Genetic investigation of patients with tall stature

in European Journal of Endocrinology

Correspondence should be addressed to A A L Jorge; Email: alexj@usp.br
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Context

Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach.

Objective

To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder.

Design

Screening by karyotype (n = 42), chromosome microarray analyses (CMA) (n = 16), MS-MLPA (n = 2) targeted panel (n = 12) and whole-exome sequencing (n = 31).

Patients and methods

We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups.

Main outcome measures

Frequencies of pathogenic findings.

Results

We identified two patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith–Wiedemann syndrome by targeted MS-MLPA analysis and nine cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1, MC4R = 1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients.

Conclusion

A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup.

 

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  • 1

    AlbuquerqueEVAScalcoRCJorgeAAL. MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature. European Journal of Endocrinology 2017 R339–R353. (https://doi.org/10.1530/EJE-16-1054)

    • Search Google Scholar
    • Export Citation
  • 2

    LaufferPKampGAMenkeLAWitJMOostdijkW & on behalf of the Dutch Working Group on Triage and Diagnosis of Growth Disorders in Children. Towards a rational and efficient diagnostic approach in children referred for tall stature and/or accelerated growth to the general paediatrician. Hormone Research in Paediatrics 2019 293–310. (https://doi.org/10.1159/000500810)

    • Search Google Scholar
    • Export Citation
  • 3

    Tatton-BrownKRahmanN. Sotos syndrome. European Journal of Human Genetics 2007 264–271. (https://doi.org/10.1038/sj.ejhg.5201686)

  • 4

    Tatton-BrownKRahmanN. EZH2-related overgrowth. In GeneReviews(R). Eds PagonRA, AdamMP, ArdingerHH, WallaceSE, AmemiyaA, BeanLJH, BirdTD, FongCT, MeffordHC, SmithRJH Seattle (WA): University of Washington, 1993.

    • Search Google Scholar
    • Export Citation
  • 5

    MalanVRajanDThomasSShawACLouis Dit PicardHLayetVTillMvan HaeringenAMortierGNampoothiriS Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome. American Journal of Human Genetics 2010 189–198. (https://doi.org/10.1016/j.ajhg.2010.07.001)

    • Search Google Scholar
    • Export Citation
  • 6

    Tatton-BrownKMurrayAHanksSDouglasJArmstrongRBankaSBirdLMClericuzioCLCormier-DaireVCushingT Weaver syndrome and EZH2 mutations: clarifying the clinical phenotype. American Journal of Medical Genetics: Part A 2013 2972–2980. (https://doi.org/10.1002/ajmg.a.36229)

    • Search Google Scholar
    • Export Citation
  • 7

    ThomsettMJ. Referrals for tall stature in children: a 25-year personal experience. Journal of Paediatrics and Child Health 2009 58–63. (https://doi.org/10.1111/j.1440-1754.2008.01428.x)

    • Search Google Scholar
    • Export Citation
  • 8

    UpnersENJuulA. Evaluation and phenotypic characteristics of 293 Danish girls with tall stature: effects of oral administration of natural 17β-estradiol. Pediatric Research 2016 693–701. (https://doi.org/10.1038/pr.2016.128)

    • Search Google Scholar
    • Export Citation
  • 9

    Tatton-BrownKLovedayCYostSClarkeMRamsayEZachariouAElliottAWylieHArdissoneARittingerO Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. American Journal of Human Genetics 2017 725–736. (https://doi.org/10.1016/j.ajhg.2017.03.010)

    • Search Google Scholar
    • Export Citation
  • 10

    MarshallWATannerJM. Variations in pattern of pubertal changes in girls. Archives of Disease in Childhood 1969 291–303. (https://doi.org/10.1136/adc.44.235.291)

    • Search Google Scholar
    • Export Citation
  • 11

    MarshallWATannerJM. Variations in the pattern of pubertal changes in boys. Archives of Disease in Childhood 1970 13–23. (https://doi.org/10.1136/adc.45.239.13)

    • Search Google Scholar
    • Export Citation
  • 12

    FredriksAMvan BuurenSvan HeelWJDijkman-NeerincxRHVerloove-VanhorickSPWitJM. Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders. Archives of Disease in Childhood 2005 807–812. (https://doi.org/10.1136/adc.2004.050799)

    • Search Google Scholar
    • Export Citation
  • 13

    KuczmarskiRJOgdenCLGrummer-StrawnLMFlegalKMGuoSSWeiRMeiZCurtinLRRocheAFJohnsonCL. CDC growth charts: United States. Advance Data 2000 1–27.

    • Search Google Scholar
    • Export Citation
  • 14

    LoeysBLDietzHCBravermanACCallewaertBLDe BackerJDevereuxRBHilhorst-HofsteeYJondeauGFaivreLMilewiczDM The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics 2010 476–485. (https://doi.org/10.1136/jmg.2009.072785)

    • Search Google Scholar
    • Export Citation
  • 15

    KatznelsonLLawsERMelmedSMolitchMEMuradMHUtzAWassJA & Endocrine Society. Acromegaly: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2014 3933–3951. (https://doi.org/10.1210/jc.2014-2700)

    • Search Google Scholar
    • Export Citation
  • 16

    GreulichWWPyleSI. Radiographic Atlas of Skeletal Development of the Hand and Wrist, 2nd ed. Stanford, CA: Stanford University Press, 1959.

    • Search Google Scholar
    • Export Citation
  • 17

    VasquesGAHisado-OlivaAFunariMFLerarioAMQuedasEPSolbergPHeathKEJorgeAA. Long-term response to growth hormone therapy in a patient with short stature caused by a novel heterozygous mutation in NPR2. Journal of Pediatric Endocrinology and Metabolism 2017 111–116. (https://doi.org/10.1515/jpem-2016-0280)

    • Search Google Scholar
    • Export Citation
  • 18

    RichardsSAzizNBaleSBickDDasSGastier-FosterJGrodyWWHegdeMLyonESpectorE Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 2015 405–424. (https://doi.org/10.1038/gim.2015.30)

    • Search Google Scholar
    • Export Citation
  • 19

    RedonRBaujatGSanlavilleDLe MerrerMVekemansMMunnichACarterNPCormier-DaireVColleauxL. Interstitial 9q22.3 microdeletion: clinical and molecular characterisation of a newly recognised overgrowth syndrome. European Journal of Human Genetics 2006 759–767. (https://doi.org/10.1038/sj.ejhg.5201613)

    • Search Google Scholar
    • Export Citation
  • 20

    ImagawaEAlbuquerqueEVAIsidorBMitsuhashiSMizuguchiTMiyatakeSTakataAMiyakeNBoguszewskiMCSBoguszewskiCL Novel SUZ12 mutations in Weaver-like syndrome. Clinical Genetics 2018 461–466. (https://doi.org/10.1111/cge.13415)

    • Search Google Scholar
    • Export Citation
  • 21

    ComeglioPJohnsonPArnoGBriceGEvansAAragon-MartinJda SilvaFPKiotsekoglouAChildA. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Human Mutation 2007 928. (https://doi.org/10.1002/humu.9505)

    • Search Google Scholar
    • Export Citation
  • 22

    VaisseCClementKDurandEHercbergSGuy-GrandBFroguelP. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. Journal of Clinical Investigation 2000 253–262. (https://doi.org/10.1172/JCI9238)

    • Search Google Scholar
    • Export Citation
  • 23

    BaronJSavendahlLDe LucaFDauberAPhillipMWitJMNilssonO. Short and tall stature: a new paradigm emerges. Nature Reviews: Endocrinology 2015 735–746. (https://doi.org/10.1038/nrendo.2015.165)

    • Search Google Scholar
    • Export Citation
  • 24

    Tatton-BrownKDouglasJColemanKBaujatGColeTRDasSHornDHughesHETempleIKFaravelliF Genotype-phenotype associations in Sotos syndrome: an analysis of 266 individuals with NSD1 aberrations. American Journal of Human Genetics 2005 193–204. (https://doi.org/10.1086/432082)

    • Search Google Scholar
    • Export Citation
  • 25

    PrioloMSchanzeDTatton-BrownKMulderPATenorioJKooblallKAceroIHAlkurayaFSAriasPBernardiniL Further delineation of Malan syndrome. Human Mutation 2018 1226–1237. (https://doi.org/10.1002/humu.23563)

    • Search Google Scholar
    • Export Citation
  • 26

    FarooqiISKeoghJMYeoGSLankEJCheethamTO’RahillyS. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. New England Journal of Medicine 2003 1085–1095. (https://doi.org/10.1056/NEJMoa022050)

    • Search Google Scholar
    • Export Citation