Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) requires lifelong glucocorticoid (GC) and mineralocorticoid therapy to prevent adrenal crises and control androgen excess. However, chronic GC overtreatment may result in sustained suppression of adrenal androgens - an underrecognized complication with significant implications for women. Androgens contribute to muscle function, mood regulation, and sexual health, yet symptoms of deficiency are easily misattributed. We report a 32-year-old woman with classical salt-wasting CAH who presented with severe muscle pain, weakness, reduced libido, and depressive symptoms. Laboratory results revealed complete suppression of adrenocorticotrophin hormone, dehydroepiandrosterone sulfate, and testosterone, with normal creatine kinase, electrolytes, metabolic and rheumatologic parameters. Extensive neuromuscular evaluation was unremarkable. Childhood medical records confirmed persistent suppression of adrenal androgens from infancy, indicating long-standing GC overtreatment as the most likely cause. Because GC dose reduction was poorly tolerated and no alternative explanation for her symptoms was identified, low-dose intramuscular testosterone (50 mg every 4-8 weeks) was introduced as compassionate therapy and subsequently stabilized at 25 mg every 4 weeks. Within three months, the patient reported substantial improvement in muscle pain, strength, libido, and mood. Over ten years of follow-up, testosterone therapy remained well tolerated, with no side effects such as virilization, erythrocytosis, hepatotoxicity, dyslipidemia, or menstrual disturbances. Bone density and trabecular microarchitecture remained stable. This case demonstrates that chronic GC overtreatment may lead to profound androgen deficiency in women with CAH, which can manifest as debilitating musculoskeletal and neurobehavioral symptoms. The patient's sustained clinical improvement underscores the physiological importance of androgens in female health and supports consideration of individualized, low-dose testosterone replacement in carefully selected cases. Recognition and targeted treatment of androgen deficiency should form part of long-term CAH management. To our knowledge, this is the first report describing the resolution of chronic myalgia after testosterone therapy in a woman with CAH and complete adrenal androgen suppression.

Early identification of classic 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia (21OH-CAH) through newborn screening (NBS) is vital to prevent morbidity from salt-wasting crises. The aim of the study is to assess the efficacy of 21OH-CAH NBS from 2006 to 2019 in the five Regions of Italy where 21OH-CAH NBS is performed. Methods included dried blood spot (DBS) tests for 17OH-progesterone (17OHP) within the first 48-72 h, with variable protocols. Dried blood spots have been screened with a time-resolved fluoroimmunoassay for 17OHP determination (DELFIA) as first tier test in all the Italian Regions. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was implemented in the Veneto region starting October 2017 as second-tier test. Among 2,933,074 screened newborns, 161 (86 males, 75 females) had classic 21OH-CAH, with a cumulative incidence of 1 in 17,699. Salt-wasting CAH was the most prevalent form (71.9%). Mean age at blood sampling for true positives was 9 ± 18 days, with 28% suspected before NBS results. In Regions with a second-tier test, the recall rate (RR) was 0.17, and positive predictive value (PPV) was 4.3. No patients had adrenal crisis and 23% of cases were symptomatic before the NBS results were reported. The study confirms the efficacy of NBS in early detection of classic 21OH-CAH, emphasizing the need for timely reporting and second-tier testing to improve outcomes.

Although there a well-known correlation in genotype and phenotype, patients with 21-OHD caused by severe pathogenic variants have better correlation, whereas inconsistencies are more common in the presence of milder variants. This study aimed to evaluate CYP21A2 genotyping and reveal the genotype-phenotype correlation in children diagnosed with 21-OHD in the South-eastern Anatolia region, where ethnic diversity and consanguineous marriage rates are high. The patients were divided into three groups: salt wasting (SW), simple virilizing (SV) and non-classical (NC). Pathogenic variants of the CYP21A2 gene were classified into six groups based on predicted 21-hydroxylase activity: null-A-B-C-D-E. CYP21A2 genotyping was performed by sequence-specific primer and sequenced with next generation sequencing (NGS), and the expected phenotypes were compared to the observed phenotypes. The overall genotype-phenotype concordance was found to be 73.1% (68/93). The expected concordance with the SW form of the null (n = 12) and A (n = 51) groups is 91.6% and 88.2%, respectively. While the percentage of the expected clinical form of SV in patients in group B (n = 5) was 80%, the concordance for the expected clinical form of NC for group C (n = 25) was not strong enough (32%). This study demonstrates that children with 21-hydroxylase deficiency show a good correlation between severe pathogenic variants and predicted clinical phenotypes; however, the correlation is not strong enough between milder variants. The discrepancies could have resulted from the complex characteristics of 21-OHD genotyping and the limitations of using NGS alone without integrating with other comprehensive methods.

Data on congenital adrenal hyperplasia (CAH) disorders in the Saudi population are limited. This retrospective study assessed the clinical characteristics ofadolescents and adults with 21-hydroxylase CAH alongside the long-term outcomes of chronic glucocorticoid replacement therapy. The study was conducted at the King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. The subjects included patients (aged ≥ 14 years) with 21-hydroxylase CAH, who attended the endocrine clinic between 2019 and 2021. The study found that among the 108 patients with 21-hydroxylase deficiency considered, predominantly females (66.67%), with a median age of 21 years (IQR: 18-30), 93.51% had the classic salt-wasting form, while 6.49% had the nonsalt-wasting form. Glucocorticoid therapy for the patients included prednisone (46.3%), hydrocortisone (37.97%), and dexamethasone (12.03%). Short stature was observed in 30% of the patients, while obesity affected 35.19%. Among the females, 58.33% had oligomenorrhea. In addition, testicular adrenal rest tumors (TARTs) were detected in 44.44% of the males. Metabolic issues included high cholesterol in 95.65%, with 17.33% exhibiting prediabetics. Genetic testing identified CYP21A2 mutations in all patients tested. short stature, obesity, and menstrual irregularities are highly prevalent in females, whereas TARTs are common in males. Although metabolic and bone health outcomes are generally favorable, the variability in hormonal control and its associated complications underscores the need for individualized glucocorticoid therapy. Continuous monitoring and improved treatment strategies are essential for optimizing the quality of life of patients with CAH.

Background: Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive disorders characterized by impaired cortisol synthesis in the adrenal glands. Over 90% of CAH cases result from a deficiency of the enzyme 21-hydroxylase (21OHD). The clinical spectrum of 21OHD ranges from the severe, life-threatening salt-wasting classic form, often presenting with prenatal virilization in females, to the non-classic (milder) form, which lacks glucocorticoid deficiency. Females with the non-classic form may experience symptoms of hyperandrogenism or infertility later in life, while males with non-classic CAH are often undiagnosed due to the subtler presentation. The coexistence of genetic anomalies and CAH is rarely reported in the literature, particularly in cases involving Triple X syndrome-a condition typically associated with a mild and frequently underdiagnosed clinical course. Case presentation: Here, we present a unique case of a 38-year-old woman with a history of premature ovarian failure and subsequent clinical features of hyperandrogenism. Further investigation revealed a novel association between partial 21OHD and a Triple X karyotype-an association not previously documented in the literature. Conclusions: This case highlights the potential for coexisting rare genetic conditions and underscores the critical importance of thorough and meticulous clinical evaluation.