Barriers to the Management of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Abstract

Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a rare genetic condition that affects approximately 1:15 000 live births (1-3). Deletions or mutations in the 21-hydroxylase gene result in impaired synthesis of cortisol and in some forms, also aldosterone (3-6). Aldosterone deficiency occurs in salting-wasting CAH, where specific mutations impair aldosterone synthesis and result in life-threatening salt-wasting crisis in neonates. Cortisol deficiency can lead to life-threatening adrenal crisis without appropriate diagnosis and treatment of both salting-wasting CAH and simple virilizing CAH. In addition, cortisol deficiency results in the loss of negative feedback on the hypothalamic-pituitary-adrenal axis, leading to increased secretion of corticotropin-releasing factor and adrenocorticotropin, which drives excess production of adrenal androgens.

Due to excess adrenal androgen production, patients with CAH are at lifelong risk for multiple disease- and treatment-related complications (1, 4, 7). Excess androgen exposure in utero and during childhood can lead to virilization in female patients, accelerated skeletal growth due to advanced bone age, precocious puberty, and short stature. In adulthood, male patients with CAH may develop testicular adrenal rest tumors, while female patients may experience hirsutism, acne, and menstrual irregularities. Furthermore, CAH can cause fertility issues both in men and women. To control androgen excess, treatment with supraphysiologic glucocorticoid doses is typically required; however, long-term exposure to high doses of glucocorticoids can cause multiple cardiovascular and metabolic complications, including obesity, insulin resistance, diabetes, hyperlipidemia, hypertension, and osteoporosis (1, 4, 7).

To balance the consequences of androgen excess with the consequences of long-term glucocorticoid exposure, CAH requires lifelong treatment with medications, comprehensive care by multidisciplinary specialist teams, and clinical and laboratory monitoring (3, 4). Goals of care include early neonatal diagnosis to minimize mortality, prevention of life-threatening adrenal crisis, and minimization of disease- and treatment-related comorbidities (4). Individuals with CAH and their families may face many challenges accessing the treatment, education, and support required for management of CAH (Fig. 1). This review highlights the multiple structural, sociocultural, and individual barriers that individuals with CAH and their families/caregivers may face, including lack of universal newborn screening, limited access to comprehensive care, stigmatization, discrimination, limited financial resources, limited education, and lack of social supports.

Figure 1.

Barriers in the diagnosis and management of congenital adrenal hyperplasia.

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Structural Barriers

Lack of Universal Newborn Screening Programs

Newborn screening for CAH, which was first introduced in the 1970s, promotes timely diagnosis and has provided clear benefit in preventing neonatal salt crisis and infant mortality (3). Newborn screening for CAH has since been adopted globally, with more than 50% coverage in at least 49 countries as of 2023, including the United States, Canada, Mexico, China, Japan, Australia, and most of South America and western Europe (8-15). An additional 23 countries have limited access to newborn screening for CAH through pilot programs or contracted services (10).

Despite the benefits of early screening and the high uptake of screening in many countries, there is still a lack of universal access to screening, especially in less-developed countries and/or underresourced areas. But even in well-developed countries, newborn screening for CAH may not be available. For example, while newborn screening in Canada includes CAH testing in most provinces and territories, several provinces (New Brunswick, Nova Scotia, Prince Edward Island, and Quebec) do not screen for CAH (10). The United Kingdom has newborn screening for multiple conditions; however, samples are not collected until day 5 of life and results are not back until week 6, which has precluded CAH screening as part of the newborn screening (10). Many western European countries have implemented newborn screening for CAH, but only 2 countries in southeastern Europe (Bosnia-Herzegovina and Bulgaria) include CAH screening as part of their newborn-screening programs (10, 16).

Access to universal screening is also limited across some parts of the Asia-Pacific region. While New Zealand and Japan implemented newborn screening for CAH in 1984 and 1989, respectively (11, 17-19), newborn screening for CAH was not implemented in Australia and Singapore until 2018 and 2019, respectively (20, 21). In Vietnam, a national pilot program for comprehensive newborn screening was implemented in 2006 (22, 23), but as of 2019, only 40% of newborns had received screening tests (10, 24). In mainland China, comprehensive newborn screening is available; however, screening is administered at the provincial level, resulting in different screening panels that may vary by location (10). In India, where there are approximately 4 million annual births and a high estimated incidence of CAH (1:5700 with regional differences), only 1 state (Kerala) provides comprehensive newborn screening for public sector programs (25); 2 additional states (Chandigarh and Goa) have piloted screening programs (26). However, these programs are limited by incomplete follow-up on babies with positive screens and limited availability of confirmatory testing (25, 26). In contrast, private hospitals in India have implemented newborn screening for CAH (10). Additional barriers to screening access in India are the high number of home births (∼277 000 home births per year) and rapid discharge following delivery at some medical facilities, which may not allow adequate time for screening.

Although newborn screening is essential for the initial diagnosis of CAH, biochemical methods may be unable to discriminate disease severity (27). Thus, genetic testing can be a useful tool in providing prognostic information on disease severity. In addition, genotyping is important for determining the carrier state of the parents of a child with CAH and for genetic counseling of future risks of having an affected child. However, as with newborn screening, access to genetic testing and counseling maybe be limited, especially in underresourced areas (28, 29).

Limited Access to Comprehensive Care

Once diagnosed, individuals with CAH need lifelong management with glucocorticoids to reduce excess adrenal androgen levels and manage cortisol deficiency; many also require mineralocorticoids to manage aldosterone deficiency (4). The goals of treatment include preventing life-threatening adrenal crisis and minimizing effects of excess adrenal androgens, including short stature, precocious puberty, virilization, infertility, and cardiovascular and metabolic complications (4). A critical aspect of medication management requires the individual and their family to increase the glucocorticoid dose in times of illness, injury, and stress (stress dosing).

The Endocrine Society Guidelines recommend regular monitoring of 17-hydroxyprogesterone (17OHP), androstenedione, testosterone, renin, and electrolyte levels for individuals with CAH (eg, every 3-6 months, depending on age) (3). Phlebotomy can be emotionally traumatic both for the parent and patient, which may lead to delays in obtaining laboratory evaluations. In addition, management of CAH often requires multiple specialist visits per year, particularly for children, who require more frequent monitoring to minimize the effect of glucocorticoids and androgen excess on linear growth and puberty (4). The 2010 Guidelines for the Development of Comprehensive Care Centers for CAH recommend multidisciplinary care teams (30), with the burden of communication between specialists often falling heavily onto the individuals and their families (Fig. 2).

Figure 2.

Multidisciplinary care team for congenital adrenal hyperplasia management.

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Despite the need for comprehensive specialist teams, there are currently just 8 CAH Comprehensive Care Centers in the United States, only 1 of which is located in the Midwest and only 4 of which have surgical expertise (31). A 2019 survey from the National Organization for Rare Disorders (NORD) found that 39% of respondents had to travel 60 or more miles (≥97 km) to receive care for their rare disease (32). This can be especially difficult for families with limited financial resources or time off from work. Indeed, survey respondents who earned less than $20 000 per year were more than 2 times as likely to consider relocating to access care than respondents in any other income category (32). In Alaska, there are fewer than 10 endocrinologists with only 3 pediatric endocrinologists (33) despite a significantly higher incidence of CAH (∼1:300 births in Alaska Natives vs ∼1:15 000 births worldwide) (4, 34, 35). The majority of children with CAH live in rural Alaska, primarily in the Yukon-Kuskokwim Delta region, and there is only one pediatric endocrinologist who travels to the region to care for the Yup'ik Alaska Natives with CAH. The Tribal Health System has just hired 2 additional pediatric endocrinologists who will care for children in southeast Alaska and Fairbanks (personal communication, email 07/03/2024). Furthermore, the nearest CAH Comprehensive Care Center is more than 1500 miles (2414 km) away in a major city (Seattle, Washington, USA), which can be challenging, geographically as well as culturally, for individuals from more rural or isolated areas (31, 33, 36). Finally, some rural or isolated areas may have limited internet access, making telehealth visits unreliable as a form of routine care.

Access to appropriate medications may be limited, both in well-resourced and underresourced areas. In Europe, prior to the introduction of hydrocortisone oral granules, the smallest dose of hydrocortisone available was 10 mg tablets, making appropriate dose delivery difficult in children with a body surface area of less than 0.5 m². In the United States, hydrocortisone sodium succinate (brand name, Solu-Cortef), an injectable form of hydrocortisone used for stress-dosing or in an adrenal crisis, is not covered by many insurance plans. Furthermore, most first responders in the United States do not carry or administer hydrocortisone sodium succinate (37). Glucocorticoids and mineralocorticoids require frequent dosing, which may be interrupted by access to medications. Especially in rural or underresourced areas, individuals may have limited access to pharmacies, medications may not be consistently stocked at the pharmacy, and/or delivery of medications to the pharmacy may take longer.

Transition from pediatric to adult care is an ongoing process that involves patient education, psychosexual and genetic counseling, increasing patient autonomy in a treatment plan, and establishing care with a provider who cares for adults for continued clinical management (4). This process introduces additional barriers to accessing appropriate care. Access to genetic counseling services may be limited, particularly in underresourced countries, due to lack of expertise, poor infrastructure, cost, inadequate numbers of genetic counselors, and/or the absence of comprehensive health policies regarding genetic services (28, 29). When establishing care with a provider for adults, retrospective and cohort studies on adults with CAH found that 10% to 50% did not receive follow-up care with an endocrinologist after the transition from pediatric to adult services (38, 39), likely due at least in part to the limited number of programs and specialists with expertise in transitioning from pediatric to adult care.

Sociocultural Barriers

Social Stigmatization and Discrimination

Cultural factors, including religion, social stigmatization, and discrimination, can influence parents’ and patients’ expectations and decision-making for CAH treatments (40). Many cultures place stigma on individuals with genital ambiguity to the extent that parents may choose to conceal their child's condition, or in more extreme cases, even abandon their child (41, 42). In India, parents of children with genital ambiguity are advised by physicians to maintain confidentiality on the diagnosis to decrease the risk of the baby being taken away by hijra (transgender groups) (25). In addition, early assignment with male sex may be more likely in some cultures due to predominance and social advantages for males (25, 40). A retrospective chart review of 43 Saudi Arabian women with CAH found that 12 (28%) had been reared as males before sexual reassignment, some for an extended period of time (eg, up to 16 years for 1 woman) (43).

One study in the United States found that two-thirds of adult women with CAH experience stigma in romantic or sexual relationships (44). They also reported anticipating stigma due to their condition, which led to avoidance of dating, intimacy, and/or sexual intercourse (44).

Adverse Experiences in Medical Settings

Individuals with CAH, particularly women with virilization, may experience stigmatization in the medical setting and/or have traumatic experiences related to genital examinations. These experiences may lead to avoidance of routine medical visits and gynecologic examinations as adults (45, 46). In a survey evaluating stigma experiences of 62 women with classic CAH, 17 (27%) reported that genital examinations during childhood and adolescence were adverse experiences and contributed to their feelings of “undesired differentness” (45). Negative experiences commonly cited included physician remarks or facial expressions while performing examinations and examinations being used as teaching experiences for students and/or residents (45). A qualitative study of 13 adult Swedish women found that all participants perceived that their genitalia had been the main focus of clinic appointments, and many reported that they had been subjected to repeated demonstrations of their genitalia, which were described as “unnecessary traumatic experiences and mostly due to the physicians’ curiosity” (46). A survey of cervical screening experiences in 38 women with CAH found that only 37% had attended their last routine cervical screening, compared to 78% of the general population, with 29% of respondents citing embarrassment around the appearance of their genitals as a reason for not attending (47).

Individual Barriers

Limited Financial Resources or Health-Care Coverage

Lack of health-care coverage or limited financial resources may affect the ability to access care for CAH (32). Care such as newborn screening may be available only within the private sector, which makes these programs financially inaccessible to many families (10, 26). In a study exploring the barriers to accessing maternal and postnatal health care in Vietnam, access to newborn screening was greatly affected by economic status, with screening conducted in 68% of newborns with the highest economic status (top 20%) (48). In contrast, only 22% of newborns within the lowest economic bracket (bottom 20%) were screened.

Financial barriers can also affect access to specialists, treatment options, and medication adherence. The 2019 NORD survey found that 61% of US patients with a rare disease had been denied treatment or had delays in accessing treatment due to preapproval authorizations from insurance, and 16% had been denied referrals to specialists for care (32). Many families in underresourced settings cannot afford daily medication, and medication supplies can be unreliable (49-51). Some families may need to ration glucocorticoid replacement medications, or may need to seek medication from black market sources, making adherence difficult and potentially life-threatening (49, 50). Humanitarian efforts, such as Care & Living as Neighbours (CLAN), have been working to establish reliable access to hydrocortisone and fludrocortisone for individuals with CAH across the Asia-Pacific region, seeking to lessen this barrier for these communities (51).

Limited Access to Education and Support

Individuals and families who are living with a rare disease need to become “experts by experience” to navigate their health conditions, which is especially difficult given the complexities of CAH (52). Learning how and when to stress-dose glucocorticoids to prevent an acute adrenal crisis can be challenging for many parents and caregivers, especially if their child has frequent dose changes based on their growth. Intramuscular hydrocortisone injections may be required in emergency situations, but its appropriate use may be affected by limited education and/or experience with administering intramuscular injections. Some individuals or caregivers may not adhere to their glucocorticoid regimen with frequent dosing due to a lack of understanding of the importance or complexity of taking all the prescribed doses. Furthermore, perceived side effects of glucocorticoids (eg, weight gain and slowed linear growth) may limit adherence by individuals or caregivers who do not fully understand the potential health consequences of excess adrenal androgens (eg, advanced bone age, short stature, infertility, testicular adrenal rest tumors, hirsutism, and irregular menses).

A recent Cochrane review of chronic diseases found that self-management can help increase the individual's knowledge, self-efficacy, and health status, and also provide physical and psychological benefits (53). However, the authors found that there was inadequate evidence to determine which specific educational interventions were the most effective; thus, further research is needed. In underresourced countries, access to educational resources for self-management may be further limited, including little public awareness about the need for newborn testing for life-endangering conditions such as CAH. To combat these barriers, an increasing number of international CAH networks have become available, offering educational resources and support for individuals with CAH and their families (Table 1). However, access to these support networks and educational materials may still be limited by lack of awareness of available resources, inadequate or no internet access, and/or translation into an insufficient number of languages.

The period of transition from pediatric to adult care is an important time to reassess patient education. Adults with CAH have reported that as children they were not active participants in medical discussions, and they did not have a discussion with their physician until adulthood (46). Transition is an ongoing process that should involve a progressive increase in knowledge and autonomy for adolescents. Merke and Poppas (54) have outlined knowledge goals for all adolescents with CAH, which include 1) understanding CAH is chronic and genetically inherited; 2) understanding the treatment plan and consequences of too little or too much medication; 3) self-sufficiency in stress-dosing; 4) knowledge of surgical history and physical implications; and 5) understanding fertility implications.

Conclusions

CAH is a chronic disease requiring frequent medication dosing and medically supervised dose adjustment to prevent life-threatening adrenal crisis and avoid disease-related comorbidities. Individuals with CAH and their families may face many structural, sociocultural, and individual barriers when managing their condition, including lack of universal screening, limited access to comprehensive care, stigmatization, discrimination, financial barriers, and limited CAH education and support. Continued efforts are needed to decrease patient burden and improve quality of life by improving access to treatment and educational resources.

Acknowledgments

Writing and graphics assistance were provided by Meghan O’Connell, PhD, and Jennifer Kaiser, PhD, from Prescott Medical Communications Group, a Citrus Health Group, Inc., company (Chicago, IL) with support from Neurocrine Biosciences, Inc. (San Diego, CA).

Supplement Sponsorship

This article appears as part of the supplement “Challenges and Opportunities in the Management of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency Throughout the Lifetime,” sponsored by Neurocrine Biosciences, Inc.

Disclosures

K.E. has no disclosures. P.F. has received research support from Neurocrine Biosciences, Inc.; Spruce Biosciences, Inc.; and Diurnal Ltd (now Neurocrine UK Ltd). She has received payment for consultative services from Neurocrine Biosciences, Inc., and Eaton Pharmaceuticals.

Data Availability

Not applicable.

References

Abbreviations

 
• 21OHD

  21-hydroxylase deficiency

 
• CAH

  congenital adrenal hyperplasia