Paula and Bobby
Parents of Lillie
Werner syndrome; WRN
What is Werner syndrome; WRN?
Werner syndrome; WRN is a rare disease.
There are currently no additional known synonyms for this rare genetic disease.
This autosomal recessive syndrome causes features of premature ageing and endocrinological abnormalities. The main features are short stature (lack of pubertal growth spurt), a slender body habitus, a beaked nose, a high pitched, weak or hoarse voice, juvenile cataracts, and hyperreflexia in the legs and flat feet. Scleroderma-like changes are seen with tight atrophic skin, telangiectasia, soft tissue calcifications and circumscribed hyperkeratosis. Diabetes or abnormal glucose tolerance is common and hypogonadism is usually seen. Premature atherosclerosis is a feature. Umehara et al., (1993) reported a case with spastic paraparesis and a polyneuropathy. Ruvalcaba et al., (1977) reported a 21-year-old male with features of Werner syndrome but without cataracts or grey hair, and without decreased replicative life-span of cultured fibroblasts (a feature of Werner syndrome). Goto et al., (1992) demonstrated linkage to markers on 8p12. Sibs reported by Yeong and Yang (2004) presented with chronic leg ulcers.
Iijima et al., (1992) reported a 42-year-old male who they suggested had features of Werner syndrome. He presented with chilblain-like eruptions in infancy. Subsequently his fingers and toes developed peripheral gangrene and the tips were lost spontaneously, although there was no obvious Raynaud's disease. A similar process seemed to affect his ears. He became grey at the age of 20 years, developed hyperkeratotic, painful callosities on his feet around the age of 35 years, and was diagnosed as having glaucoma caused by uveitis at 37 years. Cultured skin fibroblasts showed a remarkably low population growth rate and lifespan. His parents were consanguineous.
Sadakane et al., (1994) identified a 107 base pair insertion in the DNA polymerase beta gene in two independent cases with Werner syndrome. However it was not entirely certain whether these mutations were germline.
Yu et al., (1996) isolated the gene by positional cloning. It codes for a predicted 1432 amino acid protein showing significant similarities to DNA helicases (WRN). Further mutations were reported by Oshima et al., (1996), Matsumoto et al., (1997), Yu et al., (1997) and Meiblitzer et al., (1997). The mutational spectrum in the disorder is reviewed by Moser et al., (1999). Gray et al., (1997) provided further evidence that the gene codes for a DNA helicase. Auerbach and Verlander (1997) provide a good review of disorders of DNA replication and repair. Huang et al., (1998) showed that the WNR gene coded for a 3'->5' exonuclease. Mohaghegh and Hickson (2001) review the role of DNA helicases in cancer predisposition and premature ageing disorders. Goto et al., (1999) reported an immunoblot technique with specific monoclonal antibodies to the WS gene product for the diagnosis of Werner syndrome.
Ruijs et al., (2003) reported a 17 year old boy who died of hepatocellular carcinoma with features of Werner syndrome. However, a mutation analysis of the WRN gene and WRN gene protein analysis in obligate heterozygotes showed no abnormality (the patient could not be studied). The authors suggest that this might be a 'new' syndrome.
Chen et al.,(2003) found heterozygosity for novel missense mutations in the LMNA gene in 4 out of of 26 patients with atypical Werner's syndrome (with no detectable WRN mutation). The mutations altered relatively conserved residues within lamin A/C. Three cases were isolated and in one there was a dominant family history. Motegi et al., (2014) reported a similar case with a heterozygous LMNA mutation - there was no bird-like face, short stature, premature graying, cataract, diabetes or hyperkeratosis on the soles of his feet. A novel compound heterozygous mutation was reported by Muller et al., (2005). This mutation led to a markedly decreased WRN transcript stability. Two patients with mutations reported by Kluger et al., (2007) developed osteomyelitis.
Yamaga et al. (2017) performed a nationwide epidemiological study on Werner syndrome. A definitive diagnosis of Werner syndrome was confirmed genetically in 50 of 67 participants. Through the literature search, 16 additional individuals with molecular diagnosis were identified. Of these 66 individuals, 42 were homozygous for a WRN mutation, and 21 were compound heterozygotes.
* This information is courtesy of the L M D.
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What gene changes cause Werner syndrome; WRN?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 277700 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
What are the main symptoms of Werner syndrome; WRN?
The typical symptoms of the syndrome are:
Congestive heart failure, Limitation of joint mobility, Coronary artery atherosclerosis, Decreased fertility, Diabetes mellitus, Abnormality of the voice, Abnormality of retinal pigmentation, Abnormality of the pulmonary artery, Abnormality of the thorax, Abnormal testis morphology, Abnormal hair morphology, Abnormality of the cerebral vasculature, Aplasia/Hypoplasia of the skin, Convex nasal ridge, Chondrocalcinosis, Cataract, Skeletal muscle atrophy, Progeroid facial appearance, Telangiectasia of the skin, Skin ulcer, Renal neoplasm, Abnormal hair quantity, Prematurely aged appearance, Subcutaneous calcification, Premature arteriosclerosis, Short palm, Reduced bone mineral density, Rocker bottom foot, White forelock, Neoplasm of the lung, Neoplasm of the small intestine, Neoplasm of the breast, Neoplasm of the oral cavity, Neoplasm of the skin, Neoplasm of the thyroid gland, Lack of skin elasticity, Laryngomalacia, Meningioma, Narrow face, Lipoatrophy, Increased bone mineral density, Abnormal hair whorl, Se
How does someone get tested for Werner syndrome; WRN?
The initial testing for Werner syndrome; WRN can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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