Carpenter Syndrome 2

A number sign (#) is used with this entry because of evidence that Carpenter syndrome-2 (CRPT2) is caused by homozygous or compound heterozygous mutation in the MEGF8 gene (604267) on chromosome 19q13.

Description

Carpenter syndrome-2 is an autosomal recessive multiple congenital malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet, in association with abnormal left-right patterning and other features, most commonly obesity, umbilical hernia, cryptorchidism, and congenital heart disease (summary by Twigg et al., 2012).

For a discussion of genetic heterogeneity of Carpenter syndrome, see 201000.

Clinical Features

Altunhan et al. (2011) described a Turkish boy who was born with acrocephaly and a peculiar facies characterized by frontal bossing. Digital abnormalities included clinodactyly of the fifth fingers, membranous syndactyly of fingers 3 and 4, syndactyly of toes 1 and 2, and preaxial polydactyly of the big toes bilaterally. Other abnormalities included widely spaced nipples and bilateral cryptorchidism. On cardiac auscultation, heart sounds were best heard at the right intersternal border, and chest radiograph revealed dextrocardia; echocardiography did not demonstrate any other cardiac abnormalities. Abdominal ultrasound revealed that the liver was in the left upper quadrant and the spleen was in the right upper quadrant. No brain abnormalities were detected on MRI; skull x-rays and 3D CT showed metopic anterior and posterior sagittal synostosis. Altunhan et al. (2011) stated that this was the first report of Carpenter syndrome in association with situs inversus totalis.

Twigg et al. (2012) studied 5 patients with mutation in the MEGF8 gene and a phenotype closely resembling classic Carpenter syndrome (CRPT1; 201000). One of the patients was the Turkish boy previously described by Altunhan et al. (2011). In both phenotypes, the spectrum of limb anomalies was similar and consisted of brachydactyly, syndactyly, and preaxial polydactyly. Other common features included a tendency toward high birth weight and childhood obesity and the occurrence of cryptorchidism or undescended testes in males. However, craniosynostosis tended to be less severe in the CRPT2 patients and usually involved only the metopic suture; this was frequently accompanied by a paradoxical hypertelorism, associated with a distinctive dysmorphic facies comprising a broad depressed nasal bridge, epicanthus, upslanted palpebral fissures, highly arched eyebrows, and low-set poorly angulated ears. Defects of lateralization were present in at least 3 of the patients and ranged from transposition of the great arteries to dextrocardia to complete situs inversus. The remaining 2 patients were Saudi Arabian brothers who were both diagnosed with diaphragmatic eventration and central position of the liver, but their clinical information was incomplete. Wide-spaced, hypoplastic, and/or supernumerary nipples and thoracic skeletal abnormalities appeared to be more characteristic in CRPT2 patients, whereas umbilical hernia and genu valgum, prominent features in CRPT1, were less characteristic in CRPT2.

Molecular Genetics

In a consanguineous Turkish family in which the proband was a 9-year-old boy with the cardinal features of Carpenter syndrome and dextrocardia, who was negative for mutation in the RAB3 (602536) and GLI3 (165240) genes, Twigg et al. (2012) performed homozygosity mapping followed by exome sequencing and identified a homozygous missense mutation in the MEGF8 gene (604267.0001) that segregated with disease in the family. Analysis of MEGF8 in 22 additional individuals with a suspected diagnosis of Carpenter syndrome but who were negative for mutation in RAB3 revealed 3 more patients who were homozygous or compound heterozygous for mutations in MEGF8, 1 of whom was the boy previously described by Altunhan et al. (2011) (see, e.g., 604267.0002-604267.0004). No mutations were found in the MEGF3 gene in 15 patients with heterotaxy but no craniosynostosis or limb anomalies. Noting that 3 of the mutation-positive patients also had complete situs inversus, dextrocardia, or transposition of the great arteries, respectively, Twigg et al. (2012) concluded that mutation in MEGF8 causes a Carpenter syndrome subtype frequently associated with defective left-right patterning.