Mental retardation, short stature and synpolydactyly in a manifesting heterozygote of Bartsocas–Papas syndrome

To the Editor : Bartsocas–Papas syndrome (BPS) is a severe and rare autosomal recessive (AR) disorder characterized by severe popliteal webbing, oligosyndactyly, and genital abnormalities (1). In a recent case report, we described a 16-year-old mentally retarded patient in an Egyptian family with BPS (2). This patient, the maternal uncle of two cases of BPS, showed some of the typical features of the syndrome, but lacked the major criteria as pterygi and orofacial clefts. He presented with microphthalmia, ptosis of left eyelid, and thin lips. The patient also had multiple café au lait spots, truncal obesity and hypoplastic external genitalia. A striking complete right thumb-index syndactyly and a short left thumb were detected. Radiographs of hands showed an abnormal hypoplastic middle phalanx with duplication of distal phalanx of the right second finger and a hypoplastic first metacarpal in both hands (Fig. 1). Shortly after our report, the responsible gene was identified (3). Homozygous mutations in RIPK4 ; the gene encoding receptor-interacting serine/threonine kinase protein 4 (RIPK4), were shown to cause BPS in affected cases including the niece of our patient. The patient was subsequently tested; and surprisingly, he was found heterozygous for the mutation detected in his niece; a single base pair insertion in exon 5 (c.777-778insA). This insertion is predicted to cause a frameshift leading to a pre-mature stop codon (p.Arg260ThrfsX14) and a non-functional truncated protein. As an AR disorder, BPS syndrome is not expected to be manifested in the heterozygous state, as it is the case with the healthy parents of the affected cases in this family. However, our finding suggests that this patient is possibly a manifesting heterozygote of BPS and that RIPK4 can show heterozygote expression. In practice, there have been several observations of subtle and sometimes significant manifestations noted in heterozygous carriers of AR disorders (4–6). These cases have always formed an enormous clinical challenge to the geneticists. Manifesting heterozygotes have been described in a number of AR pedigrees of enzymopathies; such as phosphoglycerate mutase deficiency (6), (a)