副腎皮質刺激ホルモン不応症

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.

Primary adrenal insufficiency (PAI) is a severe and potentially life-threatening condition characterised by the inability of the adrenal cortex to produce enough glucocorticoids and/or mineralocorticoids. The clinical signs of PAI are primarily due to deficient steroid hormone synthesis and include weight loss, orthostatic hypotension secondary to dehydration, hyponatremia, hyperkalaemia, and hypoglycaemia. In the paediatric population, PAI is most commonly associated with inherited monogenic disorders, particularly enzyme deficiencies. X-linked adrenal hypoplasia congenita (AHC) is a rare condition caused by deletions or single-nucleotide variants in the NR0B1 (DAX1) gene, which encodes the DAX1 protein expressed in the adrenal cortex, gonads, hypothalamus and pituitary gland. Although molecular genetics has significantly expanded our understanding of the aetiology of PAI, clinical diagnosis remains challenging when the initial hormonal findings are atypical, often delaying recognition and treatment. Pathogenic variants of DAX1 can lead to a spectrum of phenotypes, ranging from isolated adrenal insufficiency (AI) to complex syndromic presentations combining AI with hypogonadotropic hypogonadism and impaired spermatogenesis. Here, we report a case of a male patient with AI due to a de novo pathogenic variant in the NR0B1 gene. Furthermore, we provide a non-systematic review of the available literature on the diagnostic challenges facing and clinical variability in AHC, with a particular focus on the paediatric population. This case highlights the importance of a stepwise, comprehensive diagnostic approach to suspected PAI, particularly when initial biochemical and genetic testing is inconclusive. Considering rare causes-such as NR0B1 pathogenic variants in men-can be crucial for establishing a definitive diagnosis, with significant implications for the management of patients and their families.

We report a 33-year-old woman with systemic lupus erythematosus who developed fulminant multiorgan ischemic manifestations and hematologic abnormalities. She presented with persistent fever, newly developed painful fingertip cyanosis, and acute kidney injury. Laboratory tests showed severe thrombocytopenia, hemolytic anaemia with fragmented red blood cells, positive direct and indirect Coombs tests, hypocomplementemia, and positivity for multiple autoantibodies, including a triple-positive antiphospholipid antibody profile. Within the first week of hospitalisation, in addition to digital ischemia, she developed multiple cerebral infarctions and acalculous cholecystitis, findings consistent with catastrophic antiphospholipid syndrome. Unexpectedly, the activity of a disintegrin and metalloproteinase with thrombospondin type 1 motifs member 13 (ADAMTS13) was severely reduced to 5%, whereas ADAMTS13 inhibitor was not detected by the Bethesda assay. There was no past medical or family history suggestive of congenital thrombotic thrombocytopenic purpura. After treatment with high-dose glucocorticoids and nine sessions of plasma exchange, abdominal pain resolved and digital ischemia improved, accompanied by improvement in hematologic and renal abnormalities and disappearance of fragmented red blood cells. Subsequently, ADAMTS13 activity normalised to 63% and remained stable after completion of plasma exchange. Later, non-inhibitory anti-ADAMTS13 autoantibodies were detected by enzyme-linked immunosorbent assay in a stored serum sample obtained on admission. ADAMTS13 deficiency due to non-inhibitory anti-ADAMTS13 autoantibodies may modify the complications of systemic lupus erythematosus and antiphospholipid syndrome by promoting thrombotic microangiopathy.

BACKGROUND: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency and elevated adrenocorticotropic hormone (ACTH) levels. Variants in TXNRD2, which encodes mitochondrial thioredoxin reductase 2, have recently been implicated in FGD; however, the phenotypic and mutational spectrum remain extremely limited. METHODS: Whole-genome sequencing (WGS) was performed in a proband from a Saudi family who presented in early childhood with clinical and biochemical features consistent with FGD (Low basal and stimulated cortisol of < 5 nmol/l and extremely elevated ACTH levels of > 2500 pg/ml) and seizure disorder requiring medical treatment and with basal ganglia changes noted on brain MRI at presentation. WGS identified a novel likely pathogenic TXNRD2 variant with no other potential variant in FGD-associated genes. Population frequency, segregation analysis, evolutionary conservation, and in silico pathogenicity predictions were assessed for the identified variant. RESULTS: WGS identified a novel missense homozygous TXNRD2 (NM_001282512) variant (c.575C>T (p.Pro192Leu) in the proband, and in the heterozygous state in both parents, supporting autosomal recessive inheritance. This variant has not been reported in a local population database of > 18000 exomes, is extremely rare in international population databases (minor allele frequency 0.00000479), and affects a highly conserved residue. The variant was consistently predicted by multiple in silico tools to have deleterious effects on protein structure and function. No pathogenic, likely pathogenic, or VUS was found in other genes involved in FGD, including MC2R, MRAP, STAR, CYP11A1, NNT, MCM4, or SGPL1. CONCLUSION: This report adds another patient with a novel variant to the few previously described patients and expands the genetic spectrum of the very rare TXNRD2-associated FGD, supporting the role of mitochondrial redox dysregulation in adrenal insufficiency.

A premenopausal woman was reviewed for painful vertebral fractures in the context of prednisolone exposure for her newly diagnosed systemic lupus erythematosus. Known clinical risk factors for bone loss included exposure to depot medroxyprogesterone acetate for 12 yr, cigarette smoking, a family history of osteoporosis and ongoing inflammatory arthritis. Initial investigations also identified vitamin D deficiency and low bone mass for age and sex. She was treated with vitamin D and her contraception was changed to a levonorgestrel intrauterine device. In the context of further vertebral fractures confirmed with both MRI and bone scan and having had additional secondary causes of low bone mass excluded, she commenced targeted osteoporosis treatment. We discuss the complexities of managing bone fragility in young adults and the impact of depot medroxyprogesterone acetate, inflammatory disease (systemic lupus erythematosus) and glucocorticoid-induced osteoporosis on younger adults. In this woman, antiresorptive therapy with zoledronic acid was recommended; we also explore the existing evidence-base for antiresorptive and anabolic therapies in younger adults, with a particular focus on glucocorticoid-induced osteoporosis.