Zitelli (and more!

) Review: Genetic Syndromes

February 2, 2009 Thanks to Katherine King for many of these slides!

But first

How old is the child who drew this picture?

 4-year-old child Five features: eyes, nose, mouth, hair, and legs Calculating the age equivalent: year for each of the five features, added to a base age of 3 years Drawing has an age equivalent of 4

 Drawing by the same child at age 5 Inclusion of ears and arms, as well as improvements in proportion Drawing has an age equivalent of 4 years

Ok, now for some genetics! Minor malformations

14% general population Usually a cosmetic issue rather than a functional problem

 Preauricular skin tag Clinodactyly of the fifth finger Macroglossia Microretrognathia

Major malformations
1% general population Functional significance

Encephalocele

Cleft lip and palate

Meningomyelocele

Ectrodactyly (previously termed lobsterclaw deformity)

Polydactyly (postaxial)

Bilateral clubfoot

Hypospadias

Fused labia with enlarged clitoris

Imperforate anus

Chromosomal Disorders: Aneuploidy

Midline defect Clenched hand with overlapping fingers Postaxial polydactyly Equinovarus deformity Punched-out scalp lesions of aplasia cutis congenita

Trisomy 13 (Patau)
Microphthalmia, coloboma, loose skin, rocker bottom feet, missing rib Syndactyly or polydactyly Cardiac dextroposition, ASD, PDA, VSD Incidence 1:12000 5% survive first 6 months Death usually by heart failure or infection

Trisomy 13

 Prominent occiput and low-set, posteriorly rotated malformed auricles Clenched hand showing typical pattern of overlapping fingers Rocker-bottom feet

Trisomy 18 (Edward)
Incidence 1:4000 live births Males : females 1:3 5-10% survive first year Death usually due to heart failure or pneumonia

Trisomy 18
Meckels diverticulum, horseshoe kidneys Hypertonicity clenched fists and crossed legs, prominent occiput, 5th fingernail hypoplasia, dorsiflexed short hallux Short sternum, mental retardation

 Characteristic facial features: Upward-slanting palpebral fissures Epicanthal folds Flat nasal bridge Brushfield spots

 Bridged palmar crease: two transverse palmar creases are connected by a diagonal line Wide space between first and second toes Short fifth finger

 Small ears Flat occiput

Trisomy 21
Incidence 1:600-800 Incidence increases with maternal age

Trisomy 21: Physical Findings

Hypotonia Small head Epicanthal folds Flat nasal bridge Upward slanting palpebral fissures Brushfield spots Small mouth and ears Extra skin at the nape of neck Single transverse palmar crease 5th finger clinodactylyl Sandal toe gap

Trisomy 21: Associated defects

Congenital heart defects Mental retardation Leukemia Hearing loss, otitis media Hirschsprung disease, duodenal atresia Cataracts Thyroid disease Hip dislocation Atlantoaxial instability/dislocation

 Webbed neck with low hairline Shield chest with widespread nipples, abnormal ears, and micrognathia Prominent lymphedema of hands and feet

Turner: XO
Incidence 1:10000 females Most conceptions result in miscarriage Low fertility rate and high chance of chromosomal abnormalities in offspring Estrogen replacement therapy

Turner: XO
Webbed neck, edema of hands/feet Coarctation of the aorta Triangular facies, short stature Short stature, shield chest, wide-spaced nipples Streak ovaries, absence of secondary sex characteristics

 Relatively narrow shoulders Increased carrying angle of arms Female distribution of pubic hair and normal penis but with small scrotum due to small testicular size Small testes and penis Gynecomastia

Klinefelter: XXY
Incidence 1:1000 Prepubertal boys have normal phenotype Diagnosis often made after puberty Treatment: testosterone replacement

Klinefelter: XXY
Microorchidism Sterility/azoospermia Gynecomastia Normal-borderline IQ Diminished facial hair Lack of libido Tall, eunuchoid body

Chromosomal disorders: deletions, etc

Cat-eye syndrome: extra chromosome from Chr. 22

Iris coloboma Downslanting palpebral fissures, malformed pinna Anal atresia

Wolf Hirschhorn(Del 4p)

Microcephaly, growth deficiency Hypotonia, seizures, developmental delay micrognathia, cleft palate/lip hypospadias ASD

Wolf Hirschhorn (Del 4p)

Detectable by FISH Greek warrior helmet appearance of nose and eyes

Cri du Chat (Del 5p)

Slow growth Cat-like cry Hypotonia, DD, low IQ Microcephaly Single palmar crease Hypertelorism

Cri du Chat (Del 5p)

Deletion is of paternal origin in 80% of denovo cases

Multigene sequence disorders

DiGeorge (Del 22q11)

Cardiac Abnormal facies Thymic Hypoplasia Cleft palate Hypocalcemia

DiGeorge (Del 22q11)

Mild microcephaly Cleft palate Speech delay Long tapering fingers Emotional lability

Williams (7q11.23)
Contiguous gene disorder involving elastin and other genes FISH testing available Ca restriction may be necessary

Williams (7q11.23)
Short stature Supravalvular aortic stenosis (SVAS) Elfin-facies Hypercalcemia Developmental delay Friendly personality (cocktail personality)

Miller-Dieker (17p13)
Lissencephaly (smooth brain) Severe cognitive, developmental delay and seizures

Single gene disorders

 Anteverted nostrils Low-set ears Small chin Clenched hand Ambiguous genitalia (pts may also have hypospadias or cryptorchidism)

Smith-Lemli-Opitz (11q12)
Incidence 1:20,000 Abnormality in cholesterol biosynthesis due to single gene mutation: sterol delta-7 reductase gene Autosomal recessive Cholesterol supplementation may be helpful

Smith-Lemli-Opitz (11q12)
Failure to thrive Low IQ Microcephaly, ptosis, anteverted nostrils, micrognathia Simian crease, syndactyly Genital abnormalities (hypospadias, micropenis, bifid scrotum) Renal anomalies, UPJ obstruction

 Arachnodactyly (both fingers and toes) Clubbing due to associated cardiopulmonary problems Flattening of the arch of his foot Severe pectus carinatum Significant kyphosis and joint contractures Long arms

Marfan (15q21)
Mutations in fibrillin gene Disproportionate growth Joint hyperextensibility Lens dislocation Dilation of the aortic root Genetic testing is difficult

 Marked hyperextensibility of the skin Widened atrophic scars have thin papery texture Hyperextensibility of the joints of the elbow and fingers

Ehlers Danlos 2q31

Defect in Type 3 collagen Autosomal dominant Hyperelasticity Hyperflexible, hypermobile joints

Mutation in neurofibromin gene Abnormal peripheral nerve growth Incidence of 1:4000 Autosomal dominant

Neurofibromatosis I (17q11)
Six or more caf au lait spots >5mm in diameter 2 or more neurofibromas Axillary or inguinal freckling 2 or more Lisch nodules (benign iris hamartoma) Optic pathway tumor Bowing of bone structure First degree relative with NF1

Tuberous Sclerosis

Ash leaf spot

Tuberous Sclerosis
Autosomal dominant TSC1 gene (chr. 9) or TSC2 gene (Chr. 16) are tumor suppressors Seizures/MR/adenoma sebaceum Seizures in early infancy correlate with later MR Renal lesions (cysts, angiomyolipomas) CV: rhabdomyomas Retinal hamartomas

Achondroplasia 4p16.3
Mutation in the fibroblast growth factor receptor-3 gene (FGFR3) Autosomal dominant Short-limb dwarfism

Achondroplasia
Frontal bossing, midface hypoplasia Cranio-cervical junction problems (sometimes leading to cord compression or hydrocephalus) Lumbar lordosis Normal intelligence

Rubenstein-Taybi (16p13)
Deletion in the transcriptional regulator CREB binding protein Developmental delay, feeding problems Growth failure Microcephaly, broad thumbs Prominent nose, small chin 25% detectable by FISH

Holt Oram (12q2)

Autosomal dominant Mutation in TBX1 gene Marked variability in expression Upper limb and shoulder defects:
absent thumb, triphalangeal, or bifid Syndactyly phocomelia

ASD alone, or VSD

 Long, wide, and protruding ears Elongated face Flattened nasal bridge Macro-orchidism

Fragile X Syndrome
Mutation of FMR1 gene on chromosome X (trinucleotide repeat expansion) 1:4000 males Most present with MR

Fragile X Syndrome
Language and motor delays, hypotonia Prominent ears, long face Hyperextensible joints Flat feet High arched palate Macroorchidism Hyperactivity, autistic features

Uniparental disomy

 Maxillary hypoplasia Large mouth Prognathism

Angelman
Seizures Jerky, ataxic movements Abnormal facies Chromosome 15 deletion with maternal imprinting

 Marked obesity Excess fat over the trunk, buttocks, and proximal extremities Small hands (and feet) Hypoplastic penis and scrotum

Prader-Willi
Low tone Large appetite obesity Hypogonadism Developmental delay/MR Chromosome 15 deletion, paternal imprinting

Genetics still poorly defined

Noonan (12q24)
Autosomal dominant Short stature Congenital heart disease Webbed neck Downslanting palpebral fissures Low set ears Mild developmental delay

Noonan (12q24)
Downslanting palpebral fissures
Low, posteriorly rotated ears Webbed neck

 Finely arched heavy eyebrows Long eyelashes Small upturned nose Long smooth philtrum Cupid's-bow mouth Small hands Hypoplastic proximally placed thumb Short fifth finger with mild clinodactyly

Cornelia De Lange (5p13)

Sporadically occurring Severe growth retardation, limb anomalies Congenital heart disease Synophrys Thin, downturned lips

Goldenhar (14q32)
Vertebroauriculofacial syndrome Hemifacial microsomia Ear anomalies, deafness Epibulbar dermoid (fatty tumor of eye) Vertebral anomalies (Chiari I) MR or Normal intelligence

Kabuki
Hypertelorism, long palpebral fissures, large pinnae Developmental delay Hearing loss Possibly due to 8p deletion

Pierre Robin Sequence

Glossoptosis, micrognathia, cleft palate 1:8500 live births Airway and feeding problems Unknown cause Surgical treatment

 Short palpebral fissures and ptosis Low-set, dysplastic ears Small chin Choanal atresia necessitated tracheotomy Prominent forehead Hypertelorism Narrow palpebral fissures Hypoplasia of the right naris Cupid's-bow mouth

CHARGE
Incidence 1:10,000 Coloboma Heart choanal Atresia Retardation Genital hypoplasia Ear abnormalities, deafness

 Facial features are not dysmorphic Preaxial polydactyly of the thumb (which was associated with radial dysplasia)

VACTERL
Vertebral defects imperforate Anus Cardiac malformations (VSD) TracheoEsophageal fistula Renal anomalies Limb (radial ray) anomalies

Fetal alcohol syndrome

Short palpebral fissure length Mild ptosis Long simple philtrum

MELAS
Pt presented with mild cognitive delay, short stature, neutropenia, and Wolff-ParkinsonWhite syndrome at age 4. By age 6 he had muscle weakness and visual and hearing impairment as a result of a series of strokes.