A number sign (#) is used with this entry because of evidence that poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) is caused by heterozygous mutation in the FAM111B gene (615584) on chromosome 11q12.

Poikiloderma, characterized by mottled pigmentation, telangiectasia, and epidermal atrophy, can be accompanied by tendon contractures, myopathy, and progressive pulmonary fibrosis. Clinical manifestations include poikiloderma from early childhood with telangiectasia and pigmentary anomalies on sun-exposed areas, tendon contractures that tend to involve the ankles and feet with gait disturbances, and development of pulmonary fibrosis during the second decade of life resulting in progressive dyspnea and restrictive impairment of lung function. Additional features include heat intolerance, reduced sweating, and thin hair (summary by Mercier et al., 2013).

Khumalo et al. (2006) described a 2-generation South African family of European descent in which the proband was a 26-year-old woman with a history of heat intolerance and facial skin lesions from early childhood. At 9 years of age she developed Achilles tendon contractures, requiring surgery at 14 years of age. Examination showed telangiectasia, mottled hyper- and hypopigmentation, papules, and epidermal atrophy of the cheeks and face. She had fine scalp hair, thin eyebrows, and virtually no hair on her arms or legs, which also showed variable pigmentation. There was bilateral atrophy of thenar and hypothenar eminences, and limited extension of fingers due to sclerosis, but no Raynaud phenomenon. She exhibited hypohidrosis, but teeth and nails were normal. Pulmonary evaluation showed restrictive impairment of lung function but normal chest x-ray. Her father and older brother had similar skin and tendon abnormalities and had died of diffuse interstitial pulmonary fibrosis at the age of 56 and 30 years, respectively. At autopsy, the brother was found to have tendon contractures, thin tapered limbs with clubbing, truncal obesity and encasement of mediastinal and abdominal organs by excess fat, and scleroderma-like changes of the skin with replacement of adnexal structures by fibrosis. Microscopy of the skin revealed elastic tissue degeneration with formation of elastic globes in the papillary dermis. There was diffuse interstitial fibrosis of the lungs with abnormal airspace formation consistent with usual interstitial pneumonia (178500). Fibrosis of the esophagus and mediastinal lymph nodes was also present, as well as medial mucinous degeneration of the arteries with associated elastic degeneration and medial calcification of the splenic and anterior descending coronary artery, and extensive fatty infiltration of the pancreas and peripheral skeletal muscle. At 31 years of age, another brother had similar skin and limb changes and heat intolerance, but normal lung evaluation. A half sister from their father's previous marriage was also reported to have similar skin changes. Khumalo et al. (2006) proposed the term 'hereditary sclerosing poikiloderma with tendon and pulmonary involvement' for this disorder, and suggested that Weary syndrome (173700) be designated 'hereditary sclerosing poikiloderma with cardiac involvement.'

Mercier et al. (2013) studied 5 families with fibrosing poikiloderma, including the South African family originally reported by Khumalo et al. (2006). The 4 new probands were of French, Italian, Algerian, and French/Moroccan ancestry, and all presented in childhood with poikiloderma, alopecia involving the scalp, eyebrows, and eyelashes, and muscle weakness with fibrosis and adiposis on biopsy. All had tendinous contractures of the distal lower extremities requiring lengthening, and 3 of the 4 also had contractures of the upper limbs. In addition, 3 probands exhibited hypohidrosis and/or heat intolerance, and 2 had documented restrictive disease of the lungs.

The heterozygous mutations in the FAM111B gene that were found in the probands of families 1 and 2 with POIKTMP by Mercier et al. (2013) occurred de novo. In the South African family reported by Khumalo et al. (2006), Mercier et al. (2013) found that 3 affected sibs were heterozygous for a mutation in the FAM111B gene that was not found in their unaffected mother; DNA was unavailable from the affected father of the sibs, who was deceased.

Mercier et al. (2013) performed whole-exome sequencing in 3 South African sibs with fibrosing poikiloderma and their unaffected mother, originally reported by Khumalo et al. (2006), and a French boy and his unaffected parents, and identified 2 different heterozygous missense mutations in the FAM111B gene (Y621D, 615584.0001; R627G, 615584.0002) in affected individuals from each family. Sanger sequencing of the FAM111B gene in 3 more families with fibrosing poikiloderma revealed that an Algerian man and an Italian girl also carried the R627G mutation, whereas a girl of French and Moroccan ancestry was heterozygous for an S628N mutation (615584.0003). The patients were known to be negative for mutation in the RECQL4 gene (603780), and the FAM111B mutations were not found in unaffected parents available for testing or in 388 controls, including 96 Algerian, 127 Moroccan, and 165 South African individuals.