Cardiogenetics Flashcards
How is the molecular dx of Noonan syndrome established
established in a proband w suggestive findings and a heterozygous pathogenic variant in most genes or biallelic PVs in LZTR1
molecular genetic testing including the use of a multigene panel
top 3 PVs are PTPN11 (50%); SOS1 (10-13%); LZTR1 (~8%)
What prenatal features can be seen in Noonan syndrome
APA has been observed in cohorts w simplex NS
polyhydramnios, increased distended jugular lymphatic sacs, NT, cystic hygroma, pleural effusion, and ascites
relative macrocephaly
cardiac and renal anomalies
in chromosomally normal fetuses w increased NT, it is estimated that 3-15% have PTPN11 associated NS
What are the clinical features associated w Noonan syndrome
feeding difficulties, postnatal growth failure, delayed bone maturity, more than 50% of females and nearly 40% of males have an adult height below the 3rd centile; impaired growth hormone release
cardiovascular: frequency of congenital heart dz between 50-80%; pulmonary valve stenosis most common, found in 25-71%; HCM in 10-29% in which 50% are dx by 6mo; electrocardiographic abnormality in ~90% of individuals w NS
Psychomotor development: early developmental milestones may be delayed, joint hyperextensibility, hypotonia, 50% of school age children meet dx criteria for a developmental coordination disorder; 25% have learning difficulties, 10-15% require special ED; hearing loss in 40%, language impairments, impairment in attention and executive functioning, heightened risk for ASD
Genitourinary: mild renal abnormalities in 11%, dilatation of the renal pelvis is common; cryptorchidism in 60-80%, hypogonadotropic hypogonadism; puberty may be delayed in females, normal fertility is the rule
skeletal: thoracic scoliosis in 13-30%, pectus carinatum w broad chest and increased inter-nipple distance in 28-95%; upper limb anomalies, radioulnar synostosis, brachydactyly, and fifth finger clinodactyly; micrognathia, high arched palate, dental crowding, osteopenia in adults; multiple giant cell lesions of the jaw, joints, and/or soft tissue
bleeding diathesis: 1/3 w NS have one or more coagulation defects may manifest as severe sx hemorrhage, clinically mild bruising, or lab abnormalities with no clinical consequences
lymphatic: varied abnormalities including lymphedema
ocular: ptosis, strabismus, refractive errors, amblyopia, nystagmus in 95%
OTHER: follicular keratosis, cafe au lait spots and lentigines, Arnold I Chiari malformation, hepatosplenomegaly, malignancies
What are the evolving facial features seen in Noonan syndrome
neonate: tall forehead, widely spaced eyes, low set posteriorly rotated ears w a thickened helix; short neck w excess nuchal skin and low posterior hairline
infancy: prominent eyes, depressed nasal bridge, wide base, bulbous tip
childhood: facial appearance is often lacking in affect or expression
adolescence: inverted triangle, eyes are less prominent and features are sharper, skin webbing
older adult: skin appears transparent and wrinkled
What malignancies are individuals w Noonan syndrome at increased risk for
Juvenile myelomonocytic leukemia: transient myeloproliferative disorder in neonatal/early infancy; 10% progress to JMML
PTPN11 has a predisposition to this unusual childhood leukemia but runs a more benign course; also 3X risk for ALL and AML
rhabdomyosarcoma, neuroblastoma, low grade gliomas, glioneuronal tumors
overall cancer risk is 4% by 20yo; bc it does not exceed 5% risk, no screening recommendations
What is the incidence of Noonan syndrome
1 in 1,000-2500
What are the tx recommendations for Noonan syndrome
short stature: GH therapy
feeding difficulties: consider tube feedings especially those with CHDs/cardiomyopathy
standard txs for: behavioral manifestations, CHDs, HCM, cryptorchidism, renal anomalies/hydronephrosis, bleeding diathesis, abnormal vision and/or strabismus, hearing loss, Chiari malformation, and JMML w other malignancies
What should be avoided in pts w Noonan syndrome
Aspirin since it can exacerbate a bleeding diathesis
What is the de novo rate for AD Noonan syndrome
30-75% have an affected parent (25-70% de novo rate)
in simplex cases, pat origin of the de novo pathogenic variant has been found universally to date; significant sex ratio bias favoring transmission to males
How is the dx of CHARGE syndrome established
established in a proband w suggestive clinical and imaging findings and a heterozygous PV in CHD7 identified by molecular testing
How is the molecular dx of CHARGE syndrome established
sequence of CHD7 then del dup and/or CMA
Bc CHD7 disorder typically includes multiple congenital anomalies, it is also reasonable to pursue CMA testing first, unless classic features of CHD7 disorder (ex: the CHARGE syndrome phenotype) are apparent
a distinctive epigenetic signature in blood leukocytes has been identified in individuals w CHD7 disorder; can therefore be considered to clarify the dx in individuals with (1) suggestive findings of CHD7 disorder for which no PV has been identified OR (2) a VUS has been identified
What does CHARGE stand for
Coloboma
Heart defect
Atresia of the choanal (choanal atresia)
Restricted growth and development (delayed growth)
Genital hypoplasia
Ear anomalies
What are the clinical features associated w CHARGE syndrome
CHD7 disorder exhibits a high degree of clinical variability even among individuals in the same family and those in different families
DEVELOPMENT: motor delays due to vestibular anomalies, poor head control, delayed motor milestones, reduced fine motor skills; language delay, hearing loss, vision loss, cognitive impairment; multiple sensory deficits (vision, hearing, balance and smell), intellectual outcome is within the normal range in 50% of the individuals w clinical features; ADHD, repetitive behavior, OCD; self-abuse is occasionally seen, increased pain threshold; many adults are able to live independently
GASTRO: frequently seen, GERD, constipation, abdominal pain, malrotation of the intestines, intussusception, choking due to mouth stuffing
IMMUNODEFICIENCY: decreased # or function of T cells, rarely absent thymus
SKELETAL: craniosynostosis, vertebral anomalies, scoliosis, extra/missing ribs, ectrodactyly (absence of toes/fingers), polydactyly, finger-like thumb, brachydactyly; hypermobility and contractures
NEUROMUSCULAR: hypotonia, abnormal shoulder girdle muscles
DENTAL: overbite, hypodontia, poor mineralization of the teeth
What is the life expectancy of someone w CHARGE syndrome
highly depends on the severity of manifestations, since the phenotypic spectrum of CHD7 disorder is substantial
in childhood, adolescence, and adulthood, increased mortality is likely related to a combination of residual heart defects, infections, aspiration, or choking, respiratory issues including obstructive and central apnea, and possibly seizures
life span for many individuals can be normal
What are the tx recommendations for pts w CHD7 disorder
growth failure: nutrition optimization
obesity: exercises and dietary intervention
poor visual acuity/blindness: corrective lenses
photophobia: tinted glasses or sun hat
hearing impairment/deafness: cochlear implant, tx of SNHL and conductive hearing loss depend on degree of hearing loss
poor balance: adjustments for truncal support while sitting, consideration of myofascial release (can improve posture and flexibility)
choanal atresia/stenosis: airway bypass by tracheostomy or endotracheal intubation, sx correction
esophageal atresia: standard sx repair
cleft palate: sx correction
CHDs, arrhythmias, PTS: tx per cardiologist
standard tx for constipation, cryptorchidism, severe scoliosis, seizure disorder, behavioral issues, hypogonadotropic hypogonadism, hypothyroidism, renal malformation, HTN, recurrent infections
What % of PVs are de novo in CHARGE syndrome
almost 100%
decreased function or LOF of CHD7 leads to the clinical manifestations of the disorder
How is the dx of Char syndrome established
in a proband w suggestive clinical findings and/or a heterozygous PV in TFAP2B on molecular genetic testing
sequence analysis only
What are the clinical features associated w Char syndrome
- typical facial features (86%): depressed nasal bridge and broad flat nasal tip, widely spaced eyes, downslanted palpebral fissures, mild ptosis, short philtrum, triangular mouth, thickened everted lips
- patent ductus arteriosus (68%): results in primary HTN if not corrected
- stereotypic hand anomalies (57%): aplasia or hypoplasia of the middle phalanges of the fifth finger
What is the mechanism of dz for Char syndrome
evidence for dominant negative (missense) AND loss of function; loss of function alleles are likely to act through haploinsufficiency
What does VACTERL stand for
Vertebral defects
Anal atresia
Cardiac Defects
Tracheo-
Esophageal fistula
Renal anomalies
Limb abnormalities
What are the clinical features associated w VACTERL? how is dx established?
dx is established when at least three component features are present:
vertebral defects (60-80%) commonly accompanied by rib anomalies
imperforate anus/anal atresia (55-90%)
cardiac defects (40-80%)
tracheo-esophageal fistula (50-80%) with or without esophageal atresia
renal anomalies (50-80%) including renal agenesis, horseshoe kidney, cystic and/or dysplastic kidneys
limb abnormalities (40-50%) including radial anomalies like thumb aplasia/hypoplasia
What is the etiology for VACTERL
sporadic
What is the management/tx for VACTERL? What is the prognosis
management @ centers around sx correction of the specific congenital anomalies (typically anal atresia, certain cardiac manifestations, and/or tracheo-esophageal fistula)
prognosis can be relatively good, though some pts will continue to be affected by their congenital malformations throughout life; do NOT tend to have neurocognitive impairment
What is hypertrophic cardiomyopathy
typically defined by the presence of unexplained left ventricular hypertrophy (LVH) w a max wall thickness of 15mm in adults or a z score >3 in children
if there is a FH of HCM, or if genetic testing confirms that a relative has inherited the family’s pathogenic sarcomere variant, a max LV wall thickness >13mm supports dx