The Diversity of the Clinical Phenotypes in Patients With Fibrodysplasia Ossificans Progressiva

Abstract

BackgroundThe clinical presentation, phenotypic characterization and natural history of fibrodysplasia ossificans progressiva (FOP) are diverse and the natural history of the disease is, to a certain extent, different from one patient to another.MethodsIn a series of 11 patients (eight girls and three boys, aged 0 - 16 years), variable clinical presentations were the landmarks of these patients. At birth, all of our patients manifested short great toes in a valgus position. Marfan syndrome was the suggested diagnosis in three children aged 3 - 8 years and in two pre-adult patients. Clinical symptoms were torticollis, painful spine, and painful and marked limitation of the pelvic movements. Monophalangia associated with Marfanoid habitus was also a prevailing clinical presentation.ResultsOur results were based upon the appearance of the earliest pathologic feature of FOP in correlation with the clinical presentation. In infants (0 - 1 year), three infants showed congenital hallux valgus and stiff spine. In the pediatric group (3 - 8 years), all children showed no mutation in the fibrillin-1 (FBN1) gene. Their prime presentation was a progressive torticollis with simultaneous development of erythematous subfascial nodules, most commonly located on the posterior neck and back. In pre-adult group (10 - 16 years), four patients presented with monophalangia associated with painful movements because of the progressive heterotopic ossification of the spine and the weight bearing zones and marked elevation of alkaline phosphatase. Genetic confirmation has been performed in six patients who manifested the classical mutation of the ACVR1 gene. The rest of the patients were assessed via clinical and radiographic phenotypes.ConclusionThe early recognition of FOP can be performed by noticing the short halluces and thumbs at early infancy and later on the high alkaline phosphatase activity in areas of heterotopic ossification. Misconception of FOP is of common practice and eventually unnecessary diagnostic biopsies might deteriorate the progression of the condition. The detection of ACVR1 gene mutation was a confirmatory procedure. Interestingly, the timing of the onset and the location of progressive heterotopic ossifications were extremely variable and confusing among our group of patients.

Recent advances in gene‐enhanced bone tissue engineering

“…In the past, certain clinical cases have demonstrated to physicians that osteoinduction can occur within muscle tissue. After severe soft tissue injuries or implantation of hip prostheses, or in the case of the genetic disease fibrodysplasia ossificans progressiva, the formation of osseous tissue can occur at heterotopic sites. It was not obvious that adipose tissue would represent another promising candidate tissue that is useful as an osteo‐regenerative implant for expedited ex vivo gene therapy.…”

“…or in the case of the genetic disease fibrodysplasia ossificans progressiva,123,124 the formation of osseous tissue can occur at heterotopic sites. It was not obvious that adipose tissue would represent another promising candidate tissue that is useful as an osteo-regenerative implant for expedited ex vivo gene therapy.…”

Fibrodisplasia osificante progresiva: informe de caso con diagnóstico temprano y propuesta de rehabilitación

“…4 El reto radica en el poco conocimiento y difusión de esta patología, lo que hace que el error en la detección ascienda hasta 80% de manera inicial, 5 retrasando el diagnóstico de fibrodisplasia osificante progresiva un promedio de cuatro años o más. 1,3,6 Para el diagnóstico clínico basta la presencia de osificaciones heterotópicas cuyo patrón típico inicia en las regiones dorsal, axial, craneal y proximal, para más tarde involucrar las regiones ventral, apendicular, caudal y distal. Además de la malformación congénita del primer dedo del pie, variando del primer metatarso abducto, acortamiento, hallux valgus, varus o braquisindactilia.…”

“…Además de la malformación congénita del primer dedo del pie, variando del primer metatarso abducto, acortamiento, hallux valgus, varus o braquisindactilia. [6][7][8] Las osificaciones generalmente se inician en la primera década de la vida; son precipitadas por traumatismos menores ocasionando la aparición de un nódulo subcutáneo muy doloroso que evoluciona a inflamación, induración, dolor y, finalmente, osificación del tejido involucrando columna y esqueleto axial con resultado incapacitante. [9][10][11] La calidad de vida se ve afectada severamente en el entorno personal, social y familiar, siendo la mayoría de los pacientes incapaces de auxiliarse para sus necesidades básicas conforme avanza el padecimiento.…”

Towards a cure for Fibrodysplasia ossificans progressiva

“…Noteworthy, unlike other forms of HO (i.e., progressive osseous heteroplasia, POH), HO in FOP occurs episodically, through inflammation-triggered "flare-ups". Such a strong link between FOP and inflammation might underlie the variety of phenotypes observed in FOP patients (for example, the intensity and duration of the immune response can vary among FOP patients) (1), but also has led to the establishment of the current treatment for FOP, which consists in broad spectrum anti-inflammatory drugs (2).…”