Clinical and genetic characteristics of hypophosphatasia in Chinese children

Abstract

Background Hypophosphatasia (HPP) is a rare inherited disorder, which is caused by loss-of-function mutations in the ALPL gene. HPP is a heterogeneous disease that has a wide spectrum of phenotypes. Few studies were carried out in the Chinese population with HPP, especially in children. Methods The clinical and genetic characteristics of 10 Chinese children with HPP who were referred to the Beijing Children’s Hospital were described. Previously reported HPP cases of children in China were also reviewed. Results A total of 33 cases were identified, which included 2 perinatal lethal HPP, 10 infantile HPP, 10 childhood HPP, and 11 odonto HPP. The male-to-female ratio was 24:9. The average age at onset was 0.69 years (ranged from 2 h after birth to 14 years), while the average age at clinical diagnosis was 3.87 years (ranged from 2 h after birth to 19 years). Serum alkaline phosphatase (ALP) levels were significantly decreased in patients with perinatal lethal/infantile HPP when compared with those with the mild forms of HPP childhood/odonto HPP (P < 0.01). Although serum phosphate levels were not different (P > 0.05), serum calcium levels were elevated, and serum intact parathyroid hormone levels were decreased in patients with perinatal lethal/infantile HPP in comparison with those with the childhood/odonto HPP (P all < 0.01). Genetic analyses identified 40 mutations in 31 HPP cases, including 28 missense mutations, 9 frameshift mutations, 2 splice junction alterations, and 1 regulatory mutation. Of which, 5 novel mutations were identified in our present study: 2 frameshift mutations (p.Arg138GlyfsTer27, p.Leu511Profs*272); 2 missense mutations (p.Ala176Val, p.Phe268Leu), and 1 splice junction alteration (c.297+5G>A). Compound heterozygous mutations accounted for 80.6% of all variants. No mutational “hot-spot” was found. Most mutations of ALPL were located in exons 5, 7, 10, and 3. Notably, subjects that carrying single heterozygous mutations showed milder phenotypes of HPP, while subjects with nonsense mutations were associated with a severer phenotype. Conclusions HPP is a rare disease with often delayed diagnosis, and the incidence of HPP in China may be seriously underestimated. The present study expands the phenotypic and genotypic spectrum and the understanding of HPP in Chinese children. These findings will be useful for clinical assessment and shorten the diagnosis time for pediatric HPP in China.

Clinical and Genetic Characteristics of Hypophosphatasia in Chinese Adults

“…In the current study, c.407G>A (p.Arg136His) and c.984_ 986delCTT (p.Phe328del) were found in three and two unrelated patients, respectively, indicating the high prevalence of HPP in Chinese adults. c.407G>A (p.Arg136His) was also reported in other Chinese HPP cohorts [ 27 , 28 , 29 ].…”

“…Zhang, et al [ 28 ] reported the clinical and genetic results of pediatric-onset HPP patients from five unrelated families and investigated the pathogenicity of mutations with in-depth bioinformatic analysis. Liu, et al [ 29 ] reported the clinical, laboratory, and genetic findings of 33 pediatric-onset HPP patients and explored the differences between perinatal, infantile, childhood, and odonto subtypes. However, the characteristics and current situation of adult HPP in the Chinese population remain to be elucidated.…”

Clinical and Genetic Characteristics of Pediatric Patients with Hypophosphatasia in the Russian Population

“…For example, the frequency of the c.787T > C/p.Tyr263His variant in the Japanese population is 0.31–0.55, and in the gnomAD database, 0.1833 [ 28 , 29 ] of the p.Asp378Val and p.Leu520ArgfsX86 variants are most common in the USA [ 6 ] and Japan [ 30 ], respectively. The majority of the mutations in the ALPL gene were localized in the 5th, 7th, 10th, and 3rd exons [ 18 ].…”

“…By February 2022, more than 500 pathogenic variants of the ALPL gene were registered in the Global Variome Shared International Database [ 17 ]. Among all ALPL genetic variants, missense mutations account for 71.2%, deletions 11.0%, splice mutations 4.9%, nonsense mutations 4.6%, insertions 3.4%, large deletions/duplications 2.9%, insertions/deletions 1.5%, and regulatory mutations 0.2% [ 18 ].…”

Resolution of the Advisory Council on the criteria for the appointment of pathogenetic therapy of hypophosphatasia in children

“…Ген ALPL картирован на коротком плече 1-й хромосомы -1p36.12 -и состоит из 12 экзонов. В настоящее время описано более 410 различных мутаций в гене ALPL [1].…”