A number sign (#) is used with this entry because of evidence that the XFE progeroid syndrome (XFEPS) is caused by homozygous or compound heterozygous mutation in the ERCC4 gene (133520) on chromosome 16p13.

Niedernhofer et al. (2006) reported a 15-year-old Afghan male who presented with dwarfism, cachexia, and microcephaly. The parents were consanguineous. The child was born at normal weight and achieved early developmental milestones. He was markedly sun-sensitive from birth. He had mild learning disabilities, hearing loss, and visual impairment requiring correction beginning at the age of 6. By the age of 10, his parents noted an old wizened appearance with a narrow face with prominent bone structure. Beginning at the age of 12, he began to lose weight and failed to grow in stature. Over the next 3 years weight loss progressed and the patient reported frequent dizziness. He required assistance with dressing but was able to feed himself. Physical exam revealed a remarkably small boy with an aged bird-like facies (beak nose, prominent brow, and sunken orbits), microcephaly, and scoliosis. Skin was dry, atrophic, and irregularly pigmented, with sunburn noted on the face and neck, and without lesions suggestive of skin cancer. He had enamel dysplasia without caries. Hair was normal. The patient lacked subcutaneous fat but the abdomen was distended. Testes were descended normally, but sexual maturity was delayed. The patient's musculature was hypotonic and he displayed dystrophia, mild ataxia, and poor coordination. His voice was high-pitched. He was hearing-impaired and hypertensive, and had optic atrophy but no cataracts. Electroencephalogram showed mild generalized slowing. Magnetic resonance imaging showed microcephaly with enlarged ventricles. Ultrasound of abdomen and chest revealed ascites and pleural fluid as well as abnormally small, echodense kidneys. Laboratory values indicated severe renal insufficiency and proteinuria, while liver enzymes were mildly elevated. Skin fibroblasts showed severely reduced levels of UV-induced DNA damage repair (approximately 5% of normal), consistent with a diagnosis of xeroderma pigmentosum (XP; see 278700). However, this patient's mild dermatologic features but pronounced progeroid features in numerous organs were inconsistent with XP. The combination of impaired UV-induced DNA repair, photosensitivity, and neurologic symptoms were reminiscent of de Sanctis-Cacchione syndrome (278800). However, the hypertension, anemia, renal and liver abnormalities, and pronounced progeroid appearance observed in this patient had not been reported in de Sanctis-Cacchione syndrome, implying that this patient represented a novel syndrome. The patient died at 16 years of age from severe pneumonia complicated by acute respiratory distress syndrome and died of multisystem organ failure.

Mori et al. (2018) reported a 35-year-old woman, born to nonconsanguineous parents, who presented with microcephaly, enophthalmos, and a prematurely aged appearance. She had a history of failure to thrive in infancy. She required eye glasses in kindergarten and had impaired intellectual development. She underwent premature ovarian insufficiency and menopause at age 29. All her teeth were extracted in her thirties, but it was not known if the extraction was for severe dental caries or enamel hypoplasia. She had bilateral orbital atrophy and enophthalmos. At 35 years of age, her height was at the 25th percentile, whereas her weight and head circumference were less than the 3rd percentile. She had thin hair with gray streaks, loss of subcutaneous fat, senile lentigines on the face and hands, and thin wrinkled mottled skin. She was legally blind and her ophthalmologic examination showed severe corneal scarring, no cataracts, and no salt-and-pepper retinopathy. No hearing loss was reported. She had poor breast development, thin extremities, and bilateral pes cavus. Brain MRI showed white matter lesions. She had a sister who was similarly affected.

The transmission pattern of XFEPS in the patient reported by Niedernhofer et al. (2006) was consistent with autosomal recessive inheritance.

In the patient with a progeroid syndrome described by Niedernhofer et al. (2006), cDNA from XPF-ERCC1 (XFE) fibroblasts showed a G-to-C transversion at position 458 in the ERCC4 gene, resulting in a nonconservative substitution of proline for a highly conserved arginine at amino acid 153 (R153P; 278760.0001). The patient's genomic DNA demonstrated homozygosity for this mutation.

Niedernhofer et al. (2006) noted a striking correlation between the phenotype of Ercc1-null mice (see 126380) and that of human XFE progeroid syndrome. They observed that changes in these mice correlated with those seen in aged mice and developed a model connecting DNA damage, the growth hormone axis, and aging. Different mutations in XPF result in distinct clinical outcomes: either cancer, as in xeroderma pigmentosum, or progeroid symptoms, as in XFE syndrome. One explanation is that the R153 XFE mutation, compromising both nucleotide excision repair (NER) and interstrand crosslink (ICL) repair, results primarily in cell death and senescence in response to DNA damage. This suppresses carcinogenesis but enhances aging. In contrast, the milder NER defect in classic XPF patients causes less cell death, allowing mutation accumulation and consequently cancer. The specific sensitivity of XPF-ERRC1-deficient cells to crosslink damage makes ICLs a likely candidate for contributing to the unique phenotype of the XPE progeroid syndrome. The model of aging proposed by Niedernhofer et al. (2006) reconciled 2 apparently disparate hypotheses: that aging is genetically regulated, and that aging is a consequence of the accumulation stochastic damage. In fact, both are correct. Damage drives the functional decline that is associated with aging; however, a highly conserved longevity assurance mechanism, mediated by the IGF1/insulin pathway (see 147440), influences how rapidly damage accumulates and function is lost.

By exome sequencing of 18 patients from the International Registry of Werner Syndrome in whom mutations in other genes causing premature aging (WRN, 604611; LMNA, 150330; and POLD1, 174761) had been excluded, Mori et al. (2018) identified a patient (MME1010) with 2 mutations in the ERCC4 gene (G496H and A860D), which were found to be in cis. By screening the ERCC4 gene in an additional 24 genetically undiagnosed atypical Werner syndrome patients, Mori et al. (2018) identified a patient (CALIF1010) who was compound heterozygous for a missense mutation (R799W; 133520.0011) and a frameshift mutation (133520.0012). Expression of ERCC4 was dramatically reduced to approximately 6% of control in patient CALIF1010, but no difference from control was seen in patient MME1010. Survival of cells in the presence of mitomycin C (a test of the mutation's effect on interstrand crosslink repair) was about 59% of that of control in patient CALIF1010, but was not reduced in patient MME1010. These data suggested that the ERCC4 variants found in compound heterozygosity are responsible for the progeroid features of the patient, but that the ERCC4 variants found in cis in patient MME1010 are unlikely to be pathogenic.