3-beta-hydroxysteroid dehydrogenase (3BHSD) deficiency is a rare genetic disorder in which steroidogenesis is impaired in both the adrenals and the gonads, resulting in decreased production of all three groups of adrenal steroids; mineralocorticoids, glucocorticoids, and sex steroids. The clinical spectrum of this inherited disease is heterogeneous and ranges from a severe salt-wasting form with or without ambiguous genitalia to the non salt-wasting form, with ambiguous genitalia and premature pubarche in young children. Affected neonates exhibit signs and symptoms of adrenal insufficiency of varying degrees. Males tend to show pseudohermaphroditism, while females exhibit normal sexual differentiation or mild virilization. Older females may show hirsutism and/or irregular menstruation.
Until a few years ago elevated ratio of 5-ene-to 4-ene-steroids was considered the best biological parameter for the diagnosis of 3 Beta-HSD Deficiency. However, nowadays plasma levels of 17-OH-pregnenolone greater than 100 nmol/L following ACTH stimulation is considered to be the gold standard for a proper diagnosis of the condition. Patients with the classic form of the condition require treatment with glucocorticoids, mineralocorticoids, and sex steroids. The need for replacement therapy among patients with the late-onset, non-classical form of the condition, varies depending on the severity of the condition.
3-Beta-Hydroxysteroid Dehydrogenase Deficiency is caused due to mutations in the HSD3B2 gene. This gene codes for the enzyme beta-hydroxysteroid dehydrogenase that catalyses an essential step in the biosynthesis of all classes of steroid hormones. Specifically, this is the oxidation and isomerization of Delta(5)-3beta-hydroxysteroid precursors into Delta(4)-ketosteroids. In the event of loss of function of this enzyme, the synthesis of all these classes of hormones is affected.
To date, more than 30 mutations in the HSD3B2 gene have been identified in families suffering from classical 3-beta-HSD deficiency. In the severe salt-wasting form, no functional 3betaHSD type II isoenzyme is expressed in the adrenals and gonads. The non-salt-losing form results from specific missense mutation(s) in the HSD3B2 gene, which causes incomplete loss of enzymatic activity and leaves sufficient enzymatic activity to prevent salt wasting.
Al-Maghribi (2007) conducted a retrospective study on patients with congenital adrenal hyperplasia (CAH) over a period of 10 years (1996-2006) at the King Hussein Medical Center (KHMC) in Amman. The study included 73 Jordanian children (39 females and 34 males) with CAH. First and second cousin marriages were found in parents of 24 patients and 16 patients were siblings. Forty-one patients displayed salt loss at less than 6 months of age; one of the salt-losing male patients presented with ambiguous genitalia, and his hormonal assay showed 3-beta hydroxysteroid dehydrogenase deficiency.
Bin Abbas et al. (2004) described a Saudi family with four siblings affected with 3-Beta Hydroxysteroid Dehydrogenase Deficiency. The patients included one sister and three of her brothers. The parents were first degree cousins and they had three other normal children. All patients presented within the second week of birth with hyperkalemia and hyponatremia. The boys were born with penoscrotal hypospadias, bifid scrotums, and descended palpable testes within the scrotums. One of the brothers had a micropenis at birth. The sister had normal external genitalia. In the proband (the oldest brother), 3-Beta-Hydroxysteroid Dehydrogenase Deficiency was suspected based on elevated ACTH, low serum cortisol, and low testosterone levels. This diagnosis was confirmed by ACTH simulation test. All patients were treated with administration of hydrocortisone and fludrocortisone. In addition, the patient with miocropenis was administered testosterone.
Al-Jurayyan (2011) conducted a retrospective study in the pediatric endocrine clinic at a university hospital Saudi Arabia during the period 1989-2008. Medical records of 81 children with ambiguous genitalia were reviewed. Fifty three (65%) of the patients were genetically females (46XX). Male genetic sex (46XY) was present in only 28 (35%) patients with a diversity of causes; multiple congenital anomalies in nine (32%), local anorectal anomalies in two (7%), congenital adrenal hyperplasia (3-beta-hydroxysteroid dehydrogenase deficiency) in two (7%), 5-alpha-reductase deficiency in four (14%), partial androgen insensitivity in three (11%), complete androgen insensitivity in four (14%), and hypogonadotrophin deficiency in four (14%). Twenty-five (47%) of females were wrongly assigned as males, where only two (7%) males were wrongly assigned as females.
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