AUTHOR=Lin Yunting , Guan Zhihong , Mei Huifen , Zhang Wen , Zhou Zhizi , Su Ling , Cheng Jing , Zheng Ruidan , Liang Cuili , Cai Yanna , Yin Xi , Wu Dongyan , Liu Li , Zeng Chunhua 

TITLE=Clinical characteristics and long-term outcomes of 12 children with vitamin D-dependent rickets type 1A: A retrospective study

JOURNAL=Frontiers in Pediatrics

VOLUME=Volume 10 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2022.1007219

DOI=10.3389/fped.2022.1007219

ISSN=2296-2360

ABSTRACT=Purpose: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessive disorder caused by deficiency of CYP27B1 gene. This study aims to investigate the phenotypic and genotypic features of VDDR1A children in southern China, and evaluate the long-term therapeutic effects.
Methods: Twelve children from southern China with VDDR1A were enrolled in this study. Their clinical, radiological, biochemical and molecular findings were analyzed retrospectively. The Rickets Severity Score (RSS), biochemical parameters and height standard deviation score (HtSDS) were used to evaluate clinical outcomes.
Results: Six males and 6 females were included in this VDDR1A cohort. The age of onset was from 6 months to 1.8 years, and the age at diagnosis was 2.1 ± 0.8 years. The most common clinical symptoms at diagnosis were delayed walking (10/12) and severe growth retardation (9/12). HtSDS at diagnosis was negatively associated with the age (p < 0.05). All patients presented with hypocalcaemia, hypophosphatemia, increased serum alkaline phosphatase and parathyroid hormone, and high RSS at diagnosis. Two allelic variants in the CYP27B1 gene were identified in all patients, including nine different variants, four known and five novel, with c.1319_1325dupCCCACCC(p.Phe443Profs*24) the most frequent. All patients were treated with calcitriol and calcium after diagnosis, and all patients but one were followed up from 6 months to 15.6 years. HtSDS, RSS and biochemical parameters were improved during the first few years of the treatment. However, only 5 patients had good compliance. Although RSS and biochemical parameters were significantly improved, the HtSDS change was not significant from the time at diagnosis to the last visit, and seven patients remained short stature (HtSDS < -2). 
Conclusion: Our study extends the mutational spectrum of VDDR1A and finds a hotspot variant of CYP27B1 gene in southern China. The results reconfirm the importance of early diagnosis and treatment compliance, and reveal the challenge of height improvement in VDDR1A patients.