Genetic disorder resulting in progressive skin, heart, bone, and joint abnormalities.
First described in two brothers by the Italian pediatrician C. Borrone and colleagues in 1993.
Only three case reports describing five males with the syndrome have been published.
Unclear, but postulated to be either autosomal recessive or X-linked recessive. The two Italian brothers were the offsprings of healthy parents from a small Italian village, and consanguinity was denied. The two Dutch brothers and the Australian male both had consanguineous parents. Recent research mapped the underlying defect to mutations in the SH3PXD2B (SH3 and PX domains 2B) gene located on chromosome 5q35.1. SH3PXD2B encodes a protein required for the formation and function of podosomes. These are actin-rich membrane protrusions involved in cell adhesion, motility, migration, and extracellular matrix remodeling. Podosomes ensure proper cell function in numerous cell types, including macrophages, lymphocytes, dendritic cells, vascular smooth muscle cells, endothelial cells, myoblasts, and osteoclasts.
Clinical and radiologic findings consistent with the syndrome (see “Clinical aspects”) allow for the diagnosis to be made within the first year of life. Molecular genetic testing is required to confirm the diagnosis.
Psychomotor and intellectual development are normal. The coarse facial appearance is caused by a high and broad forehead, hypertelorism, wide nose with low bridge, deep-set eyes, thickened subocular folds, prominent ears, large mandible, thick lips, short philtrum, anomalies of the teeth (delayed eruption, premature loss), and significant gingival hypertrophy in two patients. A gingival biopsy can demonstrate fibromatosis and fibroblasts with accumulation of cytoplasmic membrane-bound structures containing collagen fibers. Premature fusion of the sagittal and lambdoid sutures aggravated the facial appearance in one patient. Musculoskeletal anomalies may include kyphoscoliosis, gibbus deformity, osteolysis, genua recurvata, flexion contractures of the large joints, brachydactyly (short tubular metatarsal, metacarpal, and phalangeal bones with thin cortices), thickened interphalangeal joints and clinodactyly of the fifth fingers. Osseous lacunae and cortical erosions can be found in hands and feet. Bilateral dislocation of the radial heads, genua valga, and clubfoot deformity were present in one patient. Radiologic examinations will reveal vertebrae with reduced sagittal diameter, anterior beaking and abnormalities consistent with Scheuermann osteochondritis. Osteoporosis may be present. Thoracic wall deformity resulted in restrictive lung disease in one patient who had a more severe skeletal phenotype. Umbilical and bilateral inguinal hernias may be present. Mitral valve prolapse is severe and rapidly progressive, eventually leading to heart failure and/or requiring surgical repair. The severe and disfiguring acne conglobata with multiple cysts and pustules on face and upper torso with thickening of the skin is striking, but does not occur before puberty. Skin biopsy shows chronic dermatitis with fibrosis, hyalinosis, metaplastic ossification, and infundibular follicular cysts. ...