Clinical Characteristics And Identification of Novel TGF-β1 Mutation In Three Unrelated Chinese Families With Progressive Diaphyseal Dysplasia

BackgroundTo investigate the clinical characteristics and molecular diagnosis of progressive diaphyseal dysplasia (PDD) in three unrelated Chinese families. MethodsThe present study recruited six patients aged 14 to 45 from three unrelated families with PDD, including five females and one male. Clinical manifestations, biochemical tests, radiographic examinations were analyzed and the TGF-β1 gene mutation was further identified by Sanger sequencing. In addition, data of treatment and follow-up were also collected.ResultsThe onset age of the patients ranged from 1 to 6 years. All the affected patients had family histories and were consisted with autosomal dominant inheritance pattern. All of them exhibited gait disturbance, fatigue, progressive bone pain, as well as muscle atrophy and weakness in limbs. Notably, there was one 15-year-old girl who experienced heart valve defects and tachycardia at birth. Laboratory examinations revealed the inflammatory markers were in high level, besides the extremely increased bone metabolism indicators. The thickened diaphysis of long bones and the narrowed medullary cavity were observed by radiography. Furthermore, radionuclide bone scan detected abnormal symmetrical radioactive concentration in the affected regions of bone. Sanger sequencing identified a missense heterozygous mutation in exon 4 of TGF-β1 gene, resulting in R218C, which confirmed PDD eventually. More important, a novel mutation c.669C>G in exon 4 of TGF-β1 gene harboring C223W were detected in family 3. Subsequent bioinformatics software predicted that the novel mutation was pathogenic. Our study also showed that zoledronic acid was not effective in the control of bone turnover markers and the relief of bone pain in patients with PDD.ConclusionIn addition to the typical PDD manifestations, the new phenotypic characteristics such as tachycardia and heart valve defect were firstly reported in one female patient carried the novel mutation p.Cys223Trp in TGF-β1 gene. In addition, our study indicated that the increased bone metabolism indicators and inflammatory markers may possess auxiliary diagnosis for PDD. More importantly, zoledronic acid was used to treat PDD patients in this study. After one-year follow-up, it was proved that the drug effect was not satisfactory, and new drugs need to be developed to treat the disease.

Camurati-Engelmann disease

Camurati-Engelmann disease (CED), or progressive diaphyseal dysplasia, is a rare sclerosing dysplasia of which 250 cases have been described in the English literature. The disease affects one in a million people and is autosomal dominant with variable penetrance. It was initially described by Cockayne in 1920; Camurati was the first to suggest its hereditary nature in 1922. A single case of muscular wasting and marked bone involvement was reported by Engelmann in 1929. As the name suggests, there is progressive hyperostosis and predominant involvement of the diaphyses. The onset of the disease is usually during childhood; patients usually present by puberty and usually before age 30, with limb pain, muscular weakness, waddling gait and easy fatigue. Other symptoms and signs may include delayed growth, reduced muscle mass, anorexia and enlargement of the arms and legs. Systemic manifestations of hepatosplenomegaly, bone marrow dysfunction (anaemia and leucopaenia) and delayed sexual development occasionally occur. In a few patients, abnormal values of bone resorption and formation have been described. Radiologically, the hallmark of the disorder is bilateral, symmetrical cortical thickening of the diaphyses of the long bones on both the periosteal and endosteal sides of the diaphyses. In decreasing order of frequency, the tibia, femur, fibula, humerus, ulna and radius are affected. CED results from disturbance of intramembranous ossification (Fig.1) affecting the long bones, calvaria, mandible and facial bones. There are a few reported cases of involvement of the skull base (a site of endochondral ossification), but these occur in advanced stages.