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. Met...
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BMC
2021-04-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-021-01798-1 |
| _version_ | 1828889848689197056 |
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| author | Meijuan Liu Min Liu Xuejun Liang Di Wu Wenjing Li Chang Su Bingyan Cao Jiajia Chen Chunxiu Gong |
| author_facet | Meijuan Liu Min Liu Xuejun Liang Di Wu Wenjing Li Chang Su Bingyan Cao Jiajia Chen Chunxiu Gong |
| author_sort | Meijuan Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T12:48:29Z |
| format | Article |
| id | doaj.art-0b5befee4ec74b768d0302019aa7e524 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-13T12:48:29Z |
| publishDate | 2021-04-01 |
| publisher | BMC |
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| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-0b5befee4ec74b768d0302019aa7e5242022-12-21T23:45:25ZengBMCOrphanet Journal of Rare Diseases1750-11722021-04-0116111310.1186/s13023-021-01798-1Clinical and genetic characteristics of hypophosphatasia in Chinese childrenMeijuan Liu0Min Liu1Xuejun Liang2Di Wu3Wenjing Li4Chang Su5Bingyan Cao6Jiajia Chen7Chunxiu Gong8Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthDepartment of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthAbstract 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.https://doi.org/10.1186/s13023-021-01798-1HypophosphatasiaALPLMutationsChinaChildren |
| spellingShingle | Meijuan Liu Min Liu Xuejun Liang Di Wu Wenjing Li Chang Su Bingyan Cao Jiajia Chen Chunxiu Gong Clinical and genetic characteristics of hypophosphatasia in Chinese children Orphanet Journal of Rare Diseases Hypophosphatasia ALPL Mutations China Children |
| title | Clinical and genetic characteristics of hypophosphatasia in Chinese children |
| title_full | Clinical and genetic characteristics of hypophosphatasia in Chinese children |
| title_fullStr | Clinical and genetic characteristics of hypophosphatasia in Chinese children |
| title_full_unstemmed | Clinical and genetic characteristics of hypophosphatasia in Chinese children |
| title_short | Clinical and genetic characteristics of hypophosphatasia in Chinese children |
| title_sort | clinical and genetic characteristics of hypophosphatasia in chinese children |
| topic | Hypophosphatasia ALPL Mutations China Children |
| url | https://doi.org/10.1186/s13023-021-01798-1 |
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