Mutations in FAM111B Cause Hereditary Fibrosing Poikiloderma with Tendon Contracture, Myopathy, and Pulmonary Fibrosis

Abstract

Congenital poikiloderma is characterized by a combination of mottled pigmentation, telangiectasia, and epidermal atrophy in the first few months of life. We have previously described a South African European-descent family affected by a rare autosomal-dominant form of hereditary fibrosing poikiloderma accompanied by tendon contracture, myopathy, and pulmonary fibrosis. Here, we report the identification of causative mutations in FAM111B by whole-exome sequencing. In total, three FAM111B missense mutations were identified in five kindreds of different ethnic backgrounds. The mutation segregated with the disease in one large pedigree, and mutations were de novo in two other pedigrees. All three mutations were absent from public databases and were not observed on Sanger sequencing of 388 ethnically matched control subjects. The three single-nucleotide mutations code for amino acid changes that are clustered within a putative trypsin-like cysteine/serine peptidase domain of FAM111B. These findings provide evidence of the involvement of FAM111B in congenital poikiloderma and multisystem fibrosis.

Poïkilodermie héréditaire fibrosante, myopathie rétractile et fibrose pulmonaire (POIKTMP)

“…Le syndrome POIKTMP lié au gène FAM111B a été décrit par notre équipe en 2013 [2]. Depuis, nous avons recensé une cohorte de 10 familles dont huit cas sporadiques [3].…”

CUGC for hereditary fibrosing poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP)

“…Its mode of inheritance and its main clinical features were inferred from observations made in a twogeneration multiplex South African family, 1 the study of which contributed to the identification of causative variants in FAM111B. 2 Three FAM111B (NM_198947.3) missense variants, c.1861T4G (p.(Tyr621Asp)), c.1879A4G (p.Arg627Gly), and c.1883G4A (p.(Ser628Asn)), and one in-frame deletion, c.1262_1264delAAG (p.(Lys421del)), have been reported so far in individuals with POIKTMP. 2,3 All four variants are located in the region encoding the putative trypsin-like cysteine/serine peptidase domain of the protein.…”

“…2 Three FAM111B (NM_198947.3) missense variants, c.1861T4G (p.(Tyr621Asp)), c.1879A4G (p.Arg627Gly), and c.1883G4A (p.(Ser628Asn)), and one in-frame deletion, c.1262_1264delAAG (p.(Lys421del)), have been reported so far in individuals with POIKTMP. 2,3 All four variants are located in the region encoding the putative trypsin-like cysteine/serine peptidase domain of the protein. All published variants will be available soon in the public LOVD database under construction that is dedicated to FAM111B (www.LOVD.nl/FAM111B).…”

“…Its prevalence is therefore unknown. To date, only six families have been officially reported, 2,3 even though a few other cases reported in literature may be suspected of having the same disease. 4,5 All the POIKTMP cases reported to date have been found in individuals first diagnosed with Rothmund-Thomson syndrome (RTS), which is already a very rare form of poikiloderma suspected to be under-diagnosed precisely because of its rarity.…”

“…Myopathy can develop progressively from infancy to adulthood, and progressive pulmonary fibrosis is noted at adulthood, sometimes accompanied by other features like growth retardation, liver impairment, exocrine pancreatic insufficiency, and cataract. 2,3 Muscle MRI and histological examination are helpful for diagnosis, as they show atrophy and extensive fatty infiltration of the muscle regardless of age. Microscopic analyses of skin biopsies reveal a scleroderma-like aspect of the lesions with fibrosis and alterations of the elastic network.…”