Langer Mesomelic Dysplasia

A number sign (#) is used with this entry because Langer mesomelic dysplasia is caused by a homozygous defect in the pseudoautosomal genes SHOX (312865) or SHOXY (400020).

Because the mutation occurs in the pseudoautosomal region of the sex chromosomes, the inheritance of this disorder follows an autosomal (pseudoautosomal) recessive pattern.

Description

Langer mesomelic dysplasia (LMD) is characterized by severe limb aplasia or severe hypoplasia of the ulna and fibula, and a thickened and curved radius and tibia. These changes can result in displacement deformities of the hands and feet. Hypoplasia of the mandible is also observed (Langer, 1967).

See also Leri-Weill dyschondrosteosis (127300), a less severe phenotype that results from heterozygous defect in the SHOX or SHOXY genes.

Clinical Features

Book (1950) reported an affected kindred from northern Sweden in which the parents of the proband were first cousins. Heterozygotes in this kindred were short (the father was 160 cm and the mother 150 cm) and had relatively short fingers and broad hands, but otherwise were not strikingly abnormal. 'Chondrohypoplasia' was the designation Book used for the heterozygotes. Book (1950) thought the disorder most closely resembled that in the family reported by Brailsford (1935), in which children of normal but short parents were affected.

Blockey and Lawrie (1963) described affected brother and sister, the offspring of normal parents; there was no mention of parental consanguinity. The authors, probably mistakenly, considered their cases instances of Nievergelt syndrome (163400).

Langer (1967) studied 2 cases and referred to the entity as 'mesomelic dwarfism of the hypoplastic ulna, fibula, mandible type.' Hypoplasia of the mandible was a feature not emphasized in other reports. Mesomelic is a nonspecific term which refers to shortening most striking in the forearm and lower leg.

Inheritance

Espiritu et al. (1975) suggested that the Langer mesomelic phenotype may result from homozygosity for the Leri-Weill dyschondrosteosis gene.

In a male newborn with typical Langer type of mesomelic dwarfism, Fryns and Van den Berghe (1979) found a variable degree of Madelung deformity and mesomelic shortening in both parents and in the mother's family, providing support for the hypothesis that this type of mesomelic dwarfism is the clinical manifestation of a homozygous state for dyschondrosteosis. This hypothesis was further strengthened by the report of Kunze and Klemm (1980), in which both parents of an affected female had signs of dyschondrosteosis, including Madelung deformity. The parents were apparently unrelated Turks. The authors had information on yet 2 other instances of Langer mesomelic dysplasia with dyschondrosteosis in both parents. Jones and Pickney (1983) also observed a case of Langer mesomelic dysplasia in which both parents had subtle signs of dyschondrosteosis.

Goldblatt et al. (1987) reported a case of Langer mesomelic dysplasia with a mild deformity of the forearms similar to, but different from, Madelung deformity in the families of both the father and mother.

Diagnosis

Evans et al. (1988) demonstrated that Langer mesomelic dwarfism can be diagnosed in the second trimester by sonography. They also reported the pathologic changes in a second trimester abortion case. This was from an at-risk pregnancy of a mother with the Madelung deformity of dyschondrosteosis and an earlier-born offspring with Langer mesomelic dwarfism. The status of the father was unknown.

Molecular Genetics

Belin et al. (1998) described a family in which 4 individuals in 2 generations had Leri-Weill dyschondrosteosis (LWD; 127300) associated with heterozygous deletion of the pseudoautosomal gene SHOX (312865.0003). A woman in this family with classic LWD was the mother of a fetus that inherited her deletion of SHOX; a second event, Turner syndrome, resulted in the absence of the SHOX allele on the paternal X chromosome. Deletion of both SHOX alleles in the fetus caused Langer mesomelic dysplasia.

Robertson et al. (2000) reported a mentally retarded male with Langer mesomelic dysplasia who had inherited a SHOX deletion from each parent, both of whom had the dyschondrosteosis phenotype. The deletions did not extend into the X-specific region, and the authors concluded that the mental retardation in this case might be explained by a pseudoautosomal mental retardation locus.

Thomas et al. (2004) described a family in which several members and a fetus had mutations in the SHOX gene. The grandmother, mother, and uncle all carried an approximately 200-kb interstitial deletion that included the entire SHOX gene. Their condition was mild, with no Madelung deformity, and was originally diagnosed as hypochondroplasia. This deletion was transmitted to the fetus, who inherited an additional Xp deletion (Xpter-Xp22.12) that included the SHOX gene from her chromosomally normal father. The ultrasound scan of the fetus and subsequent autopsy findings were consistent with Langer mesomelic dysplasia.

Bertorelli et al. (2007) reported a fetus, conceived of consanguineous parents, with Langer mesomelic dysplasia resulting from a homozygous deletion extending from exon 6b of the SHOX gene downstream for 1.1 Mb and encompassing a cis-acting enhancer region (312865.0013). Both parents, who were heterozygous for the mutation, had Leri-Weill syndrome.

In affected individuals with LWD or LMD from 12 Spanish multiplex families, 2 of which had previously been studied (Sabherwal et al. (2004, 2004)), Barca-Tierno et al. (2011) identified heterozygosity or homozygosity, respectively, for an A170P mutation (312865.0014) in the SHOX gene. In all families, A170P cosegregated with the fully penetrant phenotype of mesomelic limb shortening and Madelung deformity. Microsatellite analysis revealed a shared haplotype around SHOX, confirming the presence of a common ancestor, probably of Gypsy origin, as 11 of the 12 families were of that ethnic group.

Cytogenetics

Fryns (1995) described a 15-year-old normally intelligent male who appeared to have both the blepharophimosis, ptosis, epicanthus inversus syndrome (BPES; 110100) and disproportionate dwarfism with marked shortening of the middle segments of the extremities with mandibular hypoplasia. Radiologic changes were consistent with the clinical diagnosis of Langer type mesomelic dwarfism. The karyotype was a 46,XY normal male. Fryns (1995) suggested that the patient had a contiguous gene deletion syndrome, undetectable at the resolution of available cytogenetic techniques, involving 3q22.3-q23, where BPES is known to map, and also suggested that the locus for Langer mesomelic dwarfism is located in the same region.