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Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations.

ABSTRACT: Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients.Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected.Key features consist of: (i) early-onset poikiloderma, hypotrichosis and hypohidrosis; (ii) multiple contractures, in particular triceps surae muscle contractures; (iii) diffuse progressive muscular weakness; (iv) pulmonary fibrosis in adulthood and (v) other features including exocrine pancreatic insufficiency, liver impairment and growth retardation. Muscle magnetic resonance imaging was informative and showed muscle atrophy and fatty infiltration. Histological examination of skeletal muscle revealed extensive fibroadipose tissue infiltration. Microscopy of the skin showed a scleroderma-like aspect with fibrosis and alterations of the elastic network. FAM111B gene analysis identified five different missense variants (two recurrent mutations were found respectively in three and four independent families). All the mutations were predicted to localize in the trypsin-like cysteine/serine peptidase domain of the protein. We suggest gain-of-function or dominant-negative mutations resulting in FAM111B enzymatic activity changes.HFP with tendon contractures, myopathy and pulmonary fibrosis, is a multisystemic disorder due to autosomal dominant FAM111B mutations. Future functional studies will help in understanding the specific pathological process of this fibrosing disorder.

SUBMITTER: Mercier S

PROVIDER: S-EPMC4608180 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations.

Mercier Sandra S Küry Sébastien S Salort-Campana Emmanuelle E Magot Armelle A Agbim Uchenna U Besnard Thomas T Bodak Nathalie N Bou-Hanna Chantal C Bréhéret Flora F Brunelle Perrine P Caillon Florence F Chabrol Brigitte B Cormier-Daire Valérie V David Albert A Eymard Bruno B Faivre Laurence L Figarella-Branger Dominique D Fleurence Emmanuelle E Ganapathi Mythily M Gherardi Romain R Goldenberg Alice A Hamel Antoine A Igual Jeanine J Irvine Alan D AD Israël-Biet Dominique D Kannengiesser Caroline C Laboisse Christian C Le Caignec Cédric C Mahé Jean-Yves JY Mallet Stéphanie S MacGowan Stuart S McAleer Maeve A MA McLean Irwin I Méni Cécile C Munnich Arnold A Mussini Jean-Marie JM Nagy Peter L PL Odel Jeffrey J O'Regan Grainne M GM Péréon Yann Y Perrier Julie J Piard Juliette J Puzenat Eve E Sampson Jacinda B JB Smith Frances F Soufir Nadem N Tanji Kurenai K Thauvin Christel C Ulane Christina C Watson Rosemarie M RM Khumalo Nonhlanhla P NP Mayosi Bongani M BM Barbarot Sébastien S Bézieau Stéphane S

Orphanet journal of rare diseases 20151015

<h4>Background</h4>Hereditary Fibrosing Poikiloderma (HFP) with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP [MIM 615704]) is a very recently described entity of syndromic inherited poikiloderma. Previously by using whole exome sequencing in five families, we identified the causative gene, FAM111B (NM_198947.3), the function of which is still unknown. Our objective in this study was to better define the specific features of POIKTMP through a larger series of patients.<h4>Methods ...[more]

PMID: 26471370

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Project description:ObjectiveTo report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 (RYR1) gene-related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients.MethodsEleven patients evaluated in the neonatal period with severe neonatal-onset RYR1-associated myopathy confirmed by genetic testing were ascertained. Clinical features, molecular testing results, muscle imaging, and muscle histology are reviewed.ResultsClinical features associated with the severe neonatal presentation of RYR1-associated myopathy included decreased fetal movement, hypotonia, poor feeding, respiratory involvement, arthrogryposis, and ophthalmoplegia in 3 patients, and femur fractures or hip dislocation at birth. Four patients had dominant RYR1 mutations, and 7 had recessive RYR1 mutations. One patient had a cleft palate, and another a congenital rigid spine phenotype-findings not previously described in the literature in patients with early-onset RYR1 mutations. Six patients who underwent muscle ultrasound showed relative sparing of the rectus femoris muscle. Histologically, all patients with dominant mutations had classic central cores on muscle biopsy. Patients with recessive mutations showed great histologic heterogeneity, including fibrosis, variation in fiber size, skewed fiber typing, very small fibers, and nuclear internalization with or without ill-defined cores.ConclusionsThis series confirms and expands the clinical and histologic variability associated with severe congenital RYR1-associated myopathy. Both dominant and recessive mutations of the RYR1 gene can result in a severe neonatal-onset phenotype, but more clinical and histologic heterogeneity has been seen in those with recessive RYR1 gene mutations. Central cores are not obligatory histologic features in recessive RYR1 mutations. Sparing of the rectus femoris muscle on imaging should prompt evaluation for RYR1-associated myopathy in the appropriate clinical context.

Dataset Information

Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations.

Publications

Expanding the clinical spectrum of hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis due to FAM111B mutations.

Similar Datasets

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