Adrenal Hypoplasia 

  • Author: Thomas A Wilson, MD; Chief Editor: Stephen Kemp, MD, PhD   more...
 
Updated: Feb 18, 2009
 

Background

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 AHCH gene) on the X chromosome.[4] This form is usually associated with hypogonadotropic hypogonadism.[5] 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).[6] 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).[7]
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Pathophysiology

The roles of DAX1 and the undefined autosomal recessive gene in development of the adrenal cortex are not understood.[8]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.

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Epidemiology

Frequency

International

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).

Mortality/Morbidity

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 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.

Sex

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

Age

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.[9]

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Contributor Information and Disclosures
Author

Thomas A Wilson, MD  Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook

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

Disclosure: Nothing to disclose.

Specialty Editor Board

Phyllis W Speiser, MD  Chief of Pediatric Endocrinology, Schneider Children's Hospital; Professor of Pediatrics, New York University School of Medicine

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

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine

Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

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 Federation for Clinical Research, American Medical Association, American Pediatric Society, Association of Clinical Scientists, Endocrine Society, Florida Medical Association, Lawson-Wilkins Pediatric Endocrine Society, Pituitary Society, Society for Pediatric Research, Society for the Study of Reproduction, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Merrily P M Poth, MD  Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences

Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD  Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research

Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

References

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  5. 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. Aug 15 1996;98(4):1055-62. [Medline].

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

  9. 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. May 9 2006;[Medline]. [Full Text].

  10. 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. Jan 2009;150(1):187-99. [Medline].

  11. Merke DP, Tajima T, Baron J, Cutler GB Jr. Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene. N Engl J Med. Apr 22 1999;340(16):1248-52. [Medline].

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  15. Kaiserman KB, Nakamoto JM, Geffner ME, McCabe ER. Minipuberty of infancy and adolescent pubertal function in adrenal hypoplasia congenita. J Pediatr. Aug 1998;133(2):300-2. [Medline].

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  17. Lashansky G, Saenger P, Fishman K, et al. Normative data for adrenal steroidogenesis in a healthy pediatric population: age- and sex-related changes after adrenocorticotropin stimulation. J Clin Endocrinol Metab. Sep 1991;73(3):674-86. [Medline].

  18. Heckmann M, Hartmann MF, Kampschulte B, et al. Cortisol production rates in preterm infants in relation to growth and illness: a noninvasive prospective study using gas chromatography-mass spectrometry. J Clin Endocrinol Metab. Oct 2005;90(10):5737-42. [Medline].

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

  20. Schurmeyer TH, Avgerinos PC, Gold PW, et al. Human corticotropin-releasing factor in man: pharmacokinetic properties and dose-response of plasma adrenocorticotropin and cortisol secretion. J Clin Endocrinol Metab. Dec 1984;59(6):1103-8. [Medline].

  21. Peter M, Partsch CJ, Dorr HG, Sippell WG. Prenatal diagnosis of congenital adrenal hypoplasia. Horm Res. Jul 1996;46(1):41-5. [Medline].

 
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