Familial deep endometriosis: A rare monogenic disease?

Endometriosis is a frequent cause of pelvic pain and subfertility in women of reproductive age. Presence of extra-uterine endometrial-like tissue is responsible for non-specific symptoms such as chronic pelvic pain, dysmenorrhea, dyspareunia, dyschesia and sometimes infertility. Three different phenotypes according to the location of the lesions are described, namely peritoneal, ovarian and deep infiltrating endometriosis. Deep endometriosis is considered as a distinct homogeneous disease. Heritability of endometriosis has been previously demonstrated. Despite extensive efforts to characterize candidate alleles contributing to genetic basis of endometriosis, these factors relevant to endometriosis pathophysiology remain unclear. No high penetrance pathogenic variant could be identified. We report herein two families with familial aggregation of severe deep infiltrating endometriosis, providing further evidence for monogenic mendelian inheritance of this form of endometriosis.

Female sexual pain: Epidemiology and genetic overlap with chronic widespread pain.

BACKGROUND: Increased tender spots and lowered general pain thresholds have been observed in patients with dyspareunia. Based on this, the aim of the study was to compare the co-occurrence of female sexual pain across various pain populations and to further explore the aetiological structure underlying sexual pain by dissecting the genetic and environmental covariation among sexual pain, chronic widespread pain (CWP) and the previously reported psychological correlates of anxiety sensitivity and depression. METHODS: A multivariate twin study including 1489 female twin individuals (246 full MZ pairs, 187 full DZ pairs and 623 whose co-twin did not participate). Main outcomes measures included self-reported diagnosis of osteoarthritis and rheumatoid arthritis, and validated questionnaires for the assessment of sexual pain, CWP, depression and anxiety sensitivity. RESULTS: Sexual pain showed a small but statistically significant correlation with CWP (r = 0.08; p < 0.05), anxiety sensitivity (r = 0.15, p < 0.001) and depression (r = 0.09, p < 0.01). The heritability of sexual pain was found to be 31%. Multivariate variance component analysis revealed a genetic factor common among CWP, depression, anxiety sensitivity and sexual pain, and a second genetic factor shared between anxiety sensitivity and sexual pain only. We further detected genetic and environmental factors unique to sexual pain, explaining 24.01% and 67.24%, respectively, of the phenotypic variance. CONCLUSIONS: Our findings suggest some overlap between sexual pain and CWP and point towards a shared but complex psychophysiological aetiology underlying sexual pain. Results further highlight the influence of specific environmental and contextual stressors in the development and maintenance of sexual pain. SIGNIFICANCE: Sexual pain shares a common genetic aetiology with chronic widespread pain and the frequently reported psychological comorbidities of depression and anxiety. Overall this suggests a complex psychophysiological aetiology underlying chronic pain conditions. The high proportion of variance in sexual pain explained by environmental factors further highlights the importance of specific environmental and contextual stressors in the development and maintenance of the condition.

Serotonin receptor gene (5HT-2A) polymorphism is associated with provoked vestibulodynia and comorbid symptoms of pain.

INTRODUCTION: Provoked vestibulodynia (PVD) is a common type of dyspareunia among young women. The patho-physiology remains largely unclear. Women with PVD have general pain hypersensitivity and often report additional pain symptoms. Signs point towards PVD being a chronic pain disorder similar to other syndromes of longstanding pain, including a common comorbidity of anxiety and depression. Polymorphism in the serotonin receptor gene, 5HT-2A, has been associated with other chronic pain disorders such as fibromyalgia but has not been investigated in PVD patients. AIM: We aimed to investigate a possible contribution of polymorphism in the 5HT-2A gene to the etiology of PVD as well as a potential influence on pain sensitivity. METHODS: In this case-control study 98 women with PVD and 103 healthy controls between 18 and 44 years and in the same menstrual cycle phase completed questionnaires and underwent quantitative sensory testing. Venous blood samples were collected for DNA isolation. MAIN OUTCOME MEASURES: Concomitant pain was reported, a bodily pain score was created and pressure pain thresholds (PPTs) on the arm, leg, and in the vestibule were measured. Intensity of coital pain was rated on a visual analog scale, range 0-100. The T102C (rs6313) and A-1438G (rs6311) single nucleotide polymorphisms (SNPs) in the 5HT-2A gene were analyzed. RESULTS: The probability of PVD was elevated in participants carrying the 1438G- and 102C-alleles of the 5HT-2A gene (OR 2.9). The G-/C- genotypes were also associated with more concomitant bodily pain in addition to the dyspareunia, but not with experimental PPTs or coital pain ratings. PVD patients reported more concomitant bodily pain and had lower PPTs compared with controls. CONCLUSION: The results indicate a contribution of alterations in the serotonergic system to the patho-genesis of PVD and gives further evidence of PVD being a general pain disorder similar to other chronic pain disorders.