Week 6: Endocrine, imprinting & metabolic disorders Flashcards
Disorders of GNAS include what syndromes/phenotypes?
-Psuedohypoparathyroidism 1A
-Psuedohypoparathyroidism1B
-Psuedohypoparathyroidism 1C
-Psuedopsuedohypoparathyroidism
Describe the Albright hereditary osteodystrophy phenotype
Constellation of physical features:
-Round face
-Short stature
-Brachydactyly
-Subcutaneous ossifications
-+/- DD
-+/- early onset obesity
-+/- relative macrocephaly
What GNAS related disorders is the AHO phenotype present in?
PPHP and some forms of PHP
Describe the features of PHP1A/1C
-AHO phenotype present
-Growth: progressively decreasing growth velocity, adult short stature
-Early onset obesity
-Brachydactyly:70-80%
-Advanced bone age: 70-80%
-Subcutaneous ossification: 30-60%
-PTH resistance: 100%
-TSH resistance: 100%
-Gonadotropin resistance
-Maternal origin of inactivated GNAS allele
Describe the features of PHP1B
-AHO phenotype absent
-Growth: macrosomia, avg adult stature
-Obesity: early onset
-Brachydactyly: 15-33%
-Advanced bone age: 15-33%
-Subcutaneous ossifications: 0-40%
-PTH resistance: 100%
-TSH resistance: 30-100%
-Gonads normal
-Maternal origin of inactivated GNAS allele
Describe the features of PPHP
-AHO phenotype present
-Growth: SGA, progressively decreasing growth velocity, adult short stature
-Obesity: normal weight or lean
-Brachydactyly: <30%
-Advanced bone age: unknown
-Subcutaneous ossification: 180-100%
-PTH resistance: rare and mild
-TSH resistance: rare and mild
-Gonads normal
-Paternal origin of inactivated GNAS allele
Tell me about Sotos syndrome
-AD, NSD1 variant or recurrent 5q25 deletion
-Prenatal onset overgrowth
-Mild-severe intellectual impairment
-Advanced bone age
-Cardiac anomalies
-Renal anomalies
-no cancer surveillance
Tell me about androgen insensitivity syndrome
-AR gene, X-linked
-Individuals with XY sex chromosomes but often develop phenotypically female due to androgen insensitivity
-Internal ductwork and external structures depend on how resistant cells are to testosterone signaling
-Some individuals with typical external female genitalia have have internal undescended testes that may herniate at some point
-Will develop normal breasts due to testosterone being converted to estrogen
Tell me about Smith-Lemli-Optiz (SLO)
-Problem in the cholesterol synthesis pathway
-Cholesterol is precursor to sex hormones and SLO notorious for males with significantly underdeveloped genitalia
-Other features: severe ID, growth restriction, microcephaly, cleft palate, 2-3 toe syndactyly, heart defects, behavior problems (sleep, ASD, self injurious)
-DHCR7 gene, AR
Tell me about congenital adrenal hyperplasia (CAH)
-Accounts for 60-70% of 46, XX ambiguous genitalia
-Due to enzyme deficiency in the creation of mineralocorticoids (controls salt) and cortisol (stress hormone)
-Excess precursors for aldosterone and cortisol are shunted to the testosterone creation pathway
-CYP21A gene, AR
Tell me about Beckwith-Wiedemann syndrome (BWS)
Overgrowth syndrome with variable features including:
-Overgrowth of one or more parts of the body
-Macroglossia
-Body asymmetry/hemihypertrophy
-Omphalocele
-Neonatal hypoglycemia
-Tumor risk: Wilms tumor and hepatoblastoma
-Multiple genetic etiologies; majority are epigenetic and not inherited, UPD of 11p15.5 also common
-ART/IVF conceived children increased risk for having BWS
-Also monozygotic, especially in female-female twinning, increased chance to have BWS
-Clinical diagnosis of BWSpectrum can be a challenge:
a. BWS: enough clinical features regardless of genetic testing
b. Atypical BWS: abnormal methylation but fewer features than expected
c. ILO: isolated lateralized overgrowth and abnormal methylation, can be mosaic
Tell me about Silver-Russell syndrome
-Challenging diagnosis as condition is highly variable, many features are nonspecific, and molecular testing only identifies a cause in ~60% of cases
Main features:
-Prenatal and postnatal growth failure
-Relative macrocephaly
-Protruding forehead, triangular face, fifth finger clinodactyly
-Body asymmetry
-Feeding difficulties/low BMI
Genetics
-Molecular dx in ~60% cases
-Paternal 11p15 loss of methylation
-Maternal UPD7
-Other rare etiologies
-Often de novo
-Recurrence for both 11p15.5 LOM and maternal UPD7 have LOW recurrence risks for siblings and offspring
Tell me about Fabry disease
-GLA gene, X-linked
-Inherited disorder of glycosphingolipid (fat) metabolism resulting from the absent or markedly deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This disorder belongs to a group of diseases known as lysosomal storage disorders
Features include:
-Pain in hands and feet
-Dark red spots on abdomen
-Cloudy vision
-Hearing loss
-Ringing in ears
-Stomach pain
-Hyperhidrosis
-Kidney issues and failure
-Treatment includes ERT and chaperone therapy
