Ruijs-Aalfs Syndrome

A number sign (#) is used with this entry because of evidence that Ruijs-Aalfs syndrome (RJALS) is caused by homozygous or compound heterozygous mutation in the SPRTN gene (616086) on chromosome 1q42.

Description

Ruijs et al. (2003) reported a Moroccan boy with a chromosomal breakage who died of hepatocellular carcinoma at age 17 years. The boy was noted to have growth retardation at age 3 years; at age 7 he was found to have thoracic kyphosis, frontal bossing, and a delayed bone age of approximately 3 years. He underwent surgery for severe bilateral posterior subcapsular cataracts at age 14. Examination at age 15 showed short stature and low weight, with premature graying of scalp hair, small frontotemporal diameter, small deep-set eyes, bulbous nose with high nasal bridge, small upper lip, and micrognathia. In addition, he had thoracic kyphoscoliosis, sloping shoulders, mild pectus excavatum, moderate bilateral contractures of both elbows, bilateral clinodactyly, and pes planus. At age 17, he developed abdominal pain, and ultrasonography revealed a liver mass; biopsy confirmed hepatocellular carcinoma. Because of the advanced stage, no treatment was possible, and he died 2 months later. Although his parents were not known to be consanguineous, they originated from the same small Moroccan village.

Lessel et al. (2014) studied 2 brothers from a nonconsanguineous Australian family of European ancestry who exhibited low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age, and mild joint restrictions in the fingers and elbows. In addition, both brothers developed early-onset hepatocellular carcinoma, at ages 16 and 14 years, respectively. The older brother died at age 18 from complications of acute fulminant hepatic failure. Analysis of patient tumor biopsies showed strong focal accumulations of cancer biomarkers as well as a high proliferative index compared to healthy liver or to cells from idiopathic hepatocellular carcinoma.

Cytogenetics

Ruijs et al. (2003) analyzed G-banded lymphocytes from a Moroccan boy with progeroid features who died of hepatocellular carcinoma at 17 years of age, and observed an apparently normal male karyotype, 46,XY, in approximately 50% of cells, with the remainder showing random chromosomal structural abnormalities. Patient cells exposed to the clastogens 4-nitroquinaline 1-oxide (4NQO) and diepoxybutane (DEB) demonstrated hypersensitivity compared to controls.

Molecular Genetics

In the Moroccan patient reported by Ruijs et al. (2003) and the younger brother from an Australian family with Ruijs-Aalfs syndrome, Lessel et al. (2014) performed genomewide linkage analysis and exome sequencing, and identified SPRTN as the only gene with rare, biallelic mutations in the exomes of both individuals: the Moroccan boy was homozygous for a 1-bp deletion (616086.0001), whereas the Australian brothers were compound heterozygous for a splice site mutation and a missense mutation (616086.0002-616086.0003). The mutations, which segregated with disease in both families, were not found in the dbSNP (build 137) or 1000 Genomes Project databases. Analysis of SPRTN in 48 additional patients with suspected Werner syndrome (277700) who were negative for mutations in the WRN (RECQL2; 604611) or LMNA (150330) genes revealed no other SPRTN mutations. Functional analysis showed that patient fibroblasts experienced DNA replication stress, which was almost completely corrected by transfection with wildtype SPRTN. In addition, patient cells were hypersensitive to replication-related genotoxic agents but not to ionizing radiation, consistent with a severe G2/M-checkpoint defect.

Exclusion Studies

Ruijs et al. (2003) sequenced the WRN gene in a Moroccan boy with progeroid features who died of hepatocellular carcinoma at age 17 years, but detected no mutation in the coding region. In addition, cell lines from both parents and a sister expressed normal-sized WRN proteins at levels comparable to control lines (protein samples were not available from the proband).