Meningioma in a Patient with Werner Syndrome
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.284350
Source of Support: None, Conflict of Interest: None
Keywords: Adult progeria, autosomal recessive, meningioma, new mutation, Werner syndrome, WRN geneKey Message: Werner syndrome is an extremely rare genetic disorder. We describe the index case of meningioma in Werner syndrome in India. A new mutation has been identified.
Werner syndrome (WS), also known as adult progeria, is an autosomal recessive disorder caused by a mutation in the WRN gene encoding the RecQ DNA helicase. WS patients are at elevated risk for common, clinically important age-dependent diseases such as cancer and atherosclerotic cardiovascular disease, which are the most common causes of death at a median age of 54 years. WS is extremely rare, with about 1300 known cases in the world; over 1000 of these are in Japan. 8% of WS patients have neoplasms. Tsurubuchi et al. stated that there were 37 reported cases of CNS neoplasms with 33 meningiomas, 3 gliomas and, 1 spinal neurinoma. Only 2 histopathologically confirmed atypical meningiomas are reported till date. This is the index case of CNS neoplasm in a WS patient from India.
We report the case of a 39 years old, unmarried, male patient, born out of a non-consanguineous marriage, who presented to us in the clinic with occasional numbness in right arm for three weeks. The patient was a diabetic and a hypothyroid and gave a history of undergoing a surgery for voice change. He was consulting an ophthalmologist for his visual problems and had undergone bilateral cataract surgery about 25 years back.
On enquiring about his physical features, he informed us that these features of premature aging had started appearing in his adolescence and included baldness with sparse grey hair, dry scaly skin, and shrill voice. There was no history of such features of premature aging in any of his family members. Our patient was the only child of his parents.
On examination, he had a short stature with a height of 4'11”, in comparison to the heights of his father and mother, which were 5'5” and 5'4”, respectively. The weight of the patient was about 49 kg, and therefore, he had a BMI of 21.7 kg/m2. He had thin long extremities, progeroid features with grey hair, alopecia, scaly scleroderma like skin, shrill voice, hallux valgus deformity, and dystrophic nails [Figure 1] and [Figure 2].
The patient had an insidious onset numbness in the right hand for which he consulted a neurologist and subsequently underwent an MRI, which showed a left frontal convexity extra-axial lesion measuring 3.1 × 2.4 × 2.7 cm, suggestive of meningioma. A routine pre-operative workup, which included diffusion tensor imaging and functional MRI was done. [Figure 3] The later was carried out as a part of another study being done in the department at the time. The 2D Echocardiogram, along with the routine blood workup was normal. Preanesthetic evaluation was done to look for difficult airway and cardiac status. Anticipating a difficult airway, difficult airway trolley was kept ready in the OR. Preoxygenation preceded invasive monitoring. Standard intravenous induction with etomidate 0.3 mg/kg, Atracurium 0.5 mg/kg was done and the patient was intubated. Anaesthesia was maintained with oxygen: Air-50%, sevoflurane (MAC 0.5-0.6) and atracurium infusion. The patient underwent a left frontal navigation guided craniotomy and excision of tumor under general anesthesia. After an uneventful overnight stay in the ICU, he was observed in the wards for a couple of days and was discharged. Histopathology report was suggestive of atypical meningioma, WHO grade 2.
Genetic analysis performed has identified an autosomal recessive, apparently homozygous c.3383+3A>G mutation in the patient with one copy each inherited from parents. This mutation has not been previously reported as per International Registry of Werner's Syndrome, which makes it the first and a new mutation from Indian subcontinent associated with Werner's syndrome.
Werner syndrome (WS) was first described by Otto Werner from Germany in 1904, as part of his thesis “Cataract in combination with scleroderma”. WS is an autosomal recessive disorder that occurs due to loss of function mutations in WRN gene located on chromosome 8p12. WRN gene was identified in 1996 and found to produce “Werner” protein which is a RECQ DNA Helicase/Exonuclease. This protein maintains telomere length, prevents chromosomal aberrations and protects genomic integrity by promoting cell cycle progression/acting as DNA repair enzyme. Hence, WRN gene is aptly called the “caretaker of the genome”. The loss of function mutations in WRN gene results in premature aging of cells and genomic instability with an increased predisposition to cancers.
The clinical diagnostic criteria for WS was laid down by International Registry of WS, Seattle, and includes five cardinal signs and symptoms – (1) bilateral cataracts, (2) characteristic skin changes (tight skin, atrophic skin, ulcerations, hyperkeratosis, regional subcutaneous atrophy) and characteristic “bird” facies, (3) short stature, (4) parental consanguinity or sibling affected, (5) premature greying and thinning of scalp hair. Further signs and symptoms include—diabetes, hypogonadism, osteoporosis, osteosclerosis of distal phalanges, soft tissue calcification, evidence of premature atherosclerosis, mesenchymal neoplasms, voice changes (high pitched, squeaky or hoarse voice), flat feet. The criteria laid down for the diagnosis of WS as definite are if all the cardinal signs and two further signs were present, while if the first three cardinal signs and any two others were found in a patient, it was a probable diagnosis of WS. In a case where either cataracts or dermatological alterations and any four further signs were present, terminology of possible case was used. The registry excluded all the people in whom the onset of signs and symptoms was before adolescence. Based on this our case had four out of five cardinal features (parents had a non-consanguineous marriage) with two further signs making our case a probable case of WS clinically. A similar but slightly modified diagnostic criterion have been proposed by Takemoto et al. (2013) in Japan. The prevalence of WRN gene mutations in general population is 1 per million. And that in Japanese population is 6 per 1000., This high prevalence in Japanese is because of founder effect in mountainous regions of Japan where geography has limited gene flow, thereby allowing amplification of mutant WRN alleles in their population.
The WRN gene consists of 35 exons that encode a protein of 1,432 amino acids called “Werner” protein. The WRN protein contains RecQ-helicase domains in the central region and exonuclease domains in the N-terminal region. The nuclear localization signal is present at the C-terminal region. Two consensus regions RecQ-helicase conserved region (RQC) and the helicase RNaseD C-terminal conserved region (HRDC) are present between the helicase and nuclear localization signal. The biochemical studies combined with cell biological studies suggested that this protein is potentially involved in DNA replication, repair, recombination, transcription, telomere maintenance, and/or a combination of these events. Most of the disease mutations result in truncations of the nuclear localization signals. Precise molecular mechanisms by which mutations in WRN cause the WS phenotype are currently being investigated. The c.3383+3A>G mutation detected in our patient falls in between RQC and HRDC regions of WRN gene and has not been previously reported as per International Registry of Werner's Syndrome. [Figure 4] This makes it the first and a new mutation from Indian subcontinent associated with Werner's syndrome.
A meta-analysis by Lauper et al. analyzed data of 189 cases of WS with 248 different neoplasms and found that meningioma was the third most common tumor (10.9%), following thyroid cancer (16.1%) and malignant melanoma (13.3%). Meningiomas are the commonest benign tumors in WS patients. Male to female ratio in prevalence of meningiomas in general population is 1:2, and that in WS patients is 23:10. Nakamura et al. and Marton et al. have described the only two cases of non-benign meningiomas in WS, with the latter reporting three years of recurrence free follow-up post-surgery and radiotherapy., Radiotherapy for recurrence is described but lacks significant evidence owing to the disease rarity.
Major concern for the anesthesiologists in WS patients is difficult airway attributed to multiple craniofacial abnormalities, short stiff neck, and poor dentition., The non-elastic nature of the skin makes securing an intravenous cannula also quite challenging. Intraoperatively, the risk of accelerated hypertension, myocardial ischaemia and stroke is higher. Propofol used for induction of anesthesia in patients with WS may lead to “Propofol infusion syndrome” resulting in lipemia.
Till date, there are five case reports of WS from India. Nair SP et al. and Keen A et al. each published a case report describing skin changes in WS, while Nagappa Handargal et al. published a case of WS with uncontrolled diabetes and nonhealing ulcers.,, Amalnath SD et al. described a case of WS with liver cirrhosis and genetically proven WRN mutations. Vasudha Kemmanu et al. have described endothelial cell study in a case of WS undergoing phacoemulsification and YAG laser capsulotomy. None of these case reports had any malignancies reported.
To the best of our knowledge, this is the index case of Werner syndrome with CNS tumor in India and only third histopathologically confirmed atypical meningioma in WS patients. A new genetic mutation associated with WS is reported.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]