Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel–Manzke syndrome in a fetus

Abstract

Pierre-Robin sequence, radial deviation, and ulnar clinodactyly of the index fingers due to an additional phalangeal bone, as well as heart defects are the key features of Catel-Manzke syndrome. Although mutations in TGDS were identified as the cause of this disorder, the pathogenetic mechanism remains unknown. Here, we report on a fetus with severe heart defect, nuchal edema, talipes, Pierre-Robin sequence, and bilateral deviation and clinodactyly of the index and middle fingers. Pregnancy was terminated at the 22nd week of gestation. Postmortem radiographs showed hypoplasia and V-shaped displacement of the second and third proximal phalanges of both hands as well as hypoplasia of the first metatarsals and the phalangeal bones of the halluces. The suggested diagnosis Catel-Manzke syndrome was confirmed by the detection of two compound heterozygous mutations in TGDS: The known variant c.298G>T; p.(Ala100Ser) and the so far undescribed variant c.895G>A; p.(Asp299Asn), located in the predicted substrate binding site of TGDS. This is the first report on the association of mutations in TGDS with additional anomalies of the middle fingers and halluces. We provide a detailed phenotypic characterization of the only fetus with molecularly confirmed Catel-Manzke syndrome, which is relevant for prenatal diagnosis. Our findings widen the phenotype spectrum caused by TGDS mutations and underline the phenotypic overlap with Temtamy preaxial brachydactyly syndrome. This improves our understanding of the prenatal development and the pathogenetic mechanism of Catel-Manzke syndrome.

TGDS pathogenic variants cause Catel‐Manzke syndrome without hyperphalangy

“…The two individuals described here are the first with confirmed TGDS pathogenic variants who present with almost normal hand radiographs and therefore do not show one of the clinical hallmarks of Catel‐Manzke syndrome, that is, Manzke dysostosis (Manzke, ). Until now, nine individuals (including one fetus) with biallelic TGDS pathogenic variants have been reported (Ehmke et al, ; Pferdehirt et al, ; Schoner et al, ). All individuals presented with Pierre‐Robin sequence and hyperphalangy; only in the fetus shortening of the proximal second and third phalangeal bone was detected but no hyperphalangy, which could be due to the early time point of imaging (22nd week of gestation) (Schoner et al, ).…”

“…Until now, nine individuals (including one fetus) with biallelic TGDS pathogenic variants have been reported (Ehmke et al, ; Pferdehirt et al, ; Schoner et al, ). All individuals presented with Pierre‐Robin sequence and hyperphalangy; only in the fetus shortening of the proximal second and third phalangeal bone was detected but no hyperphalangy, which could be due to the early time point of imaging (22nd week of gestation) (Schoner et al, ). Both individuals presented in this study have mild bilateral radial deviation and ulnar clinodactyly of the index fingers (Figure e,i), despite the absence of hyperphalangy or shortening of the proximal phalanx on hand radiographs.…”

“…TGDS encodes the enzyme thymidine diphosphate (TDP) glucose‐4,5‐dehydratase whose function in mammals is still unknown. So far, seven different pathogenic variants in TGDS have been published (Ehmke et al, ; Pferdehirt et al, ; Schoner et al, ). Individual 1 is homozygous for the variant c.700T>C, p.(Tyr234His), which has been reported in compound heterozygous state in another Dutch family (Ehmke et al, ; Kant et al, ).…”

“…Pierre‐Robin sequence and congenital heart defects can lead to postnatal failure to thrive and cause severe morbidity and an increased mortality. Biallelic pathogenic variants in TGDS have been described in nine individuals including one fetus with Catel‐Manzke syndrome (Ehmke et al, ; Pferdehirt, Jain, Blazo, Lee, & Burrage, ; Schoner et al, ). Individuals without one of the two major hallmarks or with additional hand malformations have been described as atypical or Catel‐Manzke‐like syndrome (Manzke et al, ).…”

“…Individuals without one of the two major hallmarks or with additional hand malformations have been described as atypical or Catel‐Manzke‐like syndrome (Manzke et al, ). Although TGDS pathogenic variants were detected in a fetus with additional shortening of the middle fingers (Schoner et al, ), and IMPAD1 pathogenic variants were detected in two other individuals with Catel‐Manzke‐like syndrome (Nizon, Alanay, et al, ), the genetic cause remains unknown in the majority of atypical cases.…”