Adrenal Hypoplasia

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Adrenocorticotropic hormone (ACTH) deficiency due to any cause and defects in the ACTH receptor result in hypoplasia of the adrenal cortex. However, this article focuses on primary disorders of adrenal gland formation (ie, primary adrenal hypoplasia). [1, 2, 3]

Four forms of congenital adrenal hypoplasia have been identified, as follows:

An X-linked form (OMIM 300200) is caused by a mutation or deletion of the DAX1 gene (dosage-sensitive sex reversal adrenal hypoplasia congenita critical region of the X chromosome, also called the NR0B1 gene) on the X chromosome. [4, 5, 6, 7, 8] This form is usually associated with hypogonadotropic hypogonadism. [9, 10] It may be part of a contiguous chromosome deletion, which may include congenital adrenal hypoplasia, Duchenne muscular dystrophy (OMIM 310200), and glycerol kinase deficiency (OMIM 307030).

The autosomal recessive form is due to a mutation or deletion of the gene that codes for steroidogenic factor 1 (SF-1) on chromosome 9q33 (OMIM 184757). [11] This form is also associated with hypogonadotropic hypogonadism.

An autosomal recessive form of uncertain etiology (OMIM 240200) has also been identified.

A form of adrenal hypoplasia associated with intrauterine growth retardation, metaphysial dysplasia, and genital abnormalities has been identified (ie, intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies [IMAGe] association; OMIM 300290). [12]

The roles of DAX1 and the undefined autosomal recessive gene in development of the adrenal cortex are not understood. [13] DAX1 appears to be necessary for differentiation of the definitive adult adrenal cortex but not the fetal adrenal cortex because the latter is preserved in patients who have deletions of DAX1. The autosomal recessive gene appears to be important in the development of both the fetal adrenal cortex and the definitive adult adrenal cortex because both are hypoplastic in this form of congenital adrenal hypoplasia.


Congenital adrenal hypoplasia is rare. Although the frequency has been estimated in Japan at 1 case per 12,500 births, clinical experience indicates that this disease is not as common as congenital adrenal hyperplasia due to 21-hydroxylase deficiency (incidence is approximately 1 per 10,000-15,000 births worldwide).

Congenital adrenal hypoplasia is a lethal disease unless promptly recognized and appropriately treated. With proper medical treatment, patients do well unless they are also affected with Duchenne muscular dystrophy. Glycerol kinase deficiency, if present, does not result in morbidity but results in hyperglycerolemia. This may be recognized by factitiously elevated serum triglyceride concentrations.

Patients with congenital adrenal hypoplasia due to a mutation or deletion of DAX1 or SF1 (gene name NR5A1) develop hypogonadotropic hypogonadism. Some patients with the X-linked form have been found to have sensorineural deafness (OMIM 300200). Patients with IMAGe association also have intrauterine growth retardation and skeletal and genital abnormalities.

Because one form of congenital adrenal hypoplasia is X-linked, the disease occurs more commonly in males.

Patients with congenital adrenal hypoplasia generally present in infancy with signs of adrenal insufficiency. However, the age of onset widely varies, and some cases are not identified until the patient is an adult. [14]

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NCBI. Online Mendelian Inheritance in Man, OMIM (TM). Available at

Li N, Liu R, Zhang H, Yang J, Sun S, Zhang M, et al. Seven novel DAX1 mutations with loss of function identified in Chinese patients with congenital adrenal hypoplasia. J Clin Endocrinol Metab. 2010 Sep. 95(9):E104-11. [Medline].

Engiz O, Ozön A, Riepe F, Alikasifoglu A, Gönç N, Kandemir N. Growth hormone deficiency due to traumatic brain injury in a patient with X-linked congenital adrenal hypoplasia. Turk J Pediatr. 2010 May-Jun. 52(3):312-6. [Medline].

Zhang Z, Feng Y, Ye D, Li CJ, Dong FQ, Tong Y. Clinical and molecular genetic analysis of a Chinese family with congenital X-linked adrenal hypoplasia caused by novel mutation 1268delA in the DAX-1 gene. J Zhejiang Univ Sci B. 2015 Nov. 16 (11):963-8. [Medline].

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Habiby RL, Boepple P, Nachtigall L, et al. Adrenal hypoplasia congenita with hypogonadotropic hypogonadism: evidence that DAX-1 mutations lead to combined hypothalamic and pituitary defects in gonadotropin production. J Clin Invest. 1996 Aug 15. 98(4):1055-62. [Medline].

Loureiro M, Reis F, Robalo B, Pereira C, Sampaio L. Adrenal Hypoplasia Congenita: A Rare Cause of Primary Adrenal Insufficiency and Hypogonadotropic Hypogonadism. Pediatr Rep. 2015 Sep 28. 7 (3):5936. [Medline].

Achermann JC, Ito M, Ito M, et al. A mutation in the gene encoding steroidogenic factor-1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999 Jun. 22(2):125-6. [Medline].

Bergada I, Del Rey G, Lapunzina P, et al. Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance. J Clin Endocrinol Metab. 2005 Jun. 90(6):3186-90. [Medline]. [Full Text].

McCabe ER. DAX1: Increasing complexity in the roles of this novel nuclear receptor. Mol Cell Endocrinol. 2007 Feb. 265-266:179-82. [Medline].

Lin L, Gu WX, Ozisik G, et al. Analysis of DAX1 (NR0B1) and steroidogenic factor-1 (SF1/Ad4BP, NR5A1) in children and adults with primary adrenal failure: ten years” experience. J Clin Endocrinol Metab. 2006 May 9. [Medline]. [Full Text].

Karsli T, Sutter J, Shekhawat PS. X-linked Adrenal Hypoplasia Congenita Due to NR0B1 (DAX1) Deficiency Presenting as Severe Respiratory Distress in Near Term Infants. Pediatr Neonatol. 2016 Oct. 57 (5):444-445. [Medline].

Manna PR, Dyson MT, Jo Y, Stocco DM. Role of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 in protein kinase A- and protein kinase C-mediated regulation of the steroidogenic acute regulatory protein expression in mouse Leydig tumor cells: mechanism of action. Endocrinology. 2009 Jan. 150(1):187-99. [Medline].

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Kazlauskaite R, Evans AT, Villabona CV, et al. Corticotropin tests for hypothalamic-pituitary- adrenal insufficiency: a metaanalysis. J Clin Endocrinol Metab. 2008 Nov. 93(11):4245-53. [Medline].

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Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, Phi Beta Kappa

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Barry B Bercu, MD Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children’s Hospital

Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Pediatric Endocrine Society, Society for Pediatric Research, Southern Society for Pediatric Research, Society for the Study of Reproduction, American Federation for Clinical Research, Pituitary Society

Disclosure: Nothing to disclose.

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children’s Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Phyllis W Speiser, MD Chief, Division of Pediatric Endocrinology, Steven and Alexandra Cohen Children’s Medical Center of New York; Professor of Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell

Phyllis W Speiser, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Adrenal Hypoplasia

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