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      A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets

      case-report

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          Abstract

          X-linked hypophosphatemic rickets is caused by loss-of-function mutations in PHEX, which encodes a phosphate-regulating endopeptidase homolog. We report a 26-year-old man with X-linked hypophosphatemic rickets who showed decreased serum phosphate accompanied by bilateral genu valgum and short stature. He had received medical treatment with vitamin D (alfacalcidol) and phosphate from the age of 3 to 20 years. He underwent surgery due to valgus deformity at the age of 14 and 15. Targeted gene panel sequencing for Mendelian genes identified a nonsense mutation in PHEX (c.589C>T; p.Gln197Ter) and a mosaic pattern where only 38% of sequence reads showed the variant allele. This mutation was not found in his mother, who had a normal phenotype. This is a case of a sporadic nonsense mutation in PHEX and up to date, this is the first case of a mosaic mutation in PHEX in Korea.

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          Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism.

          Jian Q. Feng, Leanne M. Ward, Shiguang Liu … (2006)
          The osteocyte, a terminally differentiated cell comprising 90%-95% of all bone cells, may have multiple functions, including acting as a mechanosensor in bone (re)modeling. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes and, when deleted in mice, results in a hypomineralized bone phenotype. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (P(i)) homeostasis. Both Dmp1-null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.
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            Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets.

            Meghan Mason, Pål I. Holm, Eric D. Marsh … (2001)
            PHEX is the gene defective in X-linked hypophosphatemic rickets. In this study, analysis of PHEX revealed mutations in 22 hypophosphatemic rickets patients, including 16 of 28 patients in whom all 22 PHEX exons were studied. In 13 patients, in whom no PHEX mutation had been previously detected in 17 exons, the remaining 5 PHEX exons were analyzed and mutations found in 6 patients. Twenty different mutations were identified, including 16 mutations predicted to truncate PHEX and 4 missense mutations. Phenotype analysis was performed on 31 hypophosphatemic rickets patients with PHEX mutations, including the 22 patients identified in this study, 9 patients previously identified, and affected family members. No correlation was found between the severity of disease and the type or location of the mutation. However, among patients with a family history of hypophosphatemic rickets, there was a trend toward more severe skeletal disease in patients with truncating mutations. Family members in more recent generations had a milder phenotype. Postpubertal males had a more severe dental phenotype. In conclusion, although identifying mutations in PHEX may have limited prognostic value, genetic testing may be useful for the early identification and treatment of affected individuals. Furthermore, this study suggests that other genes and environmental factors affect the severity of hypophosphatemic rickets.
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              A clinical and molecular genetic study of hypophosphatemic rickets in children.

              I Ha, Timothy H. Y. Cheong, Duk-Yong Choi … (2005)
              X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets, hereditary hypophosphatemic rickets with hypercalciuria, and tumor-induced osteomalacia share clinical and biochemical features, and are collectively referred to as hypophosphatemic rickets (HR). Recently, the molecular bases of HR were elucidated. A review of medical records and mutational analyses of the PHEX and FGF23 genes were performed on 17 unrelated Korean children with HR. The male-to-female ratio was 3:14, and 5 patients were familial. Initial laboratory tests revealed typical features of HR. Seven different PHEX mutations were detected in 8 patients: 2 missense mutations, 2 nonsense mutations, and 3 short deletions. No functional FGF23 mutation was detected in any patient. Patients with the PHEX mutation tended to have more severe skeletal disease than those without. Of the patients with this mutation, no genotype-phenotype correlation and no gene dosage effect were noted. Treatment with vitamin D and phosphate resulted in only a partial growth improvement in most cases, and was frequently complicated by hypercalciuria, hypercalcemia, nephrocalcinosis, or hyperparathyroidism. Renal glycosuria was detected in six cases and was associated with more severe skeletal disease. We conclude that current HR treatment is not fully safe or effective, and that close monitoring of treatment effectiveness and for complications should be performed during long-term treatment. No genotype-phenotype correlation in XLH was detected in this study, but a large-scaled study on this topic is warranted. The large proportion of patients with a normal genetic study suggests the possibility of other causative gene(s).
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ann Pediatr Endocrinol Metab
                Journal ID (iso-abbrev): Ann Pediatr Endocrinol Metab
                Journal ID (publisher-id): APEM
                Title: Annals of Pediatric Endocrinology & Metabolism
                Publisher: Korean Society of Pediatric Endocrinology
                ISSN (Print): 2287-1012
                ISSN (Electronic): 2287-1292
                Publication date (Print): December 2018
                Publication date (Electronic): 31 December 2018
                Volume: 23
                Issue: 4
                Pages: 4-9
                Affiliations
                [1 ]Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [2 ]Department of Pediatrics, Hanyang University Guri Hopistal, Hanyang University College of Medicine, Guri, Korea
                [3 ]Department of Pediatrics, Inha University School of Medicine, Incheon, Korea
                [4 ]Green Cross Genome, Yongin, Korea
                [5 ]Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                Author notes
                Address for correspondence: Sung Yoon Cho, MD, PhD Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3539 Fax: +82-2-3410-0043 E-mail: nadri1217@ 123456naver.com
                Address for co-correspondence: Dong-Kyu Jin, MD, PhD Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3525 Fax: +82-2-3410-0043 E-mail: jindk@ 123456skku.edu
                Author information
                http://orcid.org/0000-0003-2913-059X
                http://orcid.org/0000-0003-4162-2706
                Article
                Publisher ID: apem-2018-23-4-229
                DOI: 10.6065/apem.2018.23.4.229
                PMC ID: 6312911
                SO-VID: 85a772e0-3634-4e97-851e-4c8670307258
                Copyright © © 2018 Annals of Pediatric Endocrinology & Metabolism
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 5 February 2018
                Date revision received : 17 March 2018
                Date accepted : 17 June 2018
                Categories
                Subject: Case Report

                Keywords: phex,hypophosphatemic rickets,mosaic mutation,nonsense mutation
                Data availability:
                Keywords: phex, hypophosphatemic rickets, mosaic mutation, nonsense mutation

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