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cmackman

Genetic Syndromes

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Chromosomal Defects
Euploid-Normal chromosome number
Aneuploidy-Abnormal chromosome number
Monosomy-Turner
Trisomy-Trisomy 13, 18, 21, Klinefelters XXY
Trisomy 21
*Down Syndrome
MR
Hypotonia
Endocardial cushion defects
Duodenal atresia
Brushfield spots
Simian crease
Early alzheimer dz
Polycythemia
Hirschsprungs disease
Increased ALL risk
Sandle gap toes
3-4% due to Robertsonian translocation, the rest have extra chromosome
Risk factor for Trisomy 21
Advanced maternal age
Trisomy 21 prenatal screen shows...
Dec AFP
Dec estriol
Inc HCG
Inc inhibin
Trisomy 13
*Patau Syndrome
Midline defects (8 cut in half=3)
MR
Cleft lip/palate
Cutis aplasia
Polydactyly
Urogenital abnormalities
Congenital heart disease
Holoprosencephaly
96% die in 1st 6 months
Trisomy 18
*Edwards Syndrome
MR
Rocker bottom feet
Prominent occiput
Clenched fists w/overlapping fingers
Congenital heart disease
Horseshoe kidneys
IUGR/FTT
90% die by age 1
Turner Syndrome
*45,XO vs mosaic vs deletion on X vs ring X
Short female
Ovarian failure/primary amenorrhea/no breast development/+pubic hair
Bicuspid aortic valve and coarctation
Cubitus valgus
Webbed neck secondary to in-utero cystic hygroma
Edema of hands/feet
What diseases are associated with Turner Syndrome?
Hashimoto thyroiditis
Carb intolerance
Alopecia
Vitiligo
GI disorders
Klinefelter
*47,XXY
Gynecomastia
Small testes
Infertile (azoospermia)
Tall male
Scoliosis
Myopia
Learning and behavioral problems (worse with more X's)
Microdeletion Syndromes
Small chromosomal deletions that affect several neighboring genes.
22q11.2 Deletion Syndrome
*DiGeorge, Velocardiofacial or Shprintzen Syndrome
CATCH 22:
Cardiac defect--Truncus arteriosus, ToF
Abnormal facies
T-Cell Defect/Thymic aplasia
Cleft Palate
Hypocalcemia (Parathyroid hypoplasia/agenisis)

Hemivertebrae, Renal problems (per PREP)
Abnormal ears
Cleft palate
Small chin
5p- Syndrome
*Cri-du-chat Syndrome
*Microdeletion: Most sporadic, but 10-15% due to parental translocations.
Wide spaced eyes/Hypertelorism
Infant's cry sounds like a cat
Down-slanting palpebral fissures/epicanthal folds
Hypotonia
Microcephaly
Short stature
High-arched palate
MR
Low broad nose
4p- Syndrome
*Wolf-Hirschhorn Syndrome
'Greek Helmet' facies: Ocular hypertelorism (wide spaced eyes), prominent glabella, frontal bossing, wide broad nose
Microcephaly
Closure defects: Cleft lip/palate, coloboma, ASD/VSD
Seizures
Hypotonia
WAGR Syndrome
*Chomosome 11 microdeletion
Autosomal Dominant, Mutation in WT1 gene
Wilms tumor
Aniridia
Hypospadias/cryptorchidism/small penis
MR
Williams Syndrome
*Chromosome 7 microdeletion
Chrom 7q11 microdeletion
POOR GROWTH
MR
Friendly/"cocktail personality"
Stellate pattern of iris
Periorbital fullness
Hypoplastic nails
Supravalvular AS
Renal artery stenosis
Hypercalcemia
Single Gene Defects
Mendelian Inheritance
-Autosomal Dominant
*Marfans, Alagilles, Achrondroplasia, OI (with germline mosaicism)
-Autosomal recessive
*CF, hemoglobinopathies
-X-linked Recessive
-X-linked Dominant
Marfan Syndrome
*AD, 25% new mutation
Defect in fibrillin gene
Similar to homocystinuria (but no MR and lenses displace up instead of down!)
Tall, thin, short trunk in relation to limbs
Pectus carinatum or excavatum
Scoliosis
Flat feet
Ascending aorta dilatation/dissection
Mitral valve prolapse
Joint hypermobility
High-arched palate
Ehlers-Danlos Syndromes
*AD
Defect in collagen, COL genes
Joint hypermobility
Hyperextensible skin
Easy bruising
Abnormal scar formation
Alagille Syndrome
*AD
Jag1 and NOTCH2 genes
Cholestasis due to paucity of bile ducts
Triangular face (long & broad nose, pointed chin)
Pulmonary valve/artery stenosis, PPS
Butterfly vertebrae
Ocular defects-posterior embryotoxon
Achondroplasia
*AD, 100% penetrant, most de novo mutations
Defect in FGFR3 gene, if inherit 2 genes=lethal
Single base-pair substitution
Paternal age effect
Macrocephaly
Foramen Magnum Stenosis
Prominent forehead
Flat nasal bridge/Midface hypoplasia
Short length of proximal arms & legs
Short hands with broad fingers (trident hands)
What neurologically dangerous skeletal problem can infants with Achondroplasia have?
Foramen magnum stenosis
What are the characteristic X-ray findings in Achondroplasia?
Rhizomelic shortening (short proximal arms & legs)
Squared-off iliac wings
Flat, irregular acetabulum roofs
Thick femoral necks
CHARGE
*AD but generally sporadic
Coloboma/CNS disease
Heart defects
Atresia of choana
Retarded growth and development
GU anomalies (hypogonadism)
Ear anomalies (hearing loss)
Cornelia De Lange Syndrome
*AD, most new mutations
POOR GROWTH
GERD
Synophrys-eyebrows grow together
Long eye lashes
Limp anomalies
MR
Microcephaly
Short nose with anteverted nares
CHD
Waardenburg Syndrome
*AD
White forelock
Lateral displacement of inner canthi of eyes
Hearing loss
Cleft lip/palate
Heterochromia of iris
Apert Syndrome
*AD
Craniosynostosis
Cone shaped head
Syndactyly
Proptosis
Wide spaced eyes
Maxillary hypoplasia
Strabismus
Noonan Syndrome
*AD, often new mutation
"Male Turner's"
POOR GROWTH
Short stature
Pectus excavatum
Webbed neck
Low-set ears
Wide spaced eyes/Hypertelorism
Pulmonary valve stenosis
Holt-Oram Syndrome
*AD
Triphalangial thumb
Absent radii
ASD and other congenital heart disease
Cleidocranial Dysostosis
*AD
RUNX2 gene
SHORT
Abnormal skull bones, delayed AF closure
Absent clavicles
Teeth anomalies
Crouzon Syndrome
*AD
Craniosynostosis
Cone shaped head
Prominant forehead
Proptosis
Wide spaced eyes
Maxillary hypoplasia
Strabismus
No syndactyly!!! (compared to Apert Syndrome)
Treacher-Collins Syndrome
*AD
Mandible and variable facial and ear anomalies.
Small chin
Cleft palate
Coloboma with notched lower eyelids
Conductive hearing loss
Down-sloping palpebral fissures
Rubenstein-Taybi Syndrome
*AD
Broad thumbs & great toes
Diamond-Blackfan Syndrome
*AD
Abnormal ribosomal protein
Anemia PLUS:
Triphalangial thumb
Poor growth
Craniofacial anomalies
Congenital heart disease
Germline Mosaicism
-A proportion of gametes have a mutant allele (as opposed to a sporadic mutation where 1 gamete had a mutation).
-Therefore, can have normal parents pass on an AD disorder
Osteogenesis Imperfecta Type I
*AD with germline mosaicism
Disorder of Type 1 Collagen COL1A1
Delayed fontanelle closure
Hearing loss
Multiple fractures (rarely at birth)
Ligamentous laxity/hyperextensible joints
Blue sclera
Wormian bones (extra sutural bones)
Normal or mildly short stature
May have abnormal teeth
Osteogenesis imperfecta Type II
*AD with germline mosaicism
IUGR
Beaded ribs
Numerous fractures in newborn period
Blue sclera
Death due to respiratory insufficiency
Osteogenesis imperfecta Type III
*AD with germline mosaicism
Numerous fractures in newborn period
Blue sclera that lighten with age
Neurologic complications
Osteogenesis imperfecta Type IV
*AD with germline mosaicism
White or near-white sclera
Fanconi Anemia
*AR
Increased chromosome breakage
Pancytopenia
Bone marrow failure
Hypoplastic thumb and radius
Hyperpigmentation
Abnormal facies
Short stature
Bloom Syndrome
*AR
Abnormal BLM gene and DNA helicase
IUGR/FTT
Microcephaly
Malar hypoplasia
Facial telangiectasia
Primary hypogonadism
Malignancies
TAR Syndrome
*AR
Thrombocytopenia
Absent radii
ICH (risk decreases after age 2)
Limb anomalies but ALWAYS have a thumb (unlike Fanconi's or Diamond Blackfan)
Petechiae
Duchenne Muscular Dystrophy
*X-Linked
Defect in dystrophin
Proximal muscle weakness
Gower sign
Pseudohypertrophy of calves
Cardiomyopathy
Rett Syndrome
*X-linked dominant
Defect in MECP2
Develop normally then regress
Microcephaly
Hand-wringing
Seizures
Autistic Features
Incontinentia Pigmenti
*X-linked Dominant
Mostly females (males miscarry)
Variable presentation due to barr bodies
Lines of Blaschko-Vesicles, Warty, Hyperpigmented
Nail dysplasia
Cataracts
Teeth/Jaw problems
Aicardi Syndrome
*X-linked Dominant
Lethality in males
Agenesis of corpus callosum
Chorioretinal lacunae
Infantile spasms
Lesch-Nyhan Syndrome
*X-linked Recessive
Self-mutilation
Hyperuricemia
Severe MR
Choreiform movements
G6PD Deficiency
*X-linked Recessive
Confers resistance to malaria
Hemolytic anemia
Alport Syndrome
*X-linked, AD, AR
COL4A5
Renal faiure
Deafness
Abnormal eye exam
Atypical Inheritance
Genomic Imprinting/Uniparental disomy
Mitochondrial Inheritance
Tri-nucleotide expansions
Prader-Willi Syndrome
*Paternal chrom 15 deletion
Mild MR
Hypotonia, poor feeding, and FTT as infants
Small hands and feet
Hypogonadism
Obesity in childhood
Angelman Syndrome
*Maternal chrom 15 deletion
Severe MR
Seizures
Happy Puppet:unprovoked laughter, jerky ataxic movements
Wide mouth/Large chin
Protruding tongue
Russell-Silver Syndrome
*Uniparental disomy chrom 7, some sporadic
POOR GROWTH
GERD
Small ht and wt with NORMAL HC
Triangular face
Cafe au lait spots
Delayed bone age
Hemihypertrophy
Beckwith-Wiedemann
*AD/Imprinting Inheritance
Hemihypertrophy
Macroglossia
Coarse facies
Wilms tumor/hepatoblastoma
Omphalocele
Hypoglycemia
Cryptorchidism/hypospadius
For what tumor are patients with Beckwith-Wiedemann at increased risk?
Wilms Tumor and hepatoblastoma
Fragile X
*Tri-nucleotide repeat (CGG) on X- chrom
MR, +/- autistic features
Macroorchidism
Long face
Large ears, hands, feet
Hyperextensible joints
Thanatophoric Dysplasia Type 2
Cloverleaf skull
Ataxia-telangiectasia
*AR, chrom 11
Early-onset progressive cerebellar ataxia
Oculocutaneous telangiectasias
Recurrent infections
Malignancies due to chromosomal instability (don't repair well)
Elevated alpha-fetal-protein
Die by 20's
Xeroderma Pigmentosa
*AR
Photosensitivity
Skin atrophy
Pigmentary changes
Malignancies
Multifactorial Inheritance
Cleft lip/palate
NTD
CHD
Pyloric Stenosis
Congenial Hip Dislocation
DM
HTN
Recurrence risk for future pregnancies 2-6%
Cleft Lip/Palate
Isolated CP distinct from CL/CP
Multifactorial inheritance CL
VATER/VACTERLS
Vertebral defects
Anal atresia
Cardiac defects
TE fistula
Esophageal atresia
Renal abnormalities & Radial dysplasia
Limb abnormalities
Single umbilical artery

Clinical diagnosis
Teratogens
...
Fetal Alcohol Syndrome
Microcephaly
Smooth philtrum
Short palpebral fissures
DD
Fetal Hydantoin Syndrome
10-15% effect on developing fetus
Microcephaly, IUGR
Heart defects
Cleft lip, short upturned nose
Nail hypoplasia
Fetal Varicella Syndrome
If mom gets VZV less than 20 weeks
Maternal PKU
Similar features to FAS
Maternal Diabetes
Neural tube defects
CHD
Renal Anomalies
Congenital Sequences/Associations
...
Klippel-Feil
Defect in formation or segmentation of cervical vertebrae
Amniotic Bands
Due to early amnion rupture in FIRST trimester
Group of congenital anomalies caused by strands of amnion attaching to fetus.
Limbs, palate, vertebrae, skull
Stickler Syndrome with Pierre-Robin Sequence
*AD
Micrognathia-->glossoptosis-->cleft palate
Can have chronic hypoxia-->cor pulmonale
Feeding problems
Airway obstruction
Retinal detachement
HEARING LOSS (what makes it Stickler Syndrome--AD)
Pena-Shokeir
*AR
RAPSN gene
IUGR
Arthrogryposis
Pulmonary hypoplasia
Expressionless face
CNS anomalies
Polyhydramnios
Prune Belly Syndrome
Uncertain etiology
Deficient abdominal musculature
Cryptoorchidism
Urinary tract anomalies
M>F
Potter Sequence
Secondary to renal agenesis leading to oligohydramnios and then pulmonary hypoplasia.
Can be caused by prenatal cocaine or ACEI use due to renal damage.
Bone Disorders
...
McCune-Albright Syndrome
*AD
Polyostotic fibrous dysplasia
Cafe au lait spots
Autonomous endocrine hyperfunction
-Precocious puberty in females
-Adrenal Adenomas
-Hyperthyroid
Pseudohypoparathyroidism
*AD
Resistance to parathyroid hormone
Elevated PTH, Low Ca, Elevated Phos
Short Stature
Obesity
Abnormal teeth
Short metacarpals/short stubby fingers
Hypophosphatasia
*AR
LOW ALK PHOS
High/normal calcium and NORMAL phos
Vitamin D and PTH are NORMAL
Defect in bone mineralization
Various onset
Familial Hypophosphatemic Rickets
*AD and X-linked
LOW/NORMAL Ca, HIGH alk phos, LOW phos
Frontal bossing
Bowing limps
Short stature
Polycystic Kidney Disease
*AR (prenatal/infantile onset), AD (most common)
AD assoc findings:
-Renal failure
-Pulmonary hypoplasia
AD assoc findings:
-Liver cysts
-Pancreatic cysts
-Aneurysms
-Diverticulosis
Nephrogenic DI
*X-linked, AR, and AD forms
Polyruia
Polydipsia
FTT
Skin and Teeth Anomalies
...
Sturge-Weber Syndrome
*Sporadic
Port wine stain
Seizures (angiomas of meninges)
Glaucoma
Developmental delay
Ectodermal Dysplasia
*X-linked, AR, and AD
Abnormal hair, teeth, nails
Inability to sweat
Tuberous Sclerosis
*AD, Chrom 9 or 16
Ash leaf spots-hypopigmented macules
Shagreen patches
Adenoma sebaceum
Periungual fibromas
Cardiac rhabdomyomas-resolve with time
Renal cysts/tumors
Brain hamartomas
Infantile spasms/seizures
What neurologic complication may occur in infants with tuberous sclerosis?
Infantile spasms
What cardiac complication may occur in infants with tuberous sclerosis?
Arrythmias (due to rhabdomyomas)
NF 1
*AD, Chrom 17 (many are de novo mutations)
Neurofibromin gene
Macrocephaly
Cafe-au-lait spots (5 >5mm pre-pubertal, >15mm post-pubertal)
Axillary freckling
Lisch nodules (iris hamartomas)
Optic glioma-appear before age 6
Thinning of long bone cortex +/- pseudarthrosis
Neurofibromas-Dermal and plexiform
Increased malignancy risk-Plexiform neurofibromas undergo malignant transformation to neurofibrosarcomas , leukemias
Increased risk of pheocromocytoma
NF 2
*AD, Chrom 22
Hearing loss
Tinnitus
Imbalance
Facial weakness
Bilateral acoustic neuromas
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