Cole-Carpenter Syndrome 1

A number sign (#) is used with this entry because of evidence that Cole-Carpenter syndrome-1 (CLCRP1) is caused by heterozygous mutation in the P4HB gene (176790) on chromosome 17q25.

Description

Cole-Carpenter syndrome is characterized by bone fragility, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features (Cole and Carpenter, 1987).

Genetic Heterogeneity of Cole-Carpenter Syndrome

Cole-Carpenter syndrome-2 (CLCRP2; 616294) is caused by mutation in the SEC24D gene (607186).

Clinical Features

Cole and Carpenter (1987) described a seemingly new osteogenesis imperfecta-like disorder (see 166200) in 2 unrelated infants. Both had bone deformities and multiple fractures reminiscent of OI but also had ocular proptosis with orbital craniosynostosis, hydrocephalus, and distinctive facial features. Both infants were normal at birth; before the first birthday, however, recurrent diaphyseal fractures of the weight-bearing bones had occurred. Despite the craniosynostosis and hydrocephalus, intellectual development was unimpaired. The parents were unrelated in each case; their ages were not stated. In the first case the mother was noted to have somewhat shallow orbits and her father and grandmother had similar features; a paternal aunt had been examined for hyperthyroidism because of clinically evident proptosis. In this patient, frontal craniectomy was performed at age 9 months to relieve compression of the ocular globes because of an alarming progression of proptosis and frontal bossing. Progressive communicating hydrocephalus was noted by computer tomography at 12 months of age and a lumboperitoneal shunt was established to be replaced later by a ventriculoperitoneal shunt.

Marwaha et al. (1993) reported a 5-month-old boy, born with communicating hydrocephalus, who presented with failure to thrive and macrocephaly. Examination revealed a wide open anterior fontanel, sutural separation, mild proptosis with blue sclerae, micrognathia, high-arched palate, low-set ears, disproportionately small limbs with tiny hands and feet, left-sided metatarso-valgus deformity, and bowing of the lower limbs. There were no obvious fractures. Serum calcium, phosphorus, and alkaline phosphatase were normal. X-rays showed slender osteopenic bones with modeling deformities of the tibiae and femora, but no fractures. CT scan of the head showed a ventriculoperitoneal shunt in place, with normal-sized ventricles and marked sutural diastasis. Marwaha et al. (1993) concluded that this patient likely manifested a variant form of Cole-Carpenter syndrome.

MacDermot et al. (1995) reported the case of a male infant thought to represent either the more severe end of the spectrum of type IV osteogenesis imperfecta (166220) or the mild end of the spectrum of Cole-Carpenter syndrome. Severe hydrops fetalis developed between 19 and 28 weeks of gestation. After delivery at 32 weeks, he was treated by hemofiltration, prolonged ventilation, and intravenous feeding. He had hypertelorism, orbital hypoplasia without proptosis, brachydactyly, frontal and temporal bossing of the skull, central hypotonia, communicating hydrocephalus, and severe delay in psychomotor development. Signs of connective tissue disorder included osteopenia, pathologic fracture, yellow/gray discolored teeth, blue sclerae, and easy bruising.

Amor et al. (2000) reported a girl with clinical features similar to the 2 cases presented by Cole and Carpenter (1987). This patient had a severe progressive type of osteogenesis imperfecta, multisutural craniosynostosis, growth failure, and craniofacial findings, including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. Analysis of type I collagen was normal.

Rauch et al. (2015) provided follow-up on the 2 male patients originally described by Cole and Carpenter (1987). At age 18 years, both were wheelchair-bound with short stature, severe scoliosis, marked deformity of upper and lower limbs with 'popcorn epiphyses' of the distal femura and proximal tibiae, and low bone mineral density. Serum levels of calcium, inorganic phosphorus, creatinine, alkaline phosphatase, and parathyroid hormone (PTH; 168450) were normal.

Molecular Genetics

In 2 unrelated male patients with Cole-Carpenter syndrome, originally described by Cole and Carpenter (1987), Rauch et al. (2015) performed whole-exome sequencing and identified heterozygosity for the same missense mutation in the P4HB gene (Y393C; 176790.0001) in both patients. The mutation occurred de novo in 1 patient; in the other family, the unaffected father was mosaic for the variant, which was present in 23% of cells from saliva but was not detected in skin fibroblasts.

Exclusion Studies

In the girl with Cole-Carpenter syndrome who was originally reported by Amor et al. (2000), Garbes et al. (2015) excluded mutation in the SEC24D gene.