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Endocrine Disorders (PITUITARY GLAND AND HORMONES Screen Shot 2018-11…

- - - - 22q11.2
        
        Parathyroid hypoplasia --> hypocalcemia
        
        Thymus hypoplasia --> immune deficiencies
        
        Cleft palate
        
        Cardiac defects
        
        Postnatal short stature
        
        Learning disabilities
        
        Psychiatric disorders
        
        Pseudohypoparathyroidism (PHP)
        
        4 clinical types
        
        Type Ia
        
        Hz inactivating mutations in GNAS, the alpha subunit of the stimulatory G protein (Gsa)
        
        Couples hormone-receptor binding to adenyl cylase activation
        
        Type Ia
        
        Somatic defects: Albright's hereditary osteodystrophy (AHO)
        
        obesity
        
        rounded facies
        
        short 4th metacarpal
        
        ectopic calcification
        
        brachydactyly
        
        DD
        
        Hormonal Resistance
        
        PTH
        
        TSH, LH, FSH, glucagon
        
        Pseudo-PHP
        
        AHO only
        
        Can be caused by Paternal Imprinting
        Only expressing maternal allele
        So if you inherit from mom, you get the somatic symptoms
        If you inherit from dad, you get the hormonal resistance?
- - - - Combined Pituitary Hormone Deficiency
        
        Combined pituitary hormone deficiency is a condition that causes a shortage (deficiency) of several hormones produced by the pituitary gland
        Hypothyroidism can cause many symptoms, including weight gain and fatigue. Other features of combined pituitary hormone deficiency include delayed or absent puberty and lack the ability to have biological children (infertility). The condition can also be associated with a deficiency of the hormone cortisol. Cortisol deficiency can impair the body's immune system, causing individuals to be more susceptible to infection.
- - - - DEFECTS IN TESTICULAR DEVELOPMENT
        Ovotesticular DSD (True Hermaphrodite)
        - Mature ovarian and testicular tissue, with follicles and tubules, respectively, in the same individual Causes span all 3 categories of DSD 46, XX DSD in greater than 1/2 SRY detectable in blood in a few NR5A1 mutations rare Sex Chromosome DSD in 1/3 Chimeric 46, XX/46, XY or mosaic 46, XY/47, XXY or 45, X/46XY 46, XY DSD (a few)
        46, XY Gonadal Dysgenesis
        Not mosaic, not chromosomal, problems due to mutations in these genes
        40% due to mutations in NR5A1, SRY, MAP3K1 SOX9, WT1, DXA1 duplication
        
        Defects in WT1 - Fraiser Syndrome and Denys-Drash Syndrome
        Denys-Drash
        - 46, XY DSD - gonadal dysgenesis with ambiguous external genitalia WITHOUT uterus - diffuse mesangial sclerosis - End-stage renal failure progresses from 0-3 years - Risk for Wilms tumor and Gonadoblastoma with onset at 18 months
        Fraiser
        - 46, XY partial DSD - gonadal dysgenesis with normal external genitalia WITH uterus - Focal segmental sclerosis - End-stage renal failure progresses from 10-20 years - Risk for Wilms tumor and Gonadoblastoma with onset between 15-20 years
        SOX9 Mutations - Campomelic Dysplasia
        - Skeletal anomalies (cone-shaped fingers, hypoplastic thumb, hypoplastic nails) - bowed long bones - narrow iliac wings - Robin sequence - Pulmonary Hypoplasia - 2/3 of 46, XY patients have ambiguous genitalia - Sox9 involved in bone and testicular development
        
        Smith-Lemli-Opitz Syndrome
        - syndromes that include ambiguous genitalia - this syndrome doesn't make enough cholesterol that eventually becomes cortisol - 7-dehydrocholesterol reductase deficiency (increased 7-dehydrocholesterol, decreased cholesterol) - DD - Syndactyly - Males with ambiguous genitalia
        DEFECTS IN ANDROGEN-DEPENDENT TARGET TISSUES - ANDROGEN INSENSITIVITY
        
        Androgen receptor defect
        
        X-linked Recessive
        
        Complete = testicular feminization
        
        Partial = ambiguous genitalia
        
        Androgen Insensitivity Syndrome
        - genetically male - unable to respond to androgens (male sec hormone) - Due to this, mostly female sex characteristics or signs of both male and female sexual development
        
        5-alpha Reductase Deficiency
        - normal internal wolfian duct structures - Ambiguous external genitalia - Virilize at Puberty
    - - Congenital Adrenal Hyperplasia
        - virilization of genetic female - Block in adrenal steroid production - results in increased pituitary ACTH - Increased androgen secretion
        21-Hydroxylase Deficiency
        21-hydroxylase deficiency is a way to get to CAH
        - Simple virilizing form - decreased cortisol only - partial loss of activity - point mutations - Virilizing with Salt wasting - decreased cortisol and aldosterone - large deletions - gene conversion - premature androgens later in life - Nonclassical - increased androgens later in life
        
        not that ambiguous genitala, partial block
        
        CYP21 Mutations
        and there is a pseudogene
        Sometimes there is a transfer from the pseudogene onto the working gene and causes it not to function
        CLINICAL ISSUES
        
        NBS shows 17-OH Progesterone
        
        It's on the NBS because males will have salt-wasting and won't present with the phenotype (females show virilization)
        
        Treatment
        
        Cortisol replacement - hydrocortisone
        Increase in stressful situations
        
        Saltwasting - fludrocortisone acetate and salt
        
        Sexual Function
        Sexual orientation in genetic females who are exposed to androgens in utero
        
        In utero treatment of females to prevent virilization
        Dexamethasone before 8 weeks gestation
        
        Approach to sex assignment
        Reasons for delay to protect future autonomy for the child to decide for themselves
        Avoid surgeries that limit future potential