Clinical Focus
3 NOVEMBER 2023 ausdoc . com . au
Therapy Update
Congenital adrenal
hyperplasia
A guide to the diagnosis and management of this group of disorders , including novel and emerging treatment options .
Figure 1 . Hypothalamicpituitary-adrenal axis in CAH .
Endocrinology
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 .
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 .
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
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 .
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 supress 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