title: Clinical and genetic heterogeneity of congenital adrenal hypoplasia due to NR0B1 gene mutations.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Division of Pediatric Endocrinology, E. Wolfson Medical Center, Holon and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Landau
authors.forename: Aaron
authors.initials: A
authors.lastname: Hanukoglu
authors.forename: Joseph
authors.initials: J
authors.lastname: Sack
authors.forename: Nurit
authors.initials: N
authors.lastname: Goldstein
authors.forename: Naomi
authors.initials: N
authors.lastname: Weintrob
authors.forename: Alon
authors.initials: A
authors.lastname: Eliakim
authors.forename: David
authors.initials: D
authors.lastname: Gillis
authors.forename: Michal
authors.initials: M
authors.lastname: Sagi
authors.forename: Ruth
authors.initials: R
authors.lastname: Shomrat
authors.forename: Elka Bella
authors.initials: EB
authors.lastname: Kosinovsky
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
mesh_terms: D000309:Adrenal Insufficiency / Q000151:congenital / Q000235:genetics*; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics*; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007006:Hypogonadism / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; C539965:NR0B1 protein, human; D006854:Hydrocortisone