDAP1 (8q13-q21.1), MTMR2 (11q22), CMT4B2 (11p15), SH3TC2 (5q32), NDRG1 (8q24.3), EGR2 (10q21.1-q22.1), PRX (19q13.1-q13.2
CMTX: Axonopathy with secondary myelin changes, XLD, 10-20% of all CMT, GJB1 (Xq13.1).
Clinical Features and Diagnostic Criteria: slowly progressive weakness and atrophy of distal muscles in the feet and/or hands beginning in the 1st-3rd decade; hearing loss; pes cavus foot deformity, hip dysplasia.
Clinical Tests: nerve conduction studies, nerve biopsy
Molecular Tests: Gene sequencing
Disease Mechanism: Abnormal peripheral myelination
Treatment/Prognosis: orthopaedic surgery, TCA's, carbamazepine, or gabapentin for neuropathic pain.
DUCHENNE AND BECKER MUSCULAR DYSTROPHY (DMD/BMD)
Responsible gene: DMD
Cytogenetic locus: Xp21.2
Clinical Features and Diagnostic Criteria: DMD: Symptoms present before age 5, progressive symmetrical muscular weakness, proximal>distal, calf hypertrophy, dilated cardiomyopathy (DCM). BMD: Later onset, less severe,
weakness of quadriceps may be only sign, activity induced cramping. Preservation of neck flexor muscles (unlike DMD). DCM can occur in isolation
Clinical Tests: CK 10x nl in DMD, 5x nl in BMD. Unreliable test for carrier females, tends to decrease with age.
Molecular Tests: Multiplex PCR: DMD gene deletion (65% DMD, 85% BMD). Southern or quantitative PCR for gene duplication (6% DMD), DMD sequencing for small del/ins or point mutations (30% DMD)
Disease Mechanism: Dystrophin binds actin and other membrane proteins. Mutations that lead to lack of dystrophin expression: DMD, those that lead to abnormal quality or quantity of dystrophin: BMD.
Treatment/Prognosis: Supportive therapy, steroids may prolong walking 2-3 yrs. DMD: wheelchair dependent by age 13, ventilator by age 20, survival into 20's. BMiDs: Wheelchair after age 16 (if at all), survival 40-50's. Carrier females at risk for DCM.
Responsible gene: FRDA
Cytogenetic locus: 9q13
Clinical Features and Diagnostic Criteria: Progressive degeneration of the dorsal root ganglia, posterior columns, corticospinal tracts, and the dorsal spinocerebellar tracts of the spinal cord and cerebellum. There is progressive limb and gait ataxia before age 25 yrs, absent tendon reflexes in the lower extremities. Within 5 years of disease onset: dysarthria, areflexia, pyrimidal weakness of the legs, extensor plantar
responses and distal loss of joint position and vibration sense. Also, scoliosis, pes cavus, optic nerve atrophy, hypertrophic cardiomyopathy, DM or glucose intolerance
Clinical Tests: electrophysiologic evidence of axonal sensory neuropathy
Molecular Tests: GAA triplet repeat expansion in FRDA intron 1 (96% homozygous) Normal 5-33, premutation 34-65, and disease causing: 66-1700 repeats.
Disease Mechanism: It is believed that GAA expansion forms a stable DNA structure that interferes with transcription
Treatment/Prognosis: Treatment is supportive:psychological,
prostheses, walking aids, wheelchairs, PT, and ST
HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES
Responsible gene: PMP22
Protein: Peripheral myelin protein 22
Cytogenetic locus: 17p11.2
Clinical Features and Diagnostic Criteria: adult with recurrent focal pressure palsies, mild polyneuropathy, absent ankle reflexes, reduced DTRs, mild-mod pes cavus deformity
Clinical Tests: Prolongation of distal nerve conduction latencies (virtually 100%), normal general motor nerve conduction velocities, demyelination and tomaculous (focal nerve enlargement) on sural nerve biopsy
Molecular Tests: PMP22 sequencing (20%), 1.5-Mb PMP22 deletion (80%)
Disease Mechanism: HNPP is associated with decreased mRNA
message for PMP22 and decreased peripheral myelin protein 22 in peripheral nerve.
Treatment/Prognosis: Bracing, AFO for foot drop, unclear if surgical nerve decompression is helpful, avoid risk factors for pressure palsy: prolonged sitting with legs crossed, repetitive wrist movements, prolonged leaning on elbows, and rapid weight loss.
LIMB-GIRDLE MUSCULAR DYSTROPHY (LGMD)
Responsible gene (protein, cytogenetic locus): CAPN3 (Calpain 3, 15q15.1-q21.1), FKRP (Fukutin related protein, 19q13.1), LMNA (Lamin-A/C, 1q21.2), SGCA (alpha sarcoglycan, 17q12), SGCB beta sarcoglycan, 4q12), SGCD (delta-sarcoglycan, 5q33), SGCG (gamma-sarcoglycan, 13q12), DYSF (Dysferlin, 2p13.3)
Inheritance: most AR, some rare AD subtypes
Clinical Features and Diagnostic Criteria: AR Sarcoglycan LGMD: proximal limb weakness, difficulty running and walking, calf hypertrophy, onset age 3-15 (68% of childhood onset, 10% adult onset) Calpain AR LGMD proximal limb weakness, difficulty running and walking, calf atrophy, onset 2-40 yrs (10-30% AR LGMD). Dysferlin AR LGMD problems running and walking, foot drop, distal and/or pelvic weakness, transient calf hypertrophy, onset 17-23 yrs
Clinical Tests: Inc serum CPK, dystrophic changes on muscle biopsy, sarcoglycan protein staining
Molecular Tests: Gene sequencing (80-99%)
Disease Mechanism: Sarcoglycanopathies disrupt dystrophin-dystroglycan complex, calpainopathy: unknown, dysferlinopathy: may be die to abnl membrane fusion
Treatment/Prognosis: Supportive care to promote mobility and ambulation. Monitor for respiratory and orthopedic complications and for cardiomyopathy
MYOTONIC DYSTROPHY TYPE 1
Responsible gene: DMPK
Protein: Myotonin-protein kinase
Cytogenetic locus: 19q13.32
Clinical Features and Diagnostic Criteria: Multisystem disorder of skeletal and smooth muscle, eyes, heart, endocrine system, and CNS. MILD cataract and mild myotonia (50-150 repeats)
Classic muscle weakness and wasting, myotonia, cataract, and
arrhythmia (100-1000 repeats). Have grip myotonia (sustained muscle contraction leads to inability to quickly release a hand grip) Congenital hypotonia and severe generalized weakness at birth often with resp. insufficiency and early death, MR is common (>2000 repeats)
Clinical Tests: EMG, serum CK, muscle biopsy (internal nuclei, ring fibers, sarcoplasmic masses, type I fiber atrophy, inc # intrafusal muscle fibers), slit lamp exam
Molecular Tests: CTG triplet repeat at the 3'-UTR of the DMPK (100%). PCR: detect repeats up to ~100, southern blot (detect repeats>100)
Disease Mechanism: Cause thought to be due to gain of function RNA mechanism- the CUG repeats alter alternative splicing of other genes, including a CL- channel, resulting in myotonia
Treatment/Prognosis: Symptomatic only
Gene (protein, chromosomal locus): ACTA1 (Actin, alpha skeletal muscle, 1q42.1), NEB (Nebulin, 2q22), TNNT1 (Troponin T, slow skeletal muscle, 19q13.4), TPM2 (Tropomyosin beta chain, 9p13.2-p13.1), TPM3 (Tropomyosin alpha-3 chain, 1q22-q23)
Inheritance: AR or AD
Clinical Features and Diagnostic Criteria: weakness, hypotonia, and depressed or absent DTR's. Weakness is usually most severe in the face, neck flexors, and proximal limb muscles. Age of onset: congenital, childhood, or adulthood.
Clinical Tests: Muscle biopsy: the diagnostic hallmark is the presence of rod-like inclusions, nemaline bodies, in the sarcoplasm of skeletal muscle fibers with trichrome staining.
Molecular Tests: ACTA sequencing: 15-25% of NM, ACTA Del/dup analysis: Exon 55.
Disease Mechanism: NM is a disorder of thin filament anchoring
Treatment/Prognosis: No definitive correlation between # of rods and severity of the myopathy. Walking prior to 18 months is predictive of survival.
SPINAL MUSCULAR ATROPHY
Responsible genes: SMN1, SMN2
Proteins: survival motor neuron protein 1 and 2
Cytogenetic loci: 5q12.2-q13.3
Clinical Features and Diagnostic Criteria: arthrogryposis multiplex congenita, peripheral nerve hypomyelination. SMA I onset 0-6mo, muscle weakness, tongue fasiculations, absent DTRs SMA II muscle weakness onset after 6 months, finger trembling, low tone, absent DTRs, SMA III Weakness leads to frequent falls or trouble with stairs, onset 2-3yrs, proximal
weakness (legs>arms), SMA IV adult onset
Clinical Tests: EMG: denervation and diminished motor action potential amplitude. Muscle Bx: atrophy of type 1 and type 2 fibers
Molecular Tests: Targeted mutation analysis: deletion of SMN1 exon 7 deletion (95-98%), SMN1 sequencing (2-5%). Carriers who have two copies of SMN1 in cis (~4% of the population) will be misdiagnosed as non-carriers. SMN2 copy # modifies the severity. 2 copies SMN2- SMA I, 3 copies- SMA II, 4-8 copies- SMA III. Absence of both SMN genes: lethal
Disease Mechanism: Mutant SMN lacks the splicing-regeneration activity of wild type.
Treatment/Prognosis: Optimize feeding and nutrition, PFT's, sleep study for OSA, treat contractures, dislocations, and scoliosis
SYNDROMIC CONGENITAL MUSCULAR DYSTROPHY
(Fukuyama (FCMD), Muscle-Eye-Brain (MEB), Walker-Warburg (WWS), Congenital Muscular Dystrophy Type 1D (MDC1D)
Responsible gene (protein, cytogenetic locus): FCMD; FCMD (Fukutin, 9q31); MEB: POMGNT1 (protein O-mannosidase beta-1,2-Nacetylglucosaminyltransferase, 1p34-p33); WWS: POMT1 and POMT2 (Protein O-mannosyltransferase 1 and 2, 9q34.1, and 14q24.3); MDC1D (LARGE, glycosyltransferase-like protein LARGE, 22q12.3-q13.1
Clinical Features and Diagnostic Criteria: Muscle weakness present at birth. Hypotonia and weakness. Joint contracture (MEB and WWS: elbow, FMD: hip, knee, ankle, elbow).
Clinical Tests: Muscle bx: dystrophic or myopathic pattern; inc serum CK; Muscle Bx: immunostaining; Brain MRI: Cobblestone complex (enlarged lat ventricles, flat brainstem, cerebellar hypoplasia)
Disease Mechanism: Disruption of alpha dystroglycan (an integral component of the dystrophin-glycoprotein complex)
Treatment/Prognosis: Weight control, PT, assist devices for ambulation, surgical correction of orthopaedic problems, monitoring of respiratory function
TAY SACHS DISEASE
Responsible gene: HEXA
Protein: Hexosaminidase A
Cytogenetic locus: 15q23-q24
Clinical Features and Diagnostic Criteria: Infantile weakness starts at 6 mo, exaggerated startle, seizures and vision loss by the end of the first year, neurodegeneration continues- deaf, cannot swallow, weakening of muscles, and eventual paralysis, death in toddler years. Juvenile muscle coordination problems, seizures, and vision problems starting as young children. Chronic and adult onset start later, progress more slowly, more
Clinical Tests: HEXA enzyme activity, cherry red spot on eye exam
Molecular Tests: Follow enzyme testing with DNA testing (some with a positive enzyme assay have a pseudodeficiency allele that does not cause Tay Sachs). HEXA 6 common mutation panel: 92% of Ashkenazi Jewish
Disease Mechanism: Accumulation of GM2 gangliosides in the brain
Treatment/Prognosis: Supportive only
BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer
Responsible genes: BRCA1 and BRCA2
Proteins: Breast cancer type 1 and 2 susceptibility protein
Cytogenetic loci: 17q21, 13q12.3
Clinical Features and Diagnostic Criteria: BRCA 1 and 2: Br, ovarian, prostate cancer; ?colon. BRCA2:larynx, esophagus, colon, stomach, gallbladder, bile duct, hematopoietic system, and melanomas.
Clinical Tests: mammography, MRI, BRCA1-related breast tumors show an excess of medullary histopathology, are of higher histological grade, and are more likely to be estrogen receptor-negative and progesterone receptor-negative. BRCA1-related ovarian cancer: excess of serous adenocarcinomas
Molecular Tests: Common mutation analysis or full gene sequencing (about one third of mutations identified in BRCA1 and BRCA2 sequencing are of uncertain clinical significance). 185delAG (BRCA1) and 6174delT (BRCA2) mutation s are
found in 20-30% of Jewish women with early breast cancer and in 45-60% of Jewish women diagnosed with ovarian cancer. Dutch women with early br or ovarian ca: often one of 3 large BRCA1 deletions. BRCA2 999del5 occurs in 7.7% of women and
40% of men with breast cancer from Iceland. BRCA2 mutation 6174delT found in 1% of women of Ashkenazi Jewish descent.
Disease Mechanism: BRCA1 and 2 are tumor suppressor genes
Treatment/Prognosis: discussion of cancer screening protocols, chemoprevention trials, and options for prophylactic surgery. 85% will develop Br ca by age 70 yrs.
FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
Responsible gene: APC
Protein: Adenomatous polyposis coli protein
Cytogenetic locus: 5q21-22
Inheritance: AD (15-30% new mutation)
Clinical Features and Diagnostic Criteria: adenomatous colonic polyps (100-1000) in childhood to adolesence, abdominal desmoid tumors, jaw osteoma, absent/ supernumerary/ malformed teeth, hepatoblastoma, thyroid cancer, epidermoid cysts. Attenuated FAP: fewer polyps, more proximal in the colon. Gardner syndrome: colonic adenomatous polyposis, osteomas, and soft tissue tumors. Turcot syndrome: colon cancer and CNS tumors (medulloblastoma)
Clinical Tests: Clinical findings on colonoscopy
Molecular Tests: APC sequence analysis (up to 90%), protein truncation testing (up to 80%)
Disease Mechanism: When abnormal protein is present, high levels of free cytosolic b-catenin result which migrates to the nucleus, binds to a transcription factor Tcf-4 or Lef-1 (T cell factor-lymphoid enhancer factor), and may activate the oncogenes c-Myc and cyclin D1
Treatment/Prognosis: Without colectomy, colon cancer is inevitable, and colectomy is recommended when adenomas emerge. The mean age of cancer in untreated individuals is 39 years.
HEREDITARY NONPOLYPOSIS COLON CANCER (HNPCC)
Responsible gene (protein and cytogenetic locus): MLH1 (3p21.3, DNA mismatch repair protein MLH1), MSH2 (2p22-p21, DNA mismatch repair protein Msh2), MSH6 (2p16, DNA mismatch repair protein MSH6), and PMS2 (7p22, PMS1 protein homolog 2)
Clinical Features and Diagnostic Criteria: Amsterdam II Criteria: 3 or more family members (at least one 1st degree of the other 2) with HNPCC related cancers; 2 successive affected generations; 1 or more of the HNPCC-related cancers diagnosed before age 50; exclusion of FAP. Bethesda 2004: CRC diagnosed under age 50yrs, 2 HNPCC related tumors at once, CRC with high MSI in someone <age 60yrs, CRC in one or more 1st degree relatives with and HNPCC related tumor with 1 cancer diagnosed before age 50yrs, or CRC diagnosed in 2 or more 1st or 2nd degree relatives (any age). HNPCC-related tumors: colon, endometrium, stomach, ovary, hepatobiliary tract, urinary tract, small bowel, brain/CNS.
Clinical Tests: Microsatellite instability (MSI) of tumor tissue, immuno-histochemistry of tumor tissue for the presence or absence of DNA mismatch repair proteins MLH1, Msh2, and
Molecular Tests: Mutation scanning MLH1 (60-69%), MSH2 (50-69%). Full sequencing MLH1 (90-95%), MSH2 (50-80%). Deletion analysis MLH1 (5-10%), MSH2 (17-50%), MSH6 (rare)
Disease Mechanism: These proteins work in a recessive manner at the cellular level- LOH leads to absence of any functional protein and dysfunctional mismatch repair.
Treatment/Prognosis: 80% lifetime risk of CRC. If CRC present, full colectomy with ileorectal anastomosis indicated. Colonoscopy every 1-2yrs by age 20-25. Consider annual
pap smear, transvaginal US, endometrial bx and CA-125 level.
Responsible genes: P53, CHEK2
Proteins: Cellular tumor antigen P53, Serine/threonine protein kinase Chk2
Cytogenetic loci: 17p13, 22q12.1
Clinical Features and Diagnostic Criteria: Proband with sarcoma <age 45 yrs, 1st deg relative with cancer <45 yrs, and 1st or 2nd deg relative with any cancer <45yrs or a sarcoma at any age. Inc risk of multiple primary tumors: bone, cartilage, and soft tissue sarcoma; early onset breast cancer; spine or
brain tumor, childhood adrenocortical tumors, Wilms' tumor, and malignant phyllodes tumors
Clinical Tests: Pathology
Molecular Tests: P53 sequencing (95%), sequencing CHEK2 (<5%)
Disease Mechanism: Abnormal DNA repair: P53 protein plays a role in determining whether cells undergo arrest for DNA repair or apoptosis. CHEK2 is a checkpoint gene that is activated in response to DNA damage
Treatment/Prognosis: No cancer surveillance protocol has been shown to reduce mortality except annual exam and mammography for women over 40 yrs. Avoid or minimize exposure to radiation.
MULTIPLE ENDOCRINE NEOPLASIA TYPE 1
Responsible gene: MEN1
Cytogenetic locus: 11q13
Clinical Features and Diagnostic Criteria: MEN1= tumor in 2 of:
parathyroid, enteropancreatic endocrine tissue, or anterior pituitary OR Tumor in one and 1st degree relative with MEN1. Facial angiofibroma, collagenoma, café au lait, lipoma
Clinical Tests: Parathyroid function studies, anterior pituitary
hormone abnormalities, Brain MRI
Molecular Tests: MEN1 sequencing (70-90% familial, 65% sporadic), Dup/del testing (1-3%)
Disease Mechanism: MEN1 is a tumor suppressor gene by
regulating transcription of proteins involved in the regulation of cell proliferation and development
Treatment/Prognosis: biochemical testing of serum concentrations of calcium (from age 8 yrs), gastrin (from age 20 yrs), pancreatic polypeptide (from age 10 yrs), prolactin (from age 5 yrs), abdominal CT or MRI (from age 20 yrs) and head MRI (from age 5 yrs).
MULTIPLE ENDOCRINE NEOPLASIA 2
Responsible gene: RET
Protein: proto-oncogene tyrosine-protein kinase receptor ret
Cytogenetic locus: 10q11.2
Clinical Features and Diagnostic Criteria: MEN2A two or more of
medullary thyroid carcinoma, pheochromocytoma, or parathyroid adenoma/hyperplasia in a single person or close relatives. MEN2B mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, Marfanoid habitus, and medullary thyroid carcinoma
Clinical Tests: Calcitonin, catecholamines, catecholamine metabolites, Ca, PTH
Molecular Tests: RET sequencing: Exon 10 and 11 (95% MEN2A), Exon 16 (95% MEN2B)
Disease Mechanism: Gain of function mutations in RET lead to
consitutive activation of tyrosine kinase
Treatment/Prognosis: Prophylactic thyroidectomy, screen for
pheochromocytoma annually and prior to any surgery, annual calcitonin stim test, annual PTH screening
NEUROFIBROMATOSIS Type II
Responsible gene: NF2
Protein: Neurofibromin-2 (aka Merlin or Schwannomin)
Cytogenetic locus: 22q12.2
Clinical Features and Diagnostic Criteria: Benign nerve tumors
(schwannomas, meningiomas, ependymonas, astrocytoma).
Hallmark is bilateral acoustic schwannoma, onset age 18-24 yrs,
hearing loss, tinnitus, balance problems. Also cataracts,
mononeuropathy, café au lait (fewer than in NF-1).
Clinical Tests: MRI/CT, BAER, audiology evaluation, eye exam
Molecular Tests: NF2 sequencing (75%), dupl/del testing (10-
Disease Mechanism: NF2 is a tumor suppressor, 2nd hit leads to complete loss of function when one germline mutation present
Treatment/Prognosis: Symptomatic tumors removed surgically
(XRT may induce tumor formation). Ave age of death: 36 yrs.
PTEN HAMARTOMA TUMOR SYNDROME
Responsible gene: PTEN
Protein: Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual specificity protein phosphatase
Cytogenetic locus: 10q23
Clinical Features and Diagnostic Criteria: Cowden: Presents 2nd/3rd decade: mucocutaneous facial and oral papules, gingival cobblestoning, acral keratosis; dystrophic and adenomatous multinodular goiter, GI polyps, adenosis and
fibrocystic breast lesions, macrocephaly, dolichocephaly, lipomas, GU anom. High risk for breast, thyroid, and endometrial cancer. Bannayan-Riley-
Ruvalcaba (BRR) macroceph, polyposis, lipomas, pigmented macules of the glans penis. Proteus: CT nevi, disprop. overgrowth, dysregulated adipose tissue, vascular malformation, risk of ovarian or parotid tumor in 2nd decade
Clinical Tests: Lesion pathology, MRA/MRI, CT
Molecular Tests: PTEN seq (80%), promoter region mutations (10%)
Disease Mechanism: Wild-type protein is a major lipid phosphatase that downregulates the PI3K/Akt pathway to cause G1 arrest and apoptosis
Treatment/Prognosis: Annual derm exam, annual breast exam, annual breast MRI and mammography starting age 30, annual thyroid US starting age 18, annual endometrial bx starting age 35 until menopause then annual transvaginal US with bx of suspicious lesions
Responsible genes: TSC1 and TSC2 Proteins: Hamartin and Tuberin
Cytogenetic loci: 9q34, 16p13
Inheritance: AD (2/3 de novo)
Clinical Features and Diagnostic Criteria: Skin: hypomelanotic macules, facial angiofibroma, shagreen patch, ungual fibromata. CNS: subependymal glial nodules, cortical tubers, giant cell astrocytoma, seizures. Renal: angiomyolipomas, epithelial cysts, <1% malignant transformation Heart: cardiac rhabdomyoma, tend to regress in infancy without intervention. Lung: lymphangiomatosis (TSC2, women aged 20-40 yrs) Eye: hamartomas or achromic patches. There is a TSC2/PCKD
contiguous gene deletion syndrome with features of TS and PKD.
Clinical Tests: brain MRI, echo, renal ultrasound, Wood's lamp exam, eye exam, EEG
Molecular Tests: TSC1 sequencing (30% familial, 15% sporadic) and TSC2 sequencing (50% familial and 60-70% sporadic)
Disease Mechanism: Abnormal tumor suppressor activity
Treatment/Prognosis: Renal US q1-3 yrs, renal CT/MRI if numerous lesions on US, semiannual renal US if angiomyolipomas <3.5-4.0 cm, chest CT if pulmonary symptoms
VON HIPPEL-LINDAU SYNDROME
Responsible gene: VHL
Protein: Von Hippel -Lindau disease tumor suppressor
Cytogenetic locus: 3p25
Clinical Features and Diagnostic Criteria: Hemangioblastoma
(cerebellum, retina, spinal cord), pheochromocytoma (hypertension), renal cell carcinoma (40%). Acquired VHL mutations can give rise to sporadic VHL associated tumors.
Clinical Tests: CT or MRI, urine catecholamine metabolites, renal US
Molecular Tests: VHL sequencing (72%), southern blot for partial or complete gene deletion (28%)
Disease Mechanism: Abnormal tumor suppressor function. Truncating or missense mutations that grossly disrupt protein folding lead to VHL Type I: low risk for pheo. Other missense mutations lead to VHL Type II: high risk of pheo.
Treatment/Prognosis: Reduced risk of renal cancer in those with
complete gene deletion. Starting at age 5: annual eye exam, urine catecholamines, BP. Starting age 15 annual abdominal US. Temporal bone MRI if documented HL.
Responsible genes: Most common: XPA, XPC, ERCC2, POLH
Proteins: DNA-repair protein complementing XP-A cells, DNA-repair protein complementing XP-C cells, TFIIH basal transcription factor complex helicase subunit, DNA polymerase theta
Cytogenetic loci: 9q22.3, 3p25, 19q13.2-q13.3, 6p21.1-p12
Clinical Features and Diagnostic Criteria: severe sun sensitivity, UV exposure to conjunctiva, cornea, and lids-> severe keratitis, progressive neurologic deterioration: acquired microcephaly, dec/absent DTR's, prog. SNHL, cognitive impairment. > 1000x inc. risk of skin and eye neoplasms
Clinical Tests: Cellular UV hypersensitivity (a post UV exposure cellular survival plot reflecting capacity for DNA repair.
Molecular Tests: Research only direct DNA testing of XPA (25%), XPC (25%), ERCC2 (15%), POLH (21%)
Disease Mechanism: Impaired ability to sense, excise, and repair UV induced DNA damage
Treatment/Prognosis: Regular detailed skin and eye exam, regular audiometry, protection of all body surfaces from UV light, UV meter to detect unexpected sources of high levels of UV light (eg halogen lamps). Treat cancers
Responsible genes: CDKN1C, H19, KCNQ1OT1
Proteins: cyclin-dep kinase inhib 1C, H19 maternally expressed untranslated mRNA, potassium voltage-gated channel, KQT-like subfamily, member 1
Cytogenetic locus: 11p15.5
Inheritance: AD (15%)
Clinical Features and Diagnostic Criteria: hemihyperplasia, macrosomia, macroglossia, visceromegaly, embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities
Clinical Tests: AFP, abdominal CT
Molecular Tests: Cytogenetically detectable abnormalities of 11p15 (<1%); loss of methylation at DMR2 (50%); gain of methylation at DMR1 (2% -7%); pat. UPD for 11p15 (10-20%); mutations in the CDKN1C (40% of familial cases and 5-10% of sporadic cases)
Disease Mechanism: imprinted genes including growth factors and tumor suppressor genes in the 11p15.5 region
Treatment/Prognosis: 20% mortality, Screening for embryonal tumors: abdominal US every three months until eight years. Serum AFP concentration is monitored in the first few yrs of life for hepatoblastoma.
BECKWITH-WIEDEMANN SYNDROME face
Anterior linear ear lobe creases
Posterior helical ear pits
Facial nevus flammeus
Responsible gene: NSD1
Protein: Histone-lysine N-methyltransferase, H3 lysine-36 and H4 lysine-20 specific
Cytogenetic locus: 5q35
Clinical Features and Diagnostic Criteria: classic: macrocephaly,
pointed chin, tall stature and increased body mass, delayed motor skills, delayed cognitive, verbal, and social development, advanced BA. Less common: phobias, aggression, OCD, ADD, abnormal EEG and seizure, chronic OM and constipation, congenital heart defects, strabismus, hyper/hypothyroidism, possible inc risk of tumors (saccrococcygeal teratoma and neuroblastoma).
Clinical Tests: Bone age. Brain MRI or CT may show inc ventricles
Molecular Tests: MLPA or FISH for 5q35 microdeletion including NSD1: ~15% (70% in Japanese). NSD1 sequencing: 27-93% (12% in Japanese)
Disease Mechanism: Haploinsufficiency of NSD1. May be related to genes affecting growth.
Treatment/Prognosis: Supportive treatment, most end up of ave adult Ht, IQ ranges from normal to ID. Cancer screening is not rec. (risk ~1%)
SOTOS SYNDROME face
sparse frontotemporal hair
high bossed forehead
downslanting palpebral fissures
long narrow face
prominent narrow jaw
head is said to resemble an inverted pear
ATAXIA WITH OCULOMOTOR APRAXIA TYPE 1 and TYPE 2
Responsible genes: APTX, SETX
Proteins: Aprataxin, Probable Helicase Senataxin
Cytogenetic loci: 9p13.3, 9q34
Clinical Features and Diagnostic Criteria: childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. Oculomotor apraxia progresses to external ophthalmoplegia.
Clinical Tests: Cerebellar atrophy, axonal neuropathy on EMG and biopsy, low serum albumin, high cholesterol. Type 2: Inc AFP
Molecular Tests: sequencing APTX (Inc incidence in Portugal and Japan) and SETX. Mutation detection rate unknown.
Disease Mechanism: There is direct involvement of aprataxin in the DNA single-strand break repair mechanisms; mutations in the APTX gene destabilize aprataxin and cells from individuals with AOA1 are characterized by enhanced sensitivity to agents that cause single-strand breaks in DNA
Treatment/Prognosis: PT, wheelchair by age 15-20 yrs, educational support, high protein low cholesterol diet
COCKAYNE SYNDROME (CS)
Responsible genes: ERCC6, ERCC8
Proteins: DNA excision repair protein ERCC-6 and ERCC-8
Cytogenetic loci: 10q11, Chromosome 5
Clinical Features and Diagnostic Criteria: CS Type I: normal prenatal growth, severe FTT in first 2 years, progressive deterioration of vision, hearing, CNS, and peripheral nervous syndrome. Type II: growth failure at birth, little or no postnatal neurological development, kyphosis, scoliosis, joint contracture. Type III: normal growth and development or late onset. Xeroderma Pigmentosum-CS: facial freckling, early skin
cancer, ID, spasticity, short stature, hypogonadism (no demyelination).
Clinical Tests: Brain MRI: leukodystrophy. Eye exam: pigmentary
retinopathy, cataracts, demyelinating peripheral neuropathy. Abnormal DNA repair on skin fibroblasts
Molecular Tests: Gene sequencing ERCC6 (75%), ERCC8 (25%)
Disease Mechanism: Abnormal transcription-coupled nucleotide
excision repair (preferential removal of UV-induced pyrimidine dimers and other transcription blocking lesions)
Treatment/Prognosis: PT, dental exams, skin exams, sunscreen if photosensitive. Death in 1st-2nd decade Type I, by age 7 yrs Type II.
HUTCHINSON-GILFORD PROGERIA SYNDROME
Responsible gene: LMNA Protein: Lamin-A/C
Cytogenetic locus: 1q21.2
Inheritance: AD (all de novo, paternal age effect)
Clinical Features and Diagnostic Criteria: short stature, wt<<ht, head large for face, diminished sc fat, prominent scalp veins, generalized alopecia, delayed and crowded teeth, delayed fontanelle closure, pear shaped thorax, small chin, thin limbs, tight joints, wide based shuffling gate. Sclerodermatous skin changes over lower abdomen and thighs
Clinical Tests: Elevated urine hyaluronic acid (unreliable for Dx). ECG, echo, and carotid duplex scans for stenosis. X-ray for clavicular absorption, acroosteolysis, coxa valga
Molecular Tests: LMNA G608G Exon 11 (100%)
Disease Mechanism: G608G leads to abnl splicing and the mutant form of prelamin A that results is thought have a dominant negative effect leading to progressive defects in nuclear architecture
Treatment/Prognosis: Optimize nutrition, age appropriate schooling, PT, aspirin. Annual ECG, echo, carotid duplex, lipid profiles, dental exam and xray. Hip x-rays every few yrs to evaluate for avascular necrosis of the femoral head. Severe atherosclerosis develops even with nl lipid profiles, usually die of MI or CVA (avg lifespan 13 yrs)
Responsible gene: SERPINA1
Cytogenetic locus: 14q32.1
Clinical Features and Diagnostic Criteria: Adult COPD,
childhood and adult liver disease (obstructive jaundice and raised transaminases in kids, cirrhosis and fibrosis in adults). Age of onset 40-50y if a smoker, 60's if not.
Clinical Tests: Low plasma AAT (also low in other resp d/o inc
CF), Demonstration of deficient variant of the AAT protein by
protease inhibitor typing
Molecular Tests: Targeted mutation testing of SERPINA (95%
Disease Mechanism: Loss of sufficient protease inhibition by
Treatment/Prognosis: Liver transplant is a cure (donor liver
produces AAT). Research: IV AAT if rapid decline in FEV1.
CFTR RELATED DISORDERS
Responsible gene: CFTR
Protein: cystic fibrosis transmembrane conductance regulator
Cytogenetic locus: 7q31.2
Clinical Features and Diagnostic Criteria: Cystic fibrosis (CF): chronic airway infection, chronic sinusitis, meconium ileus, malabsorption due to pancreatic insufficiency, male infertility due to azoospermia. Progression to end stage lung disease. Congenital bilateral absence of the vas deferens (CBAVD) occurs in men without pulm. or GI Sx of CF.
Clinical Tests: sweat test, decreased semen volume with low pH, high [citric acid], high [acid phosphatase], low [fructose]
Molecular Tests: Common mutation testing or full gene sequencing. Intron 8 5T variant: variably penetrant, test for if R117H mutation. 5T with 12 or 13 TG tract (just 5' of 5T) has the strongest adverse effect on proper intron 8 splicing.
deltaF508: 30-80% of mutant alleles depending upon ethnic group.
Disease Mechanism: CFTR forms a regulated cell membrane chloride channel. 4 mutation classes: I. reduced or absent synthesis, II. block in protein processing, III. block in regulation of CFTR chloride channel, IV. altered conductance of CFTR
Treatment/Prognosis: antibiotics, bronchodilators, steroids, mucolytics, chest PT, lung transplant, pancreatic enzymes, fat soluble vitamins, microscopic sperm aspiration.
ALPORT SYNDROME AND THIN BM NEPHROPATHY
Responsible genes: XL: COL4A5, AR: COL4A3 and COL4A4, AD: COL4A3 and COL4A4
Proteins: Collagen alpha-3(IV) chain, Collagen alpha-4(IV) chain, Collagen alpha-5(IV) chain
Cytogenetic loci: 2q36-q37 (COL4A3 and COL4A4), Xq22.3 (COL4A5)
Inheritance: 80% X linked, 15% AR, 5% AD
Clinical Features and Diagnostic Criteria: Spectrum from progressive renal disease with cochlear and ocular abnormalities (Alport) to isolated hematuria with a benign course (thin BM nephropathy).
Clinical Tests: Microhematuria, eventually proteinuria. Anterior lenticonus virtually pathognomonic, EM on renal biopsy
Molecular Tests: Sequencing and deletion testing COL4A3, COL4A4, COL4A5 (80-100%)
Disease Mechanism: Type IV Collagen is found ubiquitously and is the major collagen component of BMs. Alport due to abnl secretion of collagen alpha 3,4,and 5 (IV) chains
Treatment/Prognosis: ESRD: 60% by 30 yrs and 90% by 40 yrs and Deafness: 80-90% SN deafness by age 40 in males, later in life in females with XL Alport. Renal progression and deafness is slower in AD Alport and ocular lesions uncommon. Juvenile onset HL in AR Alport.
POLYCYSTIC KIDNEY DISEASE
Responsible genes: PKD1, PKD2 and PKHD1
Proteins: Polycystin-1, Polycystin-2, Fibrocystin
Cytogenetic loci: 16p13.1, 4q21, and 6p21.1-p12
Inheritance: AD (PKD1, PKD2) AR (PKHD1)
Clinical Features and Diagnostic Criteria: AD PKD Enlargement of both kidneys, renal cysts, hematuria, polyuria, flank pain, renal stones, urinary infection. Cysts in liver, pancreas, and intestine; heart valve defects, intracranial aneurysm. AR PKD Fetal or neonatal death, impaired lung formation, pulmonary hypoplasia due to oligohydramnios, renal failure, hepatic fibrosis. Most present prenatally or early infancy
Clinical Tests: Abdominal US, prenatal US, MRI
Molecular Tests: PKD1 and PKD2 sequence analysis (85%). Large deletion including PKD1 and TSC2: manifestations off PKD and tuberous sclerosis
Disease Mechanism: Unclear, decreased amount of functional
Treatment/Prognosis: PKD2 mutations show later onset and slower rate of progression. ESRD age 60 yrs
Responsible gene: FGFR3
Protein: Fibroblast growth factor recepter 3
Cytogenetic locus: 4p16.3
Inheritance: AD; 80% de novo
Clinical Features and Diagnostic Criteria: short stature,
rhizomelic shortening, trident hand, frontal bossing, midface
hypoplasia, macrocephaly, OSA, spinal cord compression
Clinical Tests: Narrowing of interpediculate distance, caudal
spine; notch-like sacroiliac groove, circumflex or chevron seat
on the metaphysis
Molecular Tests: 98% FGFR3 G1138A; ~1% FGFR3 G1138C
Disease Mechanism: Constitutive activation of FGF R (GOF
mutations)- activation of negative growth control
Treatment/Prognosis: achondroplasia growth curves, surgery
or CPAP for OSA, role of GH unclear, leg lengthening,
suboccipital decompression, spinal fusion, LPA support group
Responsible gene: RUNX2
Protein: Runt-related transcription factor 2
Cytogenetic locus: 6p21
Inheritance: AD (high proportion de novo)
Clinical Features and Diagnostic Criteria: delayed closure of the
cranial sutures, hypoplastic or aplastic clavicles, multiple dental
abnormalities. Abnormally large wide open anterior fontanel, midface hypoplasia, brachydactyly, recurrent OM, hearing loss, normal intellect.
Clinical Tests: X-ray: clavicular hypoplasia, open sutures, wormian bones, poor or absent sinus pneumatization, hypoplastic scapulae, wide symphysis pubis and sacroiliac joints, large femoral neck and epiphyses, pseudoepiphyses of the metacarpals and metatarsals, deformed and short middle phalanges, osteopenia.
Molecular Tests: RUNX2 sequencing and array for microdeletions (60-70%).
Disease Mechanism: Independently mediates DNA binding and
protein heterodimerization; mutations abolish DNA binding
Treatment/Prognosis: Hearing test, dental referral, ear tubes, helmets if large skull defects
Responsible gene: SLC26A2
Protein: Sulfate transporter
Cytogenetic locus: 5q32-q33.1
Clinical Features and Diagnostic Criteria: limb shortening, normal-sized skull, hitchhiker thumbs, small chest, large joint contracture, cleft palate, cystic ear swelling, ulnar deviation of fingers, clubfoot, low tone, normal IQ
Clinical Tests: x-ray: cervical kyphosis, incomplete thoracic vertebrae ossification, coronal clefting of lower thoracic and lumbar vertebrae, narrowed interpedicular distance L1 to L5, distal humerous can be bifid or v shaped, rounded distal femur, advanced bone age. Cartilage histopathology: paucity of sulfated proteoglycans in cartilage matrix. Abnormal incorporation of sulfate into macromolecules in cultured chondrocytes
Molecular Tests: SLC26A2 targeted mutation analysis (65% one of 5 mutations), SLC26A2 sequencing(>90%)
Disease Mechanism: Undersulfation of proteoglycans affects the
composition of the extracellular matrix and leads to impaired proteoglycan deposition which is necessary for proper enchondral bone formation
Treatment/Prognosis: Maintain joint positioning and mobility as much as possible, clubfoot deformities tend to recur after surgical correction, scoliosis surgery best if postponed until after puberty. Joint contractures and spine deformity worsen with age. Total arthroplasy may diminish joint pain.
(Pfeiffer, Apert, Crouzon, Beare-Stevenson, FGFR2-related Isolated Coronal Synostosis, Jackson-Weiss, Crouzon with Acanthosis Nigricans, and Muenke)
Responsible genes: FGFR1, FGFR2, FGFR3
Proteins: Basic fibroblast growth factor receptor 1, 2, and 3
Cytogenetic loci: 8p11.2-p11.1, 10q26, 4p16.3
Clinical Features and Diagnostic Criteria: All but Muenke and FGFR2-related Isolated Coronal craniosynostosis are associated with bicoronal craniosynostosis or cloverleaf skull, distinctive facial features, and variable hand and foot anomalies (broad and/or syndactylous). Developmental delay/ID, hearing loss, and visual impairment common.
Clinical Tests: Brain CT or MRI for hydrocephalus, spinal x-rays for vertebral anomalies
Molecular Tests: FGFR1 sequencing (5% Pfeiffer 1); FGFR2 sequencing (100% Crouzon, Jackson-Weiss, Apert, Pfeiffer 2 and 3, and FGFR2-related isolated coronal synostosis); FGFR3 sequencing (100% Crouzon with Acanthosis Nigricans); FGFR3 targeted mutation analysis (100% Muenke)
Disease Mechanism: Mutations cause increased R affinity thought to promote excessive receptor down-regulation.
Treatment/Prognosis: Coordinated neurosurgical, ENT, and dental care, follow for scoliosis, limb anomalies rarely benefit from surgery
Responsible gene: FGFR3
Protein: Fibroblast growth factor receptor 3
Cytogenetic locus: 4p16.3
Clinical Features and Diagnostic Criteria: Short stature, stocky
build, rhizo- or mesomelia, limited elbow extension, brachydactyly, mild joint laxity, macrocephaly, scoliosis, genu varum, lumbar lordosis, mild-mod ID, LD, adult onset osteoarthritis
Clinical Tests: x-ray: elongated distal fibula, short lumbar pedicles, short distal ulna, chevron deformity of distal femur metaphysis, flattened acetabular roof
Molecular Tests: Targeted mutation analysis: N540K (C1620A) (49%), N540K (C1620G) (21%). Exon 9, 10, 13, or 15 sequencing (80%)
Disease Mechanism: unknown but mouse models suggest FGFR3 is a negative regulator of bone growth
Treatment/Prognosis: Monitor for S/Sx spinal cord compression (MRI or CT foramen magnum), sleep study id history c/w OSA, ortho eval if severe genu varum impairs walking.
MULTIPLE EXOSTOSES SYNDROME
Responsible genes: EXT1, EXT2
Proteins: Exostosin-1, Exostosin-2
Cytogenetic loci: 8q24.11, 11p11.2
Clinical Features and Diagnostic Criteria: Exostoses (benign
cartilage-capped bony growths) arising from the growth plate of the long bones or from the surface of flat bones (scapula). Limb length inequity and bowed long bones can develop. Short metacarpals. Can have mass effect compression of nerves and blood vessels.
Clinical Tests: x-ray may detect mildly affected individuals
Molecular Tests: EXT1 and EXT2 sequencing: >70% detection
rate, del/dup studies: 20%
Disease Mechanism: EXT1/2 encode glycosyltransferases,
mutations lead to actin accumulation and cytoskeletal abnormalities
Treatment/Prognosis: Growth ceases after skeletal maturation.
0.5-2% of cases degenerate to chondrosarcoma. Treatment is
Responsible genes: COL1A1 and COL1A2
Proteins: Collagen alpha 1(I) chain, Collagen alpha 2(I) chain
Cytogenetic loci: 17q21.33, 7q21.3
Inheritance: AD and rare AR
Clinical Features and Diagnostic Criteria: Fractures with little or no trauma, relative short stature, blue sclera, dentinogenesis imperfecta, post-pubertal HL, ligamentous laxity, easy bruising. OI Type II: perinatal lethal, palpable callus formation on ribs, hips in "frog-leg" position, short bowed extremities. OI Type III: severe, skull descends on cervical spinebrainstem
compression, obstructive hydrocephalus, syringomyelia
Clinical Tests: x-ray: fractures of varying ages, spinal compression fracture, wormian bones, protrusio acetabuli, osteopenia. Cultured fibroblasts (98% Type II, 87% all others)
Molecular Tests: COL1A1 and COL2A1 sequencing: ~100% Type I, 98% Type II, 60-70% Type III, 0-80% Type IV
Disease Mechanism: Type I: premature stop codon->unstable mRNA->dec amount type I collagen. Types II, III, IV: mutations alter collagen structure
Treatment/Prognosis: Bisphosphonate to decrease bone resorption, GH to increase linear growth and bone formation
Responsible gene: TWIST1
Protein: Twist-related protein 1
Cytogenetic locus: 7p21
Clinical Features and Diagnostic Criteria: coronal synostosis, facial asymmetry, ptosis, 2/3 hand syndactyly, mild-moderate developmental delay in a minority, short stature, parietal foramina, vertebral fusions, radioulnar synostosis, cleft palate, maxillary hypoplasia, congenital heart defect
Clinical Tests: echo, x-ray for vertebral abnormalities, audiologic
testing, and karyotype: translocations, inversions, or ring chromsome 7 have been reported
Molecular Tests: TWIST1 sequencing: >50%, del/dup testing:
complete deletion of the TWIST1 gene 11-28%
Disease Mechanism: haploinsufficiency by gene deletion, rapid
degradation of abnormal protein, or altered subcellular localization of abnormal protein
Treatment/Prognosis: endocrine eval if plateau in growth, craniofacial team management, surgical repair of cleft palate and craniosynostosis, eye exams to monitor for evidence of increase ICP
SAETHRE-CHOTZEN SYNDROME face
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