Download PDF
CC BY 4.0 · Rev Bras Ginecol Obstet 2018; 40(09): 570-576
DOI: 10.1055/s-0038-1670684
Case Report
Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil

Diagnosis of Atelosteogenesis Type I suggested by Fetal Ultrasonography and Atypical Paternal Phenotype with Mosaicism

Diagnóstico de atelosteogênese tipo I sugerido por ultrassonografia fetal e fenótipo paterno atípico com mosaicismo
Joanna Goes Castro Meira
1   Department of Medical Genetics, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BA, Brazil
,
Manoel Alfredo Curvelo Sarno
2   Maternidade Climério de Oliveira, Universidade Federal da Bahia, Salvador, BA, Brazil
,
Ágatha Cristhina Oliveira Faria
3   Center for Studies of the Human Genome and of Stem Cells Department of Genetics and Evolutionary Biology, Institute of Biosciences, Universidade de São Paulo, São Paulo, SP, Brazil
,
Guilherme Lopes Yamamoto
3   Center for Studies of the Human Genome and of Stem Cells Department of Genetics and Evolutionary Biology, Institute of Biosciences, Universidade de São Paulo, São Paulo, SP, Brazil
,
Débora Romeo Bertola
3   Center for Studies of the Human Genome and of Stem Cells Department of Genetics and Evolutionary Biology, Institute of Biosciences, Universidade de São Paulo, São Paulo, SP, Brazil
,
Gabriela Gayer Scheibler
1   Department of Medical Genetics, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BA, Brazil
,
Dione Fernandes Tavares
1   Department of Medical Genetics, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BA, Brazil
,
Angelina Xavier Acosta
1   Department of Medical Genetics, Hospital Universitário Professor Edgard Santos, Universidade Federal da Bahia, Salvador, BA, Brazil
› Author Affiliations
Further Information

Publication History

14 December 2017

13 June 2018

Publication Date:
19 September 2018 (online)

   Permissions and Reprints

Abstract

Atelosteogenesis type I (AOI) is an autosomal dominant skeletal dysplasia caused by mutations in the filamin B (FLNB) gene with classic and well-recognizable clinical findings. However, parents affected with a mild phenotype, probably with somatic mosaicism, can generate offspring with a much more severe phenotype of AOI. In the present report, we describe a female newborn with classic AOI leading to early neonatal death, whose diagnostic was based on prenatal radiological findings and on the physical examination of the father. Since her father had limb deformities and corporal asymmetry, suggesting somatic mosaicism, his biological samples were analyzed through a gene panel for skeletal dysplasias. A missense mutation not previously described in the literature was detected in the FLNB gene, affecting ∼ 20% of the evaluated cells and, therefore, confirming the diagnosis of mosaic AOI in the father. The molecular analysis of the father was crucial to suggest the diagnosis of AOI in the newborn, since she died early and there were no biological samples available.

Resumo

A atelosteogênese tipo I (AOI) é uma displasia esquelética autossômica dominante causada por mutações no gene filamina B (FLNB) com achados clínicos clássicos e bem reconhecíveis. No entanto, pais afetados com um fenótipo mais leve, provavelmente com mosaicismo somático, podem gerar uma prole com um fenótipo muito mais grave de AOI. No presente relato, descrevemos um recém-nascido do sexo feminino com AOI clássica, que levou à morte neonatal precoce, e cujo diagnóstico foi baseado em achados radiológicos pré-natais e no exame físico de seu genitor. Como o genitor apresentava deformidades em membros e assimetria corporal, que sugeriam mosaicismo somático, suas amostras biológicas foram analisadas por meio de um painel de genes para displasias esqueléticas. Uma mutação missense, não descrita anteriormente na literatura, foi detectada no gene FLNB, afetando ∼ 20% das células avaliadas, e, portanto, confirmando o diagnóstico de AOI em mosaico no genitor. A análise molecular realizada no genitor foi fundamental para sugerir o diagnóstico de AOI na recém-nascida, uma vez que esta morreu precocemente, e não havia amostras biológicas disponíveis.

Keywords

atelosteogenesis - somatic mosaicism - skeletal dysplasia - FLNB - exome-target sequencing - fetal ultrasonography

Palavras-chave

atelosteogênese - mosaicismo somático - displasia esquelética - FLNB - sequenciamento do exoma - ultrassonografia fetal
 

  • References

  • 1 Krakow D, Robertson SP, King LM. , et al. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Nat Genet 2004; 36 (04) 405-410 . Doi: 10.1038/ng1319
    CrossrefPubMedGoogle Scholar
  • 2 Sillence DO, Lachman RS, Jenkins T, Riccardi VM, Rimoin DL. Spondylohumerofemoral hypoplasia (giant cell chondrodysplasia): a neonatally lethal short-limbed skeletal displasia. Am J Med Genet 1982; 13 (01) 7-14 . Doi: 10.1002/ajmg.1320130105
    CrossrefPubMedGoogle Scholar
  • 3 Farrington-Rock C, Firestein MH, Bicknell LS. , et al. Mutations in two regions of FLNB result in atelosteogenesis I and III. Hum Mutat 2006; 27 (07) 705-710 . Doi: 10.1002/humu.20348
    CrossrefPubMedGoogle Scholar
  • 4 Stern HJ, Graham Jr JM, Lachman RS. , et al. Atelosteogenesis type III: a distinct skeletal dysplasia with features overlapping atelosteogenesis and oto-palato-digital syndrome type II. Am J Med Genet 1990; 36 (02) 183-195 . Doi: 10.1002/ajmg.1320360212
    CrossrefPubMedGoogle Scholar
  • 5 Bicknell LS, Farrington-Rock C, Shafeghati Y. , et al. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet 2007; 44 (02) 89-98 . Doi: 10.1136/jmg.2006.043687
    CrossrefPubMedGoogle Scholar
  • 6 Schultz C, Langer LO, Laxova R, Pauli RM. Atelosteogenesis type III: long term survival, prenatal diagnosis, and evidence for dominant transmission. Am J Med Genet 1999; 83 (01) 28-42 . Doi: 10.1002/(SICI)1096-8628(19990305)83:1<28::AID-AJMG7>3.0.CO;2-G
    CrossrefPubMedGoogle Scholar
  • 7 Ngo C, Viot G, Aubry MC. , et al. First-trimester ultrasound diagnosis of skeletal dysplasia associated with increased nuchal translucency thickness. Ultrasound Obstet Gynecol 2007; 30 (02) 221-226 . Doi: 10.1002/uog.4028
    CrossrefPubMedGoogle Scholar
  • 8 Luewan S, Sukpan K, Udomwan P, Tongsong T. Prenatal sonographic features of fetal atelosteogenesis type 1. J Ultrasound Med 2009; 28 (08) 1091-1095 . Doi: 10.7863/jum.2009.28.8.1091
    CrossrefPubMedGoogle Scholar