先天性副腎低形成症

BACKGROUND: Cytochrome P450 oxidoreductase deficiency (PORD) is an ultra-rare autosomal recessive disorder within the congenital adrenal hyperplasia (CAH) spectrum, characterized by a broad clinical spectrum involving steroidogenesis defects, genital anomalies, and skeletal abnormalities. CASE PRESENTATION: We report a phenotypically female neonate with a 46,XY karyotype whose postnatal diagnostic evaluation was initiated after newborn screening revealed elevated 17-hydroxyprogesterone (17-OHP) concentration. The patient presented with mild hypertelorism, mild nasal hypoplasia, and low-set bilateral ears, along with female external genitalia consistent with disorder of sex development (DSD) and anal atresia. Radiological evaluation revealed femoral bowing and subsequent fracture. The craniofacial and skeletal abnormalities were consistent with the features of Antley-Bixler syndrome (ABS). Endocrine evaluation revealed elevated progesterone, markedly reduced testosterone, and secondary hyperaldosteronism. Genetic analysis identified three novel variants in the POR gene (NM_001395413.1): the patient harbored a paternal c.1187_1195dup (p.Pro396_Glu398dup) variant and two maternally inherited variants in cis, c.1447G>A (p.Gly483Ser) and c.1806 + 4_1806 + 28del. Protein structural modeling predicted that the p.Pro396_Glu398dup and p.Gly483Ser may disrupt the flavin adenine dinucleotide (FAD)-binding domain. RNA sequencing (RNA-seq) confirmed that the intronic variant c.1806 + 4_1806 + 28del caused aberrant splicing, resulting in partial intron retention and predicted impairment of the nicotinamide adenine dinucleotide phosphate (NADPH)-binding domain. According to American College of Medical Genetics and Genomics (ACMG) guidelines and incorporating functional evidence, c.1187_1195dup and c.1806 + 4_1806 + 28del were reclassified as likely pathogenic (LP), whereas c.1447G>A remained a variant of uncertain significance (VUS). CONCLUSIONS: This study describes a neonate with PORD caused by three novel POR variants and expands the known clinical spectrum of PORD by identifying rare manifestations including anal atresia and hearing loss. RNA-seq provided valuable functional evidence for variant interpretation and facilitated accurate molecular diagnosis. These findings highlight the importance of integrating genetic phasing, transcript-level functional analysis, and comprehensive clinical evaluation for precise diagnosis and counseling in rare endocrine disorders.

OBJECTIVE: To investigate the molecular etiology in a male child clinically suspected of congenital adrenal hyperplasia (CAH) with negative conventional genetic testing, and to elucidate the genetic characteristics of his pedigree. METHODS: Clinical data from the proband and his family members were collected. Molecular diagnostics proceeded sequentially: initial targeted CAH testing (CYP21A2 and POR sequencing/MLPA, plus targeted NR0B1 CNV analysis) was followed by whole-exome sequencing coupled with genome-wide CNV analysis. RESULTS: The proband presented with neonatal cyanosis and hyperpigmentation. Laboratory tests showed markedly elevated ACTH (354.68 pmol/L) and low aldosterone (57.24 pg/mL). Molecular genetic testing identified a hemizygous deletion of approximately 4.44 Mb at Xp21.3-p21.1 (chrX:g.27080000_31520000), encompassing the NR0B1, GK, IL1RAPL1, and DMD genes. CNV-seq confirmed that the mother carried a heterozygous deletion of 4.38 Mb in the same region, while the father and four maternal aunts showed normal genotypes. CONCLUSION: This study ultimately diagnosed the proband with Xp21 contiguous gene deletion syndrome. The adrenal insufficiency resulted from X-linked congenital adrenal hypoplasia (AHC) due to NR0B1 haploinsufficiency, rather than CAH. These findings highlight the considerable clinical overlap between AHC and CAH, indicating that CNV analysis of the Xp21 region should be included in the diagnostic workup for male infants with suspected CAH but negative routine genetic testing. This provides a basis for the precise diagnosis and genetic counseling of such patients.

BACKGROUND: Lipoid congenital adrenal hyperplasia (LCAH) is an uncommon but life-threatening autosomal recessive disorder. It is caused by a mutation in the steroidogenic acute regulatory protein (StAR), encoded by the STAR gene. METHODS: Clinical manifestations of two siblings with primary adrenal insufficiency (PAI) were described. A female infant was admitted to the hospital at six months of age for vomiting and failure to thrive. The diagnosis of PAI of unknown etiology was established. The girl's younger brother was diagnosed with PAI at the age of 1.5 years during a febrile illness. His external genitalia showed undescended testes, scrotal hypoplasia, and hypospadia. Their family history was normal, and both parents were healthy. Clinical exome sequencing was used to identify mutations in candidate genes. RESULTS: Two heterozygous STAR mutations, p.Trp250Ter and p.Arg188Cys, were identified in both children. The mother was heterozygous for the p.Trp250Ter mutation, and the father was heterozygous for the p.Arg188Cys mutation. CONCLUSION: Glucocorticoid, mineralocorticoid, and sex hormone therapy should be individualized according to the clinical presentation and laboratory findings. Because genotype and phenotype do not correlate consistently in LCAH, therapy and follow-up must be individualized.

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.