[Clinical phenotypes and genotypes of congenital adrenal hyperplasia in children]

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.