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Novel asymptomatic CNS findings in patients with ACVR1/ALK2 mutations causing fibrodysplasia ossificans progressiva
  1. Mariasavina Severino1,
  2. Marta Bertamino2,
  3. Domenico Tortora1,
  4. Giovanni Morana1,
  5. Sara Uccella3,
  6. Renata Bocciardi4,5,
  7. Roberto Ravazzolo4,5,
  8. Andrea Rossi1,
  9. Maja Di Rocco2
  1. 1Neuroradiology Unit, Istituto Giannina Gaslini, Genoa, Italy
  2. 2Rare Disease Unit, Istituto Giannina Gaslini, Genoa, Italy
  3. 3Neuropsychiatry Unit, Istituto Giannina Gaslini, Genoa, Italy
  4. 4Medical Genetics Unit, Istituto Giannina Gaslini, Genova, Italy
  5. 5Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy
  1. Correspondence to Dr Mariasavina Severino, Neuroradiology Unit, Istituto Giannina Gaslini, via Gaslini 5, Genoa 16147, Italy; mariasavinaseverino{at}gaslini.org

Abstract

Background Fibrodysplasia ossificans progressiva is an autosomal dominant disorder due to germline mutations of ACVR1/ALK2 causing progressive heterotopic endochondral ossifications. Evidence of central nervous system involvement has emerged only recently.

Methods We performed an observational cross-sectional brain MRI study in 13 patients (8 females, mean age 20 years), examining the relationship of clinical and neuroradiological findings.

Results All patients presented small asymptomatic lesions similar to hamartomas at the level of the dorsal medulla and ventral pons, associated with minor brainstem dysmorphisms and abnormal origin of the vestibulocochlear and facial nerves. The size of the brainstem lesions did not correlate with patient's age (p=0.061), age at first flare-up (p=0.733), severity of disability (p=0.194), history of head trauma (p=0.415) or hearing loss (p=0.237). The radiologic features and the absence of neurological symptoms were consistent with a benign process. Variable signal abnormalities and/or calcifications of the dentate nuclei were noted in all patients, while basal ganglia abnormalities were present in nine subjects. Brain calcifications positively correlated with patient's age (p<0.001) and severity of disability (p=0.002).

Conclusions Our data support the hypothesis that the effects of mutation of the ACVR1/ALK2 gene are extended to the central nervous system. Brainstem hamartomatous lesions and dysmorphisms, variably associated with dentate nucleus and basal ganglia signal abnormalities and/or calcifications, may represent useful disease hallmarks.

  • Clinical genetics
  • Diagnostics
  • Fibrodysplasia Ossificans Progressiva
  • Brain MRI

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