Molecular diagnosis of bilateral coronal synostosis.

The authors performed a prospective study evaluating molecular diagnosis in patients with bilateral coronal synostosis. The patients were divided into two groups: (1) those clinically classified as having Apert, Crouzon, or Pfeiffer syndrome and (2) those clinically unclassified and labeled as having brachycephaly. Blood samples were drawn for genomic DNA analysis from 57 patients from 1995 to 1997. Polymerase chain reactions were performed using primers flanking exons in FGFR 1, 2, and 3. Each exon was screened for mutations using single-strand confirmation polymorphism, and mutations were identified by DNA sequencing. Mutations in FGFR2 or FGFR3 were found in all patients (n = 38) assigned a phenotypic (eponymous) diagnosis. All Apert syndrome patients (n = 13) carried one of the two known point mutations in exon 7 of FGFR2 (Ser252Trp and Pro253Arg). Twenty-five patients were diagnosed as having either Crouzon or Pfeiffer syndrome. Five patients with Crouzon syndrome of variable severity had mutations in exon 7 of FGFR2. Fifteen patients (12 with Crouzon, 3 with Pfeiffer) had a mutation in exon 9 of FGFR2, many of which involved loss or gain of a cysteine residue. A wide phenotypic range was observed in patients with identical mutations, including those involving cysteine. Two patients labeled as having Crouzon syndrome had the Pro250Arg mutation in exon 7 of FGFR3. All three patients with the crouzonoid phenotype and acanthosis nigricans had the same mutation in exon 10 of FGFR3 (Ala391Glu). This is a distinct disorder, characterized by jugular foraminal stenosis, Chiari I anomaly, and intracranial venous hypertension. Mutations were found in 14 of 19 clinically unclassifiable patients. Three mutations were in exon 9, and one was in the donor splice site of intron 9 on FGFR2. The most common mutation discovered in this group was Pro250Arg in exon 7 of FGFR3. These patients (n = 10) had either bilateral or unilateral coronal synostosis, minimal midfacial hypoplasia with class I or class II occlusion, and minor brachysyndactyly. No mutations in FGFR 1, 2, or 3 were detected in five patients with nonspecific brachycephaly. In conclusion, a molecular diagnosis was possible in all patients (n = 38) given a phenotypic (eponymous) diagnosis. Different phenotypes observed with identical mutations probably resulted from modulation by their genetic background. A molecular diagnosis was made in 74 percent of the 19 unclassified patients in this series; all mutations were in FGFR2 or FGFR3. Our data and those of other investigators suggest that we should begin integrating molecular diagnosis with phenotypic diagnosis of craniosynostoses in studies of natural history and dysmorphology and in analyses of surgical results.

[1]  M. Cohen.  Let's call it "Crouzonodermoskeletal syndrome" so we won't be prisoners of our own conventional terminology. , 1999, American journal of medical genetics.

[2]  J. Heath,et al.  Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. , 1998, Human molecular genetics.

[3]  D. Rice,et al.  FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. , 1998, Development.

[4]  G. Vriend,et al.  The mutations in FGFR2-associated craniosynostoses are clustered in five structural elements of immunoglobulin-like domain III of the receptor , 1998, Human Genetics.

[5]  D. Donoghue,et al.  Enhanced signaling and morphological transformation by a membrane-localized derivative of the fibroblast growth factor receptor 3 kinase domain , 1997, Molecular and cellular biology.

[6]  C. Basilico,et al.  Mutation associated with Crouzon syndrome causes ligand‐independent dimerization and activation of FGF receptor‐2 , 1997, Journal of cellular physiology.

[7]  D. Donoghue,et al.  FGFR activation in skeletal disorders: too much of a good thing. , 1997, Trends in genetics : TIG.

[8]  M. Cohen,et al.  Transforming Growth Factor βs and Fibroblast Growth Factors and Their Receptors: Role in Sutural Biology and Craniosynostosis , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[9]  J. Mulliken,et al.  Jugular foraminal stenosis in Crouzon syndrome. , 1996, Pediatric neurosurgery.

[10]  R. Friesel,et al.  Ligand-independent Activation of Fibroblast Growth Factor Receptors by Point Mutations in the Extracellular, Transmembrane, and Kinase Domains* , 1996, The Journal of Biological Chemistry.

[11]  A. N. Meyer,et al.  Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2/Neu chimeras. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[12]  J. Mulliken,et al.  Molecular genetics and craniofacial surgery. , 1996, Plastic and reconstructive surgery.

[13]  S. Kreiborg,et al.  Hands and feet in the Apert syndrome. , 1995, American journal of medical genetics.

[14]  M. Cohen,et al.  Craniosynostoses: phenotypic/molecular correlations. , 1995, American journal of medical genetics.

[15]  J. Mulvihill.  Craniofacial syndromes: no such thing as a single gene disease , 1995, Nature Genetics.

[16]  J. Mulliken,et al.  Newly recognized autosomal dominant disorder with craniosynostosis. , 1993, American journal of medical genetics.

[17]  M. Cohen,et al.  Pfeiffer syndrome update, clinical subtypes, and guidelines for differential diagnosis. , 1993, American journal of medical genetics.

[18]  J. Weber,et al.  Assignment of a gene locus involved in craniosynostosis to chromosome 5qter. , 1993, Human molecular genetics.

[19]  D. Givol,et al.  Complexity of FGF receptors: genetic basis for structural diversity and functional specificity , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[20]  S. Bartlett,et al.  Craniosynostosis: an analysis of the timing, treatment, and complications in 164 consecutive patients. , 1987, Plastic and reconstructive surgery.

[21]  A. Krishnaram,et al.  AN UNUSUAL ASSOCIATION OF ACANTHOSIS NIGRICANS AND CROUZON'S DISEASE— , 1985, The Journal of dermatology.

[22]  J. Mulliken,et al.  Crouzon syndrome: Previously unrecognized deletion, duplication, and point mutation within FGFR2 gene , 1996, Human mutation.

[23]  D. David,et al.  Pfeiffer syndrome: a clinical review. , 1995, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.