Zitelli (and more!) Review:Genetic Syndromes

February 2, 2009Thanks 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: ¼ year for each of the five features, added to a base age of 3 years

• Drawing has an age equivalent of 4¼

• 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 4¾ years

Ok, now for some genetics!Minor malformations

14% general populationUsually a cosmetic issue rather than a functional

problem…

• Preauricular skin tag• Clinodactyly of the fifth finger

• Macroglossia• Microretrognathia

Major malformations

1% general populationFunctional significance

Encephalocele

Cleft lip and palate

Meningomyelocele

Ectrodactyly (previously termed lobster-claw 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

• Meckel’s 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 café 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

• Short palpebral fissure length

• Mild ptosis• Long simple

philtrum

Fetal alcohol syndrome

MELAS

• Pt presented with mild cognitive delay, short stature, neutropenia, and Wolff-Parkinson-White syndrome at age 4.

• By age 6 he had muscle weakness and visual and hearing impairment as a result of a series of strokes.