Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: Our objective was to evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH)-associated genes among patients with systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). METHODS: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in patients with sJIA from an established cohort. Sequence data from control participants were obtained in silico (database of Genotypes and Phenotypes: phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test package. Significance was defined as P < 0.05 after 100,000 permutations. RESULTS: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3,000 controls. Quality control operations produced a set of 480 cases and 2,924 ancestrally matched control participants. RVT of cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF] < 0.01) of STXBP2 (P = 0.020) and ultrarare variants (MAF < 0.001) of STXBP2 (P = 0.006) and UNC13D (P = 0.046). A subanalysis of 32 cases with known MAS and 90 without revealed a significant difference in the distribution of rare UNC13D variants (P = 0.0047) between the groups. Additionally, patients with sJIA more often carried two or more HLH variants than did controls (P = 0.007), driven largely by digenic combinations involving LYST. CONCLUSION: We identified an enrichment of rare HLH variants in patients with sJIA compared with controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

Enrichment of Rare Variants of Hemophagocytic Lymphohistiocytosis Genes in Systemic Juvenile Idiopathic Arthritis.

Objective: To evaluate whether there is an enrichment of rare variants in familial hemophagocytic lymphohistiocytosis (HLH) genes and systemic juvenile idiopathic arthritis (sJIA) with or without macrophage activation syndrome (MAS). Methods: Targeted sequencing of HLH genes (LYST, PRF1, RAB27A, STX11, STXBP2, UNC13D) was performed in sJIA subjects from an established cohort. Sequence data from control subjects were obtained in silico (dbGaP:phs000280.v8.p2). Rare variant association testing (RVT) was performed with sequence kernel association test (SKAT) package. Significance was defined as p<0.05 after 100,000 permutations. Results: Sequencing data from 524 sJIA cases were jointly called and harmonized with exome-derived target data from 3000 controls. Quality control operations produced a set of 481 cases and 2924 ancestrally-matched control subjects. RVT of sJIA cases and controls revealed a significant association with rare protein-altering variants (minor allele frequency [MAF]<0.01) of STXBP2 (p=0.020), and ultra-rare variants (MAF<0.001) of STXBP2 (p=0.007) and UNC13D (p=0.045). A subanalysis of 32 cases with known MAS and 90 without revealed significant association of rare UNC13D variants (p=0.0047). Additionally, sJIA patients more often carried ≥2 HLH variants than did controls (p=0.007), driven largely by digenic combinations involving LYST. Conclusion: We identified an enrichment of rare HLH variants in sJIA patients compared with healthy controls, driven by STXBP2 and UNC13D. Biallelic variation in HLH genes was associated with sJIA, driven by LYST. Only UNC13D displayed enrichment in patients with MAS. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS.

Effect of single-dose methotrexate injection to prevent neoplastic changes in high risk complete hydatidiform mole: A randomised control trial.

Background: Complete hydatidiform mole affects women in their reproductive age. About 15-20% develops persistent molar gestational trophoblastic neoplasia (GTN), which is linked with delayed (beyond 56 days) normalization of serum ßHCG after surgical evacuation. Objective: The objective of the article is to shorten the duration of normalization time of ßHCG with single-dose methotrexate injection in women with high risk complete hydatidiform mole (CHM) after suction evacuation. Methods: Total 76 women with CHM were randomized into intervention and control groups. In the intervention arm (n = 34) women received single dose 100 mg intramuscular methotrexate injection post evacuation and the control group (n = 42) had standard care. Surveillance was done in both groups at two weeks intervals for next six months and duration of normalization of ßHCG level was recorded. Results: Total 94.7% women completed follow-up. Mean of normalization time was significantly lower in the intervention group compared to controls (9.7 weeks versus 14.7 week; P < 0.01). Time to event curve showed significantly earlier cumulative normalization time for the intervention group. Conclusion: Single-dose 100 mg methotrexate injection is a low-cost, simple intervention to help one out of three women with CHM with high-risk features to achieve normalization of ßHCG within 56 days. This might be helpful for people in resource-poor countries where adherence to prolonged surveillance is poor.

Unusual presentation of metastasis in adenocarcinoma cervix.

Metastatic carcinoma in an abdominal wall incision from carcinoma cervix is an uncommon and often a preterminal event. It has been reported mostly in advanced cases, often previously treated with radiotherapy. Here a case of cervical cancer with subcutaneous and rectus sheath recurrence 4 months after abdominal hysterectomy in a previously unsuspected case of adenocarcinoma cervix is reported. The patient was treated with excision of the metastatic masses followed by chemoradiation and is doing well at 5 months since presentation.