Severe Salt-Losing 3β-Hydroxysteroid Dehydrogenase Deficiency: Treatment and Outcomes of HSD3B2 c.35G>A Homozygotes

J Clin Endocrinol Metab. 2015 Aug;100(8):E1105-15. doi: 10.1210/jc.2015-2098. Epub 2015 Jun 16.


Context: 3-β-hydroxysteroid dehydrogenase (HSD3B2) deficiency accounts for less than 5% of congenital adrenal hyperplasia worldwide, but is relatively common among the Old Order Amish of North America due to a HSD3B2 c.35G>A founder mutation.

Objective: We review clinical presentation, disease course, treatment, and outcomes of a genetically homogenous population of HSD3B2-deficient patients.

Design and participants: This was a retrospective case series: anthropometric, biochemical, and clinical data from 16 (six male) affected subjects (age, 7.2 ± 6.4 y) were compared to reference data from 12 age-matched unaffected siblings.

Setting: The setting was the Clinic for Special Children, a nonprofit rural community health center in Lancaster, Pennsylvania.

Main outcome measures: The main outcome measures were growth, skeletal maturation, sexual development, blood pressure, glucocorticoid dose, pituitary-adrenal homeostasis, and long-term morbidity.

Results: Exogenous glucocorticoid requirement was dichotomous: a standard-dose group (n = 9) required 15.4 ± 4.9 mg/m(2)/d hydrocortisone equivalent, whereas a high-dose group required much larger and more variable doses (hydrocortisone equivalent, 37.8 ± 15.4 mg/m(2)/d) (P < .0001). Despite glucocorticoid doses 2-fold higher than the standard-dose group, high-dose patients: 1) had ACTH, 17-hydroxypregnenolone, and dehydroepiandrosterone levels that were 10-fold, 20-fold, and 20-fold higher, respectively; 2) were exclusively affected by signs of sex steroid excess; and 3) tended to have more iatrogenic complications.

Conclusions: Patients with HSD3B2 deficiency and 21-hydroxylase deficiency suffer similar morbid complications from under- and overtreatment, but HSD3B2 deficiency is associated with a distinctive pattern of sex steroid dysmetabolism. Disease- and treatment-related morbidities are almost exclusively observed among subjects who have a high exogenous glucocorticoid requirement.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adrenal Hyperplasia, Congenital* / diagnosis
  • Adrenal Hyperplasia, Congenital* / epidemiology
  • Adrenal Hyperplasia, Congenital* / genetics
  • Adrenal Hyperplasia, Congenital* / therapy
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Comorbidity
  • Female
  • Homozygote
  • Humans
  • Infant
  • Male
  • Polymorphism, Single Nucleotide*
  • Progesterone Reductase / genetics*
  • Prognosis
  • Retrospective Studies
  • Severity of Illness Index
  • Water-Electrolyte Imbalance / diagnosis
  • Water-Electrolyte Imbalance / epidemiology
  • Water-Electrolyte Imbalance / genetics
  • Water-Electrolyte Imbalance / therapy
  • Young Adult


  • 3 beta-hydroxysteroid dehydrogenase type II
  • Progesterone Reductase

Supplementary concepts

  • 3b-Hydroxysteroid Dehydrogenase Deficiency