Chromosomal deletion syndromes Notes

NOTES NOTES CHROMOSOMAL DELETION SYNDROMES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Congenital syndromes: genetic deletions during parental gamete formation ▪ Mutation: permanent DNA change TYPES Numerical ▪ Entire chromosome deletion (aneuploidy) Structural ▪ Structural change due to chromosome break → separated portion rearrangement ▫ Balanced rearrangement: without genetic material gain/loss; not associated with phenotypic anomaly ▫ Unbalanced rearrangement: with genetic material gain/loss; associated with phenotypic anomaly ▪ Deletion size: proportional to clinical severity CAUSES ▪ Chromosomal breakage mechanism ▫ Endogenous: defect in DNA replication, transcription, recombination, repair ▫ Exogenous: radiation, chemical substances → DNA damage RISK FACTORS ▪ Parental genetic defect COMPLICATIONS ▪ Congenital heart defect; recurrent infection (e.g. urinary tract infections, otitis media); gastrointestinal abnormalities; severe constipation; impaired development; intellectual disability 148 OSMOSIS.ORG SIGNS & SYMPTOMS ▪ Atypical facial features, short stature, noise sensitivity, additional organ defect-related signs/symptoms DIAGNOSIS ▪ History, clinical examination LAB RESULTS ▪ Genetic tests ▫ e.g. karyotyping, fluorescent in-situ hybridization (FISH) TREATMENT OTHER INTERVENTIONS ▪ Early intervention education ▪ Physical, language, occupational therapy ▪ Associated condition treatment

Chapter 22 Chromosomal Deletion Syndromes CRI DU CHAT SYNDROME osms.it/cri-du-chat PATHOLOGY & CAUSES ▪ Chromosomal deletion syndrome: physical, neurological congenital anomalies ▫ Caused by partial/total macrodeletion in short arm of chromosome 5 (5p-) ▫ AKA cat cry syndrome, 5p- syndrome, Lejeune’s syndrome ▫ Cri-du-chat: “cat’s cry” ▪ Inheritance pattern: mostly sporadic ▫ Paternal origin (most): sporadic chromosome breakage during male gamete formation ▫ Inherited Cri du chat syndrome (rare): parent with balanced translocation → child with unbalanced translocation (rearrangement with genetic material loss) in 5p ▪ Most due to terminal deletions CAUSES ▪ Deletion ▫ 5p15.2: major clinical features (e.g. dysmorphism, intellectual impairment) ▫ 5p15.3: altered larynx anatomy, central nervous system (CNS) dysfunction → cat-like cry, high-pitched voice, speech delay ▪ CTNND2 gene loss: severe mental disability RISK FACTORS ▪ Parental genetic defect ▪ Biologically-female individuals (more common) COMPLICATIONS gastrointestinal/genitourinary abnormalities SIGNS & SYMPTOMS ▪ Cat-like cry, high-pitched voice: may resolve during infancy ▪ Poor feeding ▪ Facial features: microretrognathia (hypoplastic, posteriorly displaced mandible); round face; epicanthus (prominent eye folds); downslanting eyelids; hypertelorism (widely-spaced eyes); wide nasal bridge; low-set ears ▫ Physical signs become less prominent with age ▪ Body features: muscular hypotonia, short stature, short neck, small hands, single palmar crease, scoliosis, prenatal-growth deficiency, low birth weight ▪ Ocular: myopia, strabismus, cataracts ▪ Neurologic: noise sensitivity (hyperacusis); behavior alterations (e.g. aggression, hyperactivity, repetitive movement) ▪ Adulthood: small testes, premature hair graying (age ≥ 15), constipation ▫ Physical signs become less prominent with age DIAGNOSIS LAB RESULTS ▪ Cytogenetic tests: FISH, karyotyping, chromosomal analysis ▪ Molecular genetics tests: heteroduplex analysis; single strand conformation analysis; whole genome sequencing; Southern, northern blotting ▪ Low birth weight; postnatal failure to thrive; microcephaly; developmental, mental disability; pneumonia; congenital heart defects; craniofacial dysmorphism; respiratory distress syndrome; hydrocephalus; chronic otitis media; OSMOSIS.ORG 149

TREATMENT OTHER INTERVENTIONS ▪ Early intervention education; physical, language, occupational therapy ▪ Associated condition treatment (e.g. heart defect repair) Figure 22.1 The facial appearance of a child with Cri du chat syndrome. WILLIAMS SYNDROME osms.it/williams-syndrome PATHOLOGY & CAUSES ▪ Chromosomal deletion syndrome: affects most organ systems ▫ AKA Williams–Beuren syndrome ▪ 26–28 genes involved ▪ Inheritance pattern: sporadic (mutation during gamete formation) CAUSES ▪ Hemizygous microdeletion in long arm of chromosome 7 (7q11.23) ▫ Most chromosomal breaks in medial, centromeric duplicons (gene clusters organized in low-copy repeat blocks) ▪ May include elastin gene (ELN) deletion: involved in supravalvular aortic stenosis 150 OSMOSIS.ORG RISK FACTORS ▪ Parental genetic defect (e.g. Williams syndrome) COMPLICATIONS ▪ Hypercalcemia/hypercalciuria; nephrocalcinosis; dysfunctional voiding; chronic kidney disease; urinary tract congenital anomalies; gastrointestinal conditions (e.g. chronic constipation, cholelithiasis); diabetes mellitus; diabetic nephropathy; progressive valvular stenosis; joint limitations; systemic arterial stenosis (esp. supravalvular aortic stenosis); hypothyroidism; type I Chiari malformation (cerebellar tonsils extend to foramen magnum); recurrent otitis media

Chapter 22 Chromosomal Deletion Syndromes SIGNS & SYMPTOMS ▪ “Elfin”/pixie-like facies: flat nasal bridge, short upturned nose, long medial cleft, periorbital puffiness, full lips, wide mouth, broad forehead, medial eyebrow flare ▫ More distinctive with age ▪ Hoarse voice, high-tone sensorineural hearing loss, noise sensitivity (hyperacusis) ▪ Short stature ▪ Dental: small/abnormally shaped teeth, malocclusion ▪ Psychiatric: friendly, “cocktail party” personality; cognitive impairment; weak visuospatial/visuomotor skills; strong language skills; development delay; anxiety, phobias; obsessive-compulsive traits ▪ Neurologic: hyperreflexia; clonus; extrapyramidal signs (e.g. tremor, bradykinesia, dystonia); cerebellar signs (e.g. incoordination) ▪ Ocular: strabismus, amblyopia ▪ Gastrointestinal: constipation, gastroesophageal reflux, rectal prolapse ▪ Hypertension ▪ Hypercalcemia: irritability, ↓ appetite, constipation, hypotonia DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound, echocardiogram ▪ Urinary tract abnormalities (e.g. bladder diverticula, renal aplasia) ▪ Cardiovascular: supravalvular aortic stenosis, “hourglass” aorta, left ventricular hypertrophy (occasionally) LAB RESULTS ▪ Lab tests: altered thyroid function, hypercalcemia, hypercalciuria, ↑ serum creatinine ▪ Cytogenetic tests: FISH ▪ Comparative genomic hybridization OTHER DIAGNOSTICS ▪ Audiologic tests: high-tone sensorineural hearing loss TREATMENT OTHER INTERVENTIONS ▪ Early intervention education: physical, language, occupational therapy ▪ Associated condition treatment: e.g. aortic stenosis surgical repair, hypertension treatment OSMOSIS.ORG 151