Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort

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Abstract

Context:

Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management.

Objective:

The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology.

Design:

A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded.

Setting:

The study was conducted in 19 tertiary pediatric endocrinology clinics.

Patients:

Ninety-five children (48 females, aged 0–18 y, eight familial) with PAI of unknown etiology participated in the study.

Results:

A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged.

Conclusion:

This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

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Most cited references 26

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Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency.

Laure Gineau, Céline Cognet, Nihan Kara … (2012)

Natural killer (NK) cells are circulating cytotoxic lymphocytes that exert potent and nonredundant antiviral activity and antitumoral activity in the mouse; however, their function in host defense in humans remains unclear. Here, we investigated 6 related patients with autosomal recessive growth retardation, adrenal insufficiency, and a selective NK cell deficiency characterized by a lack of the CD56(dim) NK subset. Using linkage analysis and fine mapping, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase complex required for DNA replication. A splice-site mutation in the patients produced a frameshift, but the mutation was hypomorphic due to the creation of two new translation initiation methionine codons downstream of the premature termination codon. The patients' fibroblasts exhibited genomic instability, which was rescued by expression of WT MCM4. These data indicate that the patients' growth retardation and adrenal insufficiency likely reflect the ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues. In addition, the specific loss of the NK CD56(dim) subset in patients was associated with a lower rate of NK CD56(bright) cell proliferation, and the maturation of NK CD56(bright) cells toward an NK CD56(dim) phenotype was tightly dependent on MCM4-dependent cell division. Thus, partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency.

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The pathophysiology and genetics of congenital lipoid adrenal hyperplasia.

T. Sugawara, , S. Bose … (1996)

Congenital lipoid adrenal hyperplasia results in severe impairment of steroid biosynthesis in the adrenal glands and gonads that is manifested both in utero and postnatally. We recently found mutations in the gene for the steroidogenic acute regulatory protein in four patients with this syndrome, but it was not clear whether all patients have such mutations or why there is substantial clinical variation in these patients. We directly sequenced the gene for steroidogenic acute regulatory protein in 15 patients with congenital lipoid adrenal hyperplasia from 10 countries. Identified mutations were confirmed and recreated in expression vectors, transfected into cultured cells, and assayed for the presence and activity of steroidogenic acute regulatory protein. Fifteen different mutations in the gene for steroidogenic acute regulatory protein were found in 14 patients; the mutation Gln258Stop was found in 80 percent of affected alleles from Japanese and Korean patients, and the mutation Arg182Leu was found in 78 percent of affected alleles from Palestinian patients. We developed diagnostic tests for these and eight other mutations. Thirteen of the 15 mutations were in exons 5, 6, or 7, and all rendered the steroidogenic acute regulatory protein inactive in functional assays. Some mutants with amino acid replacements were capable of normal mitochondrial processing, indicating that the activity of steroidogenic acute regulatory protein is not associated with its translocation into mitochondria. Steroidogenic cells lacking the protein retained low levels of steroidogenesis. This explains the secretion of some steroid hormones by the ovaries after puberty before affected cells accumulate large amounts of cholesterol esters. The congenital lipoid adrenal hyperplasia phenotype is the result of two separate events, an initial genetic loss of steroidogenesis that is dependent on steroidogenic acute regulatory protein and a subsequent loss of steroidogenesis that is independent of the protein due to cellular damage from accumulated cholesterol esters.

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Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal.

C. Huot, O Kecha-Kamoun, Guy Van Camp … (2005)

Primary adrenal insufficiency (PAI) in the pediatric population (0-18 yr) is most commonly attributed to congenital adrenal hyperplasia (CAH), which occurs in about 1 in 15,000 births, followed by Addison's disease, with an assumed autoimmune etiology. However, molecular advances have increased the number of possible diagnoses. The objective of this study was to determine the incidence and etiologies of PAI in our pediatric population. All patients with a diagnosis of PAI followed by the Endocrinology Service at our institution between September 1981 and September 2001 were studied. One hundred three patients (48 boys) were identified, primarily by the Endocrinology Clinic case registry. CAH was the most frequent etiology (71.8%). However, non-CAH etiologies accounted for 28.2%, of which 55% were nonautoimmune in etiology. Importantly, the CAH sex ratio was 1:1, despite the absence of biochemical screening for this condition in Quebec newborns. Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia (APECED) developed adrenal insufficiency 4 yr earlier than those with non-autoimmune disease. Finally, we review the rare etiologies of PAI and propose an algorithm to aid in targeted genetic testing.

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Endocrinol Metab

Journal ID (iso-abbrev): J. Clin. Endocrinol. Metab

Journal ID (hwp): jcem

Journal ID (publisher-id): jceme

Journal ID (pmc): jcem

Title: The Journal of Clinical Endocrinology and Metabolism

Publisher: Endocrine Society (Washington, DC )

ISSN (Print): 0021-972X

ISSN (Electronic): 1945-7197

Publication date (Print): January 2016

Publication date (Electronic): 2 November 2015

Publication date PMC-release: 2 November 2015

Volume: 101

Issue: 1

Pages: 284-292

Affiliations

Department of Pediatric Endocrinology and Diabetes (T.G., Z.A., A.B., S.T.), Marmara University, Istanbul 34899, Turkey; Institute of Metabolism and Systems Research (T.G.), University of Birmingham, Birmingham B15 2TT, United Kingdom; Department of Genetics and Genomic Medicine (F.B., J.S., J.C.A.), University College London Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; Department of Pediatric Endocrinology and Diabetes (N.S., F.B., B.K.A., Z.Y.A.), Istanbul Faculty of Medicine, Istanbul University, 34452 Istanbul, Turkey; Clinics of Pediatric Endocrinology (M.N.O., H.D.), Diyarbakir Children's Hospital, 21100 Diyarbakir, Turkey; Clinics of Pediatric Endocrinology (Z.A., S.Y.A.), Dr Sami Ulus Obstetrics and Gynecology, Children‘s Health and Disease Training and Research Hospital, 06100 Ankara, Turkey; Department of Pediatric Endocrinology and Diabetes (S.D., S.O.), Ege University, 35040 Izmir, Turkey; Department of Pediatric Endocrinology and Diabetes (A.B., E.D.), Gazi University, 06550 Ankara, Turkey; Pediatric Endocrinology Clinic (A.G., M.Y.), Goztepe Educational and Research Hospital, 34810 Istanbul, Turkey; Department of Pediatrics (A.G.), Amasya University Medical Faculty, 05189 Amasya, Turkey; Pediatric Endocrinology Clinic (K.D.), Dr Behçet Uz Children's Hospital, Izmir, Turkey; Department of Pediatric Endocrinology and Diabetes (A.A.), Inonu University, Malatya, Turkey; Clinics of Pediatric Endocrinology (M.B.), Konya Training and Research Hospital, 42100 Konya, Turkey; Department of Pediatric Endocrinology and Diabetes (O.T.), Uludag University, 16059 Bursa, Turkey; Department of Pediatric Endocrinology and Diabetes (G.C.), Eylul University, 35210 Izmir, Turkey; Department of Pediatric Endocrinology and Diabetes (B.Y.), Cukurova University, 01330 Adana, Turkey; Clinics of Pediatric Endocrinology (T.A.), Kanuni Sultan Suleyman Education and Research Hospital, 34303 Istanbul, Turkey; Pediatric Endocrinology Clinic (A.U.), Sanliurfa Children's Hospital, 63300 Sanliurfa, Turkey; Pediatric Endocrinology Clinic (E.I.), Gaziantep Children's Hospital, 27010 Gaziantep, Turkey; Department of Pediatric Endocrinology and Diabetes (B.O.), Faculty of Medicine, Pamukkale University, 20160 Denizli, Turkey; Department of Pediatric Endocrinology and Diabetes (S.B.), Faculty of Medicine, Duzce University, 81620 Duzce, Turkey; Department of Pediatric Endocrinology and Diabetes (I.T.O.), Bezm-i Alem Vakif University, 34093 Istanbul, Turkey

Author notes

Address all correspondence and requests for reprints to: Tulay Guran, MD, Department of Pediatric Endocrinology and Diabetes, Marmara University, Fevzi Cakmak Mh. Mimar Sinan Cd. No 41, 34899 Ustkaynarca/Pendik, Istanbul, Turkey. E-mail: tulayguran@ 123456yahoo.com .

Article

Publisher ID: 15-3250

DOI: 10.1210/jc.2015-3250

PMC ID: 4701852

PubMed ID: 26523528

SO-VID: 272d2175-0575-4329-9121-3ce496ffa88b

License:

This article has been published under the terms of the Creative Commons Attribution License (CC-BY; https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s).

Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort

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Abstract

Context:

Objective:

Design:

Setting:

Patients:

Results:

Conclusion:

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Bioscientifica Open Endocrinology

Most cited references 26

Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency.

The pathophysiology and genetics of congenital lipoid adrenal hyperplasia.

Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal.

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