Craniofacial Anomalies, Part 2 - Plastic Surgery Internal

Approximately 2% of cases of isolated craniosynostosis
are inherited. 154 Cohen, Dauser, and Gorski 155
documented three close relatives with delayed onset
of exorbitism and midfacial retrusion thought to be
consistent with a diagnosis of familial, nonsyndromic
craniosynostosis. In contrast, a hereditary component
has been identified in as many as 50% of
syndromal craniosynostosis patients. 154
The Role of the Dura in Craniosynostosis
In cases of primary craniosynostosis the underlying
dura mater acts locally to supply the overlying
suture with osteogenic growth factors. Opperman in
1993 showed the role of the dura in determining the
fate of suture fusion, 156 and that these dural factors
were soluble. 157 Hobar158,159 noted the importance
of the dura in the regeneration of cranial bones in
infants. Greenwald160,161 went further, finding that
immature dura mater contained a subpopulation of
osteoblast-like cells. Levine162 showed that the region
of the dura was as important as the interaction
between the suture and the dura. The overlying
pericranium does not play a role in suture biology,
according to Opperman. 163 Clearly the dura underlying
the suture drives the timing of closure through
osteoinductive growth factors
Molecular Genetics in Craniosynostosis
Elevated FGF-R2 was identified by Delezoide164 as the first real marker of prechondrogenic condensations.
Mangasarian165 identified a tyrosine for cysteine
substitution on the mutated FGF-R2 that creates
an activated form, resulting in uncontrolled FGF
signaling and premature suture closure.
Most166 and Mehrara167 found that expression
of basic fibroblast growth factor (bFGF) was
increased in the dura beneath the suture prior to
fusion and increased in the osteoblasts at the suture
during fusion. Other growth factors have been
found to be increased in prematurely fusing
sutures: transforming growth factor B (TGF-
B) 166,168–171 and bone morphogenic proteins
(BMPs). 171 Research is now directed at inducing
craniosynostosis in animal models by the application
of exogenous FGFs to confirm their role in
suture closure. 172 Genes whose mutations result
in craniosynostosis syndromes are listed in Table
4. 173,174
SRPS Volume 10, Number 17, Part 2
TABLE 4
Genes Bearing Known Mutations
for Craniosynostosis
(Reprinted with permission from Cohen MM Jr: Discussion of
“Differential expression of fibroblast growth factor receptors in
human digital development suggests common pathogenesis in
complex acrosyndactyly and craniosynostosis”, by Britto JA,
Chan JCT, Evans RD, et al. Plast Reconstr Surg 107:1339, 2001.)
In 1993 a mutation in the homeobox gene MSX2
was identified in a single family with autosomal dominant
craniosynostosis, now known as Boston-type
craniosynostosis. 175 Recent evidence suggests that
this mutation may exert its effect through BMP pathways
176,177 and that MSX2 mutations may function
together with FGF-R2. 178
Crouzon syndrome has been extensively studied
genetically and a mapped abnormality is noted on
the long arm of chromosome 10. 179 Further analysis
localized an FGF-R2 genetic mutation within this
chromosome in subjects with Crouzon. 180
In 1994 Muenke and colleagues 181 described a
common mutation in the FGF-R1 gene as the cause
of Pfeiffer’s syndrome. In 1995 Apert and Pfeiffer
syndromes were also found to be related to FGF-R2
mutations. 182–184 Mutations in the FGF-R2 gene now
having been shown to be the cause of Jackson-Weiss
syndrome, Crouzon syndrome, Pfeiffer syndrome, and
Apert syndrome, these conditions should be seen as
defined points along a spectrum of disease (Fig 12).
FGF-R3 mutations are also implicated in isolated
unicoronal craniosynostosis. 185 Current understanding
allows a molecular diagnosis in all phenotypical
cases of bicoronal synostosis. 186 Other genetic mutations
have been associated with synostosis. The
hedgehog family of homologs, including sonic hedgehog,
play a role in vertebral embryogenesis. Recently
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