先天性副腎低形成症

OBJECTIVE: Congenital endocrine salt-wasting syndromes unrelated to 21-hydroxylase deficiency are rare disorders with overlapping clinical and biochemical features at presentation. This study described the spectrum, early clinical course, and 36-month outcomes of these conditions in the era of newborn screening, and assessed whether severity at presentation was associated with later treatment requirements and growth. METHODS: Retrospective single-center cohort study including infants diagnosed between 1989 and 2023 with endocrine salt-wasting syndromes unrelated to 21-hydroxylase deficiency. Clinical presentation, biochemical findings, treatment requirements, genetic data, and longitudinal growth outcomes up to 36 months were analysed. RESULTS: Twenty patients were included: eight with aldosterone synthase deficiency, six with renal pseudohypoaldosteronism type 1, four with systemic pseudohypoaldosteronism type 1, and two with congenital adrenal hypoplasia. Systemic pseudohypoaldosteronism type 1 presented earliest and with the most severe biochemical abnormalities, requiring higher sodium supplementation at onset. Aldosterone synthase deficiency and renal pseudohypoaldosteronism type 1 presented later, with less severe, overlapping biochemical profiles. Differences in early management across etiologies were mainly limited to sodium supplementation, whereas time to electrolyte stabilization and mineralocorticoid initiation did not differ significantly. In exploratory analyses, severity at presentation was not associated with later treatment requirements or growth outcomes, whereas growth was largely preserved, with greater auxological vulnerability in systemic pseudohypoaldosteronism type 1. CONCLUSIONS: Congenital endocrine salt-wasting syndromes unrelated to 21-hydroxylase deficiency show substantial overlap at onset, whereas disease-specific features become more recognizable during follow-up. Growth outcomes were generally preserved with appropriate management and did not appear to be influenced by clinical severity at presentation.

BACKGROUND: MIRAGE syndrome is a severe congenital disease affecting multiple systems, caused by functional variants in the SAMD9 gene. It is characterized by myelodysplasia, infections, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. There are few reports of neonatal MIRAGE syndrome. This study presents a rare case of 46,XY karyotype with distinct female external genitalia phenotype and provides a comprehensive literature review of infants under 1 year of age diagnosed with MIRAGE syndrome caused by SAMD9 gene mutations. CASE PRESENTATION: This article reports a sporadic case of neonatal MIRAGE syndrome confirmed by genetic diagnosis. The patient had a 46, XY karyotype and presented predominantly with female external genitalia, along with preterm birth, respiratory distress, growth restriction, recurrent infections, skin pigmentation, feeding difficulties, thrombocytopenia, anemia, and other manifestations. CONCLUSION: In clinical practice, when encountering newborns with unexplained premature birth, growth restriction, thrombocytopenia, recurrent infections, and a karyotype of 46, XY but with female or ambiguous external genitalia, clinicians can, based on the experience from this case, differentiate from MIRAGE syndrome and may further perform genetic testing to clarify the etiology.

MIRAGE syndrome is a multisystemic disorder with a poor prognosis, caused by gain-of-function mutations in the SAMD9 gene. To date, no comprehensive reports on the systemic manifestations and management of MIRAGE syndrome in adult survivors. Here, we present the case of a 22-year-old man long-term survivor of MIRAGE syndrome with a wide range of clinical presentations and complications. From the neonatal period, he exhibited the core features of MIRAGE syndrome: myelodysplasia, recurrent infection, growth retardation, adrenal hypoplasia, atypical external genitalia, and enteropathy. Additionally, brain imaging at 5 years of age revealed new findings, including basal ganglia and white matter lesions, calcification, infarction, and ventricular enlargement. Subsequently, proteinuria was detected at 6 years of age, which gradually progressed to end-stage renal disease. At 21 years of age, he received a living-donor kidney transplant from his father, the first transplant reported for this syndrome. Genetic analysis identified a congenital SAMD9 mutation (p.Gln1286Lys) and three acquired reversion mutations. These revision mutations mitigated his hematologic complications but did not fully restore immune function. In addition to persistent immunological and endocrine dysfunction, the patient has developed progressive neurological and metabolic abnormalities over time. Multidisciplinary management, including prophylactic intravenous immunoglobulin therapy, renal replacement therapy and transplantation, and endocrine support, was provided and may have contributed to his long-term survival. This case highlights the evolving clinical spectrum of MIRAGE syndrome and underscores the importance of careful longitudinal monitoring for patients who survive beyond early childhood.

Aldosterone synthase deficiency (ASD), which is caused by a genetic defect in CYP11B2, involves a deficiency in aldosterone alone. Newborn and early childhood ASD patients can present with salt-wasting symptoms. In severe cases, this can lead to shock and be life-threatening. ASD must also be differentiated from another disease, pseudohypoaldosteronism type 1 (PHA1), which involves resistance to aldosterone. PHA1 can be classified into PHA1a, PHA1b, and secondary PHA1. PHA1a is caused by a heterozygous defect in NR3C2, which encodes the mineralocorticoid receptor. PHA1b is an autosomal recessive disorder caused by defects in the 3 epithelial sodium channel subunits α, β, and γ, encoded by SCNN1A, SCNN1B, and SCNN1G. Since ASD is a very rare disorder, the "The Intractable Adrenal Disorders Research by the Ministry of Health, Labour, and Welfare" developed the "Diagnostic criteria and severity classification for aldosterone synthase deficiency" to better understand the disorder. The criteria are as follows: Clinical symptoms: patient meets criteria 1 and 2. 1) Presents with salt-wasting symptoms (poor feeding, vomiting, dehydration, poor weight gain). 2) No skin pigmentation. Laboratory findings: patient meets criteria 1 through 3. 1) Low serum sodium and high serum potassium. 2) Low to normal plasma aldosterone and high plasma renin activity or high plasma active renin concentration. 3) No low blood cortisol level. Diagnoses of exclusion include PHA1, 21-hydroxylase deficiency, congenital lipoid adrenal hyperplasia, and congenital adrenal hypoplasia. We believe that the diagnostic criteria of ASD will enable clinicians and researchers to better understand congenital aldosterone deficiency.

OBJECTIVE: To characterize the molecular spectrum of NR0B1 variants associated with X-linked congenital adrenal hypoplasia (X-hypoAC) in a multicenter Brazilian cohort and to highlight the clinical implications of early molecular diagnosis. METHODS: The authors investigated 12 unrelated families referred to pediatric endocrinology centers across Brazil with a clinical diagnosis of early-onset adrenal insufficiency. Clinical data, biochemical profiles, and follow-up information were collected. Genetic testing of the NR0B1 gene was performed by Sanger sequencing to detect single-nucleotide and small insertion/deletion variants, complemented by MLPA to identify large deletions or rearrangements. Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: All probands presented with adrenal insufficiency within the first months or years of life, often requiring hospitalization and lifelong glucocorticoid and mineralocorticoid replacement. Molecular analysis revealed a heterogeneous spectrum of NR0B1 pathogenic variants, including frameshift, nonsense, and missense variants, as well as large and small deletions, which together accounted for nearly half of the cases. Clinical follow-up confirmed that, in addition to adrenal insufficiency, affected individuals frequently developed hypogonadotropic hypogonadism during puberty, with infertility documented in adulthood. The identification of novel variants contributes to expanding the mutational spectrum of NR0B1and reinforces the genotype-phenotype variability in X-hypoAC. CONCLUSIONS: This study represents one of the largest Brazilian series of X-hypoAC. The present findings broaden the molecular landscape of NR0B1 variants and underscore the relevance of early genetic testing to differentiate X-hypoAC from congenital adrenal hyperplasia, optimize long-term clinical management, and provide accurate genetic counseling for affected families.