Grebe type chondrodysplasia is a rare recessively inherited acromesomelic dysplasia clinically characterized by dwarfism with severe micromelia. Radiologically, it is characterized by short and deformed middle long bones, fusion of carpal bones and several metacarpal and metatarsal, and absence of proximal and middle phalanges. Other features include obesity and delayed mental development, but facial appearance and intelligence are normal with no vertebral abnormalities.
Grebe syndrome is associated with mutations in the CDMP1 gene, which encodes Growth/differentiation factor 5 (GDF-5). GDF-5 protein is a member of the bone morphogenetic protein (BMP) family and the TGF-beta superfamily.
Hattab et al. (1996) described a 9-year-old Arab boy presenting oral and dental abnormalities associated with a distinct variety of severe short-limb dwarfism. The affected boy had delayed development and eruption of teeth, severe oligodontia of permanent dentition, hypodontia, microdontia, supplemental incisor, enamel hypoplasia of primary teeth, doubled and abnormal frenal attachments, bifid uvula, hypoplastic maxilla, and malocclusion. Clinical and radiographic examinations revealed asymmetric dysplasia and anaplasia of long bones, craniofacial dysmorphia, prominent forehead, budlike fingers and bulbous toes, dysplastic nails, severe hearing loss, and reduced joint mobility.
Al-Yahyaee et al. (2003) described the clinical, radiological and genetic findings in an Omani family with Grebe syndrome. The consanguineous parents and their three affected children (one affected female died after birth) were studied. All affected children had similar phenotypes of severely shortened and deformed limbs with their toes and fingers appearing as skin protrusions with polydactyly, but they had normal axial and craniofacial skeleton. The tibia appeared rudimentary; fibula were absent in two children, and some tarsal and metatarsal bones were absent. The proximal and middle phalanges were absent while the distal phalanges were present. These affected children were coping with their physical handicap, their intelligence was normal with the two affected males attending school with normal children and they were doing well. The mother had minor hallux valgus, and the oldest brother and youngest sister were of normal heigh with no abnormality. X-rays revealed symmetrical deformities in the limbs increasing in a proximodistal manner typical of Grebe syndrome in all affected children, with normal axial skeleton concomitant with age. In the upper limbs, the humeri were hypoplastic with distal malformations, radii had hypoplastic proximal segment with absent distal end of ulna, subluxated humero-radioulnar joint, rudimentary or absent carpal and metacarpal bones with polydactyly and absent proximal and middle but present distal phalanges. In the lower limbs, the femora were hypoplastic, with deformed distal end of right femoral and absent diaphysis and malformed ends of left femoral of the female, rudimentary tibia, absent fibula in two children and dysplastic in the third, rudimentary or absent tarsal and metatarsal with polydactyly and absent proximal and middle but present distal phalanges. Minor abnormalities were found in the parents, with short first metacarpal and middle phalynx of the fifth finger of the father and hallux valgus in the mother.
Faiyaz-Ul-Haque et al. (2008) described a multiply consanguineous Arab family from Saudi Arabia affected with Grebe-type Chondrodysplasia. The first two affected cases from this family were a 6-year old girl and her 4-year old brother. Both were under the 3rd centile for height and weight, and exhibited rhizomesomelia with deformed forearms. The lower limbs were severely shortened, and fingers and toes were merely round protrusions. There were no systemic abnormalities. Radiographic findings included short and bowed radii and ulnae, dislocated radii, non-ossified carpal, metacarpal and phalangeal bones, and short femurs with broad distal metaphyses. Their double first cousin was also found to be affected at birth with similar clinical and radiologic features. All four parents were phenotypically normal. The patients were found to carry a novel homozygous mutation in the GDF5 gene.
Al Talabani et al. (1998) studied the pattern of major congenital malformations in 24,233 consecutive live and stillbirth at Corniche hospital, which is the only maternity hospital in Abu Dhabi, between January 1992 and January 1995. A total of 401 babies (16.6/1,000), including 289 Arabs, were seen with major malformation. Single gene disorders accounted for 24% of the cases, 76% were due to autosomal recessive disorders. In their study, Al Talabani et al. (1998) observed one case of Grebe type chondrodysplasia in a consanguineous family from the United Arab Emirates. Recurrence was also reported in the family. Al Talabani et al. (1998) concluded that their study was very close to representing the true incidence of congenital abnormalities in the whole United Arab Emirates, as they studied over 98% of deliveries in Abu Dhabi, the capital of United Arab Emirates.