Whole exome screening identifies novel and recurrent WISP3 mutations causing progressive pseudorheumatoid dysplasia in Jammu and Kashmir-India

We report identification and genetic characterization of a rare skeletal disorder that remained unidentified for decades in a village of Jammu and Kashmir, India. The population residing in this region is highly consanguineous and a lack of understanding of the disorder has hindered clinical management and genetic counseling for the many affected individuals in the region. We collected familial information and identified two large extended multiplex pedigrees displaying apparent autosomal recessive inheritance of an uncharacterized skeletal dysplasia. Whole exome sequencing (WES) in members of one pedigree revealed a rare mutation in WISP3:c.156C > A (NP-003871.1:p.Cys52Ter), that perfectly segregated with the disease in the family. To our surprise, Sanger sequencing the WISP3 gene in the second family identified a distinct, novel splice site mutation c.643+1G > A, that perfectly segregated with the disease. Combining our next generation sequencing data with careful clinical documentation (familial histories, genetic data, clinical and radiological findings), we have diagnosed the families with Progressive Pseudorheumatoid Dysplasia (PPD). Our results underscore the utility of WES in arriving at definitive diagnoses for rare skeletal dysplasias. This genetic characterization will aid in genetic counseling and management, critically required to curb this rare disorder in the families

Tuberculosis masquerading as polymyalgia rheumatica

Polymyalgia rheumatica (PMR) is a connective tissue disorder of unknown aetiology. It is hypothesized that, in a genetically predisposed person, its pathogenesis is triggered by an environmental factor, possibly a hitherto unknown infectious agent. We present the case of a 68-year-old woman who is being treated for PMR. She developed tubercular lymphadenitis and erythema nodosum and improved with antitubercular treatment. We hypothesize that the trigger for pathogenesis of PMR in this lady was antigen of Mycobacterium tuberculosis

Prevalence of dementia among Kashmiri migrants

<b>Background:</b> Neurological diseases are common disorders resulting in the loss of productive life and disability. Dementia is becoming a major public health problem in the developing world also. <b> Aim:</b> To ascertain the prevalence of dementia among Kashmiri Pandit population aged 60 years and above. <b> Materials and Methods:</b> A cross-sectional survey was conducted among the elderly population of the Kashmiris living in a migrant camp. We developed and used a Kashmiri version of the Mini-Mental State Examination as the test instrument, and a score below 24 was considered indicative of dementia. A functional ability questionnaire was also administered to the subjects. A neurologist carried out the examinations. <b>Results:</b> A sample comprising 200 subjects (95 males and 105 females) were evaluated. The prevalence of dementia is 6.5&#x0025; among the Kashmiri Pandit population aged 60 years and above, which is higher than that reported from other parts of India

Inbreeding as a cause for deafness: Dadhkai study

Background: We report on the higher prevalence of deaf-mutes from a village in Jammu and Kashmir State of India. Materials and Methods: A cross-sectional study among 79 deaf mutes using pedigree analysis, audiometry, imaging and molecular analysis. Results: A high rate of hereditary deafness with 79 individuals diagnosed to be suffering from non-syndrome deafness in a total population of 2452 individuals residing in the village. Interpretation: Flourishing of intermarriages led to a population with high prevalence of deafnes

Inbreeding as a cause for deafness: Dadhkai study

Background: We report on the higher prevalence of deaf-mutes from a village in Jammu and Kashmir State of India. Materials and Methods: A cross-sectional study among 79 deaf mutes using pedigree analysis, audiometry, imaging and molecular analysis. Results: A high rate of hereditary deafness with 79 individuals diagnosed to be suffering from non-syndrome deafness in a total population of 2452 individuals residing in the village. Interpretation: Flourishing of intermarriages led to a population with high prevalence of deafnes

Fever of unknown origin - Hidden in the head

The original algorithmic approach, as outlined by de Kleijn and colleagues and practiced commonly, envisages performing computed tomography (CT) of chest, abdomen, and pelvis in patients with classical fever of unknown origin (FUO), in whom no potentially diagnostic clue exists. It further envisages performing positron emission tomography (PET) scan, if CT scan is unrevealing. Imaging of head and neck especially magnetic resonance imaging (MRI) has not been included in this algorithm, that leaves these important regions unexplored in most settings where PET scan is unavailable. MRI is a safe modality for evaluating central nervous system lesions and its role in FUO has not been adequately evaluated. We present three patients of FUO in whom the diagnosis of tuberculoma of brain as a cause of prolonged pyrexia got delayed because the MRI of head was not done initially, to comply with the approach of minimum diagnostic evaluation

“Peripheral Neuropathy Crippling Bronchial Asthma”: Two Rare Case Reports of Churg-Strauss Syndrome

Churg-Strauss syndrome (CSS) is a rare cause of vasculitic neuropathy. Although rare and potentially fatal, Churg-Strauss syndrome (CSS) is easily diagnosable and treatable. The presence of bronchial asthma with peripheral neuropathy in a patient alerts a physician to this diagnosis. This is vividly illustrated by the presented two cases who had neuropathy associated with bronchial asthma, eosinophilia, sinusitis, and positive perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) test, which improved with administration of steroids

Geographic Isolation and Endogamous Practices Provide Higher Risk of Genetic Disorders in Jammu and Kashmir

Rare disorders are poorly understood, most often remain uncharacterized or patients are misdiagnosed due to lack of specific clinical resources. Understanding the basics of inheritance is essential in such cases as it helps to figure out the plausibility of a disorder as an inherited or genetic disease. Though identification and characterization of such disorders is complicated, Next generation Sequencing has come up as a tool in recent times and is of great help. It is quite visible in literature that since the advent of this methodology, a drastic increase in identification and genetic characterization of various rare diseases across the world has occurred. We emphasize on NGS/WES, as an effective method in understanding uncharacterized Mendelian Disorders. It is of great help, especially in developing countries and regions like Jammu and Kashmir where, such familial disorders exist in abundance, due to very high consanguinity, but remain undiagnosed/misdiagnosed due to lack of specialized testing. We have collected huge number of highly extended families representing various rare genetic disorders and trying to elucidate the genetic cause and biology of the diseases in these families