Carpenter Syndrome 1

A number sign (#) is used with this entry because of evidence that Carpenter syndrome-1 (CRPT1) is caused by homozygous mutation in the RAB23 gene (606144) on chromosome 6p11.

Description

Carpenter syndrome is a rare autosomal recessive disorder with the cardinal features of acrocephaly with variable synostosis of the sagittal, lambdoid, and coronal sutures; peculiar facies; brachydactyly of the hands with syndactyly; preaxial polydactyly and syndactyly of the feet; congenital heart defects; growth retardation; mental retardation; hypogenitalism; and obesity. In addition, cerebral malformations, oral and dental abnormalities, coxa valga, genu valgum, hydronephrosis, precocious puberty, and hearing loss may be observed (summary by Altunhan et al., 2011).

Genetic Heterogeneity of Carpenter Syndrome

Carpenter syndrome-2 (CRPT2; 614976), in which the features of Carpenter syndrome are sometimes associated with defective lateralization, is caused by mutation in the MEGF8 gene (604267).

Clinical Features

Carpenter (1909) described 2 sisters and a brother with acrocephaly, peculiar facies, brachydactyly, and syndactyly in the hands, and preaxial polydactyly and syndactyly of the toes. Temtamy (1966) could find 9 other reported cases and added one. In older patients obesity, mental retardation, and hypogonadism had been noted. In all cases the parents have been normal. Parental consanguinity was suspected in 1 case.

The case of acrocephalosyndactyly with foot polydactyly reported by Owen (1952) probably represented Carpenter syndrome, as do the sibs reported by Schonenberg and Scheidhauer (1966). One patient thought to have this condition by Palacios and Schimke (1969) was 49 years old. Eaton et al. (1974) reported affected sibs.

Cohen et al. (1987) described 2 affected sibs showing marked intrafamilial variability. This experience and a review of the literature suggested that the Goodman syndrome (201020) and the Summitt syndrome (272350) fall well within the clinical spectrum of the Carpenter syndrome. Gershoni-Baruch (1990) described a brother and sister with rather striking differences in severity. The first born had craniosynostosis of the sagittal suture, normal intelligence, and no abnormalities of the hands and feet. The second born sib had polysyndactyly of hands and feet, normal intelligence, and no craniosynostosis. Gershoni-Baruch (1990) suggested that polysyndactyly is not an absolute requisite for the diagnosis of Carpenter syndrome and that the Summitt and Goodman syndromes are 'within the clinical spectrum' of Carpenter syndrome, as suggested by Cohen et al. (1987).

Alessandri et al. (2010) described 4 boys with Carpenter syndrome from a consanguineous Comoros Islands pedigree. All 4 boys presented with acrocephaly and polysyndactyly, but displayed variable severity of craniosynostosis ranging from cloverleaf skull to predominant involvement of the metopic ridge (turricephaly). All of the children also had a combination of brachydactyly with agenesis of the middle phalanges, syndactyly, broad thumbs, and postaxial polydactyly in the hands, with preaxial polydactyly and syndactyly of the toes. Mental development was normal in all; brain imaging showed hydrocephalus in 2 of the 4 boys. Additional features included corneal anomaly in 2, cryptorchidism in 3, umbilical hernia in 1, genu valgum in 2, umbilical hernia in 1, severe kyphoscoliosis in 1, patent ductus arteriosus in 1, and accessory spleen in 1.

Haye et al. (2014) reported the prenatal findings in a Turkish infant with Carpenter syndrome and a mutation in the RAB23 gene. A cystic hygroma and bowed femora were detected at 14 to 15 weeks' gestation, double-outlet right ventricle at 22 weeks, and abnormal skull shape with irregular outlines and easily visible brain structures at 28 weeks. The skeletal findings were confirmed by fetal CT scan and raised the question of osteogenesis imperfecta. Retrospectively, the postnatal findings of multiple suture craniosynostosis and bilateral preaxial polydactyly of the feet were detectable on the fetal CT scan. Haye et al. (2014) reviewed the literature and identified 6 cases of Carpenter syndrome with identifiable prenatal features, including abnormal skull shape in 6, short limbs in 2, polyhydramnios in 2, enlarged cerebral ventricles in 2, and several other features reported only once. Haye et al. (2014) suggested that heart defect associated with prenatal bowing of femora, abnormal skull shape, and polydactyly should raise the question of Carpenter syndrome.

Mapping

Using homozygosity mapping, Jenkins et al. (2007) found linkage of Carpenter syndrome to chromosome 6p12.1-q12.

Inheritance

Carpenter syndrome is an autosomal recessive disorder (Jenkins et al., 2007).

Molecular Genetics

In 15 independent families with Carpenter syndrome, Jenkins et al. (2007) identified 5 different mutations (4 truncating and 1 missense) in the RAB23 gene (see, e.g., L145X, 606144.0001; and 606144.0002). The RAB23 gene encodes a member of the RAB guanosine triphosphatase (GTPase) family of vesicle transport proteins and acts as a negative regulator of hedgehog (HH) signaling (see 600725). In 10 patients, the disease was caused by homozygosity for the same L145X mutation that resides on a common haplotype, indicative of a founder effect in patients of northern European descent.

In 4 boys with Carpenter syndrome from a consanguineous Comoros Islands pedigree, Alessandri et al. (2010) identified homozygosity for a 1-bp duplication (606144.0003) in the RAB23 gene.

In a female infant, born to consanguineous Turkish parents, with Carpenter syndrome, Haye et al. (2014) identified homozygosity for a missense mutation (V161L; 606144.0004) in the RAB23 gene. The parents were heterozygous for the mutation.

Nomenclature

The designation of Carpenter syndrome as ACPS II is a relict of an earlier classification that made the Noack syndrome ACPS I. It is now agreed by most that Noack syndrome is the same as Pfeiffer syndrome (101600).