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
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?
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
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)
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