TWIST gene mutation in a patient with radial aplasia and craniosynostosis: Further evidence for heterogeneity of Baller-Gerold syndrome

Abstract

The term Baller-Gerold syndrome was coined by Cohen [1979: Birth Defects 15(5B): 13-63] to designate the phenotype of craniosynostosis and radial aplasia. It is thought to be a rare autosomal recessive condition, which, in some patients, presents with additional abnormalities, such as polymicrogyria, mental retardation or anal atresia. A phenotypic overlap of Baller-Gerold and Roberts-SC phocomelia syndrome was noted when a patient with bicoronal synostosis and bilateral radial hypoplasia was found to have premature centromere separation, a finding characteristic of Roberts syndrome [Huson et al.,1990: J Med Genet 27:371-375]. Other cases of presumed Baller-Gerold syndrome were rediagnosed as Fanconi pancytopenia, Rothmund-Thomson syndrome or VACTERL association. These reports led to a narrowed redefinition of Baller-Gerold syndrome based on the exclusion of cytogenetic and hematopoetic abnormalities and the absence of additional malformations in patients with craniosynostosis and preaxial upper limb abnormalities. Here we report on a patient with unilateral radial aplasia and bicoronal synostosis without additional malformations and without chromosome breakage, who fits this narrow definition of Baller-Gerold syndrome. We identified a novel TWIST gene mutation in this patient, a Glu181Stop mutation predicting a premature termination of the protein carboxy-terminal to the helix 2 domain. This report provides further evidence that Baller-Gerold is of heterogeneous cause, and a thorough evaluation is indicated to identify a possibly more specific diagnosis, including Saethre-Chotzen syndrome. This differential diagnosis is of particular importance, as it is an autosomal dominant trait. Therefore, the recurrence risk for parents of an affected child can be 50% if one parent carries the mutation, as opposed to the 25% recurrence risk for autosomal recessive inheritance. Offspring of the affected patient also have a 50% risk to inherit the mutation, while the risk to bear an affected offspring for an autosomal recessive trait is very low.

Twist is substrate for caspase cleavage and proteasome-mediated degradation

“…This was also confirmed by the analysis of a number of truncation mutants, including a mutation detected in Saethre-Chotzen patients. 49 Abrogation of the putative caspase recognition site resulted in Twist resistance to degradation and enhanced protection toward apoptosis. Taken together, our results indicate that the proteolytic cleavage of Twist in the course of apoptosis functions as a destabilizing process that culminates in protein degradation, and suggest that caspase-mediated cleavage plays a role in spatio-temporal control of the antiapoptotic activity of Twist.…”

“…62,63 Finally, the Twist protein has been reported to be accumulated in sarcomas, lymphomas and certain types of carcinomas, [18][19][20] while unstable forms of Twist have often been detected in Saethre-Chotzen patients. 49 In both instances, the biochemical bases for the altered expression of Twist are presently unknown. Our data outline the possibility that defects in post-transcriptional regulation of Twist may play a role in human tumorigenesis and developmental diseases.…”

A diagnostic approach to identifying submicroscopic 7p21 deletions in Saethre-Chotzen syndrome: Fluorescence in situ hybridization and dosage-sensitive Southern blot analysis

“…In other instances, when the phenotype is not distinctive, the identification of an underlying TWIST gene mutation is crucial for the diagnosis. 13 This information can then be used to identify mutation carriers and to perform prenatal diagnosis. While TWIST sequence analysis is often successful in identifying an abnormality, some patients with Saethre-Chotzen syndrome do not show a sequence variation.…”

“…In cases with an identified TWIST mutation, analysis of first-degree relatives may be con-sidered because of the known intrafamilial variability of Saethre-Chotzen syndrome. 4,13 If no mutation in TWIST is detected, we suggest testing for the P250R mutation in FGFR3, since patients with this mutation may not always be clinically distinguishable from those with Saethre-Chotzen syndrome. 6 Analysis for the FGFR3 mutation may be included at any stage of the molecular studies.…”

The mutation spectrum in RECQL4 diseases

“…3,28,29 Baller -Gerold syndrome has overlapping clinical features with RTS and RAPADILINO, but the narrow definition of BGS is craniosynostosis with radial aplasia. 30 However, craniosynostosis has also been reported in patients diagnosed as RTS and, for instance, the London Medical Databases (www.lmdatabases.com/) list it as one of the features of both RTS and BGS syndromes.…”