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.

Ghosal Hematodiaphyseal Dysplasia: A Case Report

Ghosal hematodiaphyseal dysplasia (GHDD) is a rare autosomal recessive disorder presenting with steroid-responsive anemia and diaphyseal dysplasia of long bones. We report a 3-year-old Iranian girl with refractory anemia, splenomegaly and radiologic signs of metadiaphyseal dysplasia in long bones. The diagnosis was established by clinical presentation and X-ray bone survey. The patient was treated with oral prednisolone therapy with considerable improvement in anemia and splenomegaly.

Greenberg Dysplasia/Dappled Diaphyseal Dysplasia (Mim 215140)

Chapter 15 covers Greenberg dysplasia/dappled diaphyseal dysplasia (MIM 215140), including major clinical findings, radiographic features, and differential diagnoses.