Langer Mesomelic Dysplasia

A rare, genetic skeletal dysplasia characterized by severe disproportionate short stature with mesomelic and rhizomelic shortening of the upper and lower limbs.

Epidemiology

The exact prevalence is unknown. More than 100 cases have been described in the literature to date, with most of the patients being reported from populations with a high level of consanguinity.

Clinical description

Langer mesomelic dysplasia (LMD) is a more severe form of Léri-Weill dyschondrosteosis (LWD) and presents at birth with a severely shortened long bones of the limbs (involving both the middle and proximal segments), deformity of the humeral head, angulation of the radial shaft, carpal distortion, a short femoral neck, and absence or hypoplasia of the proximal half of the fibula. Mild hypoplasia of the mandible has been reported in some cases. In contrast to LWD, Madelung deformity is not typically present in LMD. Associated malformations are rare and intellect is normal in almost all reported LMD cases.

Etiology

LMD is inherited in a pseudoautosomal recessive manner and is associated with homozygous or compound heterozygous mutations and deletions of the Short stature HomeobOX (SHOX) gene (which maps to the pseudoautosomal region 1 (PAR1) of the sex chromosomes; Xp22.33 and Yp11.32) or of the upstream or downstream PAR1 (where SHOX enhancer elements are located). LMD is part of a spectrum of disorders (ranging from the most severe, LMD, to LWD, isolated Madelung deformity and so-called idiopathic short stature), all associated with SHOX/PAR1 anomalies. The prevalence of SHOX/PAR1 mutations is estimated at 1/1000.

Diagnostic methods

Diagnosis of LMD may be suspected on the basis of the clinical and radiologic findings and can be confirmed by molecular analysis (preferably multiplex ligation-dependent probe amplification for PAR1 deletions and DNA sequencing for point mutations, small deletions and insertions of SHOX).

Differential diagnosis

During the antenatal period differential diagnosis includes femur-fibula-ulna complex and the Reinhardt-Pfeiffer mesomelic dysplasia.

Antenatal diagnosis

LMD may be suspected by ultrasound at 20 weeks of gestation. Prenatal genetic testing is available; however, requests for testing for these disorders are uncommon but are more frequent for LMD.

Genetic counseling

Genetic counseling should be proposed and families should be informed that SHOX/PAR1 anomalies are inherited in a pseudoautosomal dominant manner. Each child of an individual with LWD has a 50% risk of inheriting the mutation. If both parents have LWD, the offspring have a 50% risk of having LWD, a 25% risk of having LMD, and a 25% risk of having neither condition. All children of an individual with LMD and an unaffected parent will present with LWD.

Management and treatment

There is no effective treatment for LMD. The symptomatic medical management of children with LMD begins at birth and continues into adulthood. Careful monitoring of height, weight, and head circumference is essential.

Prognosis

The short stature and limb deformities are severe but life expectancy is normal.