Genetics: Downs, Turners, Digeorge, Cf

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Clinical features of Down Syndrome

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microencephaly, dysmorphic features, intellectual disability, hypotonia, short stature, congenital heart defects, hearing/vision problems, sleep apnea

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Down's incidence and inheritance

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1/800 newborns; chromosomal inheritance

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Downs's mutations

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95% have trisomy 21 due to maternal nondisjunction; 3-4% due to translocation; 1-2% are mosaic with a normal cell line

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translocations

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14:21 is most common, 75% are de novo, the rest are inherited from a parent w/ a balanced translocation

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prenatal tests for Down's

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Karyotyping of peripheral blood from CVS or amnio detects nearly all cases

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Echo

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refer to peds cardio if abnormal

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thyroid testing

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newborn screen, test @6 and 12 months, annually therafter

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vision

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refer to ophtho by age 1

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growth

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use Down syndrome growth charts; obesity may be a problem in late childhood

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sleep study

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do by age 4

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Cervical spine x-rays

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between age 3-5 to assess for atlantoaxial instability, especially if child is competing in special olympics

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Recurrence risk

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women <30 have 8x their age-related risk; women >30 have 2x their age-related risk

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prenatal features of Turners

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45,X karyotype; associated with cystic hygroma, severe lymphedema, hydrops fetalis

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newborn features

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lymphedema, webbed neck, congenital heart defects (most often coarctation of aorta), normal growth until age 2-3

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childhood features

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short stature, progressive decline in growth velocity; low posterior hairline, cubitus valgus, short 4th metacarpals, short legs, broad chest, prominent ears, scoliosis, micrognathia

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adolescent features

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short stature, delayed puberty, delayed epiphuseal fusion,

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adult features

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infertility, anovulation

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Other features

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Increased risk for specific learning disabilities but no ID.
Most are infertile, will not develop secondary sexual characteristics w/o hormone replacement.

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Turner's incidence and inheritance

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1:2500 life female births; chromosomal inheritance

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Turner's mutations

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half have 45,X due to paternal meiotic nondisjunction; the rest due to structural abnormality or mosaicism

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lab tests for Turner's

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Diagnosed by karyotyping. FISH for X/Y should be completed to rule out low-level sex chromosome mosaicism. Prenatal diagnosis available using cells obtained by CVS or amniocentesis.

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adult management

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yearly screening for renal function, liver function, cholesterol, BP beginning at age 15; baseline BMD at age 18

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growth evaluation

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use turner's syndrome growth charts starting at age 2; refer to endocrinologist to discuss growth/sex hormone replacement

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risk of recurrence

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<1% for future pregnancies

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fertility and Turner's syndrome

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most are infertil; 5-10% may begin puberty spontaneously and <1% have successful unassisted pregnancies

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DiGeorge

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22q deletion syndrome

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DiGeorge presentation

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Prominent nose, small eyes/ears, ID, palate abnormalities, hypoparathyroid, congenital heart disorder, immune defic, behavioral issues

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DiGeorge inheritance and incidence

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1/4K births
chromosomal microdeletion
~10% inherited from a parent

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DiGeorge testing

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FISH for 22q11.2 deletion or microarray (particularly if the phenotype is non-specific), prenatal diagnosis available using cells obtained by CVS or amniocentesis

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Risk of recurrence w/ DiGeorge

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<1% if deletion is de novo in child, 50% if a parent carries the deletion.

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DiGeorge management

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Monitor Serum Ca++, PTH, TSH, CBC, immune evaluation, ophthalmology, audiology, renal ultrasound, baseline cardiac exam, chest x-ray to evaluate for thoracic vertebral anomalies, cervical spine films, clinical evaluation of the palate.

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CF clinical features

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chronic congestive lung dz, high level of salt in sweat, recurrent lung infection; pancreatic insufficiency, poor wt gain, male infertility

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CF incidence and inheritance

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1 in 2500 to 3200 in caucasian; AR

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CF mutations

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More than 1900 different mutations identified in CFTR (cystic fibrosis transmembrane regulator) gene

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CF dx

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gold standard is sweat chloride testing

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DNA testing

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All pregnant women should be offered carrier testing by DNA testing for CF; Prenatal testing most accurate when relevant familial mutations are known.

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newborn screen

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Newborn screening by immunoreactive trypsinogen (IRT) assays performed on blood spots has been implemented in all states. In North Carolina, newborns screened by IRT; if IRT >95%, DNA testing completed and diagnosis is confirmed by sweat testing at accredited center.

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management

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Chest physiotherapy/postural drainage, antibiotics, bronchodilators, enzyme and vitamin replacement for pancreatic insufficiency. Some may be candidates for lung transplantation.

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Leigh Syndrome

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Mitochondrial dz characterized by progressive neurologic disease with motor and intellectual disability. Onset 3-12 months, often post-viral.

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Leigh presentation

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Poor suck, vomiting, irritability, FTT, seizure, hypotonia, lactic acidosis. periods of deterioration, plateaus of stabilization.
50% die w/in 3 years

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NARP

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Mitochondrial dz characterized by sensory neuropathy, muscle weakness, and ataxia. Ocular symptoms start with a “salt and pepper” retinopathy which progress to retinitis pigmentosa. Onset typically in childhood or young adulthood. Learning disabilities and developmental delays often seen in children with NARP, adults with NARP may have a decline in intellectual functioning.

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Mito inheritance

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Leigh syndrome exhibits locus heterogeneity, with both Mendelian (autosomal recessive, X-linked) and mitochondrial inheritance possible.
NARP exhibits mitochondrial inheritance.

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heteroplasmy

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the presence of more than one type of mitochondrial DNA in the mitochondria of an individual; can complicate mitochondrial inheritance

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threshold effect

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the level of mutated mtDNA required before function is compromised and clinical symptoms become apparent

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mutations

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MT-ATP6 gene. Most mutations exhibit heteroplasmy
mutants <60% asx or mild sx (most commonly pigmentary retinopathy or migraines)
mutants 70-90% have NARP
mutant loads above 90% have Leigh syndrome

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testing for NARP/Leigh

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Need family history, blood and/or CSF lactate levels, neuroimaging and molecular genetic testing to confirm. If a mutation has been identified in the family, targeted mutation analysis could be pursued. If genetic testing does not identify a cause, enzymatic studies on a skin biopsy or muscle biopsy may be required to confirm the diagnosis.

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Leigh/NARP management

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Symptomatic treatment. Regular neurological, ophthalmological, and cardiology evaluations recommended.

Front 48

Marfan

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Variable expressivity.
-CV defects like mitral valve prob, aortic dissection; Ocular like dislocated lens, myopia, glaucoma, early cataracs
-Skeletal: tall stature with relatively long arms and legs compared to the trunk, arachnodacytly (long, thin, “spider-like” digits), dolichostenomelia (long, thin, extremities), limitation of elbow extension, joint laxity, scoliosis, pectus excavatum or carinatum, flat feet (pes planus), protrusio acetabulae.
-Other features: dural ectasia, recurrent or incisional hernia, stretch marks (striae), spontaneous pneumothorax, apical blebs, high-arched palate, dental crowding, “typical facies” (dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, downslanting palpebral fissures).

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Marfan incidence and inheritance

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1/10K, AD, 25% new mutations

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Marfan testing

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Dx based on clinical features and family history, with highest weighting given to aortic root dilation/dissection and/or ectopia lentis;
** Genetic testing by mutation scanning and sequence analysis detects between 70-93% of genetic mutations in those individuals fulfilling diagnostic criteria; however, a FBN1 mutation in itself does not confer a diagnosis of Marfan syndrome. Genotype-phenotype correlations have not yet been elucidated

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Marfan management

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Echo, beta-blockers. Monitor skeletal abnormalities. Annual ophthalmologic exams should include slit-lamp evaluation and follow-up for myopia, lens subluxation, and glaucoma.

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Marfan counseling

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no strenuous or contact sports, pregnancies are high-risk due to risk for aortic dissection

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NF1

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Diagnosis by clinical criteria require at least two of the following:
• 6 or more café au lait spots (CLS) (>15 mm postpubertal or >5 mm prepubertal)
• 2 or more neurofibromas of any type or 1 plexiform neurofibroma
• axillary or groin “freckling” (small CLS macules <5mm)
• an optic glioma
• 2 or more Lisch nodules (benign, raised iris hamartomas seen by slit lamp exam)
• a distinctive bony lesion (dysplasia of sphenoid bone, thinning of long bone cortex)
• a first-degree relative with NF1 by independent diagnostic criteria.

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NF1 presentation

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NF1 progresses with age, some features are age-dependent. Children may only have CLS. Lisch nodules and cutaneous fibromas develop late childhood to adulthood.

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NF1 inheritance and incidence

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1/3K; AD, variable expression, nearly complete penetrance. 50% are new mutations