Poikiloderma, Hereditary Fibrosing, with Tendon Contractures, Myopathy, and Pulmonary Fibrosis (POIKTMP) via the FAM111B Gene

POIKTMP is characterized by mottled pigmentation, telangiectasia, and epidermal atrophy along with tendon contracture, myopathy, and progressive pulmonary fibrosis. Abnormal skin pigmentation and telangiectasia usually occur during early childhood mainly on the face following sun exposure. These skin lesions will be improved with time; however, the extra cutaneous lesions may become worse. Patients may develop tendon contractures and pulmonary fibrosis during the second decade of life. In addition, some patients may have heat intolerance, reduced sweating, thin hair, and lymphoedema of low or upper extremities (Mercier et al. 2013; Mercier et al. 2015). POIKTMP may be clinically misdiagnosed as Rothmund-Thomson syndrome due to the overlapping clinical presentation such as abnormal skin pigmentation and telangiectasia, particular during the first year of life. Rothmund-Thomson syndrome is caused by pathogenic variants in RECQL4.

FAM111B-related POIKTMP is inherited in an autosomal dominant manner. The FAM111B protein coded by the FAM111B gene contains a trypsin-like cysteine/serine peptidase domain with unknown function. Only 5 unique missense variants were reported in 15 patients from 10 POIKTMP families, Almost 50% of these pathogenic variants occur de novo. The c.1879A>G (p.Arg627Gly) variant was observed in three families, and the 1883G>A (p.Ser628Asn) variant was found in 4 families (Mercier et al. 2013; Mercier et al. 2015). In addition, one small deletion leading to an in-frame deletion of one amino acid was reported in patients from one family affected with autosomal dominant exocrine pancreatic dysfunction (Seo et al. 2015).

One study reported that FAM111B pathogenic variants were found in all patients from 10 studied families (Mercier et al. 2015). The mutation detection rate by sequencing should be high, because all reported pathogenic variants are missense or small deletion.

This test provides full coverage of all coding exons of the FAM111B gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).