Craniosynostosis 2

A number sign (#) is used with this entry because of evidence that craniosynostosis-2 (CRS2) is caused by heterozygous mutation in the MSX2 gene (123101) on chromosome 5q35.

Description

Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by Fitzpatrick, 2013).

For a discussion of genetic heterogeneity of craniosynostosis, see CRS1 (123100).

Clinical Features

Warman et al. (1993) studied a 3-generation American family of English extraction (referred to by Li et al. (1993) as the Boston family) in which craniosynostosis was segregating in 19 individuals. Although penetrance appeared to be complete, expression varied considerably. Cranial involvement was mild in the grandmother and generally more severe in her affected children and grandchildren. Skull malformations included forehead retrusion, frontal bossing, turribrachycephaly, and the Kleeblattschaedel deformity (cloverleaf skull anomaly; trilobular skull with craniosynostosis). Most affected individuals were myopic or hyperopic and several affected members suffered from severe headaches. Four had a seizure disorder. Intelligence was normal. No hand or foot abnormalities were noted on inspection; radiographic examination in 4 affected individuals demonstrated only short first metatarsals in 3. Muller et al. (1993) emphasized the consistent finding of recession of the supraorbital region in relation to the anterior surface of the cornea.

Florisson et al. (2013) reported a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis, with 12 affected individuals. Each patient had a distinct skull phenotype, but all had craniosynostosis, variably associated with hypotelorism, forehead retrusion, and/or hand abnormalities. The proband presented at 5 months of age with turricephaly, narrow forehead, downslanting palpebral fissures, and hypotelorism. CT scan showed bilateral coronal synostosis, metopic synostosis, and wormian bones. His fingers were short and broad, but there were no bony abnormalities on x-ray. He underwent frontosupraorbital advancement at age 6 months; at 5 years of age he had normal neurologic development. The proband's 47-year-old father had metopic craniosynostosis resulting in trigonocephaly and hypotelorism, but never underwent surgery; he also had short fingers with normal shape, which x-rays showed was due to shortening of all phalanges. A 22-year-old female cousin had complex craniosynostosis for which she underwent surgery in the first year of life; skull remodeling was later performed due to retrusion of the forehead. She also had short fingers, primarily due to shortening of the distal phalanges, and both thumbs had a supination position. Her 17-year-old brother had mild dolichocephaly and had not undergone surgery; he had normal development without any other anomalies. Other affected family members included the proband's 2 paternal aunts, who had brachycephaly due to premature closure of the coronal sutures with elevation of the sphenoid wings on x-ray; both also exhibited generalized copper-beaten appearance, suggestive of elevated intracranial pressure. The paternal grandfather had unilateral coronal suture synostosis and a bony defect in the area of the anterior fontanel; his brother was known to have turricephaly but declined to participate in the study.

Mapping

In a family linkage study using short tandem repeat polymorphisms (STRPs) (Weber and May, 1989), Muller et al. (1993) demonstrated that the gene for the disorder in the Boston family is located on 5q. With D5S211, located at 5q34-qter (Weber et al., 1991), they obtained a maximum lod score of 4.8 at a recombination fraction of 0. No linkage was found in this family to markers on chromosome 7 where a gene for the Saethre-Chotzen syndrome (101400) has been mapped. Supporting the assignment of a locus for a form of craniosynostosis to 5q was the observation of craniosynostosis in an infant with partial trisomy of distal 5q (Van der Burgt et al., 1992).

In a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis, Florisson et al. (2013) performed multipoint linkage analysis and obtained 4 linkage peaks with maximum lod scores between 2 and 2.5, including a 5.9-Mb interval on chromosome 5q35.

Molecular Genetics

To determine whether expression of the MXS2 gene, which maps to the same region of chromosome 5 as craniosynostosis-2, is consistent with its being a candidate gene for the phenotype, Li et al. (1993) demonstrated by in situ hybridization that mouse Msx2 transcripts are present in osteoblasts adjacent to calvarial sutures during mouse embryonic and postnatal development. In addition, Li et al. (1993) found that a (CA)n polymorphism within the MSX2 gene segregated with craniosynostosis in the Boston family studied by Warman et al. (1993) and Muller et al. (1993); no recombination was observed, giving a maximum lod score of 4.80. All affected members were found to have substitution of histidine for proline at amino acid position 7 of the homeodomain (P148H; 123101.0001); the mutation was absent in all unaffected members of the family and 68 controls. This proline residue is conserved in all known MSX genes in organisms as diverse as insects and mammals. Li et al. (1993) claimed that this was the first report of a mutation in a homeobox gene associated with a human disorder. See Jabs et al. (1993) for the full report. This is a good example of identification of the defect in a disorder by the candidate gene approach.

In 7 affected members of a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis, Florisson et al. (2013) identified heterozygosity for a pro148-to-leu mutation (P148L; 123101.0009) in the MSX2 gene. The mutation altered the same proline as that identified by Li et al. (1993) in the Boston family with CRS2. The proband and his father, who were the only patients to manifest osteopoikilosis (see 166700), were also heterozygous for a deletion in the LEMD3 gene (607844). The LEMD3 mutation appeared to have arisen de novo in the father, and the presence of osteopoikilosis in the 2 patients was considered to be a coincidental anomaly unrelated to the craniosynostosis phenotype.