Clinical and molecular analysis of Grebe acromesomelic dysplasia in an Omani family

Abstract

Grebe syndrome is a rare autosomal recessive acromesomelic dysplasia. The syndrome was studied clinically, radiographically, and genetically in an Omani family with four affected children. The affected persons had normal axial skeletons, severely shortened, and deformed limbs with severity increasing in a proximo-distal gradient, and subluxated joints. The humeri and femora were hypoplastic with distal malformations. The radii/ulnae were shortened and deformed whereas carpal bones were invariably rudimentary or absent. The tibiae appeared rudimentary; fibulae 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. The father and mother had short first metacarpal and middle phalynx of the fifth finger and hallux valgus respectively. Transition A1137G and deletion delG1144 mutations in the gene encoding the cartilage-derived morphogenetic protein-1 (CDMP-1) were identified in this family. The A1137G is a silent mutation coding for lysine, whereas the delG1144 predicts a frameshift mutation resulting in a presumable loss of the CDMP-1 biologically active carboxy-terminal domain. The affected siblings were homozygous for the delG1144 mutation while parents were heterozygous.

Homozygous missense and nonsense mutations in BMPR1B cause acromesomelic chondrodysplasia-type Grebe

“…3 All reported mutations in GDF5 associated with ACD are caused by a homozygous functional loss of GDF5, which is caused by either deletions, duplications, or insertions leading to a premature translational stop or caused by point mutations targeting the cleavage site or the mature domain of GDF5, thereby compromising its regular function. [4][5][6][7][8][9][10][11][12][13] Interestingly, one individual with a homozygous mutation in BMPR1B has been reported presenting with a subtype of ACD with additional genital anomalies, 14 implicating that mutations in the ligand and its receptor can cause similar phenotypes. Heterozygous carriers of dominant-negative mutations in BMPR1B are usually affected by brachydactyly-type A2 (BDA2; MIM number 112600), which is characterized by a shortened middle phalanx of the index finger and variable clinodactyly of the fifth finger.…”

Spondylo-mega-epiphyseal dysplasia with prominent upper limb mesomelia, punctate calcifications, and deafness

“…The Maroteaux type [Maroteaux et al, 1971;Banapurmath et al, 1990] is caused by mutations in the NPR2 gene [Kant et al, 1998]. The Grebe [Grebe, 1952;Costa et al, 1998;Al-Yahyaee et al, 2003] and Hunter-Thompson [Hunter and Thompson, 1976;Langer et al, 1989] types are caused by heterozygous and homozygous mutations, respectively, in the CDMP1 gene [Thomas et al, 1996]. Clinically and radiographically our patient does not appear to have any of these entities.…”

Prenatal Sonographic Diagnosis of Grebe Syndrome

“…[4][5][6] The humeri and femora are relatively normal, whereas the radii and ulnae as well as the tibiae and fibulae are short and dysplastic. The hands and feet usually exhibit fusion of the carpal and tarsal bones, aplasia of the metacarpals and metatarsus, and absence of the proximal and middle phalanges.…”

“…Mutations in the human CDMP1 gene on chromosome 20q11.2 8 have been described in Grebetype chondrodysplasia 5,6 as well as HT syndrome. We did not identify the presence of a heterozygous mutation in the coding sequence of the CDMP1 gene in either parent.…”