副腎皮質刺激ホルモン不応症

Nonclassic P450 oxidoreductase (POR) deficiency (PORD) may remain suspected but unconfirmed in adult women with long-standing menstrual irregularity and infertility when skeletal anomalies, virilization, and overt adrenal insufficiency are absent. We report a 45-year-old Japanese woman in whom PORD had been suspected during infertility care at age 34 because of an inappropriately elevated, nonluteal progesterone value with no marked 17-hydroxyprogesterone elevation, but genetic testing was not pursued. Reevaluation for recurrent abnormal uterine bleeding and a large ovarian cyst prompted 3-point liquid chromatography-tandem mass spectrometry (LC-MS/MS) steroid profiling at baseline, after cosyntropin 250 µg, and during combined dexamethasone-hydrocortisone treatment. Adrenocorticotropic hormone (ACTH) stimulation produced disproportionate accumulation of adrenal steroid intermediates, which decreased markedly during combined glucocorticoid treatment, supporting ACTH-dependent adrenal steroid accumulation. Targeted POR sequencing and family segregation analysis supported compound heterozygosity for a maternally inherited p.Arg457His allele and an inferred paternal allele carrying p.Arg550Trp and p.Gly413Ser in cis. This case illustrates the value of resolving a long-standing diagnostic suspicion through dynamic steroid profiling, targeted POR sequencing, and segregation analysis; the combined glucocorticoid time point was supportive but not a stand-alone diagnostic test.

Hereditary adrenocortical unresponsiveness to adrenocorticotropin (HAUA) is a rare congenital disorder characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid production. HAUA encompasses familial glucocorticoid deficiency (FGD) and triple A syndrome (AAAS) and is caused by autosomal recessive defects in ACTH-signaling-related genes, including MC2R, MRAP, AAAS, NNT, TXNRD2, and MCM4. To clarify the current clinical characteristics of HAUA (including FGD and AAAS) in Japan, we conducted a nationwide questionnaire-based survey. The primary survey identified the number of affected patients, and the secondary survey collected detailed clinical information. Fifteen patients were identified from 12 institutions. Detailed clinical data were obtained from nine patients (mean age, 40.6 years). Most patients developed symptoms during childhood [3.75 (0-8) years]. Seven presented with chronic adrenal insufficiency, and two experienced life-threatening events, hypoglycemia or encephalopathy. Genetic confirmation was obtained in four cases. All patients received glucocorticoid replacement therapy (mean hydrocortisone-equivalent dose, 13.0 mg/m2/day). Notably, 50% of adult patients were obese (BMI ≥25 kg/m2), although no clear association between glucocorticoid dose and BMI was observed. Despite the limited cohort size, this study provides detailed clinical information on HAUA (including FGD and AAAS) in Japan and suggests a potential risk of obesity in long-term management.

Familial glucocorticoid deficiency type 2 (FGD2) is a rare autosomal recessive disorder caused by pathogenic variants in the MRAP gene, typically characterized by isolated cortisol deficiency with markedly elevated ACTH levels. We report a term male neonate born to consanguineous parents who presented with striking scrotal hyperpigmentation at birth, despite an otherwise normal appearance and a normal newborn screening limited to classical congenital adrenal hyperplasia (CAH). Initial biochemical evaluations, including glucose and electrolytes, were unremarkable; however, due to severe hyperpigmentation, further endocrine workup was pursued. Laboratory findings revealed profoundly low serum cortisol and markedly elevated ACTH, supporting the diagnosis of primary adrenal insufficiency. Hydrocortisone therapy was initiated promptly, and during follow-up, transient hyperkalemia and low-normal aldosterone levels necessitated short-term fludrocortisone supplementation, suggesting partial mineralocorticoid involvement. Genetic analysis identified a homozygous MRAP in-frame deletion (c.88_90del; p.K30del), classified as likely pathogenic according to ACMG 2015 criteria and as a variant of uncertain significance according to the ClinGen SVI recommendations. Despite the dramatic initial presentation, the patient remained euglycemic and demonstrated normal neurodevelopment under appropriate hormone replacement, with gradual resolution of hyperpigmentation. This case highlights striking neonatal scrotal hyperpigmentation as a potential early clinical clue suggestive of familial glucocorticoid deficiency in a patient with a homozygous MRAP variant. Importantly, even when newborn screening for CAH is normal, marked hyperpigmentation should prompt evaluation for other causes of primary adrenal insufficiency to prevent life-threatening adrenal crises.

PURPOSE: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by resistance to adrenocorticotropic hormone (ACTH), leading to isolated glucocorticoid deficiency. This study aims to identify the genetic basis of FGD in a Chinese patient and investigate the functional consequences of the detected MC2R mutations. METHODS: Whole-exome sequencing was performed to detect pathogenic variants in the MC2R gene. The effects of these mutations on MC2R mRNA and protein levels were analyzed using qPCR and immunoblotting. Additionally, a luciferase reporter assay was conducted to evaluate ACTH-induced cyclic adenosine monophosphate (cAMP) signaling. RESULTS: The patient was found to carry compound heterozygous mutations in MC2R (p.Leu151Pro and p.Glu28*), inherited from the father and mother, respectively. Functional studies revealed that these mutations led to reduced MC2R mRNA and protein expression. Furthermore, the luciferase assay demonstrated that these variants attenuated ACTH-induced cAMP signaling. CONCLUSION: Novel pathogenic mutations in the MC2R gene were identified, and their functional impact was characterized. These findings provide insights into the molecular mechanisms underlying FGD and contribute to the expanding genetic spectrum of the disease.