Catel–Manzke syndrome: Further delineation of the phenotype associated with pathogenic variants in TGDS

Abstract

Catel-Manzke syndrome is a rare autosomal recessive disorder characterized by Pierre Robin sequence with hyperphalangy and clinodactyly of the index finger. Recently, homozygous or compound heterozygous pathogenic variants in TGDS have been discovered to cause Catel-Manzke syndrome. Here, we describe a 12-month-old male with molecularly confirmed Catel-Manzke syndrome who presented with Pierre Robin sequence (but without cleft palate) and hyperphalangy, and we compare his phenotype with the seven previously described patients with pathogenic variants in TGDS. Our patient is on the severe end of the phenotypic spectrum, presenting with respiratory complications and failure to thrive. Furthermore, our finding of a homozygous p.Ala100Ser pathogenic variant in our patient supports that it is a common mutation in Catel-Manzke syndrome.

TGDS pathogenic variants cause Catel‐Manzke syndrome without hyperphalangy

“…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, ). She presented with retrognathia and cleft palate, and her facial appearance is similar to the Individual 2 reported by Ehmke et al () and the individual reported by Pferdehirt et al (). Individual 2 in this report carries the above mentioned variant c.700T>C, p.(Tyr234His) and the most common variant c.298G>A, p.(Ala100Ser).…”

“…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, ).…”

“…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, ).…”

Catel–Manzke syndrome without Manzke dysostosis

“…While the majority of reported cases have had Robin sequence, eight individuals did not have a cleft palate. Of these eight cases without cleft palate, two have had molecularly confirmed pathogenic variants in TGDS (Ehmke et al, ; Kant, Oudshoorn, Gi, Zonderland, & Haeringen, ; Pferdehirt, Jain, Blazo, Lee, & Burrage, ). Thirty‐nine of the 41 reported cases have had bilateral Manzke dysostosis, while in two cases, only one hand was affected (Oh, Kim, Park, Park, & Yang, ; Skinner, Stevenson, & Flannery, ).…”