A number sign (#) is used with this entry because of evidence that the
disorder results from mutation in the CDMP1 gene (601146).
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).
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 achondrodysplasia (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).
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.
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.