先天性副腎皮質酵素欠損症

Children living with congenital adrenal hyperplasia (CAH) are at increased risk of psychosocial adjustment difficulties. Parental acceptance-rejection has been consistently associated with children's psychosocial adjustment across cultures. Understanding factors associated with parental acceptance-rejection in CAH families might help genetic counselors recognize those needing additional psychosocial assessment and support, potentially improving psychosocial adjustment in affected children. To our knowledge, no study has yet examined factors associated with parental acceptance-rejection in this population. This exploratory cross-sectional study aimed to address this gap by examining the associations between parental, child, and contextual stress-related factors and parental acceptance-rejection among families of children with CAH. Data were collected from 60 parents of 45 children with classical CAH using a questionnaire assessing variables of interest, the validated Bahasa Indonesia version of the Parental Acceptance-Rejection Questionnaire (PARQ), and the Parental Burnout Assessment (PBA). Univariable linear mixed-effects models (LMM) were employed to examine these associations while accounting for the non-independence of parental responses clustered within children. Higher levels of parental burnout were associated with greater overall rejection, hostility, and indifference. Fathers reported higher levels of overall rejection and greater coldness/lack of affection toward their children compared to mothers. Compared with university-educated parents, those with senior high school education reported higher overall rejection, emotional coldness, and indifferent behavior toward their child, while those with junior high school education reported higher hostility. Later CAH diagnosis onset was associated with higher parental undifferentiated rejection. Future studies are needed before these findings can inform genetic counseling practice for families of children with CAH.

Objective: To summarize the clinical characteristics of congenital adrenal hyperplasia (CAH) in children, and explore the genetic variant spectrum and genotype-phenotype correlations of 21-hydroxylase deficiency (21-OHD). Methods: In this retrospective cohort study. clinical data were collected from 131 genetically confirmed CAH children registered in the data platform of Chinese Multicenter Collaborative Alliance of Congenital Adrenal Hyperplasia between December 2019 and June 2024. Among them, 119 patients with 21-OHD were classified into salt-wasting (SW) and simple-virilizing (SV) groups based on phenotypes. The clinical features of CAH and clinical differences across 21-OHD phenotypes were analyzed. Patients of 21-OHD with definitive genotypes were categorized into I2G homozygote, I2G/I173N, I173N homozygote and I2G/R357W groups according to genotypes to investigate variant spectrum and genotype-phenotype association. Intergroup comparisons were performed using independent-samples t-test or Mann-Whitney U test for two groups, and one-way analysis of variarce or Kruskal-Wallis H test for multiple groups. Results: Of the 131 CAH children, 68 were males and 63 females, with the age at onset and diagnosis of 0.08 (0, 0.89) years and 0.26 (0.11, 3.87) years, respectively. Twenty-two cases (16.8%) were identified through newborn screening, 17 of whom were asymptomatic. Overall, 119 cases (90.8%) were 21-OHD, including 84 SW cases and 35 SV cases. In the SW group, 35 (41.7%) presented with digestive symptoms and growth retardation. In the SV group, the predominant manifestations were penile enlargement in males (9 cases) and external genital virilization in females (14 cases). The SV group had significantly older ages at onset and diagnosis than the SW group (both P<0.05). Compared with the SW group, the SV group showed a greater bone age-chronological age difference (BA-CA) (P<0.05) and a lower height standard deviation score for bone age (P<0.05). Among the 81 patients with 21-OHD, a total of 173 variants were identified, including micro-conversions, large deletions or conversions, and other variants. The most common variants were I2G (62/173, 35.8%), p.I173N (34/173, 19.7%), and p.R357W (12/173, 6.9%). Four novel variants were detected; c.306dup and c.1452delG were classified as likely pathogenic, whereas c.331_339del and c.1328T>G were variants of uncertain significance. Among 47 patients carrying I2G variants, 37 exhibited the SW phenotype; among 25 patients with p.I173N variants, 17 presented with the SV phenotype. The I2G homozygote, I2G/I173N, I173N homozygote, and I2G/R357W groups consisted of 14, 10, 9, and 4 cases, respectively. All patients in the I2G homozygote group manifested the SW phenotype. Compared with the I2G homozygote group, the I2G/I173N group had a higher BA-CA value (P<0.05). Additionally, the I2G/R357W group exhibited significantly lower pH, base excess, and serum bicarbonate levels than the I2G homozygote group (all P<0.05). Conclusions: Children with the SW phenotype of 21-OHD commonly present with non-specific gastrointestinal symptoms and growth retardation at initial consultation, leading to earlier diagnosis, whereas those with the SV phenotype primarily present with genital ambiguity, accompanied by marked diagnostic delay and advanced bone age. The I2G and p.I173N variants are predominantly associated with the SW and SV phenotype, respectively. Compared with I2G homozygote, the I2G/I173N compound heterozygote genotype correlates with more advanced bone age, while the I2G/R357W compound heterozygote genotype is associated with more severe metabolic acidosis.

Objective: Polycystic ovary syndrome (PCOS) and nonclassic congenital adrenal hyperplasia (NCAH) overlap clinically, but direct comparative data specifically addressing non-National Institutes of Health (non-NIH) Rotterdam phenotypes of polycystic ovary syndrome are limited. We compared women with polycystic ovary syndrome, of whom 66.7% were classified as having non-NIH Rotterdam phenotypes, with women with nonclassic congenital adrenal hyperplasia and healthy controls to characterize the extent of phenotypic overlap and evaluate the discriminatory performance of individual androgen measures. Methods: This single-center, prospective, exploratory cross-sectional study evaluated 58 women divided into three groups: PCOS (n = 24, Rotterdam criteria), NCAH due to 21-hydroxylase deficiency (n = 16, previously confirmed by adrenocorticotropic hormone (ACTH)-stimulated 17-hydroxyprogesterone (17-OHP)), and healthy controls (n = 18). Demographic, clinical, metabolic, and hormonal parameters were compared using analysis of variance (ANOVA), Kruskal-Wallis with Dunn's post hoc test (Bonferroni-adjusted), and chi-square or Fisher's exact tests. A sensitivity analysis was performed after excluding 12 participants receiving oral contraceptives (n = 8) or glucocorticoids (n = 4). Results: Within the PCOS group, 66.7% had non-NIH Rotterdam phenotypes. Hirsutism, defined as a modified Ferriman-Gallwey (mFG) score ≥ 8, was more frequent in both patient groups than in controls (p = 0.003) but did not differ between PCOS and NCAH. Total testosterone levels were 0.40 [0.20-0.60], 0.59 [0.45-0.94], and 0.20 [0.15-0.20] ng/mL in the PCOS, NCAH, and control groups, respectively, and androstenedione levels were 1.40 [1.20-2.20], 2.55 [1.64-4.07], and 0.87 [0.56-1.00] ng/mL, respectively; both were higher in the patient groups than in controls (both p < 0.001), without differing between PCOS and NCAH. Basal 17-OHP was the only parameter distinguishing NCAH from both PCOS and controls (p < 0.001). Dehydroepiandrosterone sulfate (DHEAS) levels were 356.5 [217-422], 292 [156-448], and 219 [146-240] µg/dL, respectively (p = 0.020), with a significant difference only between PCOS and controls. Anti-Müllerian hormone (AMH) levels were 3.27 [3.02-4.13], 3.13 [2.87-3.54], and 3.34 [2.93-5.37] ng/mL, respectively, with no between-group difference (p = 0.600). Other metabolic parameters, gonadotropins, estradiol, and prolactin showed no between-group differences. The principal hormonal findings remained unchanged after excluding women receiving oral contraceptives or glucocorticoids. Conclusions: In this PCOS cohort, in which 66.7% of women were classified as having non-NIH Rotterdam phenotypes, PCOS and NCAH showed substantial clinical, metabolic, and hormonal overlap, whereas basal early-follicular 17-OHP was the only parameter that consistently distinguished NCAH from both PCOS and healthy controls. These findings support the inclusion of basal 17-OHP in the evaluation of women presenting with hyperandrogenism.

A retrospective analysis was conducted on the clinical data of two patients with genetically confirmed 11β-hydroxylase deficiency (11β-OHD) who were admitted to the Department of Endocrinology at the First Medical Center of Chinese PLA General Hospital between January 2023 and June 2025, and who had undergone adrenalectomy for adrenal masses prior to a definitive diagnosis. The two patients included one female (Patient 1, 37 years old) and one male (Patient 2, 22 years old); both presented with adrenal masses as a major manifestation accompanied by hypertension. Patient 1 had a history of childhood-onset clitoromegaly, primary amenorrhea, and bilateral adrenal adenomatoid hyperplasia, and underwent right adrenalectomy before the diagnosis was confirmed, with no improvement in hypertension postoperatively. Patient 2 presented with precocious puberty, hypertension, and hypokalemia, and underwent resection of a left adrenal mass, after which hypertension remained poorly controlled. Endocrine hormonal evaluation in both patients was suggestive of 11β-OHD. Genetic testing confirmed that Patient 1 carried compound heterozygous mutations in the CYP11B1 gene, namely c.1361G>A (p.Arg454His) and c.1120C>T (p.Arg374Trp), while Patient 2 carried a homozygous mutation, c.1360C>T (p.Arg454Cys). Following glucocorticoid therapy, blood pressure was well controlled in both patients; the residual left adrenal mass in Patient 1 showed no significant progression, and in Patient 2, hypokalemia was corrected and final adult height reached the genetic target height. For patients with adrenal masses accompanied by hypertension, hypokalemia, low renin and low aldosterone levels, precocious puberty, or female virilization, comprehensive endocrine hormonal evaluation and genetic testing should be performed to establish a definitive diagnosis before any treatment decisions are made, in order to avoid unnecessary adrenal surgery.

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.