Crouzon Syndrome

A number sign (#) is used with this entry because of evidence that Crouzon syndrome is caused by heterozygous mutation in the gene encoding fibroblast growth factor receptor-2 (FGFR2; 176943) on chromosome 10q26.

See also Crouzon syndrome with acanthosis nigricans (CAN; 612247), a distinct disorder caused by a specific mutation in the FGFR3 gene (A391E; 134934.0011).

Description

Crouzon syndrome is an autosomal dominant disorder characterized by craniosynostosis causing secondary alterations of the facial bones and facial structure. Common features include hypertelorism, exophthalmos and external strabismus, parrot-beaked nose, short upper lip, hypoplastic maxilla, and a relative mandibular prognathism (Reardon et al., 1994; Glaser et al., 2000).

Clinical Features

Crouzon (1912) first described this syndrome in a family.

Shiller (1959) observed autosomal dominant transmission of Crouzon craniofacial dysostosis in 23 family members spanning 4 generations. There was marked variability in both cranial and facial manifestations. Dodge et al. (1959) described 3 patients with typical Crouzon disease; 2 of these had a positive family history and one was sporadic.

Devine et al. (1984) described a completely cartilaginous trachea without ring formation in a child with Crouzon syndrome who continued to have respiratory distress despite surgical repair of choanal stenosis. Death from respiratory problems occurred at the age of 23 months.

Cohen et al. (1993) reported a mother, son, and daughter in whom serial photographs documented an insidious and late onset of exorbitism and midfacial retrusion. Papilledema resulting from increased intracranial pressure secondary to a reduction in cranial vault size was found in the 4.5-year-old daughter, whereas optic nerve sheath swelling was found on CT scan in the son.

Reddy et al. (1990) described 4 patients who presented between the ages of 2 and 9 years with 'delayed holocalvarial synostosis.'

Cinalli et al. (1995) reviewed the neurosurgical complications of Crouzon syndrome in a series of 68 patients. Nineteen of these patients required treatment for progressive hydrocephalus and 72.7% of these patients had chronic tonsillar herniation, which was symptomatic in 6 individuals. Four individuals had syringomyelia and another had a respiratory standstill, whereas the remaining patient had painful torticollis.

Phenotypic Variability

Bagheri-Fam et al. (2015) reported a 15-year-old girl with Crouzon-like craniosynostosis and a mutation in the FGFR2 gene who also exhibited 46,XY complete gonadal dysgenesis. Craniofacial features included brachycephalic craniosynostosis for which she required surgery, proptosis with downslanting palpebral fissures, and low-set dorsally rotated ears. The patient also had short stature and limited movement of the elbows and knees, but no anomalies of the hands or feet. She presented with delayed puberty, primary amenorrhea, female external genitalia, and Mullerian structures, and underwent gonadectomy due to the presence of bilateral ovarian tumors. Histologic analysis revealed bilateral dysgerminoma, which apparently developed from preexisting gonadoblastoma. The gonads lacked seminiferous tubules, and only a few Sertoli- and Leydig-like cells were detected.

Inheritance

Fogh-Andersen (1943), Flippen (1950), and Shiller (1959) traced Crouzon craniosynostosis through 4 generations of 3 different families, consistent with autosomal dominant inheritance. Pinkerton and Pinkerton (1952) observed the disorder in a mother and 2 of her 3 daughters.

Vulliamy and Normandale (1966) identified 14 cases of Crouzon disease in 4 generations of a family with several instances of male-to-male transmission.

Jones et al. (1975) found evidence of paternal age effect in new mutations for this disorder.

Rollnick (1988) described 2 brothers with Crouzon syndrome born to normal, unrelated parents, and proposed germinal mosaicism as the explanation. Kreiborg and Cohen (1990) suggested germinal mosaicism as the basis for 2 affected sibs with the same mother but different fathers. The mother and both fathers were completely normal.

Goriely et al. (2010) reported a girl with a mild form of Crouzon syndrome, confirmed by genetic analysis, whose clinically unaffected mother was found to be somatic mosaic for a heterozygous FGFR2 mutation. Levels of maternal somatic mosaicism for the mutation were estimated to range from 3.3% in hair roots to 14.1% in blood. Since her daughter inherited the same mutation, it was presumed to be present also in the mother's germline. The findings underlined the importance of parental molecular testing for accurate genetic counseling of the risk of recurrence for Crouzon syndrome, which is most often due to a de novo mutation resulting from a paternal age effect.

Mapping

In a large kindred with Crouzon craniofacial dysostosis, Preston et al. (1994) found linkage to 3 loci (D10S190, D10S209, and D10S216) spanning a 13-cM region on chromosome 10q. A maximum pairwise lod score of 4.42 at theta = 0.0 was obtained with D10S190 and the addition of a second kindred produced a combined pairwise lod score of 5.32 at theta = 0.0. In a note added in proof, Preston et al. (1994) stated that a newly available highly informative marker, D10S587, located 7 cM distal to D10S209, increased the 2-family multipoint lod score for linkage between CFD1 and D10S209 to 7.3 at theta = 0.0. Two of the genetic marker loci were within 10q25-q26.

Molecular Genetics

Reardon et al. (1994) identified mutations in the FGFR2 gene (see, e.g., 176943.0001-176943.0006) in 9 of 20 patients with Crouzon syndrome. Because no evidence of genetic heterogeneity on the basis of linkage studies had been found, Reardon et al. (1994) concluded that mutations in parts of the FGFR2 gene other than in the B exon were responsible for the remaining cases.

Jabs et al. (1994) demonstrated mutations in the FGFR2 gene in patients with Crouzon syndrome as well as in patients with Jackson-Weiss syndrome (JWS; 123150).

Charnas et al. (1989) described affected male and female second cousins, and suggested either incomplete penetrance or another molecular predisposition ('premutation'). However, Meyers et al. (1995) reported that the 2 patients described by Charnas et al. (1989) had mutations in different genes: the patient with classic Crouzon syndrome had an FGFR2 mutation (176943.0009), whereas the second cousin had Crouzon syndrome with acanthosis nigricans (612247) due to the FGFR3 A391E mutation (134934.0001).

In 22 of 41 probands with Crouzon syndrome or Pfeiffer syndrome (101600), Glaser et al. (2000) identified 11 different FGFR2 mutations. All the mutations were paternal in origin. Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals. This finding extended previous information on advanced paternal age for sporadic FGFR2 mutations causing Apert syndrome (101200) and FGFR3 mutations causing achondroplasia (100800).

In a 15-year-old girl with Crouzon-like craniosynostosis and 46,XY complete gonadal dysgenesis, Bagheri-Fam et al. (2015) sequenced the candidate gene FGFR2 and identified heterozygosity for the C342S mutation (176943.0003) that had previously been identified in 1 patient diagnosed with Crouzon syndrome, 1 patient diagnosed with Jackson-Weiss syndrome (123150), and 1 patient with an 'extreme' Antley-Bixler phenotype (207410). DNA from the proband's parents was unavailable for study. Whole-exome sequencing to search for potential modifier variants influencing the proband's phenotype revealed single-nucleotide variants or indels in 193 genes. Bagheri-Fam et al. (2015) noted that although none of the changes were located in 63 genes associated with disorders of sex development, the patient did carry novel changes or indels in 35 genes that, in mice, are expressed in pre-Sertoli cells at the time of sex determination.

Population Genetics

Cohen and Kreiborg (1992) estimated that Crouzon syndrome represents approximately 4.8% of cases of craniosynostosis at birth. The birth prevalence was estimated to be 16.5 per million births.

Animal Model

Eswarakumar et al. (2006) generated mice with a Crouzon-like craniosynostosis induced by a dominant mutation in the mesenchymal splice form of Fgfr2 (Fgfr2c) (C342Y; 176943.0001), and observed ocular proptosis, a rounded cranium, fusion of the coronal sutures, and a significantly shortened facial region. Expression of the C342Y mutation in cis with the L424A and R426A mutations of the juxtamembrane domain resulted in attenuation of signaling pathways by selective uncoupling between the docking protein Frs2a (607743) and activated Fgfr2c, thus preventing premature fusion of sutures and resulting in normal skull development. Eswarakumar et al. (2006) also demonstrated that attenuation of Fgfr signaling in a calvaria organ culture with an Fgfr inhibitor prevented premature fusion of sutures without adversely affecting the development of the skull.

History

On the basis of an affected brother and sister with unaffected nonconsanguineous parents, Juberg and Chambers (1973) suggested the existence of a recessive form of Crouzon disease.

Pseudo-Crouzon Syndrome

Franceschetti (1953) described a seemingly distinct disorder under the designation cranial dysostosis with pronounced digital impressions, or 'pseudo-Crouzon disease.' However, Gorlin (1982) concluded that it is not distinct from Crouzon disease. According to Franceschetti's appraisal, in Crouzon disease and pseudo-Crouzon disease, the pronounced digital impressions, or convolutional markings, are identical, and the essential difference is in the face: in pseudo-Crouzon disease, there is no prognathism, the nose is not curved, and divergent squint is usually lacking. Prominent forehead and some degree of exophthalmos are features. Franceschetti (1968) proposed that Walsh (1957) described a case of pseudo-Crouzon disease as Crouzon disease. None of Franceschetti's cases was familial, but Dolivo and Gillieron (1955) described affected brother and sister whose mother, grandmother, and great-grandmother were said to have oxycephaly.