Conductive hearing loss in individuals with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a very rare genetic disorder that is characterized by progressive heterotopic ossification of soft tissues and congenital malformation of the great toes. Although previous case studies have reported hearing loss in individuals with FOP, there have been no large-scale studies regarding the nature or cause of the hearing loss. Here, we report the findings of a two-part study. In Part I, we report the findings of a postal survey regarding hearing loss that was sent to 102 individuals with FOP. In Part II, we report the findings of on-site hearing evaluations of eight individuals with FOP. The findings of both studies indicate that individuals with FOP are at risk for hearing loss and that the type of loss is predominantly conductive in nature, similar to that seen in individuals who have otosclerosis.

The human bone morphogenetic protein 4 (BMP-4) gene: molecular structure and transcriptional regulation.

Bone morphogenetic protein 4 (BMP-4) is a vital regulatory molecule that functions throughout human development in mesoderm induction, tooth development, limb formation, bone induction, and fracture repair and is overexpressed in patients who have fibrodysplasia ossificans progressiva. The human gene encoding bone morphogenetic protein 4 (BMP-4) has been isolated and its structural organization characterized. The complete DNA sequence of an 11.2 kb region has been determined. BMP-4 mRNA is transcribed from four exons, although there is evidence that alternate first exons may be used. Transcript initiation occurs at variable positions within a GA-rich region of the DNA. The promoter region is GC-rich with no obvious TATA or CAAT consensus sequences, and contains both positive and negative transcriptional regulatory elements within the 3 kb 5' flanking region of the RNA start site. Comparison of the human and murine BMP-4 genes reveals highly conserved sequences not only in the exon-coding regions but also within the introns and 5' flanking regions. BMP-4 localizes to human chromosome 14q21 by fluorescence in situ hybridization, a location more centromeric than that recently reported. These studies provide a foundation for understanding the genetic regulation of this important gene in human development.

Submandibular swelling in patients with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossifcans progressive (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic ossification of soft tissues. Although ankylosis of the temporomandibular joint occurs commonly in the late stages of the disease, only one well-documented case of submandibular heterotopic ossification in a patient who had FOP exists. Twelve (11 %) of our 107 patients who have FOP had submandibular heterotopic ossification that was mistaken initially in seven of the patients for mumps, angioneurotic edema, abscess, mononucleosis, or neoplasm. Two male patients and 40 female patients ranging in age from 6 to 47 years (mean, 21 years) were studied. Ten patients survived following assiduous precautionary measures. One patient who required emergency tracheostomy and ventilatory support also survived. Another patient died of inanition from chronic swallowing difficulty. An effective treatment program includes early identification of the submandibular flare-up, nutritional support, and glucocorticoid therapy. Submandibular swelling in patients who have FOP can be a medical emergency and requires intensive precautionary measures to avoid catastrophic clinical deterioration. These measures include avoidance of lesional manipulation, airway monitoring, and aspiration precautions. Submandibular swelling should be recognized as a variable feature of FOP.

Fibrodysplasia ossificans progressiva in two half-sisters: evidence for maternal mosaicism.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of connective tissue characterized by congenital malformation of the great toes and by progressive heterotopic ossification of the soft tissues in specific anatomic and temporal patterns. We observed classic findings of FOP in 2 Native American half-sisters with the same unaffected mother and different unaffected fathers. This is the first report of FOP in sibs from different pregnancies with unaffected parents. The findings in this family indicate the possibility of maternal gonadal mosaicism in FOP and provide important new data for genetic counseling in this disease.

Mild expression of fibrodysplasia ossificans progressiva: a report of 3 cases.

We describe 3 unusually mild cases of fibrodysplasia ossificans progressiva (FOP) in an 80-year-old man, a 44-year-old woman, and a 17-year-old woman. The man, whose daughter had classic features of FOP, lacked malformation of the great toes and experienced unusually slow progression of the disease. Both women displayed late onset heterotopic ossification. The older women displayed an unusually slow progression of the disease. All 3 patients remained ambulatory at the time of examination. Recognition of a mild form of FOP will influence diagnosis, counselling, and research in this rare condition.