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Study Description

CAH is a genetic steroidogenesis disorder. The most common form, 21OHD, leads to cortisol deficiency and, in turn, an excess of androgen, a hormone that promotes the development and maintenance of male sex characteristics. As a result of this androgen excess, prepubescent males and newborn, prepubescent, and grown females exhibit mature masculine characteristics. The symptoms and severity of 21OHD vary among individuals with the disease and in adults versus children. The reasons for these differences are not yet known. Current therapy for 21OHD consists of administration of glucocorticoids to replace cortisol and suppress excessive pituitary function. With more information about what genes or factors contribute to the severity of 21OHD, researchers may be able to better treat children and adults with the disease. This study will examine participants' DNA to determine what other genes may affect the severity of 21OHD and may make the disease milder in adults than in children

This is a 3-day inpatient study. Once eligibility is confirmed through physical exam and blood analysis, eligible participants are admitted to the study site in the morning on the first study day. A blood sample is taken and participants receive one 10-mg pill of hydrocortisone. Heart rates and blood pressures are taken every 4 hours throughout the day. In the morning of Day 2, a blood sample will be obtained and a 24 hour urine collection will begin. On the morning of Day 3, another blood sample is obtained. Participants then receive intravenous cosyntropin, a synthetic form of a hormone that the body makes. About 1 hour after this, participants provide a final blood sample. Participants receive a pill of hydrocortisone prior to the end of the study.

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Study Inclusion/Exclusion Criteria

Inclusion Criteria:

  • Any adult with 21OHD with two "severe" alleles excluding the A/C656G mutation (an intronic mutation that disrupts splicing with variable severity).
  • Participants must either have an existing molecular genetic diagnosis of 21OHD or consent to genetic testing, and CYP21A2 mutations must be identified.
  • Participants must be at least 18 years old and taking <15 mg/m2 hydrocortisone per day for at least 4 weeks and in good health.

Exclusion Criteria:

  • Adrenal crisis within the past year before entry into study.
  • Coexisting condition requiring corticosteroid therapy (asthma, psoriasis).
  • History of bilateral adrenalectomy.
  • History of hypopituitarism.
  • Use of growth hormone therapy currently or within the last 3 months.
  • Serum creatinine > 2.0 mg/dL.
  • Systolic blood pressure < 90 mmHg.
  • Surgery requiring general anaesthesia or critical illness during prior month.

Study History

Congenital adrenal hyperplasia (CAH) refers to a group of inherited disorders of steroidogenesis. The most frequent form is 21-hydroxylase deficiency (21OHD), an autosomal recessive disorder which leads to cortisol deficiency and therefore to ACTH-driven excessive production of adrenal androgen precursors [1]. In the classical form of 21OHD, androgen excess causes external genital virilization and ambiguity in newborn females and progressive postnatal virilization in either sex, including precocious pubic hair, advanced somatic and epiphyseal development and induced central precocious puberty later in childhood. Therapy for 21OHD consists of administration of glucocorticoids to replace cortisol and suppress excessive pituitary ACTH production, thereby reversing hyperandrogenism. Patients with salt wasting also require therapy with a mineralocorticoid such as fludrocortisone acetate. Nonclassical 21OHD, one of the most common autosomal recessive disorders is caused by partial deficiency of the enzyme, which may manifest with milder symptoms of androgen excess, particularly in adolescent girls [2].

Since the cloning of the gene for 21-hydroxylase (CYP21A2) [3], most cases of 21OHD are found to result from a small repertoire of genetic changes in CYP21A2 [4]. These changes are infrequently de novo mutations but rather occur by the process of gene conversion. The CYP21A2 gene lies within 35 kb of the CYP21A1 pseudogene, which shares 90% identity. Conversion of all or part of the non-functional CYP21A1 gene to the CYP21A2 gene accounts for about 85% of cases of 21OHD [5], explaining why 21OHD is so common and streamlining genetic studies of 21OHD. These genotypes lead to a spectrum of deficiencies ranging from complete to mild. In general, the clinical phenotype, reflected by genital virilization in infant girls and elevation of cortisol precursors such as 17-hydroxyprogesterone (17OHP), correlates with the severity of the enzymatic defect (Table 1). However, we and other groups have observed that occasional cases with 21OHD demonstrate a clinical severity that is different from that predicted by the genotype. Even within a family, sisters with identical genotypes may show different degrees of genital ambiguity and androgen excess. Furthermore, some patients with complete, "salt-wasting" 21OHD produce cortisol and aldosterone as adults and cease to suffer salt-losing crises. These observations lead us to hypothesize that other genetic loci, called "modifier genes" [6], must modify the phenotype of 21OHD.

Table 1: Common mutations of CYP21A2 causing 21OHD

Severity CYP21A2 Mutations
Mild (MIILD) P30L
Moderate (MOD) I172N
Severe (SEV) Del
Ex3 del
Ex10 del
Ex10 R483 del/in
Ex10 N493S
Ex7 S268T
cluster: I236N, V237Q, M239K

Identification of these other genes is important not only to understand the pathophysiology and management of 21OHD, but allelic variants in these genes might contribute to milder forms of androgen excess, such as polycystic ovary syndrome, in a much larger number of cases. Furthermore, the proteins encoded by these modifier genes might be targets for new therapies of 21OHD.

  • Study Activated August 28, 2007
  • First Accrual November 23, 2007
  • Study Closed August 1, 2009
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