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Case Reports
. 2022 Sep 14;13(9):1649.
doi: 10.3390/genes13091649.

TBX3 and EFNA4 Variant in a Family with Ulnar-Mammary Syndrome and Sagittal Craniosynostosis

Moon Ley Tung  1   2 , Bharatendu Chandra  1   2 , Jaclyn Kotlarek  1 , Marcelo Melo  1 , Elizabeth Phillippi  1 , Cristina M Justice  3 , Anthony Musolf  4 , Simeon A Boyadijev  5 , Paul A Romitti  6 , Benjamin Darbro  1 , Hatem El-Shanti  1
Affiliations
Case Reports

TBX3 and EFNA4 Variant in a Family with Ulnar-Mammary Syndrome and Sagittal Craniosynostosis

Moon Ley Tung et al. Genes (Basel). .

Abstract

Ulnar-mammary syndrome (UMS) is a rare, autosomal dominant disorder characterized by anomalies affecting the limbs, apocrine glands, dentition, and genital development. This syndrome is caused by haploinsufficiency in the T-Box3 gene (TBX3), with considerable variability in the clinical phenotype being observed even within families. We describe a one-year-old female with unilateral, postaxial polydactyly, and bilateral fifth fingernail duplication. Next-generation sequencing revealed a novel, likely pathogenic, variant predicted to affect the canonical splice site in intron 3 of the TBX3 gene (c.804 + 1G > A, IVS3 + 1G > A). This variant was inherited from the proband’s father who was also diagnosed with UMS with the additional clinical finding of congenital, sagittal craniosynostosis. Subsequent whole genome analysis in the proband’s father detected a variant in the EFNA4 gene (c.178C > T, p.His60Tyr), which has only been reported to be associated with sagittal craniosynostosis in one patient prior to this report but reported in other cranial suture synostosis. The findings in this family extend the genotypic spectrum of UMS, as well as the phenotypic spectrum of EFNA4-related craniosynostosis.

Keywords: EFNA4; TBX3; Ulnar Mammary Syndrome; sagittal craniosynostosis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Phenotypic and genotypic findings in the proband and her family. (A,B) Clinical findings in the proband’s father showing a contracture of the fifth finger and duplication of the fifth fingernail. (C,D) The proband’s right hand showing the postaxial polydactyly and duplication of the fifth fingernail and the corresponding X-ray of the proband’s right hand. (E) Unilateral, fifth finger contracture in one of the proband’s twin brothers. (F) Normal hand in the other twin brother. (G) Pedigree of the family with the associated TBX and EFNA4 allele. The proband is indicated by the short arrowhead in black (Individual II:1). The proband and her siblings (II:2 and II:3) are heterozygous for the TBX3 variant. The proband’s father (Individual I:1) is heterozygous for both the TBX3 and EFNA4 variants. The proband’s mother (Individual 1:2) is wild-type for both alleles.
Figure 2
Figure 2
Chromosomal position and genomic structure of the T-Box 3 (TBX3) gene and known disease-causing variants which have been published in the literature. Our proband’s variant is highlighted in the red box.
See this image and copyright information in PMC

References

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