Late diagnosis of classic congenital adrenal hyperplasia: long-term consequences during adulthood

Abstract

Summary Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders related to enzyme deficiencies in the adrenal steroidogenesis pathway leading to impaired corticosteroid biosynthesis. Depending on the extension of enzyme defect, there may be variable severities of CAH – classic and non-classic. We report the case of a 37-year-old male patient with a previously unknown diagnosis of classic CAH referred to Endocrinology evaluation due to class III obesity and insulin resistance. A high diagnostic suspicion was raised at the first Endocrinology consultation after careful past medical history analysis especially related to the presence of bilateral adrenal myelolipomas and primary infertility. A genetic test confirmed the presence of a variant of the CYP21A2 in homozygous with an enzymatic activity of 0–1%, corresponding to a classic and severe CAH form. Our case represents an unusually late definitive diagnose of classic CAH since the definition was established only during adulthood in the fourth decade of life. The missing diagnosis of classic 21 hydroxylase deficiency during infancy led to important morbidity, with a high impact on patients’ quality of life. Learning points Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive enzyme disorders responsible for an impaired cortical adrenal hormonal synthesis. CAH may be divided into two major forms: classic and non-classic CAH. If untreated, CAH may be fatal or may be responsible for important multi-organ long-term consequences that can be undervalued during adulthood. Adrenal myelolipomas are associated with chronic exposure to high ACTH levels and continuous androgen hyperstimulation typically found in undertreated CAH patients. Testicular adrenal rest tumours (TART) and primary infertility can be the first manifestation of the disease during adulthood.

Characteristics of Congenital Adrenal Hyperplasia Diagnosed in Adulthood: A Literature Review and Case Series

“…TARTs are benign testicular tumors that develop in 30 to 50% of males with classic CAH, particularly after periods of poor control or nonadherence to treatment [ 3 , 43 ]. TARTs can cause irreversible damage to the germ cells and Sertoli cells, leading to both testicular structure and spermatogenesis disorders, and decreased testosterone production [ 42 , 44 ]. Physiologically, androgen production in the testis far outweighs adrenal androgen production, and for this reason, men generally do not experience symptoms of androgen excess requiring treatment.…”

“…Therefore, many of them remain undiagnosed. Importantly, TARTs and primary infertility can be the first manifestation of the disease during adulthood [ 44 ]. As men with CAH have the possibility of irreversible testicular failure, early diagnosis is key to preserving fertility [ 42 ].…”

Bilateral Adrenal Myelolipomas in a Female Patient With Undiagnosed Non-classic Congenital Adrenal Hyperplasia

“…There are two subtypes of 21-hydroxylase deficiency: the classic form that involves salt wasting and virilization and the milder non-classic form [2,3].…”

“…Almost all cases of the classic form of 21-hydroxylase enzyme deficiency are diagnosed in the neonatal period due to the availability of neonatal screening tests over the last few decades [2]. Due to the deficiency of both aldosterone and cortisol, treatment with steroids is essential for survival [3]. In less severe nonclassic forms, there is 20%-70% of enzyme activity not detected by neonatal screening tests, and diagnosis can be delayed as the symptoms are milder [2].…”

“…Adrenal myelolipomas are benign adrenal tumors that are usually incidental findings on imaging [2]. They could occasionally be the initial presentation of CAH [3]. This is a case of a female patient with undiagnosed CAH who presented with bilateral adrenal myelolipomas in her sixth decade of life.…”