Congenital adrenal hyperplasia

Need to know:

• Congenital adrenal hyperplasia (CAH) includes a group of severe and rare genetic diseases of cortisol biosynthesis resulting in adrenal insufficiency.
  
• 21-hydroxylase deficiency accounts for approximately 95% of cases and is the form of CAH referred to in this article.
  
• Classic CAH is typically identified through newborn screening, but missed cases may present with adrenal crises, or signs of virilisation in female neonates.
  
• Clinical features of the classic form include short stature, hirsutism, hypertension, obesity, osteoporosis, infertility and an adverse cardiovascular profile.
  
• Non-classic CAH, a milder form, is usually not detected on newborn screening and may present in childhood with premature pubarche, acne or accelerated growth, and in adults with signs of hyperandrogenism in females and infertility in both sexes. 
  
• Challenges in the management of CAH result from the difficult balance between the features related to the disease and to glucocorticoid treatment.
  
• There are currently a limited number of effective and safe treatment options available.
  
• New approaches to treatment include modified-release hydrocortisone, melanocortin type 2 receptor (MC2R) antagonists and corticotropin hormone receptor 1 (CRF1) inhibitors.

Congenital adrenal hyperplasia (CAH) consists of a group of autosomal recessive disorders resulting in enzymatic defects in cortisol biosynthesis. Approximately 95% of cases are due to CYP21A2 gene pathogenic variants resulting in 21-hydroxylase deficiency. 

The 21-hydroxylase enzyme is essential for the synthesis of cortisol and aldosterone in the adrenal glands.¹ Many mutations of the CYP21A2 gene have been identified and result in varying degrees of impairment of 21-hydoxylase activity. The clinical phenotype differs depending on how severely the allele is mutated. 

When the adrenals cannot produce enough cortisol, there is a loss of negative feedback to the hypothalamus-pituitary-adrenal axis, with a counter-regulatory overproduction of adrenocorticotropic hormone (ACTH), which leads to excessive adrenal androgen production, mainly 17-hydroxyprogesterone (17-OHP) and A4-androstenedione, and results in adrenal hyperplasia (see figure 1).²

In the 1950s, the development and introduction of synthetic glucocorticoids for the treatment of CAH meant survival and longer lifespan was achievable for affected patients. Glucocorticoids became commercially available in the 1960s, and since then advances in pharmacological options for patients with CAH have been scarce, with a high unmet need for effective therapy. Fortunately, new therapies have been developed that may help to address this gap by lessening the adverse effects of long-term glucocorticoid replacement and better controlling androgen levels.

Clinical presentation

CAH falls into a continuum determined by the degree of enzymatic impairment which correlates well with CYP21A2 pathogenic variants. It ranges from the classic salt wasting form, in which there is total absence of enzymatic activity with deficiency of both cortisol and aldosterone and the non-classic form, in which some enzyme activity occurs, resulting in less severe symptoms that may appear during childhood, adolescence or adulthood. 

Classic

The classic form is rare, with a prevalence ranging from 1:10,000 to 1:20,000 in most populations. Estimated prevalence in Australia is between 1:14,800 and 1:18,000.^3,4 This form is characterised by severely impaired cortisol synthesis with or without compromise in aldosterone production from birth, resulting in increased ACTH secretion with accumulation of steroid precursors upstream of 21-hydroxylase action (17-OHP and A4-androstenedione) that are shunted to the adrenal androgen pathway. Consequently, affected 46,XX neonates experience virilisation of external genitalia in early stages of development and life-threatening adrenal crises early in life.⁵ The classic form is typically diagnosed at birth via newborn screening, allowing treatment to be initiated before an adrenal crisis occurs. 

Typical features in childhood and adolescence include precocious puberty and advanced bone maturation with premature epiphysial closure resulting in short adult height. Later in life, long-term complications may include hirsutism, obesity, hypertension, osteopenia, mood and sleep disturbances, an adverse metabolic profile, menstrual abnormalities in females, testicular adrenal rest tumours (TARTs) in males and fertility issues in both sexes.⁶ 

Non-classic

Non-classic CAH is much more common than the classic form, with an estimated prevalence between 1:200 and 1:2,000 and wide variation among different ethnic groups.² It is usually not identified on traditional newborn screening tests, as 17O-HP levels are only mildly elevated. Symptoms appear later in life and include early adrenarche (ie, in children younger than 10 years of age) and signs of hyperandrogenism (such as acne, hirsutism, menstrual irregularities), or infertility in female adolescents and adults.

Diagnosis

Diagnosis of classic CAH due to 21-hydroxylase deficiency is based on clinical suspicion and confirmed by the elevation of 17-OHP in a morning sample. Elevation of other metabolites may also be useful to support the diagnosis.² In non-classic CAH, elevation of 17-OHP is mild, and often a provocative test using tetracosactrin (Synacthen), a synthetic ACTH, with measurement of 17-OHP levels after administration, is needed for the diagnosis.

In countries where neonatal screening is established, the diagnosis is made at birth by newborn bloodspot screening, which includes assessment of 17-OHP. Levels are typically greater than 100nmol/L and almost always above 30nmol/L in neonates with the classic form. In newborns with 17-OHP levels above 30nmol/L, a second-tier test that measures steroids by liquid chromatography followed by tandem mass spectrometry is needed to confirm the diagnosis.² 

Genotyping of CYP21A2 gene is recommended in cases where diagnosis of 21-hydroxylase deficiency is suspected but the adrenocortical profile is equivocal.⁷ 

Management 

The goal of treatment includes two main objectives: to replace deficient cortisol production and to suppress adrenal androgen overproduction. Lifelong glucocorticoid replacement is the current standard of care, but this carries risks of short- and long-term complications. Supraphysiologic doses are often needed to suppress adrenal androgen production and, in some cases, are administered in a reverse circadian treatment regimen with the maximum dose given at bedtime. This results in alternating periods of hypercortisolism and hyperandrogenism.⁸ 

Iatrogenic glucocorticoid excess causes adult short stature, obesity, hypertension, mood and sleep disturbances, osteoporosis and metabolic morbidities.⁹ On the other hand, hyperandrogenism also has deleterious consequences, such as early puberty and short adult height, hirsutism, menstrual irregularities, amenorrhoea, insulin resistance and infertility. 

The limitations of glucocorticoid therapy have been quantified in several studies, including the largest longitudinal study in which patients with CAH were followed from childhood for a median of 18.6 years.¹⁰ Hydrocortisone doses at the beginning and at the end of the study typically exceeded those recommended for adrenal replacement. Good adrenal control was achieved in just 28% of visits and 93% of patients had hypertension at one or more visits.¹⁰ Data from this observational study and others have provided insights for the development of new pharmacotherapies that are now in clinical development aiming to ameliorate morbidity and mortality of patients with CAH.⁶ 

Novel treatment options

Modified-release hydrocortisone 

A multi-particulate formulation of hydrocortisone with a delayed release coating has been developed. This preparation allows for delayed and sustained absorption. When taken at bedtime and on rising, this replicates the overnight diurnal rise in cortisol.¹¹ Modified-release hydrocortisone improves 24-hour control of 17-OHP, the traditional adrenal biomarker, and the alternative adrenal androgen pathway metabolites when compared to standard glucocorticoid therapies.⁸ 

Melanocortin type 2 receptor antagonist

ACTH activity at the melanocortin type 2 receptor (MC2R) results in the synthesis and secretion of cortisol (corticosterone in rats). By blocking this receptor, the action of ACTH has been shown to be effectively blocked in vitro. In vivo studies in rats have shown good oral bioavailability and dose-dependent acute suppression of corticosterone levels and control of ACTH levels, reversing the phenotype caused by ACTH excess.¹² Currently double blind, randomised placebo-controlled phase 1 studies with an oral MC2R antagonist (CRN04894) are underway in humans.^6,7 

Corticotropin-releasing factor type 1 receptor antagonists

ACTH suppression is another promising strategy for future treatment. The primary regulator of ACTH synthesis and release is corticotrophin-releasing factor (CRF). This hormone is released from the hypothalamus into the hypophyseal portal system and acts directly on corticotropes via two different receptors: CRF type 1 (CRF1), which is abundant in the pituitary, and the CRF type 2 (CRF2), predominantly found in peripheral tissues.

Tildacerfont is a novel CRF1 receptor antagonist that binds to CRF1 receptors in the pituitary to inhibit excessive production of ACTH and, as a result, 17-OHP and other adrenal androgens. It requires daily oral dosing. 

CRF1 receptor antagonism prevents the need for supraphysiologic doses of glucocorticoids while effectively reducing high androgen exposure. This approach mitigates the long-term negative consequences of life-long supraphysiological glucocorticoid treatment.¹³ To date, the safety profile has been acceptable in non-clinical toxicology studies and phase 2 studies in adults with classic CAH.¹³ 

A phase 2a study has demonstrated target engagement and reductions in ACTH, 17-OHP and A4-androstenedione, key hormones for disease control. There were no serious adverse events and adverse events (most frequently headache in 7.1% and upper respiratory tract infection in 7.1%) were mild and unrelated to treatment.¹³ A larger study (CAHmelia program) is currently being undertaken in Australia to further investigate the safety and efficacy of this agent (see ‘Online resources’).

Conclusions

CAH due to 21-hydroxylase deficiency is a rare genetic condition resulting in several significant hormonal imbalances. Adverse outcomes result from the disease itself and chronic glucocorticoid treatment. 

While progress has been made regarding pathophysiology, clinical features and genetics of the disease, current therapeutic options are still not optimal. 

The development of novel treatments will help improve the management, quality of life and health outcomes of these patients.¹⁴ 

Online resources:

For patient referrals, visit the CAHmelia Australia site.

Conflicts of Interest

Dr Gabriela Finkielstain is a consultant for Spruce Biosciences, a biopharmaceutical company the develops novel therapies for rare endocrine disorders, including tildacerfont.

Dr Nick Fuller is a senior research fellow in the faculty of medicine and health, University of Sydney. 

Dr Gabriela Finkielstain is a postdoctoral and clinical paediatric endocrine fellow at the National Institutes of Health in Bethesda, USA, and is a paediatric endocrinologist at Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.

Associate Professor Tania Markovic is director, metabolism and obesity service, Royal Prince Alfred Hospital, and is a clinical associate professor, Charles Perkins Centre, University of Sydney.

References on request from kate.kelso@adg.com.au