Trisomies Notes

NOTES NOTES TRISOMIES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES DIAGNOSIS ▪ Genetic disorders: trisomies (three copies of particular chromosome) → severe multiorgan defects (cardiac, gastrointestinal, genitourinary), debilitating dysmorphic features DIAGNOSTIC IMAGING CAUSES LAB RESULTS RISK FACTORS OTHER DIAGNOSTICS ▪ Meiotic nondisjunction (most common, > 90%) ▪ Mutation (e.g. translocation) ▫ Mitotic nondisjunction → mosaicism ▪ Advanced maternal age Ultrasound ▪ Prenatal diagnosis ▫ Nuchal translucency, organ defects ▪ Prenatal diagnosis ▫ Chorionic villus sampling, amniocentesis ▪ Postnatal diagnosis ▫ Karyotyping ▪ Postnatal diagnosis ▫ Clinical identification of dysmorphic features COMPLICATIONS ▪ Widespread organ dysfunction SIGNS & SYMPTOMS ▪ Depend on trisomy, affected organs TREATMENT OTHER INTERVENTIONS ▪ Genetic counseling DOWN SYNDROME osms.it/down-syndrome PATHOLOGY & CAUSES ▪ Autosomal trisomy of chromosome 21 ▪ Most common chromosomal abnormality in live births, cause of intellectual disability ▪ Range of dysmorphic features, congenital anomalies (e.g. congenital heart, otolaryngeal, gastrointestinal, hematologic, endocrine, urogenital defects) CYTOGENETIC TYPES ▪ Meiotic nondisjunction in one parent (most common) → trisomy 21 (47 XY, +21) OSMOSIS.ORG 181

▪ Chromosome 21 involved in Robertsonian translocation ▪ Trisomy 21 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +21) ▫ Duodenal atresia/stenosis, tracheoesophageal fistula, cervical spine instability, hematologic disorders RISK FACTORS ▪ Advanced maternal age, previous child with trisomy 21, parental consanguinity COMPLICATIONS ▪ Cardiac ▫ Valve disease (e.g. mitral valve prolapse) ▪ Developmental delay, intellectual disability (IQ: 20–75) ▪ Endocrine ▫ Hypothyroidism, obesity ▪ Gastrointestinal ▫ Delayed dental eruption, duodenal atresia, celiac disease ▪ Genitourinary ▫ Cryptorchidism, infertility (in individuals who are biologically male) ▪ Hematologic ▫ Anemia, ↑ risk of leukemia ▪ Musculoskeletal ▫ Atlantoaxial instability (↑ mobility of C2 in relation to C1); juvenile idiopathic arthritis, hip dislocation ▪ Neurologic/psychiatric ▫ Early onset dementia (by age 55), major depressive disorder, seizures ▪ Premature aging ▪ Respiratory ▫ Tracheal stenosis, obstructive apnea ▪ Sensory ▫ Congenital cataracts, hearing loss, frequent otitis media SIGNS & SYMPTOMS ▪ Brushfield spots (small white/grayish spots on periphery of iris) 182 OSMOSIS.ORG ▪ Dysmorphic features ▫ Microcephaly, flat occiput, flattened face; epicanthal folds; flat nasal bridge; upward-slanting palpebral fissures; small nose/mouth; protuberant tongue; low-set/small ears; short neck, excessive nuchal skin; shortened extremities; big gap between first toe (hallux), others; single transverse palmar crease; short fifth finger with clinodactyly ▪ Gastrointestinal ▫ Vomiting, constipation, poor appetite, ↓ weight gain ▪ Neuromuscular ▫ Hypotonia, diastasis recti (abnormally large inter-recti distance) ▪ Pale, dry skin; fatigue ▪ Respiratory ▫ Dyspnea, wheezing Figure 29.1 An eight-year-old boy with Down syndrome.

Chapter 29 Trisomies DIAGNOSIS DIAGNOSTIC IMAGING Ultrasound ▪ Prenatal diagnosis ▫ Nuchal translucency (weeks 11–14) LAB RESULTS ▪ Chorionic villus sampling/amniocentesis ▪ Prenatal diagnosis ▫ ↓ pregnancy-associated plasma protein A (PAPP-A), unconjugated estriol (uE3), alpha-fetoprotein (AFP) ▫ ↑ serum beta human chorionic gonadotropin (β-hCG), inhibin A ▫ Quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping OTHER DIAGNOSTICS ▪ Postnatal diagnosis ▫ Clinical identification of dysmorphic features Figure 29.2 The feet of an individual with Down syndrome. There is a large space between the great and second toes. TREATMENT OTHER INTERVENTIONS ▪ Prenatal genetic counseling ▪ Supportive management of affected body systems EDWARDS SYNDROME osms.it/edwards-syndrome PATHOLOGY & CAUSES ▪ Autosomal trisomy of chromosome 18 ▪ Second most common autosomal trisomy in live births CYTOGENETIC TYPES ▪ Meiotic nondisjunction in one parent (most common) ▫ Trisomy 18 (47 XY, +18) ▪ Translocation of chromosome 18 ▪ Trisomy 18 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +18) RISK FACTORS ▪ Family history, more common in individuals who are biologically female (3:1), advanced maternal age COMPLICATIONS ▪ ↑ risk of neoplasms (e.g. Wilms’ tumor, hepatoblastoma) ▪ Multi-organ abnormalities (e.g. cardiac septal defects, intestinal malrotation, Meckel’s diverticulum, neurological disorders, horseshoe kidney, hypotonia, pulmonary hypoplasia, cryptorchidism) ▪ Failure to thrive (FTT) ▪ Severe developmental, cognitive impairment OSMOSIS.ORG 183

▪ ↓ life expectancy (< one year old); up to 50% die within first week SIGNS & SYMPTOMS ▪ Dyspnea, hypotonia, wheezing, lack of appetite, severe mental disability, poor weight gain ▪ Dysmorphic features ▫ Clenched hand/overlapping fingers; microcephaly, prominent occiput; small mouth, low-set pointy ears; short sternum; ocular hypertelorism; abnormal retinal pigmentation; short nose with upturned nares; clubfeet, rocker bottom feet; scoliosis, narrow pelvis DIAGNOSIS DIAGNOSTIC IMAGING Abdominal ultrasound ▪ Postnatal diagnosis ▫ Presence of tumors Ultrasound ▪ Prenatal diagnosis ▫ Unchanged inhibin A; nuchal translucency (weeks 11–14) LAB RESULTS ▪ Prenatal diagnosis ▫ Amniocentesis/chorionic villus sampling (CVS), ↓ PAPP-A, serum β-hCG, uE3, AFP, quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping OTHER DIAGNOSTICS ▪ Prenatal ▫ Growth restriction: umbilical cord with two vessels; persistent clenched/ overlapping fingers; heart defects; cystic hygroma; polyhydramnios, oligohydramnios; intrauterine growth delay; omphalocele; hydrocephalus; agenesis of corpus callosum; Dandy– Walker abnormality; diaphragmatic hernia ▪ Postnatal ▫ Clinical identification: dysmorphic features TREATMENT OTHER INTERVENTIONS ▪ Treat life-threatening/disabling conditions (e.g. infections, cardiac/gastrointestinal defects) ▪ Prenatal genetic counseling ▪ Psychosocial management PATAU SYNDROME osms.it/patau-syndrome ▪ Autosomal trisomy of chromosome 13 ▪ Trisomy 13 mosaicism due to mitotic nondisjunction ▫ Some cells unchanged (46 XY), others (47 XY, +13) CYTOGENETIC TYPES RISK FACTORS PATHOLOGY & CAUSES ▪ Meiotic nondisjunction in one parent ▫ Trisomy 13 (47 XY, +13) ▪ Translocation of chromosome 13 184 OSMOSIS.ORG ▪ Family history, advanced maternal age

Chapter 29 Trisomies COMPLICATIONS ▪ Intrauterine growth restriction ▪ Multi-organ congenital anomalies (e.g. severe intellectual disability, capillary hemangioma, cardiac septal defects, cryptorchidism bicornuate uterus, intrauterine growth retardation, cerebral hypoplasia) ▪ High mortality ▫ Most fetuses die in utero/stillborn; neonates die shortly after birth (median survival is seven days) OTHER DIAGNOSTICS ▪ Postnatal ▫ Clinical identification of dysmorphic features SIGNS & SYMPTOMS ▪ Anophthalmia, microphthalmia, cyclopia, colobomas ▪ Holoprosencephaly (formation of single forebrain with single ventricle) ▪ Microcephaly, neural tube defects, deafness ▪ Cleft palate/lip, cutis aplasia, omphalocele, post-axial polydactyly, prominent heel (rocker-bottom feet), dextroposition, absent philtrum Figure 29.3 An adolescent femal with Patau syndrome. DIAGNOSIS DIAGNOSTIC IMAGING Prenatal ultrasound ▪ Unchanged inhibin A ▪ Nuchal translucency (weeks 11–14) ▫ Holoprosencephaly; ventriculomegaly; microcephaly; corpus callosum agenesis; cleft lip, palate; neural tube defects; omphalocele; single umbilical artery; radial aplasia; polydactyly LAB RESULTS ▪ Prenatal diagnosis ▫ Amniocentesis/chorionic villus sampling (CVS): ↓ PAPP-A, serum β-hCG, uE3, AFP, quadruple screen ▪ Postnatal diagnosis ▫ Fluorescence in situ hybridization (FISH), karyotyping Figure 29.4 An infant with a more severe case of Patau syndrome demonstrating cyclopia and a proboscis. OSMOSIS.ORG 185

TREATMENT SURGERY ▪ Intensive treatment ▫ Surgical repair of cardiac defect, cleft lip/ palate OTHER INTERVENTIONS ▪ Prenatal genetic counseling ▪ Noninterventional paradigm ▫ Palliative, supportive management 186 OSMOSIS.ORG