Cole-Carpenter Syndrome 2

A number sign (#) is used with this entry because of evidence that Cole-Carpenter syndrome-2 (CLCRP2) is caused by compound heterozygous mutation in the SEC24D gene (607186) on chromosome 4q26.

For a general phenotypic description and discussion of genetic heterogeneity of Cole-Carpenter syndrome, see CLCRP1 (112240).

Clinical Features

Garbes et al. (2015) reported a German boy with multiple pre- and postnatal fractures and craniofacial malformations. At birth, he was noted to have turricephaly, exophthalmos, downslanting palpebral fissures, angular root of nose, retrognathia, and gaping fontanels. Ultrasound and x-ray examination showed both new and old fractures involving the right clavicle, multiple ribs, and both radii, as well as extensive ossification defects of the cranium and craniosynostosis. Additional features observed at 9 months of age included hypertelorism, midface hypoplasia, high palate, and slight dysplasia of right concha. At 4.3 years of age, he had delayed motor development due to recurrent fractures of the extremities, but he was able to walk, run, and climb stairs. CT scan showed dilated ventricles and subarachnoid spaces, in addition to a large frontoparietoapical ossification defect, for which he wore a helmet during physical activities. At 7 years of age he had moderately reduced bone mineral density, macrocephaly of postnatal onset, and short stature, with facial features reminiscent of Cole-Carpenter syndrome. Garbes et al. (2015) also studied 2 female fetuses from terminated pregnancies in a second German family. Prenatal ultrasound had shown multiple fractures of the long bones, mildly bent extremities, and a thin, poorly ossified skull. X-ray examination of 1 of the fetuses revealed a calvarium with severely reduced and largely absent ossification, in contrast to normal ossification of the skull base and only mildly disturbed ossification and shape of the remainder of the skeleton. The ribs were thin and fractures were noted, but the thorax was not severely hypoplastic, suggesting that the skeletal defects were nonlethal.

Moosa et al. (2016) reported a 16-month-old girl, born to nonconsanguineous Chinese parents, with a more classic OI phenotype and a mutation in the SEC24D gene. Short long bones were noted on prenatal ultrasound at 18 weeks' gestation. She presented during the neonatal period with blue-gray sclerae, osteopenia, wormian bones, and deformities of the the long bones. No dysmorphic craniofacial features were present. Her coronal sutures were patent and her anterior fontanel was enlarged but not to the extent described in the patients reported by Garbes et al. (2015). She sustained a fracture of the right proximal femur at age 12 months followed by a fracture of the right tibia at age 15 months; both were treated successfully.

Zhang et al. (2017) reported 2 unrelated patients, both born of nonconsanguineous Chinese parents, with mutations in the SEC24D gene and a clinical diagnosis of OI. The first proband was a 23-year-old man (family 1) who had recurrent fractures beginning at age 1 month, deformities in both lower limbs with severe bowing of the left femur, and facial dysmorphism, including downslanting palpebral fissures, frontal protrusion, left ear dysplasia, and micrognathia. His anterior fontanel was not closed and CT of the cranium showed skull deformities associated with a broad frontoapical ossification defect, a widened sagittal suture, and wormian bones. He had dentinogenesis imperfecta but did not exhibit blue sclerae or hearing loss. The second proband was a 7-year-old boy (family 2) who had recurrent fractures beginning at age 1.5 years and severe bowing in the left femur. He had dentinogenesis but did not have blue sclerae or hearing loss. His anterior fontanel was not closed and he had no obvious facial dysmorphism. Zhang et al. (2017) noted some similarities between the proband from family 1 and the patient reported by Garbes et al. (2015) and suggested that facial dysmorphisms may be characteristic of OI patients with SEC24D mutations.

Takeyari et al. (2018) reported a 15-year-old Japanese boy with features consistent with Cole-Carpenter syndrome-2. The boy had growth failure with a short trunk and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. He had a wide open fontanel as well as low bone mineral density (BMD), with a healed iliac bone fracture observed at age 10 years. Skeletal imaging showed wormian bones, lordosis, and long thin bones. Brain imaging revealed hydrocephalus and basilar impression. Because of his low BMD and basilar impression, he received periodic bisphosphonate therapy from 6 years of age. His BMD improved, but basilar impression did not change.

Molecular Genetics

In a 7-year-old German boy with CLCRP2, Garbes et al. (2015) performed exome sequencing and identified compound heterozygosity for a missense mutation (S1015F; 607186.0001) and a nonsense mutation (Q205X; 607186.0002) in the SEC24D gene. His unaffected parents were each heterozygous for 1 of the mutations. In another German family in which 2 pregnancies with female fetuses had been terminated due to what appeared to be a severe form of osteogenesis imperfecta (OI; see 166200), Garbes et al. (2015) identified the S1015F mutation and another missense mutation (Q978P; 607186.0003) in SEC24D. Both affected fetuses were compound heterozygous for the mutations, and the unaffected parents and an unaffected sister were each heterozygous for 1 of the mutations. The mother of the first family and the father of the second family, who were both descended from families residing in southwestern Germany, carried the S1015F mutation; haplotype analysis revealed a 14-Mb shared region between rs6533681 and rs2255457 (chr4:114,309,589-128,554,154), confirming that S1015F represents a founder mutation. Garbes et al. (2015) noted overlap between features of these patients and individuals with craniolenticulosutural dysplasia (CLSD; 607812), which is caused by mutation in a related gene (SEC23A; 610511), but concluded that the phenotype of their patients more closely resembled that of Cole-Carpenter syndrome.

In a 16-month-old girl, born of nonconsanguineous Chinese parents, with a clinical diagnosis of moderate OI, Moosa et al. (2016) identified compound heterozygous mutations in the SEC24D gene (607186.0004-607186.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family.

In 2 unrelated males, both born of nonconsanguineous Chinese parents, with a clinical diagnosis of OI, Zhang et al. (2017) identified compound heterozygous mutations in the SEC24D gene (607186.0006-607186.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype in the family.

In a 15-year-old Japanese boy with Cole-Carpenter syndrome-2, Takeyari et al. (2018) identified compound heterozygous mutations in the SEC24D gene (R313H, 607186.0008 and R484X, 607186.0010). The R313H mutation was inherited from his mother, but DNA from his father was unavailable for testing. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in public or in-house exome databases.