A Case Report of Non-Classical Congenital Adrenal Hyperplasia of a Two-Year-Old Male Child

Noor Ul Ain, Fakhar Eman, Manahal Amjad

Department of Pharmacology, Government College University, Faisalabad 38000, Pakistan

METADATA

Paper history

Received: 20 November 2023

Revised: 25 April 2024

Accepted: 30 October 2024

Published online: 25 November 2024

Corresponding author Email:ananoorkhan105@gmail.com (Noor ul Ain)

Keywords

21-Hydroxylase deficiency Androgen excess Precocious puberty Hydrocortisone therapy

Citation

Noor Ul Ain, Eman, F, Amjad M (2024) A case report of non-classical congenital adrenal hyperplasia of a two-year-old male child. Innovations in STEAM: Research & Education 2: 24020205. https://doi.org/10.63793/ISRE/0020

ABSTRACT

Background: Non-Classical Congenital Adrenal Hyperplasia (NCCAH) is a relatively common autosomal recessive disorder characterized by partial deficiency of 21-hydroxylase enzyme, resulting in excessive adrenal androgen production. The patient history included a high risk of supported pregnancy with growth injections and prior miscarriage.

Objective: This case report presents a rare early-onset of NCCAH in a 2-year-old male child who was brought to the endocrinology emergency department with premature pubic hair development and increased penile length. The objective was to find out the cause of this abnormal condition and find a clinical measure to arrest the condition.

Methodology: Based on clinical features and biochemical findings, a diagnosis of NCCAH was made. Hormonal therapy with oral hydrocortisone was initiated.

Results: Laboratory investigations disclose elevated levels of luteinizing hormones, ACTH, 17-hydroxyprogesterone, progesterone, and testosterone, while other hormonal and imaging studies were within normal range. Hormonal therapy with oral hydrocortisone led to partial improvement in androgen levels over a 3-month follow- up.

Conclusion: This case highlighted the need for early recognition of atypical presentation of NCCAH to prevent complications such as precocious puberty, compromised adult height, and fertility issues by timely therapeutic interventions.

INTRODUCTION

Congenital adrenal hyperplasia (CAH) is an autosomal recessive endocrine condition that affects cortisol production. The syndrome is caused by reduced activity of cortisol- producing enzymes, which results in prolonged adrenocorticotropic hormone (ACTH) stimulation of the adrenal cortex and accumulation of steroid precursors upstream of the enzymatic block (Claahsen-van der Grinten et al. 2022). CAH has been separated into classic and non- classic (NC) variants. The current research indicates that polymorphisms in the CYP21A2 gene and their phenotypic expression are their main cause. In the classic type, enzyme activity is significantly decreased or missing, limiting cortisol production and resulting in newborn symptoms (Claahsen- van der Grinten et al. 2022). Non-classic CAH (NCCAH), also known as late-onset CAH, is the most prevalent autosomal recessive endocrine disorder. It is caused by partial

21-hydroxylase activity (about 20–50% of normal), which is adequate to sustain important cortisol and aldosterone activities; thus, hormone replacement is often needed. However, due to low cortisol levels, ACTH secretion is not controlled, resulting in adrenal hyperplasia and hyperandrogenism (Podgórski et al. 2018).

Additionally, 21-hydroxylase deficiency accounts for approximately 95% of CAH cases and can present as either the classic (salt-wasting or simple virilizing) or non-classic phenotypes. The remaining cases are primarily caused by 11β- hydroxylase or 3β-hydroxysteroid dehydrogenase deficits, in both classic and non-classic forms. In rare cases, defects in 17α-hydroxylase/17,20-lyase or cholesterol desmolase can lead to serious clinical problems (Piróg et al. 2024).

Mutations in CYP21A2 range from complete loss to partial retention of enzyme function, with the majority resulting from gene conversion events between the functional gene (CYP21A2) and its highly similar pseudogene

(CYP21A1P). Functional testing show residual activity of 0– 5% in severe mutations (Adriaansen et al. 2022). According to Kurtoğlu and Hatipoğlu (2017), classical CAH affects 1 in every 15,000–20,000 live births, while NCCAH affects 1 in 200 Caucasians and 1 in 100 of the general population.

The disease is more prevalent among Ashkenazi Jews (1 in 27), Hispanics (~1 in 40), Slavs (1 in 50), and Italians (1 in 300) (Macut et al. 2019). According to the original clinical criteria, NCCAH symptoms develop after the age of five years. Females are born without genital ambiguity, but both sexes can develop indications of androgen excess at any time throughout postnatal life. Delayed menarche is prevalent in adolescent females, and secondary amenorrhea can occur in young women (Auer et al. 2023).

Female patients may also experience hirsutism, oligomenorrhea, or polycystic ovary, while afflicted males may infrequently present with oligospermia. Untreated people of both sexes may develop small adult height, insulin resistance, and impaired fertility. Boys frequently experience premature pubertal development, precocious puberty, acne, and fast growth. Laboratory results frequently show elevated 17-hydroxyprogesterone, increased ACTH, and excessive luteinizing hormone (LH) release. Genetic testing is recommended for all CAH patients, including parents and siblings. NCCAH patients had an increased risk of testicular adrenal rest tumors, cardiovascular morbidity, and infertility (Muthusamy et al. 2010).The treatment of 21-hydroxylase deficiency began in the 1950s. Glucocorticoid replacement therapy restores insufficient cortisol while suppressing excess ACTH, lowering adrenal androgen synthesis. Hydrocortisone is the ideal replacement for 21-OHD, 11β-OHD, and 17α- hydroxylase deficits due to its favorable physiologic profile and lower risk of side effects (Muthusamy et al. 2010). The treatment of 21-hydroxylase deficiency began in the 1950s. Glucocorticoid replacement therapy restores insufficient cortisol while suppressing excess ACTH, lowering adrenal androgen synthesis. Hydrocortisone is the ideal replacement for 21-OHD, 11β-OHD, and 17α-hydroxylase deficits due to its favorable physiologic profile and lower risk of side effects (Muthusamy et al. 2010).

The medicine is commonly provided orally in divided daily doses (10–20 mg/m²/day) to maintain steady hormone levels and decrease androgens. Families receive emergency injectable hydrocortisone kits (50 mg for youngsters and 100 mg for older people). In situations of poor response, doses may be increased to 20–30 mg/m²/day or switched to more potent, longer-acting synthetic glucocorticoids such as prednisone or dexamethasone; cautious titration is required to avoid overtreatment (Finkielstain et al. 2012).

CASE PRESENTATION

Here is a case presentation of 2-year-old child who presented in the emergency to Faisalabad Diabetic and Endocrinology Centre (F-DEC) with the symptoms of pubic hair (4 cm) growth over the last 7 days. Physical examination indicates an

Fig. 1: Growth of pubic hairs (vellus hairs)

Fig. 2: Increased Penile Length

increased penile length of 7 cm that is too high according to his age, and this can be troublesome in the future, because the normal flaccid length in an adult male is 8.7 cm (Fig. 1–17). Clinical findings include the weight of the patient was 14 kg, height was 92 cm, and after laboratory analysis, the patient was diagnosed with non-classical congenital adrenal hyperplasia. There was no family history of any genetic cause; neither the father nor the mother had any disease. However, the mother had one miscarriage before this child during the first trimester, and the cause was unknown. The fetus showed no growth at all, which led to the miscarriage. About seven months later, the mother conceived again, and during the first month of pregnancy, she was given growth- supporting injections of Hydroxyprogesterone Caproate- Estradiol Valerate, four injections in total, administered once a week. This was considered an endangered pregnancy. The patient has eyesight issues, mental health was normal, he was socially active and there is growth of hair on the back of the patient. He was on hormonal therapy, taking Tab Hydrocortisone (10 mg) BD and some multivitamins.

DISCUSSION

Non-Classical Congenital Adrenal Hyperplasia (NCCAH) is a common autosomal recessive endocrine disorder resulting from partial 21-hydroxylase deficiency. Unlike the classical older children, point to early onset virilization, which can occur even in non-classical form if androgen levels are remarkably high. Such presentations are not common and often overlooked due to the milder nature of NCCAH compared to classical forms. The absence of family history

Fig. 17: Ultrasound image of the scrotum region in the patient

and the normal health status of both parents suggests a de novo carrier, indicating mutation or a recessive carrier state in one or both parents, which is consistent with an autosomal recessive inheritance pattern on CAH. The history of unexplained miscarriage in the first trimester may be coincidental, but it also raises the possibility of a previously affected fetus with a more severe phenotype or chromosomal abnormality (Finkielstain et al. 2012).

The administration of Hydroxyprogesterone Caproate and Estradiol Valerate during early pregnancy may have supported the gestation in this case, especially since it was labelled as an endangered pregnancy. However, there is limited evidence on whether these hormonal injections have any direct influence on fetal adrenal gland development. Elevated androgen levels in NCCAH result from partial 21- hydroxylase deficiency, leading to build-up of 17-OH progesterone and other precursors. In this case, early

hormonal therapy with hydrocortisone has been initiated, which is recommended as first-line treatment to reduce ACTH secretion and adrenal androgen production. The psychosocial and physical impact of such early symptoms can be significant; hence, timely diagnosis and management are crucial (Auer et al. 2023). This case highlights the importance of considering NCCAH in the differential diagnosis of premature pubarche, even in the absence of a family history. It also points out the role of detailed perinatal history and early endocrinology evaluation in patients presenting with signs of androgen excess (Auchus and Arlt 2013).

AUTHOR CONTRIBUTIONS

Noor ul Ain designed and supervised the research and final draft of the manuscript; Fakhar Eman and Manahal Amjad completed the research, assisted in write-up, rephrasing, and

final draft preparation.

DATA AVAILABILITY

The data will be made available on a fair request.

ETHICS APPROVAL

Informed consent was obtained from the patient's family.

FUNDING SOURCE

This project is not funded by any agency.

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