• Inborn error of metabolism
• Autosomal recessive
• ß cortisol production
• variable clinical manifestations depending on age, gender, enzyme deficiency
• rare
• Pathophysiology
• ß Cortisol drives Ý ACTH
• Ý ACTH drives steroid production prior to the enzyme defect and Ý androgens
•  
• note on above table: 11a -hyroxylase (not shown) converts deoxycorticosterone to corticosterone and deoxycortisol to cortisol

 Sexual Differentiation

Three Causes of Congenital Adrenal Hyperplasia – all three cause decreased cortisol

• (1) 21b -Hydroxylase Deficiency – 90% of cases, leads to Ý testosterone in utero
• Epidemiology -1:15,000 births
• 1/3 to 2/3 excrete salt if a similar 21-hydroxylase is involved in aldosterone synthesis is involved Þ ß aldosterone
• mapped to chromosome 6 between HLA type I and HLA type II, multiple point mutations found
• Clinical Features – hyperpigmentation, salt losing crisis at 1 to 6 wks if mineralcorticoid 21-hydroxylase is involved
• males – testosterone influences male development anyway, so excess testosterone does not have severe effects
• prepuberty: normal at birth, no abnormal development (often rapid growth), precocious puberty
• puberty: normal spermatogenesis, reduced adult height since testosterone Ý bone age
• control as an adult is less important
• females – presence of excess testosterone causes sexual development to be more male-like
• prepuberty: external genitalia affected (ambiguous genitalia at birth), various degrees of intermediate development
• puberty: normal if well controlled, polycystic ovary syndrome if not well controlled
• Lab Values – Ý ACTH, Ý 17 OH-Progesterone (this can be diagnostic), Ý DHEA-S, Ý androstenedione, Ý testosterone, ß Cortisol, possibly ß Na⁺ and Ý K⁺
• Heterozygous States (Carrier) – no treatment necessary; normal hormone levels
• can identify by giving ACTH and measuring 17-OH progesterone
• Evaluation – blood hormone levels, chromosome assessment, pelvic ultrasound, urethra/bladder dye study, urine electrolyte, surgery, sex assignment
• Prenatal Treatment – dexamethasone: ß ACTH levels and ß overflow to testosterone
• A woman with a child with 21-hydroxylase deficiency has a ¼ chance of having another child with the same deficiency
• Mother treated with dexamethasone, which passes through the placenta and supplies the fetus with required cortisol
• Fetus is then karyotyped – dexamethasone is continued only if fetus is female and has the 21-hydroxylase deficiency
• Postnatal Treatment – give the substance whose formation is blocked – glutocorticoids (hydrocortisone, prednisone)
• Ý glucocorticoids for stress; Florinef (oral aldosterone)
• be sure to follow growth and bone age, adrenal metabolites, and renin levels
• (2) 11b -Hydroxylase Deficiency – next enzyme after 21-hydroxylase in steroid lineage
• Epidemiology – 8% of cases, 1:100,000 births (rare), chromosome 8
• Clinical Presentation – symptoms from increased androgens (similar to 21 hydroxylase deficiency)
• also hypertension from Na⁺ retention – due to increased levels of deoxycorticosterone (DOC), which acts like aldosterone
• (3) 17a -Hydroxylase Deficiency
• Epidemiology – rare; accounts for less than 2% of cases
• Clinical Presentation – hypertension from deoxycorticosterone-induced Na⁺ retention without symtptoms of increased androgens