Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia

Abstract

Background: Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2).

Methods: Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19).

Results: The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features.

Conclusions: It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

Figure 1

Skeletal manifestations of geleophysic dysplasia. (A) Hand x-rays of patient 3 at age 3 years (top) and age 10 years (bottom). Note the very small hand with short and plump tubular bones and cone shaped epiphyses. Note also the carpal ossification delay. (B) Hip and lower limbs x-ray of patient 4 at age 8 months. Note the small capital femoral epiphyses and the shortened long tubular bones. (C) Anteroposterior view of the spine of patient 12 at age 1 year. Note the ovoid vertebral bodies.

Figure 2

ADAMTSL2 mutations. In italics: ADAMTSL2 mutations previously identified (Le Goff et al). In non-italics: novel mutations.

Figure 3

Clinical manifestations of geleophysic dysplasia in patient 28 (mutated in ADAMTSL2) and patient 31 (not mutated in ADAMTSL2). (A, E) Note the short stature, small hands and feet, stiff joints and pseudomuscular hypertrophy (patient 28 at age 9 years and patient 31 at age 4 years). (B, F, G) Note the very small hands and feet. (C) Note the tip-toe walking. (D, H) Note the common facial features, including round full face, small nose with anteverted nostrils and long philtrum (patient 28 at age 6 years and patient 31 at age 4 years). Note also the thin upper lip, and narrow palpebral fissures present only in patient 28 (mutated in ADAMTSL2). Informed consent was obtained to publish the photographs in this figure.