AnotherTWIST on Baller-Gerold syndrome

Abstract

Baller-Gerold syndrome is characterized by craniosynostosis and preaxial upper limb malformations. Wide heterogeneity exists with regard to the presence of additional anomalies. Most of the 31 reported cases involve other malformations, including cardiac, Central Nervous System (CNS), and urogenital anomalies. Baller-Gerold syndrome is thought to have autosomal recessive inheritance. However, Gripp et al. [1999: Am. J. Med. Genet. 82:170-176] recently provided the first evidence for autosomal dominant inheritance with variable expressivity and severity. A nonsense mutation was found in TWIST, a gene associated with Saethre-Chotzen syndrome (SCS). Here we report on a male Caucasian patient of nonconsanguineous parents, with synostosis of the coronal, metopic, and sagittal sutures, and bilateral radial ray hypoplasia. The patient's small, round ears with prominent crus helices, and cervical anomalies are common features of SCS. The father had very mild features of SCS. We identify direct paternal transmission of a novel missense TWIST mutation in the highly conserved Helix II domain of this bHLH-family gene. This report lends further support to the recent findings by Gripp et al. [1999]. Future TWIST mutational analysis on patients with craniosynostosis and radial ray involvement will shed light on whether Baller-Gerold syndrome should be a distinct entity or some cases should be reclassified as a heterogeneous form of SCS.

Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening

“…However, phenotypic variability and overlap among syndromes have complicated the classification of craniosynostosis conditions. For example, TWIST mutations have also been found in RobinowSorauf syndrome (Kunz et al 1999;Cai et al 2003) and Baller-Gerold syndrome (Seto et al 2001), indicating that these two disorders may not be clinically and molecularly distinct and may lie within the spectrum of Saethre-Chotzen syndrome.…”

“…Currently, at least 69 different intragenic mutations have been described for TWIST in unrelated Saethre-Chotzen patients (Gripp et al 2000a(Gripp et al , 2000bBoeck et al 2001;Dollfus et al 2001;Elanko et al 2001;Seto et al 2001;Chun et al 2002;Cai et al 2003). Significant intra-and interfamilial phenotypic variability can be present, and no significant phenotype-genotype correlation has been observed.…”

Edgotype: a fundamental link between genotype and phenotype

“…Another example is the I156V mutation of the transcription factor H-Twist, leading to Baller-Gerold syndrome. This mutation resides in the highly conserved Helix II domain of this gene, and disrupts the interaction interface with DNA targets [90]. Missense mutation H275R in KLF3 , encoding a Krüppel family zinc finger transcription factor, is associated with various cardiovascular defects.…”

Model Organisms in the Study of Development and Disease

“…The function of twist in specifying mesodermal derivatives may be very ancient as a C. elegans twist (Harfe et al, 1998) gene is required for the formation of nonstriated muscle (Corsi et al, 2000) and a twist-related gene is expressed in mesodermal cells in the jellyfish (Spring et al, 2000). Twist also plays an important developmental role in humans as mutations in this gene lead to dominant inheritance of Saethre-Chotzen syndrome (el Ghouzzi et al, 1997;Howard et al, 1997) and possible recessive inheritance of BallerGerold syndrome (Seto et al, 2001). Twist may activate FGF receptor (GFGR) expression in humans as it does in Drosophila since mutations in the FGFR-2 and FGFR-3 genes also can lead to SaethreChotzen syndrome (Lajeunie, 1997;Paznekas et al, 1998).…”