Chondrodysplasia, Grebe Type

A number sign (#) is used with this entry because of evidence that Grebe chondrodysplasia is caused by homozygous or compound heterozygous mutation in the CDMP1 gene (GDF5; 601146) on chromosome 20q11.

Description

Grebe chondrodysplasia is an autosomal recessive disorder characterized by severe abnormality of the limbs and limb joints. The severity of limb shortening progresses in a proximal-distal gradient, with the hands and feet being most affected. The fingers and toes lack articulation and appear as skin appendages. In contrast, axial skeletal structures and the craniofacial skeleton are not affected. Heterozygous individuals are of average stature and have mild skeletal abnormalities (summary by Thomas et al., 1997).

Clinical Features

Grebe (1952, 1955) described the disorder in 7- and 11-year-old sisters, offspring of a consanguineous mating. (The name is pronounced GRAY-beh.) The same disorder was found in Brazil by Quelce-Salgado (1964). In these cases, all 4 limbs are markedly shortened and end in tiny digits. The trunk and head are normal. A case with childhood and adult radiographic studies was presented by Scott (1969).

Romeo et al. (1977) described 2 patients, each with an entity similar to but distinct from Grebe chondrodysplasia. Teebi et al. (1986) reviewed the adult case reported by Romeo et al. (1977) and added the case of an infant who, in their view, has the same disorder, a condition separate from Grebe chondrodysplasia. Meera Khan and Khan (1982) described 6 cases distributed in 3 sibships in 3 generations of an inbred kindred in India. The parents were consanguineous in each of the 3 sibships and the entire pedigree gave incontrovertible support to autosomal recessive inheritance. No radiologic or other abnormality was found in heterozygotes by Meera Khan and Khan (1982) or by Garcia-Castro and Perez-Comas (1975), although Quelce-Salgado (1968) mentioned that x-ray studies of the parents of one of his patients showed absence of some phalanges of the toes and changes in other phalanges, as well as talipes equinovarus, polydactyly, and double halluces in more remote relatives.

Curtis (1986) called attention to a report of an inbred Miao Chinese kindred with 6 affected persons. The authors suggested that heterozygotes may have mild skeletal anomalies of the hands and feet. Curtis (1986) concluded that the family that she reported (Kumar et al., 1984) may have been an example of brachydactyly as a heterozygous manifestation of Grebe chondrodysplasia. Feng et al. (1985) reported an inbred kindred living in an isolated village of Yunnan province in China. Six of 13 children in 2 related sibships were affected. They stated that 65 affected individuals, including these 6, have been reported. In the 2 patients they studied in detail, the head and trunk were normal in marked contrast to severely malformed limbs. The anomalies progressed in severity distally in the limbs. The fingers and toes were replaced by small, bud-like or knob-like protrusions. Both patients were polydactylous. The skull and vertebral column were normal roentgenographically.

Costa et al. (1998) reported clinical and radiological findings in 10 affected individuals originating from Bahia, Brazil. The phenotype was characterized by a normal axial skeleton and severely shortened and deformed limbs, with a proximal-distal gradient of severity. The humeri and femora were relatively normal, the radii/ulnae and tibiae/fibulae were short and deformed, carpal and tarsal bones were fused, and several metacarpal and metatarsal bones were absent. The proximal and middle phalanges of the fingers and toes were invariably absent, while the distal phalanges were present. Postaxial polydactyly was found in several affected individuals. Several joints of the carpus, tarsus, hand, and foot were absent. Heterozygotes presented with a variety of skeletal manifestations, including polydactyly, brachydactyly, hallux valgus, and metatarsus adductus.

Other Features

Lin et al. (2001) called attention to Vietnamese sisters pictured in an April 25, 2000 article in The Boston Globe, entitled 'The Agent Orange tragedy continues.' The well illustrated features were typical of Grebe syndrome.

Molecular Genetics

Thomas et al. (1997) used the candidate gene approach to identify the genetic defect in Grebe type chondrodysplasia. They identified 20 members of the original family from the state of Bahia in Brazil described by Quelce-Salgado (1964). The cartilage-derived morphogenetic protein-1 (CDMP1; 601146) maps to 20q11.2 and is tightly linked to D20S191 and D20S195 (Lin et al., 1996). Thomas et al. (1997) demonstrated that 13 of 14 chromosomes from individuals with Grebe chondrodysplasia shared the D20S191:D20S195:CDMP1 2:1:1 haplotype. The fourteenth chromosome was detected in an affected individual with 1 copy of the 2:1:1 haplotype and 1 copy of a 1:1:1 haplotype. All obligate carriers analyzed possessed 1 copy of the 2:1:1 haplotype. They found that affected individuals homozygous for the 2:1:1 haplotype had a G-to-A transition at nucleotide 1199 (1199G-A), predicting a tyrosine for cysteine substitution at amino acid 400 (C400Y; 601146.0003) in the mature region of CDMP1. The affected individual with the 2:1:1/1:1:1 haplotype was found to be a compound heterozygote, possessing 1 allele for the 1199G-A mutation and the other for a deletion of a guanine nucleotide at position 1144 (del1144G), predicting a frameshift and premature stop codon 70 amino acids downstream. This individual was phenotypically identical to homozygotes for the 1199G-A mutation. The del1144G mutation was not present in any of the other 1:1:1 haplotypes analyzed and may have represented a sporadic mutation. Thomas et al. (1997) noted that in affected individuals the severity of limb shortening progressed in a proximal-distal gradient, with the hands and feet being most affected. The fingers and toes lacked articulation and appeared as skin appendages. In contrast, axial skeletal structures and the craniofacial skeleton, including the temporomandibular joint, were not affected. Notably, heterozygous individuals were of average stature and had a variety of mild skeletal abnormalities, including postaxial polydactyly, brachydactyly, delayed bone age, metatarsus adductus, valgus deviation of toes, and flexion contracture of fingers.

Nomenclature

Grebe chondrodysplasia may be a good term for this disorder (Scott, 1977) to distinguish it from other quite different disorders that are also called achondrogenesis. (Before the ninth edition of MIM (1990), this disorder was referred to as type II achondrogenesis. As it turned out, this only complicated the nomenclature inasmuch as this condition bears no similarity to the lethal neonatal chondrodysplasias, which are also referred to as achondrogenesis, and the designation 'type II achondrogenesis' has been used for the Langer-Saldino type of lethal neonatal achondrogenesis (200610).) Superti-Furga (1996) suggested that this disorder should be renamed chondrodysplasia, Grebe type. The definition of achondrogenesis by Grebe (1952) resulted from an incorrect conclusion based on a superficial similarity between the 2 sisters he reported and the original patient of Fraccaro (1952).