Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome.
The Saethre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with uni- or bilateral coronal synostosis and mild limb deformities. It is caused by loss-of-function mutations of the TWIST 1 gene. In an attempt to delineate functional features separating SCS from Muenke's syndrome, we screened patients presenting with coronal suture synostosis for mutations in the TWIST 1 gene, and for the Pro250Arg mutation in FGFR3. Within a total of 124 independent pedigrees, 39 (71 patients) were identified to carry 25 different mutations of TWIST 1 including 14 novel mutations, to which six whole gene deletions were added. The 71 patients were compared with 42 subjects from 24 pedigrees carrying the Pro250Arg mutation in FGFR3 and 65 subjects from 61 pedigrees without a detectable mutation. Classical SCS associated with a TWIST 1 mutation could be separated phenotypically from the Muenke phenotype on the basis of the following features: low-set frontal hairline, gross ptosis of eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and hallux valgus or broad great toe with bifid distal phalanx. Functional differences were even more important: intracranial hypertension as a consequence of early progressive multisutural fusion was a significant problem in SCS only, while mental delay and sensorineural hearing loss were associated with the Muenke's syndrome. Contrary to previous reports, SCS patients with complete loss of one TWIST allele showed normal mental development.
Kress
Wolfram
W
Institute of Human Genetics, University of Würzburg, Würzburg, Germany. wkress@biozentrum.uni-wuerzburg.de
Schropp
Christian
C
Lieb
Gabriele
G
Petersen
Birgit
B
Büsse-Ratzka
Maria
M
Kunz
Jürgen
J
Reinhart
Edeltraut
E
Schäfer
Wolf-Dieter
WD
Sold
Johanna
J
Hoppe
Florian
F
Pahnke
Jan
J
Trusen
Andreas
A
Sörensen
Niels
N
Krauss
Jürgen
J
Collmann
Hartmut
H
D000168:Acrocephalosyndactylia / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics*; D000293:Adolescent; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics; D002675:Child, Preschool; D004423:Ear / Q000002:abnormalities; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D007427:Intracranial Pressure; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D011392:Proline / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid; D013577:Syndrome; D013580:Synostosis / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics*; D051879:Twist-Related Protein 1 / Q000235:genetics*
D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D001120:Arginine; D011392:Proline; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3