Ulnar-Mammary Syndrome: expending the phenotype to include ankyloglossia and cleft lip and palate

Abstract

The ulnar-Mammary syndrome is an autosomal dominant condition with intrafamilial variability extending from non-penetrant to the known clinical manifestaions, seen within the same family. The main features are ulnar ray defects with missing digits or post-axial polydactyly, ano-genito-urinary abnormalities and hypoplasia of the apocrine glands and breasts. New clinical manifestations are being added in almost every publication making the diagnosis very difficult. We noted two additional findings: ankyloglossia and cleft lip and palate. CASE REPORT: The proband parents were first seen for abnormal fetal ultrasound at 15 weeks gestation, showing bowed and shortened humeri, single forearm bones, bilateral elbow and wrist contractures and bilateral oligodactyly. He also had fenestrated ASD, ankyloglossia, cleft lip and palate, short clavicles with slopped shoulders and unpalpable pectoralis major, laterally displaced inverted nipples and undescended left testis with hypoplastic left hemiscrotum. Karyotype and BAC microarray analysis were normal and DNA analysis for TBX5, EDA1, and TP63 genes showed no detectable mutation. .Detailed family history suggested that his paternal aunt had right upper limb findings similar to the proband and was previously diagnosed as having Holt-Oram syndrome (HOS). Further investigation showed ankyloglossia, and in her recent experience as a mother she had difficulty in lactation from her right breast. TBX3 testing was first done in her and subsequently in our proband and his asymptomatic father detected a familial heterozygous p.R131X mutation in the TBX3 gene. CONCLUSION: UMS is a rare autosomal dominant disorder caused by TBX3 mutations. The diagnostic challenge is related to the poor genotype-phenotype correlation and intrafamilial and interfamilial variability in clinical manifestations. We report two additional clinical observations: ankyloglossia and cleft lip and palate not previously reported in UMS. Different members of the family are dispersed geographically and assessed by different geneticists, making it difficult for any individual geneticist to make the diagnosis. In fact this family was reported as a new syndrome by Li et al., 2009. This illustrates the importance of detailed history and examination, inter-professional communication and sharing of investigation findings in clinical genetics.