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45. Review of Diseases of the Adrenal Gland in Children
Authors:
Bugubaeva Makhabat Mitalipovna
(Head Of Department, Hospital Pediatrics Osh State University, International Medical Faculty)
Pavitha Thulaseedharan
(4th year, Osh State University, International Medical Faculty)
Abstract
Disorders of the adrenal gland in children are rare but often life-threatening endocrine conditions, predominantly caused by inherited, monogenic defects. The primary focus of current research is Congenital Adrenal Hyperplasia (CAH), which accounts for the majority of cases of Primary Adrenal Insufficiency (PAI). CAH is an autosomal recessive disorder, most commonly due to mutations in the CYP21A2 gene, resulting in cortisol deficiency and a compensatory increase in adrenocorticotropic hormone (ACTH), leading to adrenal hyperplasia and androgen excess. These hormonal imbalances carry significant neurodevelopmental implications and risks for adrenal crisis.2
Timely diagnosis is crucial and relies on newborn screening (NBS) for 17-hydroxyprogesterone, supplemented by confirmatory corticotropin stimulation tests.21 Standard treatment involves meticulous, lifelong replacement therapy using short-acting glucocorticoids (hydrocortisone) and mineralocorticoids (fludrocortisone).32 However, this chronic treatment carries substantial long-term risk, including metabolic, cardiovascular, and skeletal complications, and is associated with a high psychosocial and economic burden, reflected in diminished Health-Related Quality of Life (HRQoL).30
Emerging therapeutic strategies aim to overcome the limitations of standard treatment by optimizing hormone delivery (e.g., modified-release hydrocortisone), introducing targeted ACTH suppression therapies (e.g., Crinecerfont), and pursuing curative approaches such as gene and cell-based therapies.39 Future success in managing pediatric adrenal disease will be measured not only by reduced mortality but by the mitigation of chronic complications and demonstrably improved patient HRQoL.
Keywords: Adrenal Gland Diseases, Congenital Adrenal Hyperplasia (CAH), Primary Adrenal Insufficiency (PAI), Pediatric Endocrinology, Glucocorticoid Replacement, Quality of Life (HRQoL), Gene Therapy, Crinecerfont, Newborn Screening
I. Introduction and Epidemiology of Pediatric Adrenal Disorders
Disorders of the adrenal gland in the pediatric population represent a complex and heterogeneous group of conditions, ranging from life-threatening deficiencies of adrenal steroid hormones to endocrine-active tumors.1 These conditions may be isolated problems or part of broader congenital syndromes. A nuanced understanding of the hypothalamic-pituitary-adrenal (HPA) axis and the precise defects in steroidogenesis is essential for effective diagnosis and management.2
Classification and Etiologic Differentiation
Adrenal gland diseases in children are typically classified into categories of Primary Adrenal Insufficiency (PAI), where the adrenal gland itself is defective; Secondary/Tertiary Adrenal Insufficiency (AI), resulting from central (pituitary or hypothalamic) disruption; and disorders of adrenal hyperfunction, often linked to tumors or congenital adrenal hyperplasia (CAH).
PAI is an uncommon, yet potentially lethal, condition in children.3 Epidemiological data demonstrate a stark contrast between pediatric and adult etiologies of PAI. In adults, autoimmune Addison’s disease predominates; however, in children, the majority of PAI cases have an inherited, monogenic origin. Congenital Adrenal Hyperplasia (CAH) constitutes the largest subgroup of impaired steroidogenesis, accounting for the most common cause of PAI in children, representing approximately 71.8% of cases in some major clinical cohorts. The overall prevalence of CAH is estimated to be between 1 in 5,000 and 1 in 15,000 births.3
A critical consideration in pediatric endocrinology is the phenomenon of secondary AI. While PAI is the primary defect in CAH, the necessary lifelong treatment with exogenous glucocorticoids (GCs) can lead to central HPA axis suppression.7 Therefore, the therapeutic intervention designed to be life-saving can paradoxically create a transient form of central AI if medication is abruptly withdrawn or inappropriately managed during stress, compounding the risk associated with the primary gland defect.7
II. Etiology, Pathophysiology, and Genetic Basis
Pathophysiology: Genetic Foundations of Primary Adrenal Insufficiency
The primary focus of research on adrenal gland diseases in children centers heavily on the genetic and molecular underpinnings of PAI. This approach is necessitated by the high prevalence of monogenic conditions in this age group.
CAH, which accounts for the vast majority of pediatric PAI cases, refers to a group of autosomal recessive disorders caused by mutations in genes that encode enzymes required for the synthesis of cortisol, and sometimes aldosterone and sex steroids, from cholesterol. The most frequent enzymatic defect, accounting for over 90% of cases, is 21-hydroxylase deficiency (21-OHD), caused by mutations in the CYP21A2 gene.2
The pathophysiological cascade is initiated by impaired cortisol synthesis, which releases the negative feedback on the pituitary gland. This triggers a compensatory surge in Adrenocorticotropic Hormone (ACTH), leading to hyperplasia of the adrenal cortex and the accumulation of hormonal precursors proximal to the enzymatic block, such as 17-hydroxyprogesterone (17-OHP). Crucially, the excess precursors are diverted into the relatively unimpaired androgen pathway, resulting in overproduction of androgens like testosterone.9 The clinical spectrum ranges from classic Salt-Wasting (SW) forms, characterized by severe cortisol and mineralocorticoid deficiency, to Non-Classical (NC-CAH), which often presents later in childhood with only symptoms of androgen excess, such as premature pubarche.1
Detailed Genetic and Syndromic Etiologies
While CAH dominates, non-CAH etiologies account for a significant minority (28.2%) of pediatric PAI cases.3 The list of known genetic causes has significantly expanded in recent years, necessitating a sophisticated diagnostic approach that integrates clinical features with targeted genetic testing.10
Beyond steroidogenic enzyme defects, PAI can arise from faults in adrenal development or steroidogenesis initiation. For instance, pathogenic variants in the NR0B1/DAX1 gene cause X-linked Adrenal Hypoplasia Congenita (AHC), characterized by salt-losing AI and hypogonadotropic hypogonadism. Similarly, defects in genes involved in the initial steps of steroidogenesis, such as the STAR protein or CYP11A1 (P450scc), result in severe salt-losing and cortisol insufficiency very early in life.10 PAI can also be a feature of complex syndromes associated with intrauterine growth restriction and sexual development disorders, such as MIRAGE syndrome (SAMD9 gene defect).10
The recognition of this genetic heterogeneity is paramount. Because many of these conditions are monogenic, the diagnostic process must employ targeted genetic testing algorithms based on the patient's specific presentation, age of onset, and associated syndromic features to rapidly confirm the cause. This focused genetic approach is vital not only for accurate diagnosis but also for carrier detection, genetic counseling, and family planning.11
Table II.1: Major Genetic Etiologies of Primary Adrenal Insufficiency in Children
Hormonal Imbalances and Neurodevelopmental Implications
The hormonal imbalances intrinsic to CAH—namely cortisol/aldosterone deficiency combined with significant androgen excess—lead to profound clinical manifestations. In classical CAH, these include atypical genitalia in newborn girls and, in older children, rapid growth, early puberty, and ultimately, short adult height and difficulties with fertility.9
Of increasing clinical relevance are the neurodevelopmental implications of these disorders. Recent studies have established the earliest evidence of neurostructural abnormalities in infants with CAH.14 This structural change suggests that regional brain development is affected during the prenatal period, potentially due to the exposure to supra-physiological levels of androgens driven by ACTH stimulation in utero.14 This finding underscores the profound, systemic impact of the hormonal environment, far beyond peripheral sexual differentiation, and mandates longitudinal studies tracking these developmental trajectories from infancy through adolescence to determine the full extent of later structural and functional changes.14
III. Diagnosis and Clinical Evaluation Protocols
Timely and accurate diagnosis is essential, as primary adrenal insufficiency is a medical emergency that can rapidly lead to death if untreated.2
Newborn Screening and Diagnostic Challenges
Newborn screening (NBS) for CAH, typically relying on the measurement of 17-OHP, has been crucial in improving outcomes and reducing mortality by detecting classic (severe) CAH early.2 However, traditional single-tier screening methods often yield a high False-Positive Rate (FPR).9 More critically, False-Negative (FN) results, particularly in preterm infants, remain a concern and risk missing infants with life-threatening salt-wasting CAH.18 Studies have documented FN rates in some cohorts, even after the introduction of a second screen.18
To address these limitations, emerging diagnostic protocols incorporate molecular genetic testing into multi-tier screening. A 3-tier approach involving a low first-tier 17-OHP cutoff, a second-tier 21-variant CYP21A2 panel, and third-tier sequencing has been shown retrospectively to eliminate FNs and significantly reduce FPs.9 However, the effectiveness of these highly accurate screening programs is intricately linked to economic accessibility. Access to comprehensive screening is often affected by financial status, raising concerns about potential disparities in early detection and subsequent life-saving interventions.22
Confirmatory Testing for Adrenal Insufficiency
For acutely ill children with unexplained symptoms suggestive of PAI (e.g., volume depletion, hypotension, hyponatremia, hyperkalemia, fever, or, specifically in children, hypoglycemia), diagnostic testing is recommended immediately.23
The standard diagnostic procedure to confirm AI is the corticotropin stimulation test. The standard dose is 250 micrograms (µg) intravenously for children two years of age and older, with age- and weight-appropriate dosing recommended for younger patients (15 µg/kg for infants and 125 µg for children under two years).23 Measurement of cortisol response 30 or 60 minutes after injection confirms the diagnosis.23
For long-term management and monitoring of CAH, consistent measurements of hormonal precursors, particularly 17-OHP, androstenedione, and testosterone, are necessary to gauge androgen suppression. Mineralocorticoid function is tracked via serum electrolytes (sodium, potassium) and plasma renin activity (PRA) or plasma renin concentration.
Evaluation of Adrenal Masses
Adrenal masses in children, which include benign adenomas and pheochromocytomas, as well as malignant adrenocortical carcinomas (ACCs), necessitate a thorough diagnostic workup. Initial evaluation includes a complete clinical examination, including systematic assessment by a pediatric endocrinologist, and abdominal/pelvic ultrasound with Doppler.20
Advanced imaging, preferably Magnetic Resonance Imaging (MRI), is recommended over Computed Tomography (CT).20 This preference for MRI stems from the high incidence of inherited cancer syndromes associated with pediatric adrenal tumors, such as Li-Fraumeni syndrome. In cases of suspected genetic predisposition, limiting or avoiding irradiation exposure via CT is a critical component of risk stratification.20 Adrenal masses must also undergo functional assessment via blood and urine tests to determine if they are hormone-producing; biopsy is generally avoided for primary adrenal masses due to the risk of hemorrhage or tumor seeding.
IV. Treatment Standards and Management Strategies
The treatment of pediatric adrenal disease revolves around two pillars: urgent intervention to prevent or manage adrenal crisis, and meticulous chronic replacement therapy aimed at minimizing long-term complications.
Acute Management: Adrenal Crisis Prevention
Adrenal crisis, a life-threatening emergency, can be triggered by infectious illness or physical stress, such as surgery.25 Patients with suspected adrenal crisis must receive immediate parenteral injection of hydrocortisone (50 mg/m2 for children), followed by aggressive fluid resuscitation and continuous intravenous hydrocortisone therapy.23
Effective management relies heavily on patient and parental education. Parents must be equipped to identify early signs of crisis (vomiting, severe dehydration, shock) and know when and how to administer high-dose oral or parenteral hydrocortisone immediately.9 All children with PAI must carry a medical alert bracelet and emergency card detailing their condition and emergency dosing protocol.27
Chronic Replacement Therapy
Glucocorticoid and Mineralocorticoid Replacement
For long-term GC replacement, hydrocortisone (HC), a short-acting GC, is the standard of care for infants and children, typically dosed at 10–15 mg/m2/day, divided three times daily. Synthetic, long-acting glucocorticoids (e.g., prednisolone, dexamethasone) are generally avoided in children with PAI due to their potential negative impact on growth velocity.23
Mineralocorticoid replacement using fludrocortisone (starting dosage, 100 micrograms/d) is recommended for patients with confirmed aldosterone deficiency, such as salt-wasting CAH.23 Infants often require supplemental sodium chloride (1–2 g/day) up to 12 months of age.
The Critical Therapeutic Challenge: The Dosing Dilemma
The management of CAH is characterized by a narrow therapeutic window. The essential goal is to maintain the lowest dose possible of glucocorticoids to control the disease, allowing for adequate growth and pubertal development while simultaneously preventing the adverse effects of chronic high doses.
This presents a dosing dilemma: insufficient GC leads to adrenal crisis and unchecked androgen excess (virilization, accelerated bone age, short adult height), while supraphysiological GC doses—often needed to adequately suppress ACTH and, consequently, androgens—result in iatrogenic Cushing syndrome, decreased growth rate, weight gain, and metabolic risks.30
Monitoring for this balance is primarily based on frequent clinical evaluation (recommended every 3–4 months in childhood).30 Clinical assessments must track growth velocity, weight changes, blood pressure, and energy levels.23 For CAH, biochemical monitoring of 17-OHP and androstenedione is used, but clinicians aim for only partial suppression of endogenous adrenal steroid secretion to avoid overtreatment.31 Signs indicating the need for a dose increase (fatigue, hyperpigmentation) must be carefully differentiated from general malaise, and signs of overtreatment (decreased growth rate with weight gain) must be recognized promptly. Routine monitoring includes annual bone age X-ray assessment after two years of age to detect advancing skeletal maturation caused by androgen excess.
Surgical Intervention
Surgical management is typically reserved for adrenal tumors. Adrenalectomy by an expert high-volume surgeon is recommended for masses suspicious of malignancy (Adrenocortical Carcinoma) or for indeterminate adrenal masses discovered in children and adolescents.12 Masses that are functionally active, growing rapidly, or large (greater than 4 cm) also warrant surgical resection.15
V. Prognosis and Long-Term Impact Assessment
With modern neonatal screening and comprehensive medical and psychosocial support, children diagnosed with CAH can generally expect to lead full, healthy lives and achieve a normal life expectancy.5 However, the disease was historically lethal, and excess mortality due to adrenal crisis, particularly in the salt-wasting phenotype, was common before the widespread introduction of newborn screening.16
Chronic Side Effects and Complications of Treatment
The effectiveness of treatment must be evaluated against the potential for long-term complications associated with chronic GC exposure. The necessary evil of prolonged GC replacement, especially at the supraphysiological doses often required to control ACTH-driven androgen production, poses significant chronic risks.
Key long-term complications include:
1. Metabolic and Cardiovascular Risks: Chronic use of high-dose glucocorticoids can lead to central obesity, dyslipidemia, and hypertension, substantially elevating the risk for cardiovascular disease later in life.
2. Skeletal Health: Patients are at high risk for bone complications, including decreased Bone Mineral Density (BMD), osteoporosis, and bone fractures. This is due both to the direct resorptive effect of GCs on bone and their contribution to negative calcium balance.
3. Growth: Chronic supraphysiological GC exposure or inadequate androgen suppression contributes to a decreased linear growth rate and a lower final adult height.30
Health-Related Quality of Life (HRQoL) and Psychosocial Burden
The assessment of treatment effectiveness for chronic conditions like CAH must prioritize metrics beyond just mortality and biochemical normalization. Health-Related Quality of Life (HRQoL) is an essential measure to evaluate the burden of living with the disease and the efficacy of long-term medical treatment.17
Current evidence indicates that despite advances in care, CAH is associated with a significant humanistic, caregiver, and economic burden.13 Patients often report poor HRQoL, psychosocial maladjustment, and challenges related to sexuality and fertility, with the effects often observed to be greater in females due to chronic non-physiological adrenal androgen excess.35 This persistence of high psychosocial burden confirms that standard glucocorticoid replacement, while life-saving, is functionally inadequate for achieving true health normalization.17
Furthermore, the economic impact is notable. Although hydrocortisone itself is inexpensive, studies show that total healthcare costs are significantly higher for CAH patients compared to controls, indicating that the majority of the financial burden is driven by managing the complications of the disease (e.g., adrenal crises, metabolic comorbidities).13 To be cost-effective, optimized treatments must demonstrably reduce complications and hospitalizations.
VI. Investigating Potential New Treatments and Viability
The current therapeutic landscape is undergoing rapid evolution, driven by the imperative to reduce the cumulative supraphysiological GC dose and better mimic the natural cortisol circadian rhythm. New therapies follow two primary tracks: optimization of existing delivery mechanisms and potentially curative approaches.
Optimized Glucocorticoid Delivery Systems
Standard hydrocortisone dosing cannot fully replicate the physiological circadian rhythm of cortisol.37 New formulations aim to address this:
● Immediate-Release Hydrocortisone Granules (Alkindi): This formulation is approved for AI treatment from birth to 18 years, facilitating easier and more accurate dose titration in young children and infants.27
● Modified-Release Hydrocortisone (Efmody/Chronocort): This dual-release formulation is approved for CAH treatment in adults and adolescents aged 12 years and older.27 It is designed to optimize GC concentration throughout the day, improving control of 21-OHD-CAH, and has been associated with patient benefits such as restoration of menses and reduced risk of adrenal crises.28
Alternative delivery methods, such as continuous subcutaneous hydrocortisone infusion (pump therapy), are also being trialed to provide a more consistent circadian replacement.27
Targeted Therapies for Androgen Excess
A major advancement in therapeutic research involves developing agents that specifically target the ACTH-driven androgen excess, thereby allowing the chronic GC dose to be lowered. This approach is designed to mitigate the long-term metabolic and skeletal complications of high-dose GCs.
CRF1 Receptor Antagonists: Crinecerfont, a corticotropin-releasing factor type 1 receptor (CRF1) antagonist, blocks the signal that drives ACTH release.39 In open-label Phase 2 studies involving adolescents with 21-OHD CAH, Crinecerfont significantly reduced elevated androstenedione levels and enabled a substantial reduction in average daily glucocorticoid doses (18% decrease).26 While common side effects (headache, pyrexia, vomiting) were noted, CRF1 antagonists hold considerable promise as a specialized therapy for patients who are poorly controlled on standard or optimized GC replacement, effectively mitigating the central conflict between controlling virilization and minimizing GC side effects.40
Other adrenal-targeted therapies, such as the steroidogenesis-blocking drug Abiraterone acetate, are also under investigation to reduce adrenal androgen biomarkers.28
Curative Approaches: Gene and Cell Therapy
Gene and cell-based therapies are currently the only therapeutic approaches that offer the potential to cure CAH by simultaneously correcting both cortisol deficiency and androgen excess, thereby removing the need for chronic drug replacement entirely.28
Gene Therapy: This involves delivering functional copies of the CYP21A2 gene via a viral vector, such as AAV BBP-631, to restore native 21-hydroxylase enzyme function.38 Initial Phase 1/2 trials in adults have demonstrated increased endogenous cortisol production and durable reductions in 17-OHP levels. Pediatric trials are planned once safety and efficacy in adults are fully established.38 A major limitation of this approach is the transient nature of the correction due to the natural turnover of adrenocortical cells; long-term correction requires the ability to insert the transgene into adrenocortical stem cells.37
Cell Therapy: Preclinical research on implantable Adrenal Bioprinted Tissue Therapeutics (BTTs) has shown highly encouraging results. These 'off-the-shelf' cell therapies successfully restored natural hormone function in animal models, crucially demonstrating the ability to replicate the physiological circadian rhythm of cortisol secretion. This represents a tangible path toward a functional cure for PAI.33
Table VI.1: Standard and Novel Therapeutic Strategies for Pediatric AI/CAH
A critical consideration for novel treatments, including specialized hydrocortisone formulations and gene therapy, is the economic accessibility. The high cost of these new, specialized options may pose a barrier to utilization, particularly in resource-constrained healthcare settings, potentially limiting the impact of clinical advancements on global pediatric patient populations.8
VII. Conclusion and Future Directions
Pediatric adrenal diseases, predominantly primary adrenal insufficiency due to Congenital Adrenal Hyperplasia, demand highly specialized and rigorous management. While early detection via newborn screening has dramatically reduced acute mortality, the long-term prognosis remains complicated by the inherent limitations of standard glucocorticoid replacement therapy, which fails to replicate natural diurnal rhythms and exposes children to chronic metabolic, cardiovascular, and skeletal risks.
The primary future direction of therapeutic development is centered on two strategic fronts:
1. Addressing Chronic Burden: Advancing optimized delivery systems (e.g., modified-release hydrocortisone) and targeted therapies (e.g., CRF1 antagonists) to reduce the necessary glucocorticoid dose, thereby mitigating the severe long-term side effects that compromise growth and metabolic health. These therapies serve as a crucial transitional mechanism to improve patient experience and reduce the economic burden associated with managing complications.36
2. Achieving Functional Cure: Translating promising preclinical cell-based therapies (e.g., BTTs) and resolving the persistence challenges of gene therapy to provide a definitive cure that eliminates lifelong dependence on exogenous hormones and fully restores native HPA axis function.37
Crucially, the success of all new treatment modalities must be assessed using holistic metrics. Future clinical investigations should integrate standardized Health-Related Quality of Life (HRQoL) and long-term neurodevelopmental assessments into trial designs to ensure that therapeutic goals prioritize the functional well-being and overall quality of life of the child, rather than relying solely on biochemical markers of disease control.14 Concurrent efforts must also address the economic barriers that restrict access to advanced diagnostic methods and novel treatments, ensuring equitable application of these life-improving scientific breakthroughs.
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