Paula and Bobby
Parents of Lillie
What is Crouzon syndrome?
Crouzon syndrome syndrome is a genetic condition which results in the premature fusion of the skull bones. This premature fusing causes most of the serious symptoms of the condition.
Crouzon syndrome occurs in around 1 in every 16 million live births. It is the most common craniosynostosis syndrome.
Craniofacial Dysostosis, Type I; Cfd1 Crouzon Craniofacial Dysostosis
What gene changes cause Crouzon syndrome?
Mutations to the FGFR2 gene, considered to be responsible for the premature formation of the bones in affected individuals. It is inherited in an autosomal dominant pattern.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
What are the main symptoms of Crouzon syndrome?
The main symptoms of the syndrome include unique facial characteristics such as a sunken face, depressed nasal bridge, and a beak nose. Other facial characteristics include a large forehead, protruding eyes, and a narrow palate which may or may not be cleft.
Other health conditions associated with the syndrome include hearing loss, fused bones and conditions that are a consequence of the bone fusion including sleep apnea, and breathing obstructions.
Possible clinical traits/features:
Acanthosis nigricans, Visual impairment, Hypopigmented skin patches, Hypoplasia of the maxilla, Hypertelorism, Hydrocephalus, High forehead, Optic atrophy, Melanocytic nevus, Autosomal dominant inheritance, Shallow orbits, Seizure, Choanal atresia, Arnold-Chiari malformation, Aplasia/Hypoplasia of the cerebellum, Abnormal sacrum morphology, Abnormal palate morphology, Abnormality of the nasopharynx, Abnormality of the cervical spine, Convex nasal ridge, Brachycephaly, Sagittal craniosynostosis, Sleep apnea, Frontal bossing, Ptosis, Respiratory failure, Strabismus, Intellectual disability, Iris coloboma, Lambdoidal craniosynostosis, Migraine, Increased intracranial pressure, Mandibular prognathia, Craniosynostosis, Craniofacial dysostosis, Abnormal facial shape, Coronal craniosynostosis, Atresia of the external auditory canal, Dental crowding, Conductive hearing impairment, Conjunctivitis
How does someone get tested for Crouzon syndrome?
The initial testing for Crouzon syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Crouzon syndrome
This is one of the most common of the craniosynostosis syndromes. It is characterised by premature closure of the coronal sutures, and facially by mid-facial hypoplasia, proptosis secondary to shallow orbits, mild hypotelorism, a beak shaped nose and a small jaw. Severe cases might show a clover-leaf skull. Cinalli et al., (1996) found evidence for a Chiari malformation in 70% of all cases and 58% of cases with associated hydrocephalus. Chiari malformations seem to correlate with early closure of the lambdoid suture. Intelligence is usually normal. The other sutures, which include the sagittal and lambdoid, might also be prematurely fused. The shape of the skull is usually brachycephalic, but can be scaphocephalic depending on the order of premature closure of the sutures. Expression can be very variable and early photographs of both parents are necessary before deciding that the patient under consideration is a fresh mutant. Davis et al., (1992) reported the association with fusion of the tracheal cartilages to give a ""tracheal cartilaginous sleeve"". A similar infant was noted by Sagehashi (1992). This infant also had a caudal appendage (as did the case reported by Lapunzina et al., 2005, with a novel FGFR2 insertion). A further case with a cartilaginous sleeve was reported by Scheid et al., (2002) who also reviewed the literature of this association. Okajima et al., (2003) studied three patients with craniosynositosis and a tracheal sleeve and could not find common FGFR2 mutations in exon IIIa or IIIc of the FGFR2 gene. Complications include optic atrophy and deafness. Another case with a tracheal cartilaginous sleeve was reported by Shimada et al., (1979). Acanthosis nigricans is an occasional, and interesting association (see Koizumi et al., 1992). Iris colobomas are occasionally seen (Kreiborg, 1981). Note the case reported by Ciuci et al., (2004) with a novel FGFR2 novel mutation, but without craniosynostosis. There was a small jaw, prominent eyes and hydrocephalus. The case reported by Maeda et al., (2004) with a mutation, was also atypical n that she was mildly retarded.
Sinus pericranii (a vascular tumour, communicating with the dural vascular system) have been reported (Mitsukawa et al., 2007).
Preston et al., (1994) mapped the gene to 10q25-q26. Ma et al., (1995) found no evidence for locus heterogeneity in six families. Reardon et al., (1994) demonstrated mutations in the fibroblast growth factor receptor 2 gene (FGFR2) in nine separate cases of Crouzon syndrome. In five cases the mutation involved a cysteine in the third extracellular, immunoglobulin-like domain of the molecule. In two cases there was an A344A mutation creating a possible new donor splice site. Li et al., (1995) demonstrated that this mutation does indeed produce a stable transcript coding for an altered receptor with a deletion in the Ig IIIc domain of FGFR2. Alternative splicing produces two forms of the receptor. The form incorporating the B exon is expressed in high concentration in bone and calvarium, whereas the form with the K exon is expressed more strongly in skin. Further mutations in the B exon were found by Jabs et al., (1994). Oldridge et al., (1995) found mutations, including a 9 base pair deletion, in the neighbouring exon which codes for the first part of the third immunoglobulin-like domain. Meyers et al., (1996) showed further mutations in the FGFR2 gene in cases with Crouzon, Pfeiffer and 'Jackson-Weiss' phenotypes. In one family with a novel exon IIIc mutation (valine 359 phenyalanine) the proband and his father exhibited classical features of Crouzon syndrome whereas the paternal aunt resembled Pfeiffer syndrome with broad thumbs and great toes. Steinberger et al., (1996) reported a family where some individuals had features of Crouzon syndrome, but in others the phenotype was more non-specific. A G1044A transition at codon 344 of exon 7 of the FGFR2 gene was found. Steinberger et al (1997) reported a child with plagio/scaphocephaly with an A886G mutation in exon 5 of the FGFR2 gene. A further comprehensive mutation series was reported by Kan et al., (2002). Glaser et al., (2000) showed that FGFR2 mutations in Crouzon syndrome were exclusively paternal in 22 cases.
Neilson and Friesel (1995) showed by microinjection of Xenopus embryos with RNA encoding an FGFR2 protein bearing a Cys332->Tyr mutation that there was FGF induction of mesoderm in animal pole explants.
Meyers et al., (1995) demonstrated mutations in the transmembrane domain of the FGFR3 gene in cases associated with acanthosis nigricans. Wilkes et al., (1996) confirmed this association. The mutation is consistently an Ala391Glu. Somatic and germline mosaicism was recorded in a mother of an affected child by Goriely et al., (2010). They stress the importance of molecular testing for accurate genetic counselling.
Schwartz et al., (1996) reported prenatal diagnosis in two cases by demonstration of FGFR2 mutations. Pulleyn et al., (1996) reported cases with unusual clinical features associated with mutations of the first immunoglobulin-like loop and the transmembrane domain. Wilkie (1997) provides an excellent review of the mutations and mechanisms of craniosynostosis in this disorder.
Okajima et al., (1999) reported three patients with a severe form of the condition who had anterior chamber anomalies. An FGFR2 Ser351Cys mutation was found in all of them.
Li et al. (2016) described five members of the same family with Crouzon syndrome. Clinical characteristics included short stature, craniosynostosis, ocular proptosis, external strabismus and mandibular prognathism. Additional features were intracranial hypertension, metacarpal-phalangeal shortening, and shallow orbits. Brain MRI showed hydrocephalus, hyperostosis of the frontal bone, cerebral atrophy, dilated paracele and subarachnoid space, and sellar and the third ventricular cysts.
* This information is courtesy of the L M D.
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