Saroj Nimkarn

Steroid 11β- hydroxylase deficiency congenital adrenal hyperplasia

Congenital adrenal hyperplasia due to steroid 11beta-hydroxylase deficiency is a genetic disorder of steroidogenesis, transmitted as an autosomal recessive trait. It is associated with low renin hypertension, hypokalemia, hyperandrogenemia and genital ambiguity in affected females. Mutations in the CYP11B1 gene, causing 11beta-hydroxylase deficiency in the zona fasciculata in the adrenal cortex, have been identified. The indicators of congenital adrenal hyperplasia caused by 11beta-hydroxylase deficiency, include increased serum concentrations of desoxycorticosterone, 11 deoxycortisol and delta4-androstenedione, and suppressed plasma renin concentrations. The disorder is treated by administration of glucocorticoids.

Apparent mineralocorticoid excess.

Apparent mineralocorticoid excess (AME) is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, hypokalemia and low to undetectable levels of renin and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in a deficiency of 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2). The 11 beta-HSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and, therefore, protects the mineralocorticoid receptors from cortisol intoxication. In 1998, a mild form of this disease was reported, which might represent an important cause of low-renin hypertension. Early and vigilant treatment might prevent or improve the morbidity and mortality of end-organ damage.

Prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) applies to a group of inherited disorders caused by an enzyme deficiency in steroid biosynthesis. The most common form of CAH is 21-hydroxylase deficiency (21-OHD), which in its severe form can cause genital ambiguity in females. Affected females experience virilization both physically and psychologically. Steroid 21-OHD can be diagnosed in utero through molecular genetic analysis of fetal DNA. Appropriate prenatal treatment by dexamethasone administration to the at-risk pregnant mother is effective in reducing genital virilization in the fetus, thus avoiding unnecessary genitoplasty in affected females. Current data from large human studies show that prenatal diagnosis and treatment are safe in the short term for both the fetus and the mother. Preliminary data from long-term studies support these results.

Prenatal diagnosis and treatment of congenital adrenal hyperplasia owing to 21-hydroxylase deficiency.

Classical forms of congenital adrenal hyperplasia are caused by a severe deficiency of 21-hydroxylase, an enzyme involved in steroid biosynthesis, which triggers excessive androgen production before birth. Affected females experience virilization both physically and psychologically. Prenatal diagnosis and treatment of congenital adrenal hyperplasia has been implemented for more than 20 years. In utero gene-specific diagnosis is now feasible for fetal cell samples derived from chorionic villi or amniotic cells in culture, and this gene-specific diagnosis guides the treatment of the affected female fetus. Appropriate dexamethasone administration to the at-risk pregnant mother is effective in reducing genital virilization in the fetus, and thus avoids unnecessary genitoplasty in affected females. Current data from large human studies show the benefit and safety of prenatal treatment. Long-term follow-up of the safety of prenatal treatment is currently underway. This practice is a rare example of effective prenatal treatment to prevent a malformation caused by an inborn error of metabolism.

Congenital adrenal hyperplasia due to 21‐hydroxylase deficiency

21‐Hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH), an inherited disorder of steroidogenesis. In its severe form, CAH causes genital ambiguity in females. Molecular genetic analysis of fetal DNA obtained by amniocentesis or chorionic villus sampling is used to diagnose steroid 21‐OHD deficiency in utero. Large ongoing studies show that appropriate prenatal treatment of pregnant mothers with dexamethasone is effective and safe for both the fetus and the mother. It reduces ambiguous genitalia in the female affected fetus and thus avoids unnecessary genitoplasty in the newborn female.

Steroid 21 Hydroxylase Deficiency Congenital Adrenal Hyperplasia

Steroid 21 hydroxylase deficiency is the most common form of congenital adrenal hyperplasia (CAH). The severity of this disorder depends on the extent of impaired enzymatic activity, which is caused by various mutations of the 21 hydroxylase gene. This article reviews adrenal steroidogenesis and the pathophysiology of 21 hydroxylase deficiency. The three forms of CAH are then discussed in terms of clinical presentation, diagnosis and treatment, and genetic basis. Prenatal diagnosis and treatment are also reviewed. The goal of therapy is to correct the deficiency in cortisol secretion and suppress androgen overproduction. Glucocorticoid replacement has been the mainstay of treatment for CAH, but new treatment strategies continue to be developed and studied.

Congenital Adrenal Hyperplasia in Adolescents

Adolescent females who have irregular menstrual periods may have the nonclassical form of congenital adrenal hyperplasia due to a mild deficiency of steroid 21‐hydroxylase (NC 21‐OHD). Hyperandrogenic signs such as acne, frontal hair loss, hirsutism, and irregular menstrual periods should alert the physician to the diagnosis of NC 21‐OHD. An ACTH stimulation test in which serum hormone concentrations of 17‐OHP, Δ4‐androstenedione, and testosterone are determined will assist in the diagnosis of NC 21‐OHD, but the definitive diagnostic test is an analysis of the mutations in the CYP21A2 gene. Typical mutations in the CYP21A2 gene in patients with NC 21‐OHD are an exon 7 or an exon 1 mutation. Once the genotype establishes the diagnosis of NC 21‐OHD, treatment should be initiated. Typical treatment is dexamethasone, 0.25 mg HS, which generally reverses the hyperandrogenic signs.

Growth and pubertal characteristics in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

This retrospective study examined the pubertal characteristics and growth in patients with 21-hydroxylase deficiency (21-OHD). There were 18 males and 31 females with salt wasting (SW), simple virilizing (SV), or non-classical (NC) 21-OHD. Mean ages at onset of puberty (AOP) in SW, SV, and NC males were 9.2 +/- 1.9, 10.3 +/- 1.1, and 10.7 +/- 0.8 years, respectively; while mean AOP in SW, SV, and NC females were 9.3 +/- 1.7, 8.6 +/- 1.6, and 8.5 +/- 1.3 years, respectively. Mean final height (FH) in SW males (159.6 +/- 7.8 cm) was less than in SV (166.8 +/- 7.5 cm, p = 0.06) and NC (173.4 +/- 6.4 cm, p = 0.005) males. Mean FH in SW females (157.1 +/- 5.5 cm) was similar to SV (156.0 +/- 8.4 cm) but less than NC (161.3 +/- 5.4 cm, p = 0.01) females. In conclusion, while the patients as a group entered puberty earlier than the general population, SW males entered puberty the earliest and had the most compromised FH outcome.

Resistance to multiple steroids in two sisters

A 14-year-old Native American girl from the Iroquois Nation was referred as a potential patient with the syndrome of Apparent Mineralocorticoid Excess. Instead, her evaluation revealed resistance to glucocorticoids, mineralocorticoids, and androgens. She lacked Cushingoid features in spite of significantly high cortisol levels. Menstruation was regular and there was no clinical evidence of masculinization despite high serum androgen levels in the male range. The patients sister had similar clinical features. Partial resistance to exogenous glucocorticoid and mineralocorticoid administration was well demonstrated in both patients. It is proposed that these patients represent the first cases of partial resistance to multiple steroids, possibly owing to a coactivator defect.

46,XY disorder of sex development and developmental delay associated with a novel 9q33.3 microdeletion encompassing NR5A1

Steroidogenic factor 1 (SF1) is a nuclear receptor encoded by the NR5A1 gene. SF1 affects both sexual and adrenal development through the regulation of target gene expression. Genotypic male and female SF1 knockout mice have adrenal and gonadal agenesis with persistent Müllerian structures and early lethality. There have been several reports of NR5A1 mutations in individuals with 46,XY complete gonadal dysgenesis (CGD) or other disorders of sex development (DSD) with or without an adrenal phenotype. To date microdeletions involving NR5A1 have been reported in only two patients with DSDs. We report a novel microdeletion encompassing NR5A1 in a patient with 46,XY DSD and developmental delay. The phenotypically female patient initially presented with mild developmental delay and dysmorphisms. Chromosome analysis revealed a 46,XY karyotype. A 1.54 Mb microdeletion of chromosome 9q33.3 including NR5A1 was detected by array CGH and confirmed by FISH. Normal maternal FISH results indicated that this was most likely a de novo event. Since most NR5A1 mutations have been ascertained through gonadal or adrenal abnormalities, the additional findings of developmental delay and minor facial dysmorphisms are possibly related to haploinsufficiency of other genes within the 1.54 Mb deleted region. This report further confirms the role of NR5A1 deletions in 46,XY DSD and reinforces the utility of aCGH in the work up of DSDs of unclear etiology.