Congenital Adrenal Hypoplasia: Clinical Spectrum, Experience with Hormonal Diagnosis, and Report on New Point Mutations of the DAX-1 Gene

abstract X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with glycerol kinase deficiency (GKD) and Duchenne’s muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne’s muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates’ persisting fetocortex. Aldosterone deficiency usually preceded cortisol deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. An ACTH test was often necessary to detect cortisol deficiency in the very young infants. In some patients, serial testing was necessary to establish the correct diagnosis. In 4 boys studied during the first 3 months after birth, we found pubertal LH, FSH, and testosterone plasma levels indicating postnatal transient activation of the hypothalamic-pituitary-gonadal axis as in normal boys. Previous studies have shown that the DAX-1 gene is deleted in the AHC patients with a contiguous gene syndrome and is mutated in nondeletion patients. Most of the point mutations identified in AHC patients were frameshift mutations and stop mutations. In the 15 patients available for molecular analysis of the DAX-1 gene, there were large deletions in 6 patients and point mutations in another 7 patients. All of the point mutations identified in the present study resulted in a nonfunctional truncated DAX-1 protein. Two brothers with primary adrenal insufficiency and a medical history that strongly suggested AHC had no mutation in the DAX-1 gene. Thus, additional, as yet unknown genes must play a part in normal adrenal cortical development.

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Congenital adrenal hypoplasia, Duchenne muscular dystrophy, and glycerol kinase deficiency: importance of laboratory investigations in delineating a contiguous gene deletion syndrome

Clinical Chemistry ◽

10.1093/clinchem/40.11.2099 ◽

1994 ◽

Vol 40 (11) ◽

pp. 2099-2103 ◽

Cited By ~ 11

Author(s):

D E Cole ◽

L A Clarke ◽

D C Riddell ◽

K A Samson ◽

W K Seltzer ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Gene Deletion ◽

Glycerol Kinase ◽

Deletion Syndrome ◽

Congenital Adrenal Hypoplasia ◽

Contiguous Gene ◽

Glycerol Kinase Deficiency ◽

Adrenal Hypoplasia ◽

Contiguous Gene Deletion Syndrome

Abstract We describe an infant with adrenal insufficiency who was subsequently diagnosed with Duchenne muscular dystrophy (DMD) and hyperglycerolemia due to glycerol kinase deficiency. Karyotyping showed a deletion on the short arm of the X chromosome (p21.1 to p22.1). Molecular mapping revealed that the deletion extended from the 3' end of the DMD gene to a site telomeric to the loci for X-linked congenital adrenal hypoplasia and glycerol kinase deficiency. These results are diagnostic for an Xp21 contiguous gene deletion syndrome--so named because the deletion manifests as a distinctive cluster of otherwise unrelated single-gene disorders in the same individual. The Xp21 syndrome should be considered in any infant with adrenal insufficiency. Measurement of serum triglycerides (without glycerol blanking) and creatine kinase activity are simple screening tests that may facilitate early diagnosis and appropriate genetic counseling about risks of recurrence in subsequent offspring.

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A rare co-occurrence of duchenne muscular dystrophy, congenital adrenal hypoplasia and glycerol kinase deficiency due to Xp21 contiguous gene deletion syndrome: case report

BMC Endocrine Disorders ◽

10.1186/s12902-021-00876-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Asanka Rathnasiri ◽

Udara Senarathne ◽

Visvalingam Arunath ◽

Thabitha Hoole ◽

Ishara Kumarasiri ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Gene Deletion ◽

Glycerol Kinase ◽

Deletion Syndrome ◽

Congenital Adrenal Hypoplasia ◽

Contiguous Gene ◽

Glycerol Kinase Deficiency ◽

Adrenal Hypoplasia ◽

Contiguous Gene Deletion Syndrome

Abstract Background Contiguous gene deletion syndromes are rare genomic disorders caused by deletion of large segments of DNA resulting in co-occurrence of apparently unrelated multiple clinical phenotypes. We report a boy with contiguous gene deletion involving Xp21 genomic location. Case presentation A Sri Lankan boy with developmental delay and failure to thrive first presented at three years of age with hypovolaemia, hyperpigmentation and drowsiness. Investigations done at that time revealed hypoglycaemia, hyponatraemia, hyperkalaemia, low cortisol, low aldosterone, high ACTH and low 17-hydroxyprogesterone. He was diagnosed to have primary adrenal insufficiency. During follow-up at five years, he was noted to have progressive difficulty in walking, waddling gait, hypotonia, calf hypertrophy and positive Gower’s sign. His creatine kinase was very high, and the electromyogram showed myopathy. Genetic analysis revealed hemizygous deletion involving the final 35 exons of the dystrophin gene confirming the diagnosis of Duchenne muscular dystrophy. Further investigations revealed pseudohypertriglyceridemia, large glycerol peak on urine organic acid analysis and hemizygous deletion of the glycerol kinase gene confirming glycerol kinase deficiency. Based on the presence of Duchenne muscular dystrophy, glycerol kinase deficiency and probable congenital adrenal hypoplasia along with genetic confirmation of deletions involving dystrophin and glycerol kinase genes, the diagnosis of Xp21 contiguous gene deletion syndrome was made. Conclusions We report a child with contiguous gene deletion syndrome who was initially diagnosed as having isolated primary adrenal insufficiency probably due to congenital adrenal hypoplasia. Later he was confirmed to have Duchenne muscular dystrophy and glycerol kinase deficiency, as well. This case report highlights the importance of pre-emptive evaluation and identification of genetic defects when patients present with seemingly unrelated diseases that could aid in accurate diagnoses of contiguous gene deletion syndromes.

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An Iranian Congenital Adrenal Hypoplasia Patient with Elevated Testosterone in Infancy due to a Novel Pathogenic Frameshift Variant in NR0B1

International Journal of Endocrinology ◽

10.1155/2021/4367028 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Samira Kalayinia ◽

Saeed Talebi ◽

Mohammad Miryounesi ◽

Peymaneh Sarkhail ◽

Nejat Mahdieh

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Point Mutations ◽

In Silico Analysis ◽

Cyp21a2 Gene ◽

Large Deletions ◽

Congenital Adrenal Hypoplasia ◽

Novel Variant ◽

Adrenal Hypoplasia ◽

Hydroxy Progesterone ◽

High Level

X-linked congenital adrenal hypoplasia due to NR0B1 mutation is characterized by hypogonadotropic hypogonadism (HH) and infertility. Here, we describe a novel pathogenic frameshift variant in NR0B1 associated with congenital adrenal hypoplasia by whole exome sequencing in an Iranian case with high level of testosterone. Clinical evaluations and pedigree drawing were performed. Point mutations, gene conversions, and large deletions of the CYP21A2 gene were checked. WES and segregation analyses were conducted. In silico analysis was also performed for the novel variant. The ACTH, 17-hydroxy progesterone c, and DHEA sulfate values were elevated up to 624.6 pg/mL, 8.6 pmol/L, and 17.8UMOL/L, respectively. No mutation was found in the CYP21A2 gene. WES identified a novel hemizygous frameshift insertion c.218_219insACCA: p.His73GlnfsTer41 variant in the NR0B1 gene with a pathogenic effect according to ACMG criteria. Genetic testing is helpful for differential diagnosis in primary adrenal insufficiency disorders. NR0B1 may be a common cause of congenital adrenal hypoplasia in our population.

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New mutations of DAX-1 genes in two Japanese patients with X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism.

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.81.2.8636263 ◽

1996 ◽

Vol 81 (2) ◽

pp. 530-535

Author(s):

T Yanase ◽

R Takayanagi ◽

K Oba ◽

Y Nishi ◽

K Ohe ◽

...

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Japanese Patients ◽

Congenital Adrenal Hypoplasia ◽

Adrenal Hypoplasia ◽

New Mutations

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Congenital Adrenal Hypoplasia with Hypogonadotropic Hypogonadism

Encyclopedia of Molecular Mechanisms of Disease ◽

10.1007/978-3-540-29676-8_8064 ◽

2009 ◽

pp. 401-401

Author(s):

Nils Peters ◽

Martin Dichgans ◽

Sankar Surendran ◽

Josep M. Argilés ◽

Francisco J. López-Soriano ◽

...

Keyword(s):

Hypogonadotropic Hypogonadism ◽

Congenital Adrenal Hypoplasia ◽

Adrenal Hypoplasia

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Delayed-onset adrenal hypoplasia congenita and hypogonadotropic hypogonadism caused by a novel mutation in DAX1

Journal of International Medical Research ◽

10.1177/0300060519882151 ◽

2019 ◽

Vol 48 (2) ◽

pp. 030006051988215

Author(s):

Siyue Liu ◽

Libin Yan ◽

Xinrong Zhou ◽

Chen Chen ◽

Daowen Wang ◽

...

Keyword(s):

Novel Mutation ◽

Hypogonadotropic Hypogonadism ◽

Molecular Testing ◽

Delayed Onset ◽

Adrenal Hypoplasia Congenita ◽

Congenital Adrenal Hypoplasia ◽

Translation Start ◽

Adrenal Hypoplasia ◽

Relevant Family History ◽

Mild Clinical Phenotype

In this study, we described a male who presented with delayed-onset adrenal hypoplasia congenita (AHC) and mild hypogonadotropic hypogonadism (HHG) without a relevant family history. A novel mutation in the DAX1 (dosage-sensitive sex reversal, congenital adrenal hypoplasia critical region on the X chromosome, gene 1) gene was shown to cause X-linked AHC and HHG. Genetic analysis revealed a novel nonsense mutation, c.154G > T (p.Glu52Term), in the DAX1 gene. Molecular testing demonstrated that the milder phenotype caused by this mutation was due to expression of a partially functional, amino-truncated DAX1 protein generated from an alternate in-frame translation start site (methionine at codon 83). This unusual case revealed a potential mechanism for a novel mutation that resulted in an unusual delayed-onset mild clinical phenotype. It expands the spectrum of adrenal hypoplasia congenita and hypogonadotropic hypogonadism.

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Clinical and molecular characterization of five Spanish kindreds with X-linked adrenal hypoplasia congenita: atypical findings and a novel mutation in NR0B1

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2014-0472 ◽

2015 ◽

Vol 28 (9-10) ◽

Cited By ~ 1

Author(s):

Amaia Rodríguez Estévez ◽

Gustavo Pérez-Nanclares ◽

Joaquin Fernández-Toral ◽

Francisco Rivas-Crespo ◽

Juan P. López-Siguero ◽

...

Keyword(s):

Molecular Level ◽

Novel Mutation ◽

Hypogonadotropic Hypogonadism ◽

Gene Mutations ◽

Delayed Puberty ◽

Salt Wasting ◽

Adrenal Hypoplasia Congenita ◽

Intrafamilial Variability ◽

Adrenal Hypoplasia

AbstractX-linked adrenal hypoplasia congenita (AHC) is caused byTo characterize clinically and at the molecular level a cohort of Spanish patients with AHC.Nine boys (from five families) with AHC were screened forgene mutations were found in all analyzed patients, one of them being novel (p.Gln305*). One patient presented with preserved hypothalamic-pituitary-gonadal axis. Salt-wasting episodes, delayed puberty, and hypogonadotropic hypogonadism were common, although no association was observed between AHC phenotype and genetic mutations. None of the patients has had descendants.AHC phenotype cannot be predicted based on genetic results as there is no definite genotype-phenotype relationship, including intrafamilial variability. Nevertheless, genetic testing for

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