Novel Insights from Clinical Practice

A Novel Missense Mutation in Dax-1 with an Unusual Presentation of X-Linked Adrenal Hypoplasia Congenita
Imran Ahmad^a, Wendy F. Paterson^a, Lin Lin^c, Peter Adlard^d, Philippa Duncan^e, John Tolmie^b, John C. Achermann^c, Malcolm D.C. Donaldson<sup>a

a</sup>Department of Child Health and
^bFerguson-Smith Centre for Clinical Genetics, Royal Hospital for Sick Children, Yorkhill, Glasgow,
^cDepartment of Endocrinology, UCL Institute of Child Health, University College London, London,
^dStoke Mandeville Hospital, Aylesbury, and
^eWessex Regional Genetics Laboratory, Salisbury, UK

Address of Corresponding Author

Horm Res 2007;68:32-37 (DOI: 10.1159/000099835)

  Key Words

• DAX-1
• NR0B1
• Adrenal insufficiency
• Adrenal hypoplasia congenita, X-linked
• Mineralocorticoid

  Abstract

A male presented at age 2.2 years with a 6-week history of intermittent vomiting and hyperpigmentation. Investigations showed salt wasting with hyperkalaemia, a grossly impaired cortisol response to ACTH stimulation, elevated renin and ACTH. Family history revealed that two maternal uncles had died soon after birth. A third uncle failed to thrive during infancy but improved with a course of cortisone, then being untreated until further investigation revealed adrenal insufficiency. A fourth uncle died aged 10 days, with urinary salt loss and hypoplastic adrenal glands at postmortem. Molecular studies on the proband, his mother, maternal grandmother, and surviving uncle showed a novel C to G substitution at nucleotide position 794 (missense mutation T265R) in the DAX1 (NR0B1) gene. The proband has responded well to steroid replacement but has proved sensitive to 9-fludrocortisone treatment, developing hypertension on a dose of 133 µg/m²/day. At 8.8 years he was noted to have testicular volumes of 4 ml, despite no other evidence of secondary sexual development and prepubertal gonadotrophin levels. Novel features of this family include a novel DAX1 mutation, marked variability in age of presentation, hypertension on 'standard' doses of 9-fludrocortisone and mild testicular enlargement.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Dr. Malcolm D.C. Donaldson
Department of Child Health
Royal Hospital for Sick Children, Yorkhill
Glasgow G3 8SJ (UK)
Tel. +44 141 201 0241, Fax +44 141 201 0837, E-Mail mdcd1t@clinmed.gla.ac.uk

  Article Information

Received: October 16, 2006
Accepted: December 19, 2006
Published online: February 16, 2007
Number of Print Pages : 6
Number of Figures : 2, Number of Tables : 0, Number of References : 27