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. 2015 Oct 15:10:135.
doi: 10.1186/s13023-015-0352-4.

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

Sandra Mercier  1   2   3 , Sébastien Küry  4 , Emmanuelle Salort-Campana  5 , Armelle Magot  6   7 , Uchenna Agbim  8 , Thomas Besnard  9 , Nathalie Bodak  10 , Chantal Bou-Hanna  11 , Flora Bréhéret  12 , Perrine Brunelle  13 , Florence Caillon  14 , Brigitte Chabrol  15 , Valérie Cormier-Daire  16 , Albert David  17 , Bruno Eymard  18 , Laurence Faivre  19   20 , Dominique Figarella-Branger  21 , Emmanuelle Fleurence  22   23 , Mythily Ganapathi  24 , Romain Gherardi  25 , Alice Goldenberg  26 , Antoine Hamel  27 , Jeanine Igual  28 , Alan D Irvine  29   30   31 , Dominique Israël-Biet  32 , Caroline Kannengiesser  33 , Christian Laboisse  34   35 , Cédric Le Caignec  36 , Jean-Yves Mahé  37   38 , Stéphanie Mallet  39 , Stuart MacGowan  40   41 , Maeve A McAleer  42   43 , Irwin McLean  44 , Cécile Méni  45 , Arnold Munnich  46 , Jean-Marie Mussini  47 , Peter L Nagy  48 , Jeffrey Odel  49 , Grainne M O'Regan  50 , Yann Péréon  51   52 , Julie Perrier  53 , Juliette Piard  54 , Eve Puzenat  55 , Jacinda B Sampson  56 , Frances Smith  57 , Nadem Soufir  58 , Kurenai Tanji  59 , Christel Thauvin  60   61 , Christina Ulane  62 , Rosemarie M Watson  63 , Nonhlanhla P Khumalo  64 , Bongani M Mayosi  65 , Sébastien Barbarot  66 , Stéphane Bézieau  67   68
Affiliations

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

Sandra Mercier et al. Orphanet J Rare Dis. .

Abstract

Background: 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.

Methods: Clinical and molecular data of two families and eight independent sporadic cases, including six new cases, were collected.

Results: 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.

Conclusions: 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.

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Figures

Fig. 1
Fig. 1
Facial and scalp skin lesions. Poikiloderma and alopecia of the scalp, eyebrows, and eyelashes in individuals F1, F4, F5, F6, F8 and F9 (a-f)
Fig. 2
Fig. 2
Skin lesions of upper and lower limbs. Eczema-like and psoriasis-like dermatosis of the upper limbs in individual F4 (a); hyperpigmentated regions in individual F5 (b); chronic lymphoedema of lower limbs and hands in individuals F4 (c, d), F6 (e), F8 (f); diffuse skin lesions of lower limbs and cellulitis in individual F6 (e, g)
Fig. 3
Fig. 3
Muscle and skin microscopy. a-d Fatty tissue, fragmented muscle fascicles next to normal fascicles in individuals F1 (a-b) or nonspecific myopathic changes with variation in fiber size in proband F2 (c-d) (Hematoxylin and eosin staining [H&E]; ×20 (a) and ×100 magnification (b-d)). e-f Epidermal atrophy, scleroderma-like features with a diffuse mild collagen sclerosis (e) (individual F1; H&E; ×20 magnification); elastic dystrophy with formation of elastic globes (arrowheads) in the papillary dermis (f) (individual F1; Weigert staining; ×150 magnification)
Fig. 4
Fig. 4
Muscle MRI (coronal images: thighs (up); calves (down); T1-weighted sequence). Diffuse bright appearance of the anterior compartment of the thighs, particularly in the vastus lateralis muscles, and the posterior compartment of the calves in individual F1 at 7 years of age (a); more severe stage with a relative sparing of the posterior compartment of the thighs in proband F2 at 30 years (b). Specific involvement of the vastus lateralis muscles (asterisks) with sparing of other thigh muscles in individual F9 (c)
Fig. 5
Fig. 5
Missense variants identified in FAM111B. Conserved amino acid sequences among mammals and cluster within a putative cysteine/serine trypsin-like peptidase domain of FAM111B. Variant #1 [c.1289A > C (p.Gln430Pro)] identified in individual F9; variant #2 [c.1861 T > G (p.Tyr621Asp)] in the South-African family F10; variant #3 [c.1874C > A (p.Thr625Asn)] in individual F8; variant #4 [c.1879A > G (p.Arg627Gly)] in individuals F1, F3 and family F2; variant #5 [c.1883G > A (p.Ser628Asn) in individuals F4, F5, F6 and F7
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