[Monogenic variants in Laccase domain-containing 1 (LACC1) as the cause of juvenile arthritis]. / Monogene Varianten in "laccase domain-containing 1" (LACC1) als Ursache einer juvenilen Arthritis.

Monogenic mutations in laccase domain-containing 1 (LACC1) are associated with clinical pictures that mimic severe courses of polyarticular or systemic juvenile idiopathic arthritis. The diseases are characterized by an early onset during the first year of life, a familial clustering and a high inflammatory activity. The courses are mostly difficult to influence and often lead to sequelae. In this article four cases from two families are presented in which the homozygous mutation p.T276fs* in LACC1 was detected. The children initially suffered from polyarticular or systemic forms of juvenile arthritis. Of the patients two are currently being treated with tocilizumab and methotrexate and one female patient without a basis treatment is currently only receiving local repeated intra-articular steroids. A fourth female patient underwent an allogeneic bone marrow transplantation due to a relapse of an acute lymphatic leukemia. Since then, no further inflammatory symptoms have occurred. The cases presented are compared with the other 50 courses published to date. In addition, recent studies investigating the influence of LACC1 mutations, particularly on macrophage function, are summarized.

Weighing psychosocial factors in relatives for the risk of psychopathology: a study of patients with depressive and anxiety disorders and their siblings.

PURPOSE: Siblings of probands with depressive and anxiety disorders are at increased risk for psychopathology, but little is known about how risk factors operate within families to increase psychopathology for siblings. We examined the additional impact of psychosocial risk factors in probands-on top of or in combination with those in siblings-on depressive/anxious psychopathology in siblings. METHODS: The sample included 636 participants (Mage = 49.7; 62.4% female) from 256 families, each including a proband with lifetime depressive and/or anxiety disorders and their sibling(s) (N = 380 proband-sibling pairs). Sixteen psychosocial risk factors were tested. In siblings, depressive and anxiety disorders were determined with standardized psychiatric interviews; symptom severity was measured using self-report questionnaires. Analyses were performed with mixed-effects models accounting for familial structure. RESULTS: In siblings, various psychosocial risk factors (female gender, low income, childhood trauma, poor parental bonding, being single, smoking, hazardous alcohol use) were associated with higher symptomatology and likelihood of disorder. The presence of the same risk factor in probands was independently associated (low income, being single) with higher symptomatology in siblings or moderated (low education, childhood trauma, hazardous alcohol use)-by reducing its strength-the association between the risk factor and symptomatology in siblings. There was no additional impact of risk factors in probands on likelihood of disorder in siblings. CONCLUSION: Our findings demonstrate the importance of weighing psychosocial risk factors within a family context, as it may provide relevant information on the risk of affective psychopathology for individuals.

Familial risk associated with lung cancer as a second primary malignancy in first-degree relatives.

BACKGROUND: Aggregation of lung cancer (LCa) in family members is well-documented. However, little is known on the familial risk of LCa when first-degree relatives (FDRs, parents or siblings) are diagnosed with LCa as a second primary malignancy (LCa-2). We aimed to investigate whether and to what extent a family history of LCa-2 was associated with an increased LCa risk. METHODS: In this Swedish national cohort we identified 127,865 individuals who had one FDR affected by LCa as a first primary cancer (LCa-1) and 15,490 individuals who had one FDR affected by LCa-2, respectively. We then estimated relative risk (RR) of LCa using those without cancer family history as reference. RESULTS: The number of LCa-2 has been increasing annually and rather similarly in men and women in the last decade. Familial RR of LCa was 1.96 (95%, 1.85-2.07) for LCa-1 family history and 1.89 for LCa-2 (1.62-2.21). Risk was especially high when FDR was diagnosed with early-onset LCa-2 and when siblings were affected by LCa-2. The RR was 1.53 (1.10-2.12) when LCa-2 in FDR was diagnosed within 26 months after first primary cancer, and it increased to 2.16 (1.62-2.90) when LCa-2 was diagnosed between 74 to 154 months. Higher risk was observed for first primary cancer of the ovary (4.45, 1.85-10.7), nervous system (3.49, 1.45-8.38), upper aerodigestive tract (2.83, 1.78-4.49) and cervix (2.55, 1.41-4.61), and for non-Hodgkin lymphoma (3.13, 1.57-6.27). CONCLUSIONS: LCa risk is associated with diagnosis of LCa-2 in FDR to a similar degree as LCa-1 in FDRs.

Colorectal cancer risk in association with colorectal cancer as a second malignancy in relatives: a nationwide cohort study.

BACKGROUND: Increasing number of individuals will have first-degree relatives (FDRs) diagnosed with colorectal cancer (CRC), as a second primary malignancy (CRCa-2) after a non-CRC cancer. We aimed to estimate whether and to what extent a family history of CRCa-2 is associated with an increased CRC risk. METHODS: In this Swedish nationwide cohort study, rate ratio (RR) and cumulative incidence of CRC were estimated among 172,531 individuals with a family history of CRC as a first primary malignancy (CRCa-1) and 17,830 with a family history of CRCa-2, respectively, using individuals without cancer family history as the reference group. RESULTS: A cumulative incidence of CRC by age 80 was 6.3 and 5.6% for individuals with a parental and a sibling family history of CRCa-2, respectively. RRs of CRC for one FDR diagnosed with CRCa-1 and CRCa-2 were respectively 1.72 (95% CI, 1.65-1.79) and 1.50 (1.32-1.70); the latter RR was lower than the former (P = 0.0356), but no difference was observed after adjusting age of diagnosis of CRC in FDR and family relationship (P = 0.6898). Increased RRs were found to be associated with a CRCa-2 diagnosis in FDR that occured after cancers in upper aerodigestive tract, breast, prostate, kidney and nervous system. CONCLUSIONS: Individuals who have relatives with CRCa-2 have an increased risk of CRC, but the magnitude is lower than those having relatives with CRCa-1, which is related to different ages of diagnosis of CRC in FDR and family relationships.

Familial Clustering of Aortic Size, Aneurysms, and Dissections in the Community.

BACKGROUND: Ruptured aortic aneurysm and aortic dissections are potentially preventable disorders associated with high mortality. Screening of individuals at risk may translate into elective surgical interventions and lowered mortality. It is uncertain if the risk of aortic dilation of varying degrees aggregates within families. METHODS: We investigated the risk of having thoracic and abdominal aortic sizes in the highest quartile (measured by computed tomography scans and indexed for body size) if at least 1 parent did so in the Framingham Heart Study cohorts, and estimated the incidence rates and hazard ratios of developing aortic aneurysm or dissection among first-degree relatives of those with aortic aneurysm or dissection, in comparison with age- and sex-matched controls (1:10 for aortic aneurysm and 1:100 for aortic dissection) using the Danish nationwide administrative registries. RESULTS: In the Framingham Heart Study, offspring (n=235) whose parent(s) had a sex- and age-standardized aortic size in the upper quartile had a multivariable-adjusted ≈3-fold increased odds ratio of belonging to the upper quartile themselves. In Denmark, a total of 68 939 individuals (mean age, 42 years) had a first-degree relative with aortic aneurysm and 7209 persons (mean age, 39 years) had a first-degree relative with aortic dissection. During an average follow-up of 7 years, first-degree relatives of patients with aortic aneurysm and dissection had a hazard ratio of 6.70 (95% CI, 5.96-7.52) for developing aortic aneurysm and a hazard ratio of 9.24 (95% CI, 5.53-15.44) for dissection in comparison with matched controls. These estimates remained unchanged on adjusting for several comorbidities, including prevalent hypertension, bicuspid aortic valve, and the Marfan syndrome. For both aortic aneurysm and dissections, the absolute event rates approached 1 per 1000 person-years for first-degree relatives versus 11 to 13 (aortic aneurysm) and 2 to 3 (aortic dissections) per 100 000 person-years among controls. CONCLUSIONS: Increased aortic size, a precursor of aortic aneurysm and a risk factor for dissection, clusters in families. The incidence rates of aortic aneurysm and dissections approach the incidence rates of other common cardiovascular conditions in first-degree relatives, supporting the use of systematic screening for these conditions.

Risk-adapted starting age of breast cancer screening in women with a family history of ovarian or other cancers: A nationwide cohort study.

BACKGROUND: There is a lack of evidence-based recommendations for the age at which women with a family history of cancers other than breast cancer should start breast cancer screening. METHODS: Using Swedish family cancer data sets, the authors conducted a nationwide cohort study including 5,099,172 Swedish women born after 1931 (follow-up, 1958-2015). Accounting for calendar time, they calculated the relative risk of breast cancer for women with a family history of a discordant cancer in 1 first-degree relative. Furthermore, the authors used 10-year cumulative risk to determine the ages at which women with a family history of discordant cancer reached risk thresholds at which women in the general population were recommended to start breast cancer screening. RESULTS: A family history of cancer at 15 sites was associated with an increased risk of breast cancer. Among women younger than 50 years, the highest risk of breast cancer was observed for those with a family history of ovarian cancer (standardized incidence ratio, 1.44; 95% confidence interval, 1.26-1.64). In these women, the risk of breast cancer associated with a family history at other cancer sites ranged from 1.08-fold for prostate cancer to 1.18-fold for liver cancer. When breast cancer screening was recommended to be started at the age of 50 years for the general population, women with 1 first-degree relative with ovarian cancer attained the threshold risk for screening at the age of 46 years. Women with a family history of other discordant cancers did not reach the risk thresholds for screening at younger ages. CONCLUSIONS: Many cancers showed familial associations with breast cancer, but women with a family history of these cancers (except for ovarian cancer) did not reach risk thresholds for screening at younger ages.

Family history of breast cancer as a second primary malignancy in relatives: a nationwide cohort study.

BACKGROUND: With the increasing number of breast cancer (BC) diagnosed as a second primary malignancy after a first primary non-breast cancer (BCa-2), it is unclear about the familial risk of BC among women with a first-degree relative (FDR, parents or siblings) affected by a BCa-2. METHODS: In this Swedish nationwide cohort study, 5315 women with a FDR affected by BCa-2 and 115,048 women with a FDR affected by BC as the first primary cancer (BCa-1) were followed for the first primary invasive BC diagnosis. Relative risk (RR) of BC was estimated through Poisson regression by using 2,743,777 women without a family history of cancer as reference. The risk was stratified by the diagnostic age of BC in FDR, proband type, the time interval between the first primary cancer and BCa-2 in FDR as well as the site of first primary cancer diagnosed in FDR before BCa-2. We also calculated the cumulative incidence of BC from birth to a specific age for the three groups. RESULTS: The cumulative incidence from birth to age 70 was 10% among women with a family history of BCa-2. The RR of BC with a family history of BCa-2 (RR, 1.68, 95%CI, 1.49 to 1.88) was comparable to that with BCa-1 (1.68, 1.63 to 1.73). The risk was largely consistent irrespective of proband type. The age of onset of BCa-2 in FDR (RR early-onset, 1.72 vs. RR late-onset 1.67) had less influence on the risk compared to BCa-1 in FDR (1.89 vs. 1.63). In the analysis stratified by the time between the first primary cancer and BCa-2 in relatives, the risks were largely similar. For the site of first primary cancer diagnosed in FDR before BCa-2, the increased BC risk was found in women whose FDRs were diagnosed with first primary gastric, colorectal, endometrial, ovarian, nervous system and endocrine gland cancers, and non-Hodgkin lymphoma. CONCLUSIONS: Women with a family history of BCa-2 have a similar overall BC risk as those with a family history of BCa-1. The risk varied according to the site of first primary cancer diagnosed in FDR before BCa-2.

Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a motor neuron disorder characterized by a pure upper motor neuron degeneration in the bulbar and spinal regions. The key difference with amyotrophic lateral sclerosis (ALS) is the lower motor neuron system integrity. Despite important literature on this disease, the pathophysiology of PLS remains unknown, and the link with ALS still balances between a continuum and a separate entity from ALS. METHODS: We report nine families in which both PLS and ALS cases occurred, in general among first-degree relatives. RESULTS: The patients with PLS and ALS had a typical disease presentation. Genetic studies revealed mutations in SQSMT1, TBK1, and TREM2 genes in two PLS patients and one ALS patient. CONCLUSIONS: These results strongly support a phenotypic continuum between PLS and ALS.

Familial clustering of hepatitis C virus in a Pakistani population.

Pakistan has the second-highest burden of hepatitis C patients in the world. A total of 683 individuals, who visited the Liver Clinic during the study period, were screened for the presence of hepatitis C virus (HCV) infection. A total of 534 individuals who showed positive HCV infection were grouped into the case group and 149 individuals with HCV negative status were grouped into the control group. A detailed questionnaire was used to collect demographic, clinical, HCV risk factor, and familial clustering data. HCV familial clustering was found in 30.1% in the case group compared with 17.4% in the control group. We also found 17% of patients had spouses who were also infected with HCV compared to 4% spouse infection in the control group. Only 3.7% of patients had HCV positive mothers. These results were further expanded by regression analysis that showed that family history and sexual history are independent risk factors for transmission of hepatitis C infection and mother's history has no significance as a risk factor for transmission. The major risk factor for getting HCV infection are dental procedures, unsafe injections, surgery, and blood transfusions. There is a strong need to increase awareness about HCV transmission routes among positive patients to reduce the chances of HCV familial clustering.

Familial clustering of COVID-19 skin manifestations.

The medical community in the past months has seen a flourishing of information related to the SARS-CoV-2 virus responsible for the COVID-19 pandemic. From the early days of the pandemic, the SARS-CoV-2 virus has been linked to multiple different types of skin involvement. To the best of our knowledge, we are the first to report on a case of familial clustering of a maculopapular COVID-19 rash. Eight persons presented COVID-19 symptoms, six were confirmed via SAR-CoV-2 chemoluminescent immunoassays, and the four related by blood presented skin manifestations. Although, it has not been fully established if the SARS-CoV-2 can in fact cause viral exanthems, our observations regarding the familial clustering and the temporal evolution seen in this family seem to present strong evidence of a viral exanthema related to SARS-CoV-2 infection.

Risk factors for familial clustering of hepatitis C virus infection in a Chinese Han population: a cross-sectional study.

BACKGROUND: Hepatitis C is a curable disease, but reinfection from household contact may occur in patients who have achieved sustained viral response (SVR). METHODS: A total of 997 ethnic Han HCV treatment-naïve adult patients were enrolled in a cross-sectional study with stratified sampling based on the populations of five geographic regions across China to examine the genetic and physiological parameters associated with the phenomenon of HCV familial clustering. RESULTS: Of the total 997 patients, there were 59 patients who had at least one family member with HCV infection according to patient self-report. Comparison between patients with and without HCV familial clustering by univariate regression analysis showed that genotype 2, sexual transmission, long-term exposure to HCV patients, monthly family income per person less than 2000 yuan, farming occupation, and the southern and northern regions were associated with HCV familial clustering. Blood transfusion was negatively associated with HCV familial clustering. Multivariate logistic regression analysis suggested that long-term exposure to HCV patients and low family income were correlated with HCV familial clustering, whereas blood transfusion was negatively associated, which meant that blood transfusion was not the main transmission route in HCV familial clustering. CONCLUSION: Long-term exposure to HCV patients and low family income were correlated with HCV familial clustering, whereas blood transfusion was not the main transmission route in HCV familial clustering. To reduce reinfection from household contacts, education and awareness of HCV transmission routes and familial clustering should be strengthened, especially among HCV patients' family members, low-income families and non-blood transmission hepatitis C patients.

Family aggregation of language impairment in an isolated Chilean population from Robinson Crusoe Island.

BACKGROUND: It has been reported that the inhabitants of the Chilean Robinson Crusoe Island have an increased frequency of specific language impairment (SLI) or developmental language disorder (DLD). AIMS: To explore the familial aggregation of DLD in this community. METHODS & PROCEDURES: We assessed the frequency of DLD amongst colonial children between the ages of 3 and 8;11 years (50 individuals from 45 nuclear families). Familial aggregation rates of language disorder were calculated by assessing all available first-degree relatives (n = 107, 77 parents, 25 siblings, five half-siblings) of the probands. OUTCOMES & RESULTS: We found that 71% of the child population performed significantly below expected in measures of phonological production or expressive and receptive morphology. The majority of these children presented with severe expressive and/or receptive language difficulties. One-quarter of language-disordered probands primarily had phonological difficulties. Family members of affected probands experienced a higher risk of language disorder than those of typically developing probands. This increased risk was apparent regardless of non-verbal IQ. CONCLUSIONS & IMPLICATIONS: The study substantiates the existence of a familial form of speech and language disorder on Robinson Crusoe Island. Furthermore, we find that the familiarity is stable regardless of non-verbal IQ, supporting the recent movement to reduce the importance of non-verbal IQ criterion in DLD diagnoses.

A novel CCM2 variant in a family with non-progressive cognitive complaints and cerebral microbleeds.

Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid-beta-42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE-ϵ4; one heterozygous. The cognitive complaints, reduced amyloid-beta-42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Characterization of Mesoamerican Nephropathy in a Kidney Failure Hotspot in Nicaragua.

BACKGROUND: Mesoamerican nephropathy (MeN) is a kidney disease of unknown cause that mainly affects working-age men in Central America. Despite being a major cause of morbidity and mortality in this region, its clinical characteristics have not been well defined. STUDY DESIGN: Cross-sectional family-based study. SETTING & PARTICIPANTS: 266 members of 24 families with high chronic kidney disease (CKD) burdens in a MeN hotspot in Northwestern Nicaragua. We compared clinical and biochemical characteristics of affected individuals first with their unaffected relatives and then with NHANES (National Health and Nutrition Examination Survey) participants with CKD in order to reveal identifying features of MeN. PREDICTOR: CKD defined as serum creatinine level ≥ 1.5mg/dL in men and ≥1.4mg/dL in women. OUTCOMES: Clinical and biochemical parameters, including serum sodium, potassium, bicarbonate, calcium, magnesium, phosphorus, and uric acid. RESULTS: Hyperuricemia, in many cases severe, was common among patients with MeN. Uric acid levels in patients with MeN were higher than those in NHANES participants (mean, 9.6 vs 7.4mg/dL for men in each group) despite more frequent use of uric acid-lowering medications in Nicaraguan individuals (71.7% vs 11.2%). In multivariable linear mixed-effects regression analysis, uric acid levels were 2.0mg/dL (95% CI, 1.0-3.0; P<0.001) higher in patients with MeN compared with their NHANES counterparts after adjusting for age, estimated glomerular filtration rate, and uric acid-lowering therapies. In contrast to prior reports, hyponatremia and hypokalemia were not common. LIMITATIONS: CKD defined by single serum creatinine measurement; population likely not representative of full MeN phenotype spectrum across Central America; major differences between MeN and NHANES groups in important characteristics such as age, ancestry, and recruitment method. CONCLUSIONS: Hyperuricemia out of proportion to the degree of decreased kidney function was common among Nicaraguan patients with MeN. Our results suggest that rather than being solely a consequence of CKD, hyperuricemia may play a role in MeN pathogenesis, a hypothesis that deserves further study.

A Heritable Predisposition to Osteoarthritis of the Hip.

Using THA as a proxy for underlying osteoarthritis, we describe population-based familial clustering of osteoarthritis of the hip. The GIF test for excess relatedness on 1049 patients that underwent THA (and do not have a diagnostic code for other conditions leading to THA) showed excess relatedness (P<0.001). Even when close relationships were ignored (closer than third-degree relationships), excess relatedness was observed (P=0.020). Relative risk was elevated in first-degree (RR 2.59; 95% CI 1.84-3.53, P=2.0e(-7)), second-degree (RR 1.66; 95% CI 1.11-2.39; P=0.0075) and third-degree relatives (RR 1.46; 95% CI 1.17-1.81; P=5.7e(-4)). Excess relatedness of individuals who had undergone THA for osteoarthritis and elevated risks to both near and distant relatives were observed.

Polydactyly-Myopia Syndrome: Genetic and Ophthalmologic Perspectives.

Polydactyly-myopia syndrome is a rare genetic condition characterized by the co-occurrence of polydactyly and myopia. Herein, we present the case of a 28-year-old Muslim male, born of consanguineous parents, who presented with complaints of diminished vision since childhood. Ophthalmologic examination revealed severe myopia with characteristic fundus changes indicative of high myopia. Additionally, the patient exhibited polydactyly in all limbs, with a positive family history of both polydactyly and myopia. This case underscores the importance of recognizing and managing rare syndromes to provide appropriate genetic counseling and clinical care. Further research is warranted to elucidate the underlying genetic mechanisms and optimize therapeutic strategies for polydactyly-myopia syndrome. Awareness of this syndrome among healthcare providers is essential to facilitate early diagnosis and intervention for affected individuals and their families.

Families with non-Hodgkin lymphoma and plasma cell dyscrasias in their pedigrees.

Although reports of familial clustering of hematologic malignancies have appeared for decades, the cause(s) of this uncommon occurrence is still not completely understood. Most modern investigations, however, support a genetic rather than an environmental exposure as a cause of this observation. Most pedigrees of families with familial hematologic malignancies demonstrate age of onset anticipation, with the disease diagnosed at an earlier age in successive generations. The cause of this phenomenon is clear in some familial neurologic disorders (trinucleotide repeat expansion) but not at all clear in familial hematologic malignancies. In preparation for molecular studies of familial clustering of hematologic malignancies, we have collected pedigrees on 738 families and have previously demonstrated anticipation in those with familial plasma cell myeloma, chronic lymphocytic leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma (NHL). Here we present data on 36 families with both plasma cell myeloma and NHL in their pedigrees and demonstrate strong evidence for anticipation in these families. We encourage all health care personnel to ask patients multiple times about family medical history and carefully take note of family histories from individuals with uncommon illnesses and to refer families with clustering of such illnesses for further investigation.

A person-to-person transmission cluster of severe fever with thrombocytopenia syndrome characterized by mixed viral infections with familial and nosocomial clustering.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease with sporadic occurrence and high mortality. Herein, we report an example of the in-hospital transmission of SFTS virus (SFTSV) infections with familial and nosocomial clustering in Zhejiang Province, eastern China, from March to April 2023. The epidemiological investigation and genomic analysis revealed that at least eight suspected cases of SFTS occurred in this cluster, including one death and one asymptomatic case. Our report reemphasizes the risk of familial and nosocomial SFTSV infections in healthcare settings and the urgent need for the long-term systematic surveillance of SFTSV evolution in humans and animals in the eastern coastal regions of China.

Recurrence risk of autoimmune thyroid and endocrine diseases.

BACKGROUND AND OBJECTIVE: The recurrence risk ratio (λ) expresses the risk ratio of index patients' first-degree relatives developing a disease as compared to the general population and is a quantitative measure of the genetic contribution to the disease. This paper offers the results of a specialized center as well as a review of the pertinent literature. METHODS: Data from 3315 consecutive subjects followed at an ORPHAN academic tertiary referral expert center for endocrine autoimmunity as well as 419 unrelated German families were collected. λ was assessed based on 806 well-documented subjects, 299 index patients with autoimmune glandular (AIGD) and non-endocrine diseases and 507 of their first-degree relatives (328 children, 179 siblings). RESULTS: As many as 36% of relatives of patients with autoimmune diseases (AID) were affected by various autoimmune conditions. Twenty-five percent and 23% of all relatives had an AIGD or an autoimmune thyroid disease (AITD), respectively. Furthermore, 29% and 25% of relatives of index cases with polyglandular (PGA) and monoglandular (MGA) autoimmunity were affected. The recurrence risk for AITD was increased 16-fold in both children and siblings compared to the general population (λ, 95% CI 16, 11-21 and 16, 12-19, respectively). Furthermore, λ for AITD/AIGD was 21.62 (95% CI 14.17-30.69)/17.57 (11.80-24.36) and 13.48 (8.42-20.52)/10.68 (6.76-16.02) for siblings of patients with PGA and MGA, respectively. Overall, a strong genetic component for AITD and AIGD with a significant genetic impact on the development of PGA was demonstrated. CONCLUSION: These novel results strongly recommend the screening for AITD and AIGD in children and siblings of index patients with AITD.

Prostate cancer incidence and survival in relation to prostate cancer as second cancer in relatives.

OBJECTIVES: To investigate if the risk of prostate cancer (PC) differs based on the order of primary PC diagnosed in first-degree relatives (FDRs) given possibly different risk factors for PC as first primary cancer (PCa-1) and second primary cancer (PCa-2). SUBJECTS AND METHODS: In this Swedish nationwide cohort, PC diagnosis was followed for among 149,985 men with one FDR affected by PCa-1, 10,972 with one FDR affected by PCa-2 and 2,896,561 without any FDRs affected by cancer in a maximum of 57 years. PC patients were further followed for death due to PC since diagnosis. Relative risk (RR) of PC was estimated with Poisson regression and hazard ratio (HR) with Cox proportional hazard model. RESULTS: Compared to men without any FDRs affected by cancer, the RRs of PC in men with one FDR affected by PCa-1 and PCa-2 were 2.12 (95% confidence interval [CI]: 2.07-2.17) and 1.69 (1.54-1.85), respectively. The risk in men with one FDR affected by PCa-2 was significantly lower than those with one FDR affected by PCa-1 after additionally adjusting for family relationship (father-son and brothers) and age at diagnosis of PC in FDR (RR PCa-2 vs PCa-1 , 0.85, 95% CI, 0.78-0.94). PC patients with a family history of PCa-2 were more likely to be detected at late-stage and less likely to be diagnosed by screening, compared to those with a family history of PCa-1. Patients whose PC was diagnosed after the diagnosis of PCa-1 in FDRs had a better survival than those without a family history of cancer (HR, 0.88, 95% CI, 0.80-0.97), but no such association was observed among patients with a family history of PCa-2. CONCLUSION: Our study indicates a discrepancy between PC risks associated with a family history of PCa-1 and PC-2 and the reason behind it may be multifactorial.