Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations

Zohar Landau, Aaron Hanukoglu, Joseph Sack, Nurit Goldstein, Naomi Weintrob, Alon Eliakim, David Gillis, Michal Sagi, Ruth Shomrat, Elka Bella Kosinovsky, Yair Anikster

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Introduction X-linked adrenal hypoplasia congenita (AHC) is a rare disorder caused by mutations or complete deletion of the NR0B1 gene that encodes the DAX-1 protein, an orphan member of the nuclear receptor superfamily. AHC is characterized by adrenal insufficiency in infancy and early childhood. Later, hypogonadotropic hypogonadism (HH) manifests as pubertal failure. Patients and methods We evaluated the clinical, endocrine and molecular characteristics of 12 AHC patients from 5 families diagnosed between 1984 and 2007 in Israel. Results Most of the boys (10/12) presented with signs of adrenal insufficiency such as salt wasting and failure to thrive during the neonatal period. Aldosterone deficiency usually preceded cortisol deficiency requiring early mineralocorticoid therapy. Serum cortisol levels in the first weeks of life varied from very low to high levels (<2·76 to >1776 nmol/l). Five boys showed signs of precocious sexual development during infancy and childhood, including enlargement of the penis and testes. In four patients the initial diagnoses were erroneous. Molecular analysis of the NR0B1 gene identified point mutations in six patients including a novel splice site mutation in one patient and his family (IVS1-1G→C). Contiguous gene deletion was found in six patients from two families who manifested impaired mental development. Conclusions In X-linked AHC caused by different molecular defects in NR0B1 gene, the clinical spectrum of the disease is quite variable and precocious sexual development is a prominent feature. Genetic testing is indicated in boys presenting with salt-wasting with or without cortisol deficiency if congenital adrenal hyperplasia has been ruled out.

Original languageEnglish
Pages (from-to)448-454
Number of pages7
JournalClinical Endocrinology
Issue number4
StatePublished - 1 Apr 2010
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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