Chromosome 8q22.1 Duplication Syndrome

A number sign (#) is used with this entry because Leri pleonosteosis is caused by heterozygous microduplication of chromosome 8q22.1 encompassing the GDF6 (601147) and SDC2 (142460) genes.

Description

Leri pleonosteosis is an autosomal dominant skeletal disorder characterized by flexion contractures of the interphalangeal joints, limited movement of multiple joints, and short, broad metacarpals, metatarsals, and phalanges. Additional features may include chronic joint pain, short stature, bony overgrowths, spinal cord compression, scleroderma-like skin changes, and blepharophimosis. The clinical features overlap with several other musculoskeletal conditions, including Myhre syndrome (MYHRS; 139210), and geleophysic dysplasia (GPHYSD1; 231050) (summary by Banka et al., 2015).

Clinical Features

Rukavina et al. (1959) reported Leri pleonosteosis in 4 generations of a family. The features were short stature, narrowed palpebral fissures, short spade-like hands, broad thumbs in valgus position, genu recurvatum and generalized limitation of joint mobility, thickening of the palmar and forearm fasciae, enlargement of the posterior neural arches of the cervical vertebrae, and shuffling short-stepped gait.

Booth (1975) observed father and son with this condition. Both had laryngeal stenosis.

Hilton and Wentzel (1980) reported 7 affected members in 1 family and reviewed literature on the disorder. They found that the most constant abnormalities were limitation of joint movement and flexion contractures, particularly of the interphalangeal joints of the fingers. The hands and feet showed short, broad metacarpals, metatarsals and phalanges. Block vertebrae were present in some family members. Blepharophimosis was common in their family and was described in 2 patients reported by Rukavina et al. (1959).

Friedman et al. (1981) reported 2 unrelated boys with Leri pleonosteosis. Shaw (1981) provided a follow-up on one of the boys (case 1), noting that shortening and broadening of the metacarpals, metatarsals, and phalanges with flexion deformities are important features in young patients.

Banka et al. (2015) reported a 27-year-old white man of British descent with Leri pleonosteosis. He had progressive stiffness and aching of all joints, flexion contractures of all interphalangeal joints, and short hands and feet with brachydactyly. Radiographs showed fusion of the C2 and C3 vertebrae and short, broad metacarpals, metatarsals, and phalanges. Other features included short stature, short and narrow palpebral fissures, and thickened skin, particularly on the plantar and palmar surfaces. Family history was unavailable.

Inheritance

The transmission patterns of Leri pleonosteosis in the families reported by Rukavina et al. (1959) and Hilton and Wentzel (1980) were consistent with autosomal dominant inheritance.

Cytogenetics

In affected members of the family with Leri pleonosteosis reported by Hilton and Wentzel (1980), Banka et al. (2015) identified a heterozygous 1-Mb duplication of chromosome 8q22.1. The duplication was confirmed by RT-PCR analysis of cultured dermal fibroblasts from 2 patients. An overlapping 1.2-Mb duplication was found in the proband from a second white family of British origin with the disorder, although it was not possible to determine segregation in this family. Neither copy number variant was present in public databases or in 190 control microarray samples. The overlapping 0.95-Mb region contained 6 genes, but studies of cultured dermal fibroblasts from 2 affected individuals from the first family, aged 77 and 20 years, showed significant overexpression only of the GDF6 gene (601147) (40.2- and 13.2-fold increases, respectively). The SDC2 gene (142460) was overexpressed 2.8-fold in the 77-year-old patient but not in the younger patient. The expression patterns of genes relevant to TGF-beta-mediated extracellular matrix homeostasis differed somewhat between the 2 cultures, and Banka et al. (2015) postulated that the differences may be age-related. Western blot analysis showed an increase in SMAD4 (600993) expression in the younger patient's cells and a decrease in SMAD4 expression in the older patient's cells. Both samples showed decreased expression of SMAD6 (602931). Banka et al. (2015) hypothesized that the aberrant expression of GDF6 and/or SDC2 underlies the phenotype.