Review
Congenital Adrenal Hyperplasia

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Abstract

The congenital adrenal hyperplasias comprise a family of autosomal recessive disorders that disrupt adrenal steroidogenesis. The most common form is due to 21-hydroxylase deficiency associated with mutations in the 21-hydroxylase gene, which is located at chromosome 6p21. The clinical features associated with each disorder of adrenal steroidogenesis represent a clinical spectrum that reflect the consequences of the specific mutations. Treatment goals include normal linear growth velocity and “on-time” puberty in affected children. For adolescent and adult women, treatment goals include regularization of menses, prevention of progression of hirsutism, and preservation of fertility. For adolescent and adult men, prevention and early treatment of testicular adrenal rest tumors is beneficial. In this article key aspects regarding pathophysiology, diagnosis, and treatment of congenital adrenal hyperplasia are reviewed.

Introduction

The congenital adrenal hyperplasias (CAHs) comprise a family of autosomal recessive disorders that disrupt adrenal steroidogenesis. Three specific enzyme deficiencies are associated with virilization of affected women. The most common form is 21-hydroxylase deficiency (21-OHD) due to mutations in the 21-hydroxylase (CYP21A2) gene. Other virilizing forms include 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and 11β-hydroxylase deficiencies associated with mutations in the HSD3B2 and 11β-hydroxylase (CYP11B1) genes, respectively. Oxidoreductase deficiency, due to mutations in the cytochrome P450 oxidoreductase (POR) gene can result in virilization of affected female fetuses and undervirilization of affected male fetuses. POR encodes a flavoprotein that serves as an electron donor for cytochrome P450 steroidogenic enzymes such as CYP21A2. Most of this review will pertain to 21-OHD.

In 1865, Luigi de Crecchio, a Neapolitan anatomist, reported the earliest documented description of a patient presumed to have 21-OHD. At autopsy, the cadaver was described as having labioscrotal fusion, a 10-cm curved phallus with hypospadias, bilateral undescended testes, a vagina, a uterus, fallopian tubes, ovaries, and markedly enlarged adrenal glands. This individual had ambiguous genitalia at birth, reportedly presented as a male throughout his adult life, and presumably died of adrenal insufficiency in his 40s during an episode of vomiting, diarrhea, and prostration.1 Just over 100 years later in 1957, the nonclassic or mild form of 21-OHD was described by Jacques Decourt, Max-Fernand Jayle, and Ettiene Baulieu.2

The features associated with CAH comprise a clinical spectrum reflecting the consequences of the specific mutation. In the case of 21-OHD, the continuum ranges from salt-losing and simple virilizing forms to the mild form. Collectively, the salt-losing and simple virilizing forms are considered to be the classic forms. The mild form is also known as the late-onset or nonclassic form (NCAH). However, this classification system is somewhat artificial because disease severity is better represented as a continuum on the basis of residual enzyme activity. The incidence of the classic forms is reported to range from 1:5000 to 1:15,000 and varies among ethnic/racial backgrounds.3 Ethnic-specific mutations have been reported among populations of Ashkenazi Jews, Iranians, Yupik-speaking Eskimos, and East Indians.4 Additionally, the prevalence of 21-OHD is lower among African-American than Caucasian individuals in the United States.5 Screening of 2 million newborns in New York State detected 105 confirmed cases of classical CAH; the incidence was approximately 1:15,500 for Asian and white infants, 1:17,450 for Hispanic infants, and 1:24,840 for black infants.6 Incomplete ascertainment confounds accurate determination of the incidence of NCAH. However, available data indicate that NCAH is more common than the classic forms with an incidence of 1:1000 and increased prevalence among Hispanic, Yugoslavian, and Ashkenazi Jewish people.7

Section snippets

Molecular Genetics

The CYP21A2 gene is located in a complex genetic region at chromosome 6p21.3 where it lies in close proximity to a highly homologous pseudogene, CYP21A1PCYP21A2 and CYP21A1P are arranged in tandem repeats with the complement component 4A (C4A) and complement component 4B (C4B) genes, which encode complement 4 (Fig. 1). The tenascin and serine threonine nuclear protein kinase genes are also mapped to this region. These 4 genes, serine threonine nuclear protein kinase, complement component 4 (C4

Pathophysiology

The hypothalamic-pituitary-adrenal axis regulates cortisol secretion by the adrenal cortex. The hypothalamus produces corticotrophin releasing hormone (CRH), which regulates the release of pituitary adrenocorticotropic hormone (ACTH). ACTH subsequently stimulates the adrenal cortex. Cortisol secretion by the adrenal gland, in turn “feeds back” to the hypothalamus to regulate CRH and ACTH production. Within the adrenal gland, the classical pathway begins with conversion of cholesterol to

Infants

Classic CAH presents in the neonatal period; the presentations differ depending on the sex of the affected infant. Diagnosis of salt-losing CAH is a medical emergency because of the risk for hyponatremia, hyperkalemia, hypotension, and potential fatal outcome within the first 2-3 weeks of life if not recognized. In addition, the extent of prenatal virilization can lead to misassignment of sex at birth. Hence, a possible diagnosis of 21-OHD needs to be promptly investigated and verified.

Female

Hirsutism

Hirsutism is defined as excessive growth of coarse terminal hairs in androgen-dependent areas in women. Hirsutism reflects the apparent sensitivity of the pilosebaceous unit/hair follicle to circulating androgen as well as local androgen concentrations. Importantly, the extent of the hirsutism correlates poorly with circulating androgen concentrations.42

Hair growth per unit skin area is similar in unselected white and black women. However, women from several Asian countries have been shown to

Laboratory Aspects of Diagnosis

Clinicians depend on consistent validated hormone determinations to confirm the diagnosis of disorder of steroidogenesis. Bioassays were followed by the development of immunoassays in which small molecules were covalently linked to immunogenic proteins that elicited antibodies directed to epitopes of the target steroid molecule. However, immunoassays, particularly free testosterone assays, lack adequate sensitivity to accurately measure low hormone concentrations. More robust mass spectrometry

Treatment

Upon confirming the diagnosis of classical salt-losing or simple virilizing 21-OHD, glucocorticoid and mineralocorticoid hormone replacement therapies need to be initiated. Although patients with simple virilizing 21-OHD are not overt salt-losers, they might benefit from mineralocorticoid replacement therapy. For patients with NCAH, treatment needs to be focused on the individual's symptoms and should not be initiated merely to decrease abnormally elevated hormone concentrations.95 For children

Transition to Adult Care

Although transition can be compared with “graduation” from pediatric to adult care, transition from pediatric to adult care involves a multistep process.100 This process requires communication, education, and cooperation among patient, family members, and health care providers. Potential obstacles and challenges include the patient's comprehension of the pathophysiology of CAH, continued access to experienced health care providers, the patient's willingness and ability to assume responsibility

Sexuality

Most women with CAH report heterosexual preferences. Although the exact frequency is unclear, up to 25% of women with CAH report homosexual inclinations when surveyed.112 Adult women with CAH manifest increased gender-atypical behavior regarding their choices for professional occupations, sporting interests, and spare time activities. The extent of the gender-atypical behavior was correlated with the severity of the CYP21A2 genotype. Additional potential consequences of prenatal androgen

Contraception, Fertility, and Pregnancy

In addition to concerns regarding sexuality, women with CAH and NCAH might experience difficulty in achieving pregnancy.121 Similarly, irregular menses and anovulatory cycles might lead female patients to infer that contraception is unnecessary. Thus, reproductive counseling should include discussion regarding goals for family planning. Although anovulatory cycles will not result in conception, female patients with CAH and NCAH are indeed fertile and should be offered contraception if sexually

Prenatal Dexamethasone Treatment

Prenatal dexamethasone treatment has been used in the past to prevent or ameliorate the genital virilization of female infants with classical CAH, with the goal of reducing the need for feminizing genital reconstructive surgery.128 In normal circumstances, the human fetal adrenal cortex does not synthesize significant quantities of cortisol during early pregnancy.129 The fetus is protected from maternal glucocorticoids by placental expression of the 11β-hydroxysteroid dehydrogenase type 2

Outcome Data and Potential Sequelae Associated With CAH

With improvements in treatment, more children with CAH are transitioning to adulthood. Available outcome studies are disappointing, but it must be remembered that the standard management for CAH was different 20-40 years ago. Many patients appear to be lost to follow-up medical care. Outcome studies from the United Kingdom and the United States have reported that obesity, adverse metabolic profile, and osteopenia were common.140, 141 There are no apparent correlations between genotype and

Bone Health

Chronic use of glucocorticoids has deleterious effects on bone health.151 Because of the requirement for chronic glucocorticoid replacement therapy, individuals with CAH experience a greater risk for decreased bone mineral density. Bone is comprised of 3 cell types: osteoblasts, osteocytes, and osteoclasts. Glucocorticoids influence all 3 cell types. Glucocorticoids decrease the number of osteoblasts by decreasing replication of osteoblastic precursors, redirecting differentiation of bone

Oxidoreductase Deficiency

This flavoprotein serves as a mandatory electron donor for several steroidogenic enzymes including 7α-hydroxylase (CYP17A1), CYP21A2, and also P450 aromatase. However, activities of these steroidogenic enzymes might be differentially affected by specific POR mutations.161 Generally, affected infants present in the newborn period. Clinical features include ambiguous genitalia, adrenal insufficiency, and skeletal anomalies. Affected women might develop large ovarian cysts prone to spontaneous

Future Directions

Evolving technologies offer the opportunity for prenatal and even preconception diagnosis of CAH. Although early diagnosis might be helpful for counseling of parents, with increasing awareness of the potential consequences of prenatal androgen exposure, continued discussions regarding gender of rearing for severely virilized girls is warranted. Similarly, further studies regarding sexuality and quality of life measures are warranted for this population. Most importantly, novel therapeutic

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