11β-Hydroxysteroid Dehydrogenase Type 1 Deficiency (‘Apparent Cortisone Reductase Deficiency’) in a 6-Year-Old Boy

Abstract

Objective: We present the 1st case of prepubertal hyperandrogenism because of a defect in the conversion of cortisone (E) to cortisol (F) by hepatic11β-hydroxysteroid dehydrogenase type 1. Methods and Results: Clinical and anthropometric data were obtained. Serum androgens and gonadotropins with luteinizing hormone releasing hormone stimulation test, dexamethasone suppression test, and corticotropin-releasing hormone stimulation test were evaluated. Adrenal imaging and urinary steroid profiling by gas chromatography/mass spectrometry were employed. A 6.9-year-old boy presented with precocious pubarche, height (+2.6 SD), accelerated bone age (11.5 years), and Tanner stage 2 pubic hair and genitalia. Serum androgen levels were elevated and dexamethasone suppressible. Serum F was normal, but the E concentration was increased. Central precocious puberty and congenital adrenal hyperplasia were excluded. The excretion of androgen metabolites was moderately increased, but a highly increased tetrahydrocortisone (THE) and a diminished tetrahydrocortisol (THF + allo-THF) excretion was found with a [THF + allo-THF/ THE] ratio of 0.032 (normal controls 1.05 ± 0.17). The corticotropin-releasing hormone stimulation test showed an exaggerated adrenocorticotropic hormone response, suggesting a relative deficiency of F. Two months of hydrocortisone treatment (17.5 mg daily) failed to suppress androgens adequately. Treatment with dexamethasone (0.375 mg/daily) resulted in androgen suppression. Conclusions: In the case of precocious pubarche and accelerated growth, the diagnosis of 11β-hydroxysteroid dehydrogenase type 1 deficiency (‘apparent cortisone reductase deficiency’) should be considered. The diagnosis is based on determinations of urinary steroid metabolites.

11β-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action

“…The CRD cases, one of which is male, all exhibited characteristically low urinary THF+allo-THF:THE ratios of between 0·03 and 0·04 (reference range 0·7-1·1), and have been described previously in the literature (Jamieson et al 1999, Laing et al 2002, Malunowicz et al 2003. In all three CRD cases, two polymorphisms in complete linkage disequilibrium within intron 3 of HSD11B1 were identified; an A insertion (83557), and 40 base pairs downstream a T to G substitution (83597) (Fig.…”

“…(It is of interest that similar patterns of cortisol metabolism are observed in the normal neonatal period.) These data, together with an attenuated plasma cortisol response following oral cortisone acetate, suggest defective 11-oxo-reductase activity (and thus 11 -HSD1 Malunowicz et al 2003 Test., testosterone; DHEAS, dehydroepiandrosterone sulphate; Androst, androstenedione; CAH, congenital adrenal hyperplasia; 17OHP, 17-alpha hydroxyprogesterone.…”

Premature adrenarche: novel lessons from early onset androgen excess

“…In humans, ACRD is characterised by decreased urinary excretion of cortisol metabolites and ACTHdriven adrenal androgen excess manifesting as PA and PCOS (141)(142)(143). To date, approximately eight cases have been reported in the literature that have a biochemical and clinical presentation consistent with ACRD.…”

“…To date, approximately eight cases have been reported in the literature that have a biochemical and clinical presentation consistent with ACRD. In four of these cases, a complete clinical, biochemical and genetic work-up has been published (135); three adult women presented with a PCOS phenotype and one 6-year-old boy presented with PA (143,144). In all cases, hyperandrogenaemia was confirmed with markedly elevated serum levels of DHEAS, androstenedione and testosterone.…”

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“…The ability of these subjects to convert cortisone to cortisol upon dexamethasone suppression was apparently compromised [154-158]. These patients appeared to be normal except for mild adrenal hyperplasia in some cases, and hirsutism, and elevated plasma cortisol levels [154-158]. Unfortunately, insufficient insulin sensitivity data have been reported with these patients.…”