A number sign (#) is used with this entry because of evidence that the Penttinen type of premature aging syndrome (PENTT) is caused by heterozygous mutation in the PDGFRB gene (173410) on chromosome 5q32.

Penttinen syndrome (PENTT) is characterized by a prematurely aged appearance involving lipoatrophy and epidermal and dermal atrophy, as well as hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acroosteolysis (Johnston et al., 2015).

Penttinen et al. (1997) reported a 10-year-old Finnish boy with a prematurely aged appearance, delayed bone maturation and dental development, pronounced acroosteolysis with brachydactyly, and distinctive cutaneous findings including hard, confluent skin lesions with some clinical and histologic resemblance to those of juvenile hyaline fibromatosis (228600). He also had hyperopia, sensorineural hearing loss, and elevated thyroid stimulating hormone (188540) levels. Linear growth and intellectual functions were normal.

Zufferey et al. (2013) reported 2 unrelated patients, a 15-year-old girl of North Vietnamese and Chinese ancestry and a 20-year-old French man, who exhibited a progeroid syndrome of the Penttinen type. Although they lacked the classic progeroid facial gestalt, the patients presented a prematurely aged appearance, with premaxillary and maxillary retraction, pseudoprognathism, proptosis, and a flat occiput Their thumbs and halluces were large, broad, and spatulate. Their hair was sparse but without alopecia. Their permanent teeth were normal, despite retention of deciduous teeth. They exhibited ocular pterygia, diffuse keloid-like skin lesions, and acroosteolysis. Linear growth was increased, despite stature limitations due to kyphoscoliosis. Skin retraction and joint contractures developed during adolescence, and the French patient died at age 20 years due to restrictive respiratory insufficiency and cachexia.

Johnston et al. (2015) provided follow-up on the Finnish boy originally described by Penttinen et al. (1997) and reported 2 additional similarly affected individuals. The Finnish patient, who was reexamined at 29 years of age, reported experiencing multiple fractures, scoliosis requiring surgical treatment, and osteoporosis. His anterior and posterior fontanels were still open, each measuring approximately 5 cm by 3 cm. He had sparse hair, bitemporal prominences, closely spaced eyes, long nose with convex ridge, extremely narrow philtrum and palate, partial eruption of 4 maxillary teeth, and retrognathia. He displayed severe contractures and shortening of his fingers and toes, with small, broad, and thick toenails. Ophthalmologic examination showed bilateral temporal and nasal corneal edema, occludable anterior segment angles, simple microphthalmia (nanophthalmos), and retinal striae with shallow orbits. The previously observed nodules and scarlike lesions had resolved, although he had thin skin with prominent venous patterning and hyperkeratotic palms and soles, with significant callous formation on the soles. Johnston et al. (2015) also studied a boy of Indonesian and Chinese ancestry and a girl of Pakistani descent, who both initially presented in early childhood due to star-shaped scar-like skin lesions. Biopsy of a new nodule in the boy showed epidermal atrophy, hyperkeratosis, and dermal fibrosis. Both patients exhibited proptosis; the boy had widely spaced eyes whereas the girl had closely spaced eyes. Skin was thin with marked vascular patterning on the face, trunk, and limbs. Skeletal survey showed small maxilla and thin long bones, as well as acroosteolysis of all distal phalanges and delayed bone age. At age 14 years, the Pakistani girl had severe contractures of fingers and toes, progressive acroosteolysis, hyperkeratotic plaques on her soles that limited her walking, and a swollen appearance of the elbows and knees due to progression of scarring and loss of subcutaneous tissue in the extremities. Her facial features had become more striking, with proptosis, loss of subcutaneous tissue, and thinning of her hair. Intelligence was reported to be normal in the Finnish man and the Pakistani girl, whereas the boy was functioning below grade level.

Bredrup et al. (2019) reported 2 unrelated patients with a phenotype that included lipodystrophy, acroosteolysis, corneal neovascularization leading to vision loss, and scoliosis, consistent with a severe form of Penttinen syndrome. The first patient, a 24-year-old woman from Norway, was born with large hemangiomas on both shoulders and close to the right eye, which were removed shortly after birth. She had hydrocephalus requiring a shunt at 2 weeks of age. A progeria-like condition was first suspected at age 10 months. Her height was normal, and she had normal intelligence. Health issues included maxillary hypoplasia, shallow orbits, lipodystrophy, corneal neovascularization resulting in visual impairment, and contractures of large and small joints. She developed progressive scoliosis at age 14 years. She had vertebral osteopenia, but no degenerative changes in her spine. She developed a squamous skin carcinoma on the sole of her right foot, which necessitated a below-the-knee amputation. The second patient, a 24-year-old man from Australia, who had hemangiomas on both flanks, right ear, right foot, forehead, and one inside the skull, all of which regressed with steroid treatment. He had hydrocephalus requiring a shunt as a newborn. Seizures, noted on the first day of life, responded to to phenobarbital; recurrence of seizures at age 2 years responded to carbamazepine. He was initially tall (length at 97th centile). He was noted to have a progeria-like appearance from an early age. He had thin skin with little to no subcutaneous fat, with areas of skin hypertrophy and skin depigmentation and hyperpigmentation. He had contractures in large and small joints. He also had maxillary hypoplasia and eye protrusion due to shallow orbits. He developed scoliosis before age 10 years.

The transmission pattern of PENTT in the patients reported by Johnston et al. (2015) was consistent with autosomal dominant inheritance.

In a boy of Indonesian and Chinese ancestry with a premature aging syndrome of the Penttinen type, Johnston et al. (2015) performed exome sequencing and identified heterozygosity for a de novo missense mutation in the PDGFRB gene (V665A; 173410.0006). Sequencing PDGFRB in 3 more affected individuals, including the Finnish patient originally described by Penttinen et al. (1997) and a girl of North Vietnamese and Chinese ancestry previously reported by Zufferey et al. (2013), revealed heterozygosity for the same V665A mutation in all 3 patients. The mutation was confirmed to have arisen de novo in a Pakistani girl; parental DNA was not available for the other 2 patients.

In 2 unrelated patients with lipodystrophy, acroosteolysis, and severe vision impairment, reminiscent of a severe form of Penttinen syndrome, Bredrup et al. (2019) identified the same de novo missense mutation in the PDGFRB gene (N666S; 173410.0008). Functional studies using patient fibroblasts and transduced HeLa cells showed that the variant caused autophosphorylation of PDGFR-beta and induced phosphorylation of several downstream signaling proteins. Extensive apoptosis was seen in short-term patient-derived skin fibroblast cultures. Imatinib was a strong in vitro inhibitor of the mutant PDGFR-beta protein, suggesting an option for treatment of these patients.

Exclusion Studies

In a 20-year-old French man with a progeroid syndrome of the Penttinen type, Zufferey et al. (2013) excluded mutation in the FGFR1 (136350), FGFR2 (176943), TWIST (601622), LMNA (150330), and BANF1 (603811) genes. In a similarly affected 15-year-old girl of North Vietnamese and Chinese ancestry, mutations in the COL3A1 (120180), ZMPSTE24 (606480), and LMNA genes were excluded, and 2 homozygous variants detected in the 3-prime UTR of the BANF1 gene could not be further assessed due to early growth arrest of patient fibroblasts.