Mutations within the putative protease domain of the human FAM111B gene may predict disease severity and poor prognosis: A review of POIKTMP cases

Abstract

Hereditary fibrosing poikiloderma with tendon contractures, myopathy and pulmonary fibrosis (POIKTMP) is a unique multi-systemic fibrosing and autosomal dominant genetic syndrome. The development of poikiloderma is one of the earliest signs of this disorder. 1 Consequently, this disease is often misdiagnosed in infants and neonates as Rothmund-Thomson syndrome (RTS), Bloom syndrome, dyskeratosis congenita, Baller-Gerold syndrome, poikiloderma neutropenia, Weary syndrome and Kindler syndrome. 1 Clinical features in POIKTMP include poikiloderma, myopathy, hypohidrosis, alopecia, tendon/muscle contractures, papules and epidermal atrophy, growth retardation, liver impairment, exocrine pancreatic insufficiency, cataracts and haematological abnormalities. [2][3][4][5][6] The affected individuals may also experience progressive weakness of proximal and distal muscles. 7 Furthermore, some patients develop fibrosis of the lungs in later life, causing recurrent bronchitis and abnormal lung function. 3 Pulmonary fibrosis, however, occurs around the second decade of life and is life-threatening, 3,4 with some earlier case reports also mentioning fibrosis of the oesophagus

Case Report: Diverse phenotypes of congenital poikiloderma associated with FAM111B mutations in codon 628: A case report and literature review

“…The same mutation could lead to different phenotypes and an association between genotypes and phenotypes was not established ( Mercier et al, 2013 ; Mercier et al, 2015 ; Goussot et al, 2017 ), suggesting that other factors, such as racial factor and environmental variables, might influence the clinical characteristics of this disease. To date, including our case in the present study, a total of 37 patients with this rare disorders have been reported globally ( Arowolo et al, 2022a ). For patients with congenital poikiloderma, the predominant manifestation is early onset poikiloderma, telangiectasia, and epidermal atrophy.…”

Case Report: Hereditary Fibrosing Poikiloderma With Tendon Contractures, Myopathy, and Pulmonary Fibrosis (POIKTMP) Presenting With Liver Cirrhosis and Steroid-Responsive Interstitial Pneumonia

“…Furthermore, an important new insight with implications for genotype-phenotype correlation was recently reported. Arowolo et al suggested that patients with mutations within the putative protease domain of the FAM111B protein may have higher disease burden and poorer prognoses compared to patients with mutations outside the domain ( Arowolo et al, 2022 ). Among the reported causative mutations in FAM111B, all except three are within this domain ( Figure 2C ), as is the present mutation.…”

“…Some patients develop pulmonary fibrosis, which has been reported to lead to poor prognosis. In a previous review, only symptomatic therapy was recommended for those with respiratory failure ( Arowolo et al, 2022 ). Only two patients with POIKTMP have been reported to be treated for pulmonary involvement.…”

Proposed Cellular Function of the Human FAM111B Protein and Dysregulation in Fibrosis and Cancer

“…Mutations of the human FAM111B gene are also associated with a rare multisystemic fibrosing disease-poikiloderma, tendon contracture, myopathy, and pulmonary fibrosis (POIKTMP, which is the adopted terminology for this disease) (1)(2)(3)(4). FAM111B gene mutations are also implicated in other clinical manifestations such as progressive osseous heteroplasia (POH) (5), autism spectrum disorders (6), modification of genes associated with cognitive development (7), nevus of Ota with choroidal melanoma (8), and mutations of unknown clinical significance/common genetic polymorphism (9).…”

“…Moreover, the overexpression of this gene in cancer cells is associated with increased cancer progression and poor clinical outcomes ( 13 – 16 ). Although there are about 19 reported FAM111B mutations ( Supplementary Table 1 ) to date ( 3 – 5 , 10 , 12 , 17 – 24 ), the physiological function(s) of the FAM111B protein and its dysfunctional role in diseases like fibrosis and cancers are not well established.…”