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Master Boards Review -- Peds and Adult
Terms in this set (135)
Noonan features and genes
Short stature, short webbed neck, pulmonic stenosis, facial gestalt, café-au-lait spots, pectus deformity, cryptorchidism, lymphadema, scoliosis, coagulopathy, renal anomalies.
Increased risk for cancer
50-80% CHD: thickened dysplastic pulmonary vlave, cardiomyopathy, coartaction.
PTPN11 (50%), SOS1 (13%), KRAS (<2), RAF1
Cardio-facial-cutaneous (CFC) syndrome features and genes
Cardio: atrial septal defect, pulmonary valve dysplasia, hypertrophic cardiomyopathy, VSD, PSD, rhythm disturbances.
Facial: tall forehead, bitemporal narrowing ptosis w/ downslanting fissures, coarse face compared w/ Noonan, earlobe creases, absent eyebrows.
Cutaneous: follicular hyperkeratosis sparse, slow-growing hair, lymphedema.
Additional features: Macrocphaly, short stature, ocular, musculoskeletal, GI abnormalities
Unknown risk for cancer
BRAF (75%), MEK1, MEK2, KRAS
Costello syndrome features
Distinctive facial gestalt (coarse), failure to thrive, thickened skin/palms, hypertrophic cardiomyopathy, pulmonic stenosis or arrhythmia. Curly or sparse, fine hair. Loose, soft skin, increased pigmentation, deep palmar/plantar creases
15% risk for malignant tumors (rhabdomyosarcoma, neuroblastoma, transitional cell carcinoma of bladder). .Overlap w/ noonan and cfc syndrome.
HRAS sequence analysis detects 80-90%, some labs have panel. (del/dup not reported)
LEOPARD features, gene, inheritance
Lentigines (liver spots), ECG abns, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, Deafness.
Gene: PTPN11 (also associated w/ Noonan) and RAF1 (Noonan)
NF1 diagnostic criteria
2 or more of the following: 6+ CAL macules, 2+ neurofibromas (any type) or one plexiform neurofibroma, Freckling in the axillary or inguinal regions, optic glioma, 2+ lisch nodules (iris hamartomas), a distinctive oseous lesion such as sphenoid dysplasia or pseudarthrosis, FDR w/ clinical dx of NF1.
90% sequence variants, whole gene deletions 4-5%. 50% de novo rate. Incidence: 1/3000. Fully penetrant by reproductive age.
Iimpulsive, lack of judgement, hyperactivity, small stature, microcephaly, dev delay, short palpebral fissures, long philitrum that is smooth, thin upper lip.
Risk for FAS 40% w/ maternal ingestion of 6+ drinks per day. Risks w/ infrequent "binge drinking"
Cornelia de lange
DD/MR, distinctive facial gestalt, microcephaly, growth retardation, limb, GI. NIPBL (60%), few SMC1A and SMC3
Large gestational age, excessive growth in childhood, macrocephaly, hypotonia, long face/tall forehead, pointed chin, recessed hairline, high and narrow palate, mild borderline MR, macrocrania w/o megalencephaly, dolichocephaly, structural brain changes, hypertelorism, disproportionately large hands/feet, developmental delay, autism, behavior problems are common. Gene: NSD1
Weaver syndrome features, gene
Accelerated skeletal maturation, unsual fascies, camptodactyly, excessive postnatal growth, macrocephaly, ocular hypertelorism, normal to severe ID. Overlap w/ Sotos phenotype. Gene: EZH2
DD/MR, broad thumbs, broad toes, distinctive facial profile, behavioral profile, growth retardation, short stature, developmental delay. Sequence mutations in CREBBP gene in 30-50%, microdeletion of CREBBP in 10%, EP300 mutations 3%.
NF2 features and expressivity
Features: uni/Bilateral vestibular schwannomas, glioma, neurofibroma, posterior subcapslar lenticular opacity, multiple menigiomas, unilateral HL in 45%. Expressivity: More interfamilial variability than intrafamilial variability. Clinical course in older family members is predictive. About 90% penetrance w/ screening/evals. MERLIN gene. Incidence 1:30,000
Bardet-biedl features and inheritance
RP, truncal obesity, diabetes, postaxial polydactyly. Other features: ID, renal dysfuction, speech delays, dental anomalies, hypogonadism, female genitourinary malformations. Inheritance: AR, sometimes digenic, triallelic inheritance.
Stargardt features, inheritance and genes
juveline macular degeneration, changes to central visual acuity usually in childhood, peripheral vision is stable. Inheritance: Usually AR, but there can be forms of AD (ELOVL4), can be pseudodominant. Genes: ABCA4, CNGB3, ELOVL4
Leber congenital amaurosis features and inheritance
Severe retinal dystrophy, usually w/ nystagmus. Inheritance: AR. 16 genes associated.
Albinism and ocular albinism
Albinism -- Key features: nystagmus, decreased visual acuity, photophobia. Other features: Hypopigmentation, iris transilummination, foveal hypoplasia, abnormal decussation of optic nerve fibers. Cause: Defective production of melanin from tyrosine. Inheritance is always AR, except for 1 form of ocular albinisim. Ocular Albinism -- Only ocular features, there can also be sensorineural deafness if there are other gene deletions. XL recessive inheritance, gene OA1
Leber hereditary optic neuropathy (LHON) features and inheritance
Asymptomatic then visual blurring in one eye, then the other in 2-3 months (VA < 20/200). Neuro abnormalities: postural tremor, peripheral neuropathy, nonspecific myopathy, MS-like illness. Males are 4-5X more likely than females to be affected. Mitochondrial inheritance. Dx based on optical findings. About 90% have 1 of 3 specific point mutations in mtDNA.
Clinical findings: Higher risk for nystagmus, photophobia, ectopia lentis, visual acuity ranges, cataracts, glaucoma. Isolated aniridia gene: PAX6 (AD inheritance), 55-62% sequence variants, 17-22% deletion. 23% with no molecular dx
CHARGE, name features, gene
Coloboma, heart defect in 50% (TOF, AVSD), atresia choanae, retarded growth and development, genital abnormality, ear abnormality. Features: Growth retardation, square-shaped auricles, coloboma, cochlear abnormalities. Gene: CHD7 mutations in 60%
SMA types, de novo rate, genes, presentation
Lethal/type 0: 0-1 copies SMN2.
Type 1: 70% of all cases, 2 copies of SMN2.
Type 2: 3 copies of SMN2.
Type 3: 4+ copies of SMN2, ambulatory.
2% de novo rate.
Genes: SMN1 and SMN2, adjacent on chrom 5q.
Homozygous loss of exon 7 of SMN1 accounts for 94% of all SMA mutations.
SMN2 normal cnv ranges from 0-5 in cis on each chromosome. SMN2 codes an unstable protein with 10% yield of stable protein.
Type 1 presentation: Onset age 0-6yrs, normal at birth w/ progressive muscle weakness. Hypotonic, loss of bulbar function, tremor, tongue fasciculation. Never sit unsupported, crawl, stand, walk. Normal intelligence, normal imaging studies.
Complications: poor weight gain, resp insufficiency, joint contractures, scoliosis, pneumonia. Death w/in 2 years.
Incidence: 1 in 10,000. Carrier frequency 1/40 - 1/60, may be as high as 1/35 among Caucasians.
Copy numbers of SMN1 and SMN2 are determined by quantitative dosage analysis of genomic DNA. Identified 94% of carriers.
4% of population have 2 copies of SMN1 in cis and 0 copies on other chromosome (not detected by dosage analysis).
2% of carrier have a point mutation only detected by sequence analysis.
BWS features and genes
Large for gestational age (LGA), hypoglycemia, omphalocele, macroglossia, hemihyperplasia, ear creases/pits, flamus nevus, organomegaly, cardiomegaly/cardiac anomalies.
4-10% risk for embryonal tumors:
US studies for hepatoblastoma and wilms tumors. Also at risk for rhabdomyosarcoma, adrenocortical carcinoma, neuroblastoma.
Chrom 11p15.5 with hypermethylation of H19, condition of abnormal maternal imprinting. Manifests only when the mutant gene is inherited from the mother. Maternal allele is not normally methylated, it is methylated in BWS and IGF2 expression is increased, H19 is silenced. Also KCNQ1 is usually methylated on maternal allele, but in BWS there is no methylation and silenced CDKN1C, which shuts off the brakes for growth
Inheritance and Recurrence Risks:
85% have no family history, 15% have AD inheritance pattern
1 - Methylation analysis: detect loss of methylation on IC2 of maternal chromosome (50% of cases) and gain of methylation on IC1 of mathernal chromosome (5% cases), very low RR
2 - Sequence analysis (if fhx of BWS, or last resort): Detects mutations in 5% of individuals w/ no fhx BWS and 40% in pt w/ fhx of BWS. If no fhx and CDKN1C mutation is detect, parents shoudl be tested for mutation. RR up to 50%.
3 - UPD analysis: paternal uniparental disomy of 11p15.5 (20% of cases), RR very low.
4 - Karyotype/FISH/microarray: Duplication, inversion or translocation of 11p15.5 (1% detection by Karyotype). Consider parental testing, RR can be as high as 50%.
Silver Russel syndrome features and gene
IUGR, SGA, normocephalic, hypoglycemia, hypospadias, 5th digit clinodactyly, limb asymmetry.
1 - Methylation Analysis
35-50% Abnormal paternal methylation: Hypomethylation of H19 at 11p15.5. H19 has increased expression and IGF2 is silenced
3 - UPD analysis: 10% maternal UPD of chrom 7
2 - Deletion/duplication analysis 11p15.5
Duplication of maternal 11p15.5, translocations or inversions, % unknown, small proportion.
4 - Del/dup analysis of chrom 7 (rare)
Low, but germline mosaicism has been reported for methylation defects.
Dx of RSS and supportive lab testing should be considered for individuals w/ 3 major OR 2 major and 2 minor:
Postnatal growth <3rd percentile
Normocephalic (3-97th percentile)
Limb, body, facial asymmetry
Short arm span w/ normal upper to lower segment ratio
5th finger clinodactyly
Frontal bossing/prominent forehead
CAL spots or skin pigment changes
GU anomalies (cryptorchidism, hypospadias)
Motor, speech, cognitive delays
SRS and BWS imprinting
Maternal imprint is growth supressing (SRS) and paternal imprint is growth enhancing (BWS)
Angelman / prader willi imprinting
15q11.2 region. Angelman: UBE3A maternal imprinting, if there is a maternal mutation it causes angelman. Prader willi locus is paternal imprinting and paternal mutation causes disease
Presentation: severe DD/ID, gait ataxia, happy, microcephaly, seizures.
Genetics/Testing: 15q11.2 UBE3A (Mom is missing)
Methylation analysis detects 78%
70% maternal deletion by FISH or CMA
7% Paternal UPD
0.5% Imprinting defect deletion at IC
RR as high as 50% if mother also has deletion
2.5% Imprinting defect without deletion in the IC
11% Sequence analysis of UBE3A (del/dup UBE3A rare)
10% unknown cause
<1% have visible chrom rearrangement
As high as 50% when: unbalanced chrom translocation or small interstitial deletion (<1% of cases), imprinting defect w/ deletion on the IC (<0.5% of cases), inherited UBE3A maternal deletion (11% of cases)
Paternal UPD w/ predisposing paternal translocation (<1% of cases), RR could be 100% for paternal UPD w/ father having 15;15 Robertsonian translocation (rare).
Prevalence 1 in 15,000 to 25,000
Severe hypotonia and feeding difficulties in early infancy, hypogonadism, late infancy/childhood excessive eating, obesity, motor/language delay, ID, behavioral phenotype, short stature, facial features, diabetes.
Methylation testing detects >99% of cases (15q11.2)
70% paternal deletion (FISH/microarray)
25% Maternal UPD
<5% Imprinting defect sequence analysis to detect microdeletions
Usually <1%for deletion or UPD, up to 50% for imprinting defect, up to 25% for parental chromosomal translocation.
RR IS <1%. INCREASED RR IN <3% OF CASES (inherited chromosomal rearrangement, maternal UPD w/ predisposing translocation or marker chromosome, imprinting defect w/ deletion in the IC)
Branchio-oto-renal (BOR) syndrome features, gene, inheritance
Branchial (neck) cysts, cup-shaped auricles, atretic ear canals, hearing loss, preauricular pits, renal dysplasia.
Gene: EYA1 (also SIX1 and SIX5). AD inheritance
Oculo-auriculo-vertebral (OAV) syndrome features
Oculo: microtia, preauricular tag. Auriculo: conductive hearing loss. Vertebral: cervical hemivertebrae. Hemifacial microsomia, epibulbar dermoid, facial asymmetry (unknown cause)
Usher syndrome features, gene, inheritance
Early onset senorineural hearing loss w/ RP. Type 1 is most severe, type 3 is least severe
Type 1: Profound SNHL, delayed walking, RP by school age.
Type 2: moderate congenital HL, RP by 20 yrs.
Type 3: Postlingual progressive HL, late onset RP, variable vestibular dysfunction. AR inheritance, 9 genes includeing MYO7A gene. Prevalence up to 10% in profoundly deaf children.
Pendred syndrome features
Bilateral, severe, congenital progressive hearing loss, bilateral enlargement of the vestibular aquducts (LVA), euthyroid goiter (10% hypothyroidism). Gene: SLC26A4. AR inheritance. 1/2 of pt with LVA have mutation in SLC26A4
Wolfram syndrome features, gene, inheritance
low freq progressive hearing loss, diabetes insipidus, diabetes mellitus, optic atrophy, dysgenesis of corpus callosum, polymicrogyria. Gene: WFS1, AR inheritance
Waardenburg syndrome features, gene, inheritance
Telecanthus, broad nasal root, heterochromia (different colored eyes), white forelock, hearing loss (30-50%). PAX3, AD inheritance
Kabuki syndrome features
Postnatal growth delay, long palpebrae/lashes, large ears, coarctation of the aorta, 5th finger clinodactyly, sensoryneural or conductive hearing loss (40-50%). Gene: MLL2, AD inheritance (de novo)
Hearing Loss - most common non-syndromic genetic causes
Connexin 26 -- GJB2
Accounts for 20% of prelingual deafness. Most common cause of AR hearing loss. Prognosis: little or no progression of hearing loss, normal intellect, good response to cochlear implant. Carrier rate: 1/33 caucasians
Connexin 30 -- GJB6
Compound het for GJB2 mutation and GJB6 deletion accounts for 2-4% of newborns w/ profound SNHL. Homozygous GJB6 deletions are rare. AR inheritance.
Account for 1-2% of newborns with profound SNHL
Cutaneous anomalies: telangiectasia, nevus flammeus, hirsutism. Leg-length discrepancy and scoliosis. Risk for Wilms tumor, adrenal cortical carcinoma and hepatoblastoma (level of risk is undefined)
Overgrowth, asymmetry, gigantism of limbs, increased size of organ, body or bones, deep venous thromboses (can result in stroke), PTEN
Rhizomelic Chondrodysplasia punctata features, gene, inheritance
Peroxisome biogenesis disorder. Gene: PEX7, AR inheritance
proximal limb shortening, dysmorphic features, congenital contractures, cartilage calcifications, vertebral clefts, cataracts, seizures, hearing loss in 70%, severe intellectual disability w/ spasticity. Symmetrical shortening of femur and humerus w/ irregular and broad meaphysis. Calcific stippling is present at birth and disappears in older pt after 18 mo.
Disproportionate short stature (rhizomelic shortening, longer thorax, macrocephaly), decreased elbow extension, trident hands, bowed legs, lordosis, facial features, obstructive sleep apnea. Narrowing of the foramen magnum at C1 canal.
Gain of function mutation in FGFR3. 7/8 cases are de novo.
FGFR3 phenotype genotype correlation
Hypochondroplasia: most mild, single mutation in exon of kinase domain. Thanatophoric dysplasia: most severe form, mutations of coding and non-coding regions. Achondroplasia: mutations of transmembrane region
Most common lethal skeletal dysplasias
thanatophoric dysplasia, OI, achondrogenesis/ hypochondrogenesis, short-ribbed polydactyly
Short-limb dwarfism usually lethal in the prenatal period. brachydactyly, redundant skin folds along limbs. FGFR3 mutations
Type I: micromelia, bowed femurs, uncommonly cloverleaf skull.
Type 2: micromelia, straight femurs, always cloverleaf skull moderate/severe. Other features: short ribs, narrow throax, macrocephaly, distinctive facial features, hypotonia.
Key US findings: platyspondyly, short ribs, very small chest, severe micromelia.
Shortening of long bones possibly visible as early as 12 to 14 weeks.
At 20 weeks US: growth deficiency w/ limb length below 5th centile, well ossified spine and skull.
2nd/3rd trimester: ventriculomegaly, narrow chest cavity, polyhydramnios
Skeletal dysplasia. Distinctive facies, Pierre Robin sequence w/ CP, shortening and bowing of long bones, club feet.
Other findings: laryngotracheomalacia w/ resp compromise, ambiguous genitalia or normal femal external genitalia in most individuals w/ 46,XY karyotype. Many die shortly after birth.
Long term problems (if they survive): short stature, c-spine instability, progressive scoliosis, hearing impairment.
Gene: SOX9 only. Mutations detected in about 95% of affecteds (90% sequence variants). Typically de novo.
Severe, AR, short-limbed skeletal dysplasia. Flat mid-face, small nose, anteverted nares. Shortening of all limb segments w/ relatively normal hands. Bell-shaped thorax w/ protuberant abdomen. Most likely COL11A1 gene
OI types, features, gene
Features: fractures, wormian bones, short stature, blue/grey sclera, dentinogenesis imperfecta, progressive post-pubertal hearing loss, ligamentous laxity, fhx of OI.
Type 1 Classic non-deforming w/ blue sclerae: 60% of cases de novo, most common, mild, normal to short stature and some fractures, blue sclarae, HL in about 50%, rarely dentigenisis imperfecta (DI).
Type 2 perinatal lethal: 100% de novo, Multiple prenatal fractures prevents lung development, dark blue sclerae, DI. Most live in utero and die shortly after birth, dx by 20 week gestation on US.
Type 3 progressively deforming: 100% de novo, very short stature, blue sclerae, thin bones, many fractures, "popcorn" epiphyses, DI
Type 4 Common variable w/ normal sclerae: next most common, moderately deforming, variable short stature, normal to gray sclerae.
Gonadal mosaicism in 3-5% of cases, sometimes DI.
GENE: COL1A1 (70%) or COL1A2 (30%). Dominant negative mutations. Seq analysis (>95%) followed by del/dup (1-2%)
Stickler syndrome findings, inheritance, genes
Ocular: myopia, spontaneous retinal detachment, congenital vitreous anomaly; Auditory: sensorineural hearing loss; Orofacial: cleft palate w/wo Robin sequence, bifid uvula; Skeletal: early onset degenerative joint disease. Usually AD. Genes: COL2A1 (80-90%), COL9A1, COL11A1, COL11A2
Non-ocular Stickler: Moderate, mixed, congenital hearing loss, prominent forehead, low nasal root, pierre robin sequence, cleft palate, large joints, normal vision. COL11A2, AD inheritance
Alport syndrome features, gene, inheritance
Eyes, hearing, kidneys
Males: 60% have end stage renal disease by 30 and 90% by 40, progressive, bilateral, high-req HL, 80-90% signifiant by 40 years, lenticonus or other ocular disease in 40%.
Female carriers: renal disease 12% end stage by 40 years, 40% by 80 years, HL infrequent, lenticonus uncommon.
80-85% are X-linked: COL4A5
15-20% AR: COL4A3 or COL4A4
Ehlers-Danlos syndrome (EDS) features, gene
Skin hyperextensibility, skin fragility, nodules below skin surface on arms/shins, hypermobility, bruising and hematomas after trivial injuries. Internal: heart murmer, mitral valve prolapse, weakened walls of intestines, arteries and uterus. GENE: COL5A1, COL5A2, COL3
Types 1 and 2. Dx is made based on family history and clinical exam. Major and minor dx criteria. Major: skin hyperextensibility, widened atrophic scars, joint hypermobility, fhx. Clinical features: skin hyperextensivility, abnormal wound healing, joint hypermobility. Skin smooth, velvety, hyperelastic, and fragile (splitting w/ minor trauma). Delayed wound healing. Complications from joint dislocations are easily managed by individual. Hypotonia, delayed motor development, fatigue, muscle cramps, easy bruising. Less common: mitral and tricuspid valve prolapse, aortic root dilation, spontaneous rupture of large arteries. 50% have identifiable mutation in COL5A1 (46%), COL5A2 (4%). Deletions/duplications have not been reported. Rarely COL1A1. 50% de novo mutations.
EDS hypermobility type
Type 3. Least severe type of EDS. Skin often soft or velvety, normal to mildly hyperextensible. Subluxations and dislocations are common (spontaneous or minimal trauma). Degenerative joint disease is common. Chronic pain distinct from acute dislocations is a serious complication (physically and psych disabiling). Easy brusing is common. Aortic root dilation is mild with no increased risk of dissection. Common psych dysfunction. Dx based on clinical evaluation and fhx. AD inheritance. TNXB gene has been identified as causative in a small subet of affected individuals.
Type 4. Thin translucent skin, easy bruising, facial features in some, arterial, intestinal and/or uterine fragility. Presenting signs: vascular dissection or rupture, GI perforatioin or organ rupture. Arterial rupture may be spontaneous or preceeded by aneurysm, arteriovenous fistulae or dissection. Neonates: clubfoot, congenital dislocation of hips. Childhood: inguinal hernia, pneumothorax, recurrent joint subluxation or dislocation. Pregnancy 12% risk of death. Median age of death 48 years. Major criteria: arterial rupture, intestinal rupture, uterine rupture during pregnancy, fhx. Dx based on clinical findings, confirmed by testing COL3A1. 50% de novo mutations. 95% of people with EDS detected by seq analysis, 2% deletions.
EDS Kyphoscoliotic form
Type 6. Friable, hyperextensible skin, thin scars, easy bruising, generalized joint laxity, sever muscular hypotonia at birth, progressive scoliosis present at birth or within the first year of life, scleral fragility with increased risk for rupture of globe. Risk of rupture of medium-sized arteries and respiratory compromised if kyphoscoliosis is severe. Gene: PLOD1. AR inheritance. Rare, carrier freq 1:150
Type 7A and B. AD inheritance, rare. Congenital hip dislocation and more severe skin manifestations. Mutations in exon 6 of COL1A1 and CoL1A2.
Loeys-Dietz syndrome features, gene
AD connective tissue dysplasia w/ generalized arterial involvement, craniofacial and skeletal features. Triad of features: widely distrubuted arterial tortuosity and/or aneurysm, cleft palate or wide/bifid uvula, hypertelorism. Also macrocrania, craniosynostosis, cervical instibility, dev disability, CNS involvement, cardio defect, pectus deformity, long long bones and fingers, scoliosis, camptodactyly, contracture, hyperextensibility. Unique findings: transluscent, velvety skin, blue sclera, atrophic scarring. GENE: TGFBR1 (25%) and TGFBR2 (75%). >95% have detectable mutation by seq analysis, deletions not reported. 75% de novo rate.
Marfan syndrome features, gene, de novo rate
Three organ systems must be affected for dx w/ one major finding in cariac, eye or skeletal.
EYE: Myopia most common, ectopia lentis (lens displacement) is hallmark and seen in 60%, increased risk for retinal detachment, glaucoma, early cataract.
SKELETAL: excessive linear growth of long bones and joint laxity, long extremities (dolichostenomelia), long, narrow face w/ deep set eyes.
CARDIO: dilation of the aorta, predisposition for aortic tear and rupture, mitral valve prolapse, tricuspid valve prolapse, enlargement of pulmonary artery.
Other findings may be pulmonary, dermatologic or CNS. GENE: FBN1 (dominant negative). Shortened fibrillin 40%, missense 60%. 25% de novo rate. Clinical sensitivity of sequence analysis of FBN1 is 70-93%. Del/dup unknown. Incidence 1:5000 - 10,000
Marfan syndrome dx criteria
No family history:
Aortic root enlargement and one of the following: ectopia lentis, pathogenic FBN1 variant, or a systemic score 7+.
OR ectopia lentis and FBN1 pathogenic variant previously associated with aortic enlargement.
Postive family hisotry (based on these criteria):
Systemic score of 7+
Aortic root enlargement
Systemic score includes wrist/thumb sign, pectus, flat foot, scoliosis, striae, myopia, mitral valve prolapse, etc.
Craniosynostosis syndromes, mutations in FGFR genes
FGFR1: pfeiffer syndrome. FGFR2: apert, pfeiffer, crouzon, beare-stevenson, jackson-weiss syndromes. FGFR3: crouzon, non-syndromic craniosynostosis
Crouzon syndrome features, gene
Normal intellect, craniosynostosis, shallow orbits, atretic auditory canal, normal extremeties, proptosis, mandibular prognathism, hydrocephalus. Gene: FGFR2. Crouzon w/ acanthosis nigricans: 5% of people with Crouzon syndrome have AN. AN can present in neonatal period or later, FGFR3
Apert syndrome features, gene
Variable ID/DD, syndactyly (mitten glove), mid-face hypoplasia, fused cervical vertibrae, can look similar to pfeiffer. Gene: FGFR2
Pfeiffer syndrome features, gene
Type 1: mild, brachycephaly, midface hypoplasia, finger/toe abnorm, normal intellectually. Type 2: cloverleaf skull, extreme proptosis, finger/toe abnorm, elbow ankylosis/synostosis, ID, neuro complications. Type 3: similar to type 2 but no cloverleaf skull. GENE: primarily FGFR2, 5% of type 1 have FGFR1 mutation
Muenke syndrome features, gene
hearing loss, DD, normal to mild ID, carpal/tarsal bone coalition. Gene: FGFR3
Normal intellect, mandibular prognathism, broad great toe. Gene: FGFR2
Severe ID, mid-face hypoplasia, furrowed palms, pyloric stenosis, cutis gyrate, bifid scrotum. Gene: <100% FGFR2
Summary of FGFR1
Pfeiffer syndrome. Broad first digits, hypertelorism
Summary of FGFR2
Apert, pfeiffer, crouzon, beare-stevenson, jackson-weiss syndromes. Digital fusion, mid-face hypoplasia, broad first digits, ocular proptosis, corrugated skin, foot anomalies.
Summary of FGFR3
Crouzon syndrome, non-syndromic craniosynostosis. Mid-face hypoplasia, ocular proptosis, acanthosis nigricans, digital defects, hearing loss
Mandibulofacial dysostosis features (Conditions gene and inheritance)
Down-sloping palpebrae, midface/orbital hypoplasia, microtia/middle ear anomalies, cleft palate, micrognathia, eyelid coloboma.
Treacher collins: 40% HL TCOF1, AD inheritance.
Nager: preaxial defects. Hypoplastic tumb, duplicated thumb, radial hypoplasia, radioulnar synostosis. Sporadic, AR and AD inheritance, cause unknown
Miller: Postaxial defects. Postaxial agenesis of digits. DHODH gene, AR
Treacher collins syndrome
Mandibulofacial dysostosis. Bilateral, malformed ears, malar and mandibular hypoplasia, lower lid coloboma, cleft palate, hearing loss, microtia, micrognathia.
AD. TCOF1 gene (treacle protein) mutation result in premature termination of protein.
Triad: imperforate anus, dysplastic ears w/ or w/o ear tags, tumb malformation (triphalangeal, duplication or hypoplasia).
Also Renal abnormalities, CHD, foot or GU malformations. SALL1 gene, AD inheritance
Included hemifacial microsomia, Goldenhar syndrome. Phenotypically variable and causally heterogeneous. May include vertebral defects and epibulbar dermoids. Less hypoplasia of the malar bones and normal lower eyelids.
Resembles mandibulofacial dysostosis w/ limb involvement. Hypoplastic limbs, mandible more severely affected, lower lid colobomas rarer.
Char by AVM in lungs, brain and liver. Telangiectases in skin of hands, face, mucosa of mouth and intestines (lips most suggestive). Pulmonary AVM: 30-40% of pt. Symptoms: exercise intolerance, shortness of breath, migraine, TIA, or none. Risks: embolic stroke, brain abscess, hemorrhage. Cerebral AVM: 10% of pt. Symptoms: headache, seizure, hemiparesis, none. Risk: intracranial hemorrhage. Can be fatal in asymptomatic children. DX criteria: Epistaxis (recurrent nosebleed), multiple characteristic telangiectases (lips/hands), internal AVM, fhx. Suspected for 2, definate for 3. Genes: endoglin (HHT1), ACVRL1/ALK1 (HHT2), SMAD4 (juvenile polyposis/HHT)
Fragile X features and repeat size
Most common form of inherited intellec dis. Tri-nucleotide repeat expansion resulting in abnormal methylation of FMR1 gene. XLD inheritance. Mosaicism in 15-20% of FMR1. Explosive expansion transmitted through maternal line.
Presentation: Dev delay, distinct face, macro-orchidism, hyperextensibility, ADHD, anxiety or ASD, seizures (20%), sensory integration issues.
Full-mutation carrier female: lower frequency and milder features of the condition
Premutation carrier POI: cessation of menses before age 40, 20% of women with premutation will have POI, 2-14% of women with POI have premutation.
Premutation carrier fragile X assoc tremor/ataxia: female risk is 8-16%, male risk is age dependent, 75% by age 80.
Prevalence Affected: 1/4000 males, 1/8000 females.
Premutation carriers: 1/1000 males, 1/350 women (according to ACMG).
About 2-6% of children diagnosed with autism have Fragile X
5-44 stable, non-carrier, unaffected
45-58 gray zone, some instability, unaffected
59-200 premutation, unaffected/mildly affected, risk for POF/FXTAS >200 methylation of FMR1, affected (Not all fragments w/ >200 repeats are methylated.)
>200 w/ mosaicism highly variable
Huntington disease features and repeat size
Late-onset neuro disorder, movement disorder (voluntary movement impairment, chorea), dementia (memory loss, behavior changes), dpression.
Early signs: Clumsiness, Agitation, Irritability, Apathy, Anxiety , Disinhibition, Delusions, Hallucinations, Abnormal eye movements, Depression
Memory: Memory deficits with greater impairment for retrieval of information occur early are usually much less severe than in Alzheimer disease.
Average age of onset 35-44 years or as late as 70s and 80s. Average course of disease 15-18 yrs. CAG repeat in HTT gene.
<27 normal range
27-35 nonpenetrant w/ meiotic instability
36-39 variable penetrance
40+ affected. Loose correlation btwn repeat size and age of onset
DMD gene and phenotypes
Dystrophin protein mutations, X-linked. Spectrum of phenotypes w/ mildest asyptomatic and slight increase of CK. Deletion of one or more exons account for 60-70% of mutations for DMD and BMD. Duplications deleterious in 5-10% of males with DMD and BMD, may be slightly more common in BMD. Point mutations account for 25-35% of DMD and 10-20% of BMD. Testing strategy: del/dup first, then sequence analysis. 15-20% of female carriers may have mild sx (muscle weakness, myalgia/cramps, lft ventricle dilation, dlated cardiomyopathy in DMD) in families with DMD and BMD. Germline mosiacism in mothers with no detectable mutation by DNA analysis is 15-20%. De novo rate 1/3.
Duchenne Muscular Dystrophy
Progressive symmetric muscular weakness (proximal greater than distal) often w/ calf hypertrophy. CK markedly elevated. Sx present before 5 yrs (clumsiness, toe walking, calf pseudohypertrophy), wheelchair dependency before 13yrs. Other features: contractures of ankles, hips, knees, scoliosis, resp insufficiency, cardiomyopathy esp >15yrs, cognitive difficulties in 1/3 of pt. Affected females w/ skewed X-inactivation. Manifesting female carriers may have adult onset cardiomyopathy (carrier screening important in mothers), or muscle pain/cramping on exhertion.
Incidence: 1/3,500 male births.
Becker muscular dystrophy
Mutations of dystrophin gene w/ residual expression. Onset late childhood/early adolescence. Ambulatory to early adulthood. Progressive muscle weakness/atrophy, weakness of quads may be only sign. Activity-induced cramping (sometimes), flexion contractures of elbows (late in course if present). Preservation of neck flexor muscle strength differentiates BMD from DMD.
Myotonic dystrophy (DM1)
AD inheritance, expansion of CTG repeat in DMPK gene. (CNPB is gene for DM2). Anticipation, usually inherit from mother. Severity based on # repeats. Incidence 1:8,000. DM2 is milder and presents in adulthood. DM1 has a congenital form.
Presentation: Progressive muscle deterioration (skeletal/cardiac), weakness, atrophy in face, distal extremities, myotonia, cognitive difficulties, cardiac conduction defects, cataracts, frontal balding, hypersomnolence (sleepyness). Percussion myotonia, handshake, bi-temporal narrowsing, fish-shaped mouth, myopathic facies, atrophy of forearms. High penetrance, variable expressivity, somatic mosaicism.
Facioscapulohumeral (FSHD) muscular dystrophy
Presents before 20 years with weakness of facial muscles and stabilizers of scapula or dorsiflexors of foot. Highly variable severity, slowly progressive, 20% eventually require wheelchair. Normal life expectancy.
90% penetrant by age 20.
Genetics: derepression and dysregulation of DUX4 within the microsatellite repeat D4Z4. Mechanism is complicated and controversial.
10-30% de novo
Limb Girdle Muscular Dystrophy (LGMD)
Descriptive term for childhood or adult onset muscular dystrophy that is distinct from the more common X-linked dystrophies (DMD/BMD).
Type 1 have AD inheritance
Type 2 have AR inheritance
>50 loci have been shown to cause LGMD
Features: weakness and wasting restricted to the limb musculature, proximal (shoulders, upper arms, upper legs, pelvid girdle) greater than distal, typically skeletal muscle only, nonsyndromic, elevated CK
>50 loci have been identified, difficult to identify molecular dx, about 50% of LGMD will have no gene identified after molecular testing
Pierre robin sequence
U-shaped cleft palate due to glossoptosis w/ micrognathia typically present. Incomplete closure of palate. Assoc w/ many syndromes including: Stickler, 22q11, Treacher collins
Incidence overall: 1/600
Risk in 20s is about 1/1500, 30s rises, 40s levels out around 1/100. 50% of babies w/ DS born to mothers <35 years, average maternal age 31.5.
Cardiac defect: VSD, endocardial cushion defect
50% of babies with DS have one or more congenital abnormality: 40-60% of babies with DS have a heart defect and 12% have a gastrointestinal defect that may require surgery.
Life expectancy into 50s or 60s
Other features: hypothyroidism, leukemia.
Males typically infertile, but there are reports of fathering pregnancies. Theoretical chance for offspring w/ DS is 50% one affected parent, 66% two affected parents. Empiric data shows 30-50% risk.
95% have extra chromosome 21 (non-disjunction)
RR: age at previous trisomy <35 is age-related risk X3.5 for T21 and any aneuploidy is X1.3
RR: age at prev trisomy 35+ is age-related risk X1.7 and any aneuploidy is 1.5
No increased recurrence risk for 2nd+ degree relatives
90% maternal origin, 10% paternal origin
3-4% have translocation, about 1/3 of which are inherited
If father is carrier of a Robertsonian translocation, risk is 0.5-1.5% depending on chromosomes involved
If mother is carrier, risk is about 10-15% in offspring (0-11% for 15;21)
If neither is a carrier, recurrence risk is similar to non-disjunction T21
RARE if t(21;21) translocation, risk is 100% for future offspring.
1% have mosaicism
Similar RR as non-disjunction, though it may overestimate riks
Cannot distinguish T21, translocation or mosaicism based on clinical features.
Delivering news of Down Syndrome
Meet with both parents together
Provide accurate, up-to-date info w/ balanced perspective of positive and challenges related to DS
Use neutral language and avoid using vaue judgements when starting the conversation, such as "I'm sorry" or "Unfortunately I have bad news".
Baby should be present and should be referred to by name.
Information resources should be provided, opportunity to meet other families raising a child w/ DS, referrals to specialists when appropriate.
Pre and postnatal growth retardation, microcephaly, apnea, seizures, hearing loss, facial features, clenched fists, short sternum, hernia, spina bifida, renal anomalies, contractures, medically significant malformations. CHD, arthrogryposis/club feet. Feeding difficulties, GE reflux, seizures.
Older children: scoliosis, photophobia/visual acuity, profound dev disability, wilms tumors <1%.
95% with CHD: polyvalvar nodular dysplasia, AVSD, VSD, ASD, patent ductus arteriosus
Overall incidence: 1/3000
Orofacial clefts, hypotelorism, microphthalmia, postaxial polydactyly, cutis aplasia of the scalp, facial features. CHD, holoprosencephaly, renal malformations (cystic kidneys), omphalocele, seizures, apnea, cleft lip/palate, feeding difficulties, growth retardation, genital anomalies, polydactyly.
CHD: VSD, ASD, patent ductus arteriosus, dextrocardia, TOF.
Survival of T18/T13
5-10% survive to 1 year, 2% survive 5 years. Children progress in dev milestones.
Distinctive facial features, developmental delay, cognitive impairment, behavioral abnormalities. Infants have hypotonia and lethargy.
Behavioral phenotype starting at 18 months: sleep disturbance, stereotypies, self-injurious behavior.
Adult behavior also: Hyperactivity, impusivility, aggression, self-hug, finger lick and page flipping.
Insterstitial deleion of 17p11.2 detected by karyotype (can be overlooked)
Molecular testing of RAI1
Virtually all de novo mutations.
Gene: MECP2 on X chromosome. 8 mutations account for 2/3 of cases. Prevalence 1 in 10,000 live female births. 99.5% de novo. Abnormal brain development.
Variants: early seizure (CDKL5), congenital variant (FOXG1), preserved speech variant (MECP2).
Features: normal development to age 7-18 months, stagnation then deterioration of brain function. ID (severe dementia), autism, acquired microcephaly, joint contractures, seizures/spilepsy, teeth grinding, scoliosis, osteopenia, gait ataxia/apraxia, tremors, dystonia, hand movements, behavior (panic attacks, screaming/crying, self-injury)
DDx for severe hypotonia at birth
Zellweger, Pompe, Prader willi, SMA
Major features: distinct facial appearance, growth delay, psychomotor retardation, seizures. Deletion of distal 4p16.3, including critical region (WHSCR). 40-45% have unbalanced translocation inherited from parent (parental testing is always recommending to understand recurrence risk). 2:1 female/male ratio
Sporadic transmission. Stands for: Vertebral anomalies, Anal atresia, Cardiac anomaly (VSD), Tracheo-Esophageal fistula, Renal anomalies, Limb anomalies. Diagnosis of exclusion. (shorter version is VATER)
1 in 4000 female births, majority are miscarried.
Features: Short stature, facial features, webbed neck, no menstration (no ovaries), low hairline, many nevi, CHD (bicuspid aortic valve, CoA, occasional right aortic arch, Horsehoe kidney
50% have 45,X karyotype
25% structural abnormality of the second X
25% have 45,X mosaicism
Cause: NOT assoc w/ advance maternal or paternal age
70-80% from sperm lacking a sex chromosome
Loss of sex chr from a cell in the early embryo is likely the cause of mosaicism
<1% of 45,X conceptions result in liveborn infant
Approx 25% of mosaic patients will have Y-bearing cell like and 15-20% risk for gonadoblastoma.
Elfin face, hypercalcemia, coctail party personality, mild mental retardation, irritable infants, hypothyroidism, renal artery stenosis, radio-ulnar stenosis, short stature. Deletion 7q11.23, including ELN and GTF21
Hemochromatosis type 1
Most common monogenic disease in Caucasians. AR inheritance, with env contributors. Enhanced intestinal absorption of dietary iron, particulary heme type. Leads to organ damage. Sx: liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism, skin pigmentation. Sx occur after age 40. Tx therapeutic phlebotomy. Testing: blood test for free and stored iron high levels (serum ferritin and transferrin saturation), genetic testing. Genes: HFE1 (C282Y, H63D, S65C). Carrier freq among N Europeans 1:7 to 1:10
Sx: GI findings, iron deficiency anemia, dermatitis herpetiformis, chronic fatigue, infertility/recurrent fetal loss, vitamin deficiencies. Genes: HLA gene heterodimers HLA-DQA1 and HLA-DQB1. Prevalence 1:400 to >5000. Genetic testing of DQ2 and DQ8 can rule out Celiac. 1% of people with variant develop Celiac.
Progressive neuro condition. Rest tremor, bradykinesia, rigidity, postural instability, gait abnormalities, speech changes, may develop dementia, positive response to L-DOPA. Prevalence: 1% people over 60 in US. Most common neurodegenerative disease after Alz. 3:2 men:women. 5-10% is monogenic (AD or AR inheritance), up to 35% is familial. 3-5% of monogenic is de novo. About 16 PARK loci w/ about 7 causal genes. LRRK2 is most common form of AD PD, common AJ mutation. PARK2 accounts fo 50% of juvenile onset PD w/ AR fhx.
Syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal positions. Hereditary and sporadic. Over 20 different DYT loci. TOR1A early onset primary dystonia, AD w/ reduced penetrance (30-40%).
Impaired ability to coordinate movement, usually caused by degeration of / lesions to the cerebellum or cerebellar pathways. Wide-based staggering gait, imbalance, dysarthria, eye movement abnormal. Causes genetic and sporadic.
Average age of onset 75 years. Severe memory loss, milder other cog symptoms, slowly progressive. 1-6% have early onset. Genes associated w/ early-onset Alz (1-2% of all Alz): PSEN1, PSEN2, APP (chr 21, susceptibility in Down syndrome)
Hemophilia A and B incidence, presentation, de novo rate
Incidence A: 1/4000 - 5000 live male births, rare in females. B: 1/25,000 males. Deficiency of clotting factors 8 (A) and 9 (B). X-linked recessive inheritance. Female carriers may have low factor levels (not always) and may experience abnormal bleeding sx, 10% are symptomatic and usually mildly affected. 30% de novo mutations. Factor levels: severe <1% spontaneous hemorrhage about 1 per week, moderate 1-5% hemorrhage w/ incidental injury, mild >5% hemorrhage w/ injury or surgery. Joint damage, muscle bleeds, functional disability.
Hemophilia A testing strategy, genotype/phenotype correlation
Dx of hemophilia A: low factor VIII activity w/ normal von Willebrand factor level (molecular testing is not first line). Clinical sensitivity: inversion at intron 22A 48%, intron 1 3%, large deletions 6%, point mutations 43%. Inversion or large deletion: severe hemophilia. Large F8 duplications: severe, mild or benign depending on location. Pathogenic sequence variants: mild, moderate or severe. Hx severe hemophilia, or severity unknown, start w/ inversion/del/dup testing. Hx mild/moderate hemophilia, start with sequencing.
Hemophilia B testing strategy and mutation types
97% are sequence variants, 3% whole gene or large gene deletions/duplications
Von Willebrand Disease
Most common inherited bleeding disorder. Overlap w/ Hemophilia A
Quantitative or qualitative defect in Von Willebrand factor (VWF). General popualtion prevalence is 1%. Variable expression and penetrance (about 30% non-penetrant).
Features: nosebleeds, heavy periods, abnormal bruising, oral/GI bleeding, excessive bleeding w/ trauma or surgery.
Testing low results by FVIII activity, VWF antigen, ristocetin cofactor activity, multimers, collagen binding, blood type. Genetic testing not routinely performed.
Factor V Leiden
Prothrombin (F2 gene): AD inheritance, risk for DVT, late pregnancy loss, IUGR, placental abruption, pre-eclampsia. 2-4% of population are carriers.
Protein C deficiency: AD inheritance, risk for DVT, IUGR, placental abruption, pre-eclampsia, pregnancy loss.
Protein S deficiency
Factor V Leiden
One specific mutation in the gene for factor V.
Heterozygotes: 2-6X risk for thrombosis in upper extremity, also increased risk for pregnancy loss, preeclampsia and fetal growth retardation, pulmonary embolism
Homozygotes: 20X risk DVT
4-10% of Caucasians are carriers, can be treated w/ Heparin or Warfarin
Split hand/split foot malformation
Syndactyly, medial clefts of hands and feet, aplasia and/or hypoplasia of findger bones (lobster claw). Five genes (SHFM1, SHFN2, SHFM4, TP63, SHFM5). AD, may be reduced penetrance.
Hereditary neuropathy. Chronic motor and sensory polyneuropathy. Usually distal muscle weakness and atrophy, often moderate sensory loss, depressed tendon reflexes, high-arched feet. >40 genes/loci associated, testing available for some types of CMT. Inheritance can be AD, AR or X-linked.
GAA repeat expansion of FRDA gene. AR inheritance. No parental bias. Most common inherited form of ataxia, incidence 1:50,000. Onset 5-15 years. Slowly progressive, cognition preserved, degeneration of nerve tissue in spinal cord of nerves of peripheral areas
Freeman sheldon syndrome
Gene DA2A. Multiple congenital contractures, scoliosis, oropharngeal abnormalities (whistling mouth)
Cholestasis (bile can't flow from liver to duodenum), CHD usually pulmonary arteries, posterior embrotoxin in eye, facial features, butterfly vertibrae, renal and CNS abnormalities. Highly variable, multi-system (liver, heart, face, skeleton). Half of people w/ mutations don't meet clinical criteria. JAG1 gene, AD inheritance. 50-70% de novo.
Coartation of Aorta, associated syndrome
13% risk for Turner syndrome
Common heart defects in 22q11
50% of pt w/ 22q11 have cardio defects. Proportion of heart defects w/ 22q11 deletion. Interrupted aortic arch type B 47%, truncus arteriosus 19%, tetralogy of fallot 12%, perimembranous VSD 10%, VSD 1%. Testing for 22q11 for all cases of IAA, TOF , truncus, VSD/arch anomaly.
Supravalar aortic stenosis associated syndromes
Supravalvar aortic stenosis Assoc w/ Williams syndrome. ELN gene mutations, familial SVAS. Pulmonic stenosis 7% assoc w/ Noonan syndrome, usually dysplastic valve. AV canal assoc w/ T21
Thoracic Aortic Aneurysm and Dissection (TAAD) syndromes and non-syndromic
Marfan: FBN1 mutations, ocular, skeletal, cardio findings, dilation mainly in sinuses of valsalva.
Loeys-dietz: TGFBR1/2 mutations, cardio, craniofacial, skeletal abnormalities.
Vascular ehlers danlos syndrome: COL3A1, transluscent skin, easy bruising, arterial, intestinal and/or uterine fragility.
Turner syndrome 1-2% aortic dissection.
Non-syndromic: 20% of all TAAD cases, and about 20% of thoses will have a mutation identified by genetic testing (ACTA2, MYH11, TGFBR1/2, SMAD3, FBN1, MYLK, TGF2)
Hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhthymogenic right ventricular dysplasia/CM, left ventricular non-compaction, restrictive cardiomyopathy
Most common genetic cardio disease. Incidence 1 in 500. Hypertrophied, non-dilated left ventricle. Onset at puberty (variable). Onset puberty to 20s.
Dx based on: Left ventricular hypertrophy and histopath findings.
Features: may be asymptomatic, heart failure symptoms, sudden death. Most common in young adults, esp athletes.
Causes: Acquired (athlete's heart, hypertension, storage disorders) or idiopathic (mostly genetic).
Heritable causes accounts for 60-70% of cases: familial, neuromuscular, inborn errors of metabolism (pompe or fabry), syndrome (noonan, wolf-parkinson-white secondary cause, mitochondrial disease RAF1 gene).
GENES: 18+ identified genes
2 genes account for 80%: MYH7 and MYBPC3.
Inheritance AD, XL and mitochondrial.
Incidence 1:2500. Dx based on impaired ventricular systolic function, enlargement of ventricles. Presents w/ heart failure symptoms, arrhythmias, sudden death, thrombotic events.
Causes: Acquired (viral, ischemic injury, alcohol/drug use, CHD, other) or heritable (familial 20-50%, neuromuscular DMD or metabolic) or idiopathic (50%).
>20 genes identified, panels yield 20-40% detection rate.
AD, AR, XL and mito inheritance.
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
Incidence: 1:2500 - 5000. Fibrofatty replacement, myocyte loss, wall thinning. Ventricular tachyarrhythmias w/ left bundle branch block. Complex diagnostic criteria. Onset in adolescence or young adulthood (mean age dx 30 years). Presentation: ventricular arrhythmias, syncope, palpatations, sudden cardiac death. Exercise induced. More prevalence in young adults and athletes. Up to half of cases are familial. 8 known genes, with detection rate of 40-50%.
Left ventricular non-compaction (LVNC)
Trabeculations of heart muscle and poor systolic function, with or without HCM or DCM. Arrest of normal cardiac compaction (congenital). Syndrome association genes: Barth syndrome, TAZ, LDB3, X-linked.
20-40% detection for panels.
Long QT syndrome
Incidence: 1:3000. Channelopathy, delayed repolarization causes QT wave abnormalities. Presentation: onset typically before 40, history of syncope, ventricular arrhythmias, seizures, sudden cardiac death (10-15%). 12 types. Classic type: 5 genes, phenotypes.
LQTS1: KCNQ1 and KCNE1.
LQTS2: KCNH2 and KCNE2.
Jervel, Lange-Nielsen: Congenital bilateral profound deafness, Long QTc interval, family history of sudden death. Gene: KCNQ1, KCNE1. AR inheritance
Other inheritance is AD.
Genetic testing has 75% detection rate.
4-5% sudden cardiac death risk overall.
Triggers: emotion, exercise, sleep.
Channelopathy. ST wave abnormalities. Presentation: adult onset, syncope, ventricular arrhythmias, sudden death.
8 genes identified. SCN5A most common (20-30%).
De novo mutation rare. Episodes at rest, during sleep. Males are 8-10 times more likely to develop symptoms.
Tetralogy of Fallot
Tetrad: pulmonary stenosis, ventricular septal defect, overriding aorta, right ventricular hypertrophy. Range of severity.
Symptoms: Blue color skin, passing out, difficulty feeding, poor growth and development. Difficult to diagnose prenatally.
Associated with 22q11, T13, T18 and T21. Recurrence risk 2.5% for 1 sibling, 8% for 2 siblings.
Atrioventricular septal defect (VSD, ASD, common AV valve). Hole in the wall between right and left ventricles. Common heart defect, 5% of all CHD. AKA endocardial cushion defect, or AV canal. 22% isolated, 78% syndromic. Associated syndromes: Tri 21, 18, 13, deletion 8p23, SLO, Holt-Oram, deletion 3p25. 15-20% of Down syndrome have AVSD. CRELD1 gene implicated in isolated AVSD.
Most common congenital hert lesion (20%). Presentation depends on size, can present w/ failure to thrive, congestive heart failure and pulmonary hypertension. Associated syndromes: T21, 18, 13, holt-oram, kabuki, townes-brock, rubenstein-taybi. Exposures: alcohol, maternal PKU, diabetes, valproate, thalidomide, trimethadione. Other: VATER and OAVS (goldenhar syndrome)
Common: 10% of congenital heart disease. May be asymptomatic into adulthood. Can be complicated by pulmonary hypertension. Associated syndromes: T21, 13, 22, deletion 4p, holt-oram, noonan, kabuki, ellis-van creveld. Alcohold exposure.
Coartation of the aorta
5% of congential heart disease. Severe: heart failure in newborn, Mild: may present late w/ murmur.
Cardio conditions recommended for genetic testing
LQT (75-80% detection), CPVT (70% detection), HCM (50-60% detection), DCM (>20% detection), sudden unexpected death cases w/ suspicion of cardiomyopathy or arrhythmia (15% for SIDS <1yo, 25-35% for 1-35 yo). Also can be useful for Brugada syndrome type 1, ARVC and LVNC.
Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Incidence 1/10,000. 3 genes associated, AD and AR inheritance. 50% of AD cases are de novo.
Features: enlarged kidneys with numerous fluid-filled cysts; an occipital encephalocele, polydactyly. Most affected individuals also have liver fibrosis.
Other features: oral clefting; genital anomalies; CNS malformations, including Dandy-Walker and Arnold-Chiari malformation. Pulmonary hypoplasia is the leading cause of death. Prenatal diagnosis as early as 10 weeks' gestation
Typically die before or shortly after birth.
8 genes, AR inheritance
Androgen Insensitivity Syndrome
Male 46,XY karyotype
Feminization of external genitalia at birth, abnormal secondary sexual development in puberty and infertility.
Complete: typical female genitalia. Tx may include removal of testes because of cancer risk (cancer risk is low and removal of gonads is increasingly controversial)
Partial: predominantly female or male or ambiguous genitalia
Mild: typical male external genitalia
Genetics: gene is "AR", inheritance is X-linked
10% of female carriers have symptoms: asymmetric/sparse pubic/axillary hair
30% De novo mutation
Classically defined as triad of: fibrous dysplasia of bone, CAL macules, precocious puberty
Other features: endocrinopathy, hyperthyroidism, growth hormone excess, Cushing syndrome.
Skin lesions evolve through 4 stages:
1 - Blistering age birth to 4 months
2 - Wart-like rash for several months
3 - Swirling macular hyperpigmentation 6 months to adulthood
4 - linear pigmentation
Other features: alopecia, hypodonitia, abnormal tooth shape, dystrophic nails. Sometimes neovasularization of retina cuasing retinal detachment.
Gene: IKBKG, 80% is deletions of exons 4-10, clinical sensitivity of genetic testing is about 90%
X-linked inheritance, often embryonic lethal in most males
Van Der Woude (VDW)
Lower lip pits, cleft lip/palate
IRF6 gene, mutation testing detects 72% of VDW
AD inheritance, incomplete penetrance
Polycystic kidney disease
Late onse, bilateral renal cysts, cysts in other organ (liver, pancreas, etc), intracranial aneurysms, dilation/dissection of aortic root, abdominal wall hernias. Renal hypertension/pain/insufficiency. End stage renal disease by 60 years in 50%. RCC not more frequent, but younger age of onset. Genes: PKD1 and PKD2
Present in neonatal period w/ enlarged echogenic kidneys. Renal disease/dysfunction. 50% have end stage renal disease w/in 10 years. Gene PKHD1
oculocutaneous albinism, immunodeficiency, mild bleeding tendency
AR inheritance, LYST gene
Slowly progressive incoordination of gait, often associated w/ poor coordination of hands, speech and eye movements. Atrophy of cerebellum is frequent.
Autosomal Dominant Ataxia
Spinocerebellar Ataxia: SCA1 through SCA23 are all AD inheritance, caused by CAG repeats in associated genes (ATXN1, ATXN2, ATXN3, and others)
Autosomal Recessive Ataxia
Friedreich ataxia (FXN)
Ataxia with oculomotor apraxia (APTX and SETX)
Refsum disease( PHYH, PEX7)
X-linked sideroblastic anemia and ataxia. Carrier females have normal neuro exam. ABC7 gene.
Deletion on 8Q
benign bone tumors (exostoses), short stature, epiphyses (cone-shaped ends of long bones), sparse scalp hair, rounded nose, cutis laxa in childhood. Dev delay.
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