‘Isolated’ germline mosaicism in the phenotypically normal father of a girl with X-linked hypophosphatemic rickets

in European Journal of Endocrinology

Correspondence should be addressed to L Liu; Email: liliuchina@qq.com
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Objective

X-linked hypophosphatemic rickets (XLHR) is the most common form of inherited rickets caused by pathogenic variants of PHEX gene with an X-linked dominant inheritance pattern. Precise molecular diagnosis of pathogenic variant will benefit the genetic counseling and prenatal diagnosis for the family with XLHR. Here, we presented an ‘isolated’ germline mosaicism in the phenotypically normal father of a girl with XLHR.

Methods and results

For the initial molecular screen of PHEX gene, DNA samples of the proband and her parents were extracted from their peripheral blood samples respectively. Sanger sequencing found a ‘de novo’ novel heterozygous variant, c.1666C>T(p.Q556X), at the PHEX gene in the proband, but not in her phenotypically healthy parents. Due to an occasional abnormality of his serum phosphate previously, further examinations for the father were taken to exclude the possibility of paternal mosaicism. Eight samples from different tissues were analyzed for PHEX gene by Sanger sequencing. Surprisingly, one ‘isolated’ germline mosaicism was detected only in his sperm with an estimated frequency of 26.67%. The mosaic allele was identical to the c.1666C>T(p.Q556X) variant in the proband.

Conclusions

This is the first case of ‘isolated’ germline mosaicism with pathogenic PHEX variant. Our study provides accurate diagnosis and valuable counseling for this family. This report also alerts clinicians and geneticists to exclude the possibility of the isolated germline mosaicism and prevent intrafamilial recurrences of inherited diseases.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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  • 1

    Jan de BeurSMLevineMA. Molecular pathogenesis of hypophosphatemic rickets. Journal of Clinical Endocrinology and Metabolism 2002 24672473. (https://doi.org/10.1210/jcem.87.6.8688)

    • Search Google Scholar
    • Export Citation
  • 2

    PavoneVTestaGGioitta IachinoSEvolaFRAvondoSSessaG. Hypophosphatemic rickets: etiology, clinical features and treatment. European Journal of Orthopaedic Surgery and Traumatology 2015 221226. (https://doi.org/10.1007/s00590-014-1496-y)

    • Search Google Scholar
    • Export Citation
  • 3

    GaucherCWalrant-DebrayONguyenTMEsterleLGarabédianMJehanF. PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Human Genetics 2009 401411. (https://doi.org/10.1007/s00439-009-0631-z)

    • Search Google Scholar
    • Export Citation
  • 4

    HolmIANelsonAERobinsonBGMasonRSMarshDJCowellCTCarpenterTO. Mutational analysis and genotype-phenotype correlation of the PHEX gene in X-linked hypophosphatemic rickets. Journal of Clinical Endocrinology and Metabolism 2001 38893899. (https://doi.org/10.1210/jcem.86.8.7761)

    • Search Google Scholar
    • Export Citation
  • 5

    TyynismaaHKaitilaINäntö-SalonenKAla-HouhalaMAlitaloT. Identification of fifteen novel PHEX gene mutations in Finnish patients with hypophosphatemic rickets. Human Mutation 2000 383384. (https://doi.org/10.1002/(SICI)1098-1004(200004)15:4<383::AID-HUMU18>3.0.CO;2-#)

    • Search Google Scholar
    • Export Citation
  • 6

    RuppeMDBrosnanPGAuKSTranPXDominguezBWNorthrupH. Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets. Clinical Endocrinology 2011 312318. (https://doi.org/10.1111/j.1365-2265.2010.03919.x)

    • Search Google Scholar
    • Export Citation
  • 7

    Beck-NielsenSSBrock-JacobsenBGramJBrixenKJensenTK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. European Journal of Endocrinology 2009 491497. (https://doi.org/10.1530/EJE-08-0818)

    • Search Google Scholar
    • Export Citation
  • 8

    EndoIFukumotoSOzonoKNambaNInoueDOkazakiRYamauchiMSugimotoTMinagawaMMichigamiT Nationwide survey of fibroblast growth factor 23 (FGF23)-related hypophosphatemic diseases in Japan: prevalence, biochemical data and treatment. Endocrine Journal 2015 811816. (https://doi.org/10.1507/endocrj.EJ15-0275)

    • Search Google Scholar
    • Export Citation
  • 9

    RafaelsenSJohanssonSRæderHBjerknesR. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. European Journal of Endocrinology 2016 125136. (https://doi.org/10.1530/EJE-15-0515)

    • Search Google Scholar
    • Export Citation
  • 10

    QuinlanCGueganKOffiahANeillROHiornsMPEllardSBockenhauerDHoffWVWatersAM. Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatric Nephrology 2012 581588. (https://doi.org/10.1007/s00467-011-2046-z)

    • Search Google Scholar
    • Export Citation
  • 11

    ChoHYLeeBHKangJHHaISCheongHIChoiY. A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatric Research 2005 329333. (https://doi.org/10.1203/01.PDR.0000169983.40758.7B)

    • Search Google Scholar
    • Export Citation
  • 12

    LuoSHuangWXiaQXiaYDuQWuLDuanR. Cryptic FMR1 mosaic deletion in a phenotypically normal mother of a boy with fragile X syndrome: case report. BMC Medical Genetics 2014 125. (https://doi.org/10.1186/s12881-014-0125-2)

    • Search Google Scholar
    • Export Citation
  • 13

    SlavinTPLazebnikNClarkDMVengoecheaJCohenLKaurMKonczalLCroweCACortevilleJENowaczykMJ Germline mosaicism in Cornelia de Lange syndrome. American Journal of Medical Genetics: Part A 2012 14811485. (https://doi.org/10.1002/ajmg.a.35381)

    • Search Google Scholar
    • Export Citation
  • 14

    LinYXuAZengCChengJLiNNiuHLiuLLiX. Somatic and germline FOXP3 mosaicism in the mother of a boy with IPEX syndrome. European Journal of Immunology 2018 885887. (https://doi.org/10.1002/eji.201747445)

    • Search Google Scholar
    • Export Citation
  • 15

    WaltonRJBijvoetOL. Nomogram for derivation of renal threshold phosphate concentration. Lancet 1975 309310. (https://doi.org/10.1016/s0140-6736(75)92736-1)

    • Search Google Scholar
    • Export Citation
  • 16

    TakedaEYamamotoHNashikiKSatoTAraiHTaketaniY. Inorganic phosphate homeostasis and the role of dietary phosphorus. Journal of Cellular and Molecular Medicine 2004 191200. (https://doi.org/10.1111/j.1582-4934.2004.tb00274.x)

    • Search Google Scholar
    • Export Citation
  • 17

    LiuSTangWFangJRenJLiHXiaoZQuarlesLD. Novel regulators of FGF23 expression and mineralization in Hyp bone. Molecular Endocrinology 2009 15051518. (https://doi.org/10.1210/me.2009-0085)

    • Search Google Scholar
    • Export Citation
  • 18

    MartinALiuSDavidVLiHKarydisAFengJQQuarlesLD. Bone proteins PHEX and DMP1 regulate fibroblastic growth factor FGF23 expression in osteocytes through a common pathway involving FGF receptor (FGFR) signaling. FASEB Journal 2011 25512562. (https://doi.org/10.1096/fj.10-177816)

    • Search Google Scholar
    • Export Citation
  • 19

    IgakiJMYamadaMYamazakiYKotoSIzawaMAriyasuDSuzukiEHasegawaHHasegawaY. High iFGF23 level despite hypophosphatemia is one of the clinical indicators to make diagnosis of XLH. Endocrine Journal 2011 647655. (https://doi.org/10.1507/endocrj.k10e-257)

    • Search Google Scholar
    • Export Citation
  • 20

    AndrukhovaOSlavicSSmorodchenkoAZeitzUShalhoubVLanskeBPohlEEErbenRG. FGF23 regulates renal sodium handling and blood pressure. EMBO Molecular Medicine 2014 744759. (https://doi.org/10.1002/emmm.201303716)

    • Search Google Scholar
    • Export Citation
  • 21

    ClausmeyerSHesseVClemensPCEngelbachMKreuzerMBecker-RosePSpitalHSchulzeERaueF. Mutational analysis of the PHEX gene: novel point mutations and detection of large deletions by MLPA in patients with X-linked hypophosphatemic rickets. Calcified Tissue International 2009 211220. (https://doi.org/10.1007/s00223-009-9260-8)

    • Search Google Scholar
    • Export Citation
  • 22

    JonssonKBZahradnikRLarssonTWhiteKESugimotoTImanishiYYamamotoTHampsonGKoshiyamaHLjunggrenO Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. New England Journal of Medicine 2003 16561663. (https://doi.org/10.1056/NEJMoa020881)

    • Search Google Scholar
    • Export Citation
  • 23

    WeberTJLiuSIndridasonOSQuarlesLD. Serum FGF23 levels in normal and disordered phosphorus homeostasis. Journal of Bone and Mineral Research 2003 12271234. (https://doi.org/10.1359/jbmr.2003.18.7.1227)

    • Search Google Scholar
    • Export Citation
  • 24

    LiSSGuJMYuWJHeJWFuWZZhangZL. Seven novel and six de novo PHEX gene mutations in patients with hypophosphatemic rickets. International Journal of Molecular Medicine 2016 17031714. (https://doi.org/10.3892/ijmm.2016.2796)

    • Search Google Scholar
    • Export Citation
  • 25

    MoreyMCastro-FeijóoLBarreiroJCabanasPPomboMGilMBernabeuIDíaz-GrandeJMRey-CordoLAricetaG Genetic diagnosis of X-linked dominant hypophosphatemic Rickets in a cohort study: tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type. BMC Medical Genetics 2011 116. (https://doi.org/10.1186/1471-2350-12-116)

    • Search Google Scholar
    • Export Citation
  • 26

    MummSHuskeyMCajicAWollbergVZhangFMadsonKLWenkertDMcAlisterWHGottesmanGSWhyteMP PHEX 3′-UTR c.*231A>G near the polyadenylation signal is a relatively common, mild, American mutation that masquerades as sporadic or X-linked recessive hypophosphatemic rickets. Journal of Bone and Mineral Research 2015 137143. (https://doi.org/10.1002/jbmr.2307)

    • Search Google Scholar
    • Export Citation
  • 27

    GojiKOzakiKSadewaAHNishioHMatsuoM. Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait. Journal of Clinical Endocrinology and Metabolism 2006 365370. (https://doi.org/10.1210/jc.2005-1776)

    • Search Google Scholar
    • Export Citation
  • 28

    WengCChenJSunLZhouZWFengXSunJHLuLPYuPQiM. A de novo mosaic mutation of PHEX in a boy with hypophosphatemic rickets. Journal of Human Genetics 2016 223227. (https://doi.org/10.1038/jhg.2015.133)

    • Search Google Scholar
    • Export Citation
  • 29

    YangMKimJYangAJangJJeonTYChoSYJinDK. A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets. Annals of Pediatric Endocrinology and Metabolism 2018 229234. (https://doi.org/10.6065/apem.2018.23.4.229)

    • Search Google Scholar
    • Export Citation
  • 30

    CaoYTokitaMJChenESGhoshRChenTFengYGormanEGibelliniFWardPABraxtonA A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing. Genome Medicine 2019 48. (https://doi.org/10.1186/s13073-019-0658-2)

    • Search Google Scholar
    • Export Citation