Identification of Novel Mutations of the <i>DAX-1</i> Gene in Patients with X-Linked Adrenal Hypoplasia Congenita

Abstract

Objective: X-linked adrenal hypoplasia congenita (AHC) is a condition clinically featuring adrenal insufficiency and hypogonadotropic hypogonadism caused by mutations of DAX-1. This study was undertaken to characterize the molecular defects of DAX-1 in 3 unrelated Korean patients with AHC. Patients and Methods: Patient 1 is a 6-year-old boy who presented with a salt-losing adrenal crisis in the neonatal period. Patient 2 is a 3-year-old boy who manifested aspiration pneumonia and adrenal insufficiency at the age of 1 month. Patient 3 is a 7-year-old boy who developed an adrenal crisis at the age of 3 days. In each of these patients, DAX-1 was analyzed by direct DNA sequencing after polymerase chain reaction amplification of the entire coding region. Results: Direct sequencing of DAX-1 revealed two novel mutations, 1156_1157delCT in patient 1 and another novel nonsense mutation W105X in patient 2. Patient 3 had complete deletion of DAX-1. In patient 3, serum transaminases and creatine kinase levels were elevated while the glycerol kinase activity of leukocytes was decreased. Markedly elevated glycerol excretion was detected by urine organic acid analysis. Patient 3 was diagnosed as Xp21 contiguous gene syndrome associated with deletions of the entire IL1RAPL, GK genes and the C-terminal region of DMD gene. Conclusions: Two novel mutations of DAX-1 were detected in 2 unrelated patients with AHC, and complete deletion of DAX-1 in a patient with Xp21 contiguous gene syndrome who also presented with glycerol kinase deficiency, Duchenne muscular dystrophy, and AHC.

Deletion of the immunoglobulin domain of IL1RAPL1 results in nonsyndromic X‐linked intellectual disability associated with behavioral problems and mild dysmorphism

“…IL1RAPL1 is often included in large deletions that may involve neighboring NROB1, GK, and DMD genes leading to clinical findings of congenital adrenal hypoplasia [Carrie et al, 1999;Muroya et al, 1999;Sasaki et al, 2003;Choi et al, 2005], glycerol kinase deficiency [Carrie et al, 1999;Zhang et al, 2004] and Becker muscular dystrophy [Love et al, 1990;Jin et al, 2000], respectively. Copy number variants due to deletion and duplication mutations involving the IL1RAPL1 gene are also associated with either ID [Menten et al, 2006;Froyen et al, 2007] or ASD [Piton et al, 2008].…”

A truncating mutation in the IL1RAPL1 gene is responsible for X‐linked mental retardation in the MRX21 family

“…However, IL1RAPL1 appears to be often involved in larger deletions including the neighboring DAX1 , GK , and possibly DMD genes. In this case patients may present with congenital adrenal hypoplasia [Muroya et al, 1999; Sasaki et al, 2003; Choi et al, 2005], glycerol kinase deficiency [Zhang et al, 2004] and Becker muscular dystrophy [Love et al, 1990; Jin et al, 2000]. Isolated microdeletions of the region harboring IL1RAPL1 were reported even before the identification of the gene [Billuart et al, 1996; des Portes et al, 1998].…”

Primary Adrenal Insufficiency in a Newborn With Adrenal Hypoplasia Congenita Caused by a Mutation of theDAX1Gene

“…Although details of AHC patients and mutations in the DAX1 gene have been reported worldwide, there have only been a few case reports from Korea 2,11,12) . Considering the many reports of AHC patients in the Japanese population 13) , the incidence of AHC might be underestimated in Korea 11) .…”

“…Because AHC results from a mutation in the DAX1 gene, a definitive diagnosis can be made by molecular genetic analysis of the DAX1 gene 2) . Distinguishing between CAH and AHC is crucial because they are dissimilar in their clinical course and prognosis, as well as in steroid management and genetic counseling approaches 1) .…”