Endocrine system Flashcards
X-LINKED ADRENAL HYPOPLASIA CONGENITA
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Clinical Features and Diagnostic Criteria: Carrier females:
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Responsible gene: NROB1
Protein: Nuclear receptor 0B1
Cytogenetic locus: Xp21.3-p21.2
Inheritance: X-LR
Clinical Features and Diagnostic Criteria: acute onset adrenal insufficiency (hyperkalemia, acidosis, hypoglycemia, shock), cryptorchidism, delayed puberty. Carrier females: may have adrenal insufficiency or hypogonadotropic hypogonadism
1/3 contiguous gene deletion with glycerol kinase, DMD del
2/3 isolated CAH (half are de novo)
Clinical Tests: Dec Na+, Inc K+, acidosis, incACTH with low cortisol, dec17 hydroxyprogesterone. If GKD: serum triglyceride, urine glycerol. If DMD: elevated CK
Molecular Tests:NROB1 FISH deletion (100%)
Disease Mechanism: OB1 is a negative regulator of nuclear receptor pathways
Treatment/Prognosis: Treat adrenal crisis, replacement steroids and stress dosing, HRT for hypogonadism,
21-HYDROXYLASE-DEFICIENT CAH
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Responsible gene: CYP21A2
Protein: Cytochrome P450 XXI
Cytogenetic locus: 6p21.3 Inheritance: AR
Clinical Features and Diagnostic Criteria: virilizedfemale, precocious puberty or adrenarche, childhood virilization in males, infant with Na+ losing crisis at birth. Nonclassicform: moderate enzyme deficiency with variable postnatal virilization, no salt wasting, but rare cortisol def.
Clinical Tests: Elevated serum 17-OHD at baseline or after ACTH stim, elevated testosterone and adrenal androgen precursors in females and prepubertal males. Part of NBS (17-OHD level)
Molecular Tests:CYP21A2 common mutation and deletion panel detects 80-98%
Disease Mechanism: cortisol production pathway is blocked-> accumulation of 17-OHP->shunted into the intact androgen pathway->17,20-lyase enzyme converts the 17-OHP to –androstenedione->converted into androgens. The mineralocorticoid pathway requires minimal 21-hydroxylase activity->salt wasting
Treatment/Prognosis: Hydrocortisone (monitor closely: too little will have excess androgen, too much causes Cushing;s, skeletal maturation), stress dose steroids
ANDROGEN INSENSITIVITY
SYNDROME (Testicular Feminization)
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Responsible gene: AR
Protein: Androgen receptor
Cytogenetic locus: Xq11-q12Inheritance: XLR
Clinical Features and Diagnostic Criteria: Evidence of feminization (i.e., undermasculinization) of the ext. genitalia, abnlsecondary sexual development, and infertility in those with a 46,XY karyotype. Spectrum:complete androgen insens. syndrome (CAIS), with typical female genitalia; partial androgen insens. syndrome (PAIS) with predominantly female, predominantly male, or ambiguous genitalia; and mild androgen insens. syndrome (MAIS) with nlmale genitalia.
Clinical Tests: impaired spermatogenesis, absent or rudimentary müllerianstructures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, normal or increased LH, and deficient or defective androgen-binding activity of genital skin fibroblasts
Molecular Tests:AR sequence analysis (>95% CAIS, <50% PAIS, unknown % MAIS)
Disease Mechanism: Impaired androgen binding
Treatment/Prognosis: To prevent testicular malignancy, treatment of CAIS includes either removal of the testes after puberty when feminization is complete or prepubertal gonadectomy accompanied by estrogen replacement therapy. Systematic disclosure of the diagnosis of AIS in an empathic environmen
Male with female genitelia
KALLMAN SYNDROME TYPE 1 and 2
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Responsible genes: KAL, FGFR1
Proteins: Anosmin1, fibroblast growth factor receptor 1
Cytogenetic loci: Xp22.3, 8p11.1-11.2
Inheritance: XLR, AD
Clinical Features and Diagnostic Criteria: Type 1and 2: hypogonadotropic hypogonadism and anosmia. Usually present with delayed pubertal development. Type 1can also include mirror hand movements, ataxia, GU anomaly, high palate, pes cavus. Type 2ID, CL/P, cryptorchidism, choanal atresia, CHD, SNHL.
Clinical Tests: Low FSH and LH; low testosterone in males; low estradiol in females. MRI: hypo/aplasia olfactory bulbs and tracts.
Molecular Tests:Sequencing KAL (5-10%), FGFR1 (8-16%)
Disease Mechanism: Lack of anosminstops olfactory axons from interectingwith their target. It is thought that FGFR1 may play a role in olfactory bulb formation and possibly interacts with anosmin
Treatment/Prognosis: Normalize gonadal steroid levels.
KLINEFELTER SYNDROME
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Clinical Features and Diagnostic Criteria: Tall stature, slightly delayed motor and language skills, inclearning probs, testosterone plateaus age 14, small fibrosedtestes, azoospermia and infertility, gynecomastia, inccholesterol, slightly incrisk of autoimmune disorders and mediastinal germ cell tumors (1% risk)
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Molecular Tests:karyotype, at least one extra chromosome to a 46,XY Karyotype
Disease Mechanism: 1stor 2ndmeiotic division nondisjunction of either parent. Maternal>paternal origin. +AMA effect
Treatment/Prognosis: Testosterone in mid-late adolescence for bone density, secondary sex characteristic development, muscle mass, cholesterol, increase libido, improved energy. Can do testicular biopsy and use any retrieved sperm for ICSI (incrisk sex chromabnormality so follow with PGD
MCCUNE-ALBRIGHT SYNDROME
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Responsible gene: GNAS
Protein: Guanine nucleotide-binding protein G(s), alpha subunit
Cytogenetic locus: 20q13.2
Inheritance: sporadic
Clinical Features and Diagnostic Criteria: polyostoticfibrous dysplasia, pathologic fracture, cranial foramina thickening->deafness and blindness, large irregular café au lait(“coast of Maine”), precocious puberty, hyperthyoidism, incGH, PRL, or PTH, ovarian cysts
Clinical Tests: x-ray, pelvic US, vision and hearing testing, pituitary hormone analysis
Molecular Tests:Targeted mutation analysis
Disease Mechanism: Activating mutations (a stimulatory G-protein) leads to persistently high cAMP (de-activating mutations cause Albright Heredity Osteodystrophy)
Treatment/Prognosis: Aromatase inhibitor to block testosterone, bisphosphonate for fibrous dysplasia, anti-thyroid meds, octreotide (somatostatin analog) and bromocriptine (dopamine receptor agonist)
TRANSIENT NEONATAL DIABETES MELLITUS
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Responsible genes: HYMAI, PLAGL1
Proteins: unknown (HYMAI), zinc finger protein PLAG1
Cytogenetic loci: 6q24 (HYMAiand PLAG1)
Inheritance: UPD isodisomy chromosome 6, paternal 6q24 duplication, or 6q24 methylation defect
Clinical Features and Diagnostic Criteria: DM in the first six weeks of life, resolves by 18 months, severe IUGR, dehydration, hyperglycemia. Occassionalmacroglossiaand umbilical hernia.
Clinical Tests: High serum glucose and low plasma insulin, no islet cell antibodies, no ketoacidosis. 2% have a visible 6q24 duplication
Molecular Tests:UPD6 (35%), 6q24 duplication (35%), imprinting mutation (20%)
Disease Mechanism: PLAGL1and HYMAIare normally only expressed on the paternal allele, unclear why overexpression causes DM. HYMAI may regulate PLAGL1expression
Treatment/Prognosis: Rehydration, IV insulin and then subcutaneous insulin within two weeks, close blood glucose monitoring. Inc risk to later develop type II DM during illness, puberty or during pregnancy
TURNER SYNDROME
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Responsible genes: X genes that escape inactivation, SHOX
Proteins: SHOX: Short stature homeobox protein
Cytogenetic locus: SHOX: Xpter-p22.32
Inheritance: sporadic
Clinical Features and Diagnostic Criteria: congenital lymphedema, growth failure, normal intelligence (10% sig delays), coarctation of the aorta, bicuspid aortic valve, HLHS, hyperlipidemia, gonadal dysgenesis (10% 45,X go into puberty), hypothyroidism, diabetes, strabismus, recurrent OM, SNHL, Crohns, renal malformation, osteoporosis.
Clinical Tests: echo, renal US, TFTs, GH testing, FISH SRY
Molecular Tests:Karyotype
Disease Mechanism: SHOX: thought to act as a transcription regulator with many down-stream targets that modify growth and stature. SHOX protein has been id’edin the growth plate from 12 weeks GA to late childhood.
Treatment/Prognosis: GH, HRT, gonadectomy if Y chromosome mosaicism (risk for gonadoblastoma). Need lifelong cardiac follow-up, at risk for aortic dilation and dissection with bicuspid aortic valve.
