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D-bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency. Loss-of-function variants typically result in no residual enzyme activity; however, splice variants may result in protein with residual function. We describe a full-term newborn presenting with hypotonia, seizures, and unexplained hypoglycemia, who was later found to have rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed RNA from the patient’s father with RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three amino acids from the new reading frame. This RNA-seq analysis was correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble vitamin deficiencies to reduce complications.

Pyoderma gangrenosum (PG) is a sterile neutrophilic dermatosis manifesting as painful inflammatory plaques and ulcers, frequently associated with inflammatory bowel disease, rheumatoid arthritis, myelodysplastic syndrome, and acute myeloid leukemia.1 We present a case of a young woman with a novel mutation in NFkB1 who experienced common variable immunodeficiency (CVID) and severe recurrent PG episodes.

Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. BMP1 variants have been reported in the rare OI type XIII, specifically referred to herein as BMP1-associated autosomal recessive (AR) OI. We report the clinical presentation and diagnostic evaluation of a patient found to have a novel homozygous variant in BMP1. We also provide an overview of reported BMP1 variants to date, with discussion focusing on the use of bisphosphonate therapy in these patients. A 7-year-old male with speech and motor delay sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6, he developed severe back pain after a fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3, and L5 were identified. Total hip BMD was generous (adjusted Z-score* = 1.76), and femoral neck BMD was high (adjusted Z-score* = 2.67). VCFs precluded assessment of lumbar spine BMD. Genetic analysis identified a homozygous missense variant in exon 4 of BMP1 (c.C505T; p.Arg169Cys). Unlike most forms of OI, patients with BMP1-associated AR OI may have normal or paradoxically increased BMD, making BMD and fracture risk correlation difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and underlying bone pathology, often in the setting of increased BMD, complicate management. HR-pQCT assessment of bone microarchitecture and quality may aid in the decision of BP therapy and subsequent monitoring. Evidence is limited with respect to the effectiveness of BP in this rare form of OI. *Z-score was adjusted for height Z-score.

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50–80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.

Background & Aims Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse. Methods We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US. Results Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB. Conclusions Genomic analysis yielded an actionable diagnosis in a substantial number (∼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice. Lay summary We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.

// Amruta Phatak 1 , Mohammad Athar 2 , James A. Crowell 3 , David Leffel 4 , Brittney-Shea Herbert 1 , Allen E. Bale 5 and Levy Kopelovich 6 1 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA 2 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA 3 NCI-DCTD-DTP, Bethesda, MD, USA 4 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA 5 Department of Genetics, Yale School of Medicine, New Haven, CT, USA 6 Department of Medicine, Weill Cornell Medical College, New York, NY, USA Correspondence to: Levy Kopelovich, email: kopelovichl@gmail.com Allen E. Bale, email: allen.bale@yale.edu Keywords: Gorlin syndrome; basal cell carcinoma; patched; HH signaling; rapamycin Received: December 09, 2018 Accepted: January 11, 2019 Published: February 15, 2019 ABSTRACT Studies of dominantly heritable cancers enabled insights about tumor progression. BCNS is a dominantly inherited disorder that is characterized by developmental abnormalities and postnatal neoplasms, principally BCCs. We performed an exploratory gene expression profiling of primary cell cultures derived from clinically unaffected skin biopsies of BCNS gene-carriers ( PTCH1 +/- ) and normal individuals. PCA and HC of untreated keratinocytes or fibroblasts failed to clearly distinguish BCNS samples from controls. These results are presumably due to the common suppression of canonical HH signaling in vitro . We then used a relaxed threshold (p-value

Purpose Pregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of exome sequencing (ES) in identifying the genetic etiology for pregnancy loss. Methods A cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy-number variants were selected for ES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated. Results ES detected 6 pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multisystem abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders, and renal diseases. Conclusion These results supported the clinical utility of ES for detecting monogenic etiology of pregnancy loss. The identification of disease-associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

PurposePregnancy loss ranging from spontaneous abortion (SAB) to stillbirth can result from monogenic causes of Mendelian inheritance. This study evaluated the clinical application of whole exome sequencing (WES) in identifying the genetic etiology for pregnancy loss.MethodsA cohort of 102 specimens from products of conception (POC) with normal karyotype and absence of pathogenic copy number variants were selected for WES. Abnormality detection rate (ADR) and variants of diagnostic value correlated with SAB and stillbirth were evaluated.ResultsWES detected six pathogenic variants, 16 likely pathogenic variants, and 17 variants of uncertain significance favor pathogenic (VUSfp) from this cohort. The ADR for pathogenic and likely pathogenic variants was 22% and reached 35% with the inclusion of VUSfp. The ADRs of SAB and stillbirth were 36% and 33%, respectively. Affected genes included those associated with multi-system abnormalities, neurodevelopmental disorders, cardiac anomalies, skeletal dysplasia, metabolic disorders and renal diseases.ConclusionThese results supported the clinical utility of WES for detecting monogenic etiology of pregnancy loss. The identification of disease associated variants provided information for follow-up genetic counseling of recurrence risk and management of subsequent pregnancies. Discovery of novel variants could provide insight for underlying molecular mechanisms causing fetal death.

Renal thrombotic microangiopathy (TMA) involves diverse causes and clinical presentations. Genetic determinants causing alternate pathway complement dysregulation underlie a substantial proportion of cases. In a significant proportion of TMAs, no defect in complement regulation is identified. Mutations in the major mammalian 3' DNA repair exonuclease 1 (TREX1) have been associated with autoimmune and cerebroretinal vasculopathy syndromes. Carboxy-terminal TREX1 mutations that result in only altered localization of the exonuclease protein with preserved catalytic function cause microangiopathy of the brain and retina, termed retinal vasculopathy and cerebral leukodystrophy (RVCL). Kidney involvement reported with RVCL usually accompanies significant brain and retinal microangiopathy. We present a pedigree with autosomal dominant renal TMA and chronic kidney disease found to have a carboxy-terminal frameshift TREX1 variant. Although symptomatic brain and retinal microangiopathy is known to associate with carboxy-terminal TREX1 mutations, this report describes a carboxy-terminal TREX1 frameshift variant causing predominant renal TMA. These findings underscore the clinical importance of recognizing TREX1 mutations as a cause of renal TMA. This case demonstrates the value of whole-exome sequencing in unsolved TMA.

Non alcoholic fatty liver disease (NAFLD) is a leading cause of liver damage in childhood, its occurrence is influenced by genetic and environmental factors. Recently, the rs626283 polymorphism in the MBOAT7 gene has been found to be associated with alcoholic liver disease and NAFLD in adults.In a multiethnic cohort of obese children and adolescents we genotyped the rs626283 polymorphism in the MBOAT7 gene, evaluated insulin sensitivity by an oral glucose tolerance test, and measured the intra-hepatic fat content (HFF%) by magnetic resonance imaging.In Caucasian youth, the minor allele (C) was associated with HFF% in (P=0.003), fasting insulin (P=0.03), area under the curve of glucose (P=0.03), and lower degree of whole-body insulin sensitivity (P=0.01) independent of age, gender, and body mass index z-score. A partial correlation showed that the association between the rs626283 variant and insulin resistance was driven by the presence of hepatic steatosis (P=0.009). However, there was no association between the rs626283 and hepatic steatosis among Hispanic and African American children and youth. The association between the rs626283 in the MBOAT7 gene among Caucasians was independent of the PNPLA3 rs738409, GCKR 1260326, and TM6SF2 rs58542926 (P=0.01). The four polymorphisms combined explained~19% of the HFF% in Caucasian obese children and adolescents.The rs626283 variant in the MBOAT7 gene is associated with NAFLD and may affect glucose metabolism by modulating intra-hepatic fat content in Caucasian obese children and adolescents.

Introduction Basal cell carcinoma (BCC) is the most common malignancy in the US. Body mass index (BMI) and height have been associated with a variety of cancer types, yet the evidence regarding BCC is limited. Therefore, we evaluated BMI and height in relation to early-onset BCC (under age 40) and explored the potential role of ultraviolet (UV) radiation exposure and estrogen-related exposures in the BMI-BCC relationship. Methods BCC cases (n = 377) were identified through a central dermatopathology facility in Connecticut. Control subjects (n = 389) with benign skin conditions were randomly sampled from the same database and frequency matched to cases on age (median = 36, interquartile range 33–39), gender, and biopsy site. Participants reported weight (usual adult and at age 18), adult height, sociodemographic, phenotypic, and medical characteristics, and prior UV exposures. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models. Results Adult BMI was inversely associated with early-onset BCC (obese vs. normal OR = 0.43, 95% CI = 0.26–0.71). A similar inverse association was present for BMI at age 18 (OR = 0.54, 95% CI = 0.34–0.85). Excluding UV exposures from the BMI models and including estrogen-related exposures among women only did not alter the association between BMI and BCC, indicating limited mediation or confounding. We did not observe an association between adult height and BCC (OR per cm = 1.00, 95% CI = 0.98–1.02). Conclusions We found a significant inverse association between BMI and early-onset BCC, but no association between height and BCC. This association was not explained by UV exposures or estrogen-related exposures in women.

Background: Array comparative genomic hybridization (aCGH), karyotyping and fluorescence in situ hybridization (FISH) analyses have been used in a clinical cytogenetic laboratory. A systematic analysis on diagnostic findings of cytogenomic abnormalities in current prenatal and pediatric settings provides approaches for future improvement. Methods: A retrospective analysis was performed on abnormal findings by aCGH, karyotyping, and FISH from 3,608 prenatal cases and 4,509 pediatric cases during 2008–2017. The diagnostic accuracy was evaluated by comparing the abnormality detection rate (ADR) and the relative frequency (RF) of different types of cytogenomic abnormalities between prenatal and pediatric cases. A linear regression correlation between known prevalence and ADR of genomic disorders was used to extrapolate the prevalence of other genomic disorders. The diagnostic efficacy was estimated as percentage of detected abnormal cases by expected abnormal cases from served population. Results: The composite ADR for numerical chromosome abnormalities, structural chromosome abnormalities, recurrent genomic disorders, and sporadic pathogenic copy number variants (pCNVs) in prenatal cases were 13.03%, 1.77%, 1.69%, and 0.9%, respectively, and were 5.13%, 2.84%, 7.08%, and 2.69% in pediatric cases, respectively. The chromosomal abnormalities detected in prenatal cases (14.80%) were significantly higher than that of pediatric cases (7.97%) (p < 0.05), while the pCNVs detected in prenatal cases (2.59%) were significantly lower than that of pediatric cases (9.77%) (p < 0.05). The prevalence of recurrent genomic disorders and total pCNVs was estimated to be 1/396 and 1/291, respectively. Approximately, 29% and 35% of cytogenomic abnormalities expected from the population served were detected in current prenatal and pediatric diagnostic practice, respectively. Conclusion: For chromosomal abnormalities, effective detection of Down syndrome (DS) and Turner syndrome (TS) and under detection of sex chromosome numerical abnormalities in both prenatal and pediatric cases were noted. For pCNVs, under detection of pCNVs in prenatal cases and effective detection of DiGeorge syndrome (DGS) and variable efficacy in detecting other pCNVs in pediatric cases were noted. Extend aCGH analysis to more prenatal cases with fetal ultrasonographic anomalies, enhanced non-invasive prenatal (NIPT) testing screening for syndromic genomic disorders, and better clinical indications for pCNVs are approaches that could improve diagnostic yield of cytogenomic abnormalities.

Background: AMP-activated protein kinase (AMPK) is implicated in several aspects of lipid metabolism including the suppression of de novo lipogenesis, promotion of fatty acid oxidation, and regulation of adipose tissue biology. We report a patient with severe hypertriglyceridemia harboring a heterozygous mutation in the PRKAA1 gene which codes for the α1-subunit of AMPK. Clinical case: A 22-year-old Mexican woman with history of morbid obesity and T2DM presented with eruptive xanthomas in the upper and lower extremities, back, and chest. VS:141/80, P 86, RR 20, 122 kg BMI 43.42 kg/m2. She was misdiagnosed on multiple occasions and had been treated with steroids until a biopsy revealed foamy histiocytes consistent with xanthomas. A lipid panel showed Triglycerides 8,513 mg/dl (0-150 mg/dl) Cholesterol 555 mg/dl (0-199 mg/dl) HDL 29 mg/dl (≥ 41 mg/dl) Direct LDL 44 (0-99). There was no family history of hyperlipidemia. After ~24-months of follow-up abnormal lipid levels persisted: Triglycerides 4527-8513 mg/dl (0-150 mg/dl) Cholesterol 408-555 mg/dl (0-199 mg/dl) HDL 22-29 mg/dl (≥ 41 mg/dl). She had microalbuminuria 87.7 mcg/mg (0-29.9 mcg/mg) and an HbA1c of 7.8%. She endorsed depression and was inconsistent with her diet due to insatiable appetite but reported medication compliance. Lipoprotein electrophoresis showed a pattern consistent with type IV Hyperlipoproteinemia. Sequencing of lipid metabolism genes revealed no abnormalities but upon whole exome scanning she was found to have a heterozygous nonsense variant in PRKAA1 (exon4:c.C394T:p.Q132X) which codes for the α1-subunit of AMPK resulting in a premature stop codon. We hypothesize that this variant results in defective AMPK activity, and given the role of AMPK in lipid and adipose tissue metabolism, it may result in disinhibition of lipogenesis, reduced fatty acid oxidation, and altered adipose tissue biology, together promoting extreme hypertriglyceridemia. Conclusion: This is the first case to implicate a PRKAA1 gene mutation as a cause of severe hypertriglyceridemia in humans.

Objective Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by elevated serum calcium with relatively low urinary calcium excretion. It typically results from an altered set point in calcium homeostasis originating from mutations in the calcium-sensing receptor (CASR), AP2S1, or GNA11 genes, which encode for the calcium-sensing receptor (CaSR), adaptor-related protein complex 2, and G-protein alpha-11 subunit, respectively. Despite numerous reports of novel variants in these genes associated with FHH, new variants continue to be discovered. Methods We describe a 20-year-old man with a family history of hypercalcemia who had clinical findings compatible with FHH and no evidence of multiple endocrine neoplasia who underwent CASR gene sequencing for evaluation of hypercalcemia. Parathyroid gland single-photon emission computerized tomography scan was normal. Results CASR gene sequencing revealed a previously unreported heterozygous intronic variant at position 1608+3A>G (chromosome 3: 121994892) resulting in a 77-residue deletion. His mother has a history of bipolar disorder and hyperparathyroidism with an adenoma found on imaging, yet our patient had no evidence of adenoma and therefore no surgical intervention was recommended. Given that CaSR plays a role in parathyroid growth, some variants in CASR may ultimately lead to parathyroid hypertrophy and be mistaken for primary hyperparathyroidism. Conclusion Long-term clinical follow up will be helpful in understanding the ultimate effects of specific CASR mutations on parathyroid growth or progression to significant hypercalcemia.

Mutations in Kelch-like family member 7 (KLHL7) have recently been described as a cause of a constellation of clinical findings with descriptions of both a Crisponi syndrome (CS)/cold-induced sweating syndrome type 1 (CISS1)-like, as well as a Bohring-Opitz syndrome (BOS)-like presentation. Here we report two siblings of Guatelmalan descent with a novel homozygous nonsense mutation (p.Arg326*) in KLHL7. These children have multiple dysmorphic features and developmental delay. Interestingly, their clinical traits inconsistently overlap both the CS/CISS1-like and BOS-like phenotypes, and the siblings also have subtle differences from each other, suggesting that clinicians need to be aware of the degree of variability in the presentations of these patients. Still, there is enough in common between patients with recessive KLHL7 mutations to define a novel multisystem disease that features various neurodevelopmental, musculoskeletal, dysmorphic, and other unique components. This report adds to the clinical features and disease-associated variants of the newly-recognized spectrum of KLHL7 mutations, and offers a new description, PERCHING, for the resulting syndrome.

Background Hereditary factors play an important etiologic role in thoracic aortic aneurysm and dissection (TAAD), with a number of genes proven to predispose to this condition. We initiated a clinical program for routine genetic testing of individuals for TAAD by whole exome sequencing (WES). Here we present our initial results. Methods The WES was performed in 102 patients (mean age 56.8 years; range 13 to 83; 70 males [68.6%]) with TAAD. The following 21-gene panel was tested by WES: ACTA2, ADAMTS10, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, ELN, FBLN4, FLNA, FBN1, FBN2, MYH11, MYLK, NOTCH1, PRKG1, SLC2A10, SMAD3, TGFB2, TGFBR1, TGFBR2. Results Seventy-four patients (72.5%) had no medically important genetic alterations. Four patients (3.9%) had a deleterious mutation identified in the FBN1, COL5A1, MYLK, and FLNA genes. Twenty-two (21.6%) previously unreported suspicious variants of unknown significance were identified in 1 or more of the following genes: FBN1 (n = 5); MYH11 (n = 4); ACTA2 (n = 2); COL1A1 (n = 2); TGFBR1 (n = 2); COL3A1 (n = 1); COL5A1 (n = 1); COL5A2 (n = 1); FLNA (n = 1); NOTCH1 (n = 1); PRKG1 (n = 1); and TGFBR3 (n = 1). Identified mutations had implications for clinical management. Conclusions Routine genetic screening of patients with TAAD provides information that enables genetically personalized care and permits identification of novel mutations responsible for aortic pathology. Analysis of large data sets of variants of unknown significance that include associated clinical features will help define the mutational spectrum of known genes underlying this phenotype and potential identify new candidate loci.

Summary Background Previous epidemiological studies of overall alcohol intake and basal cell carcinoma (BCC) are inconsistent, with some evidence for differences by type of alcoholic beverage. While alcohol may enhance the carcinogenicity of ultraviolet (UV) radiation, this has not been evaluated in existing epidemiological studies. Objectives To evaluate alcohol intake in relation to early-onset BCC, and explore potential interactions with UV exposure. Methods Basal cell carcinoma cases (n = 380) and controls with benign skin conditions (n = 390) under 40 years of age were identified through Yale Dermatopathology. Participants provided information on lifetime alcohol intake, including type of beverage, during an in-person interview. Self-reported data on indoor tanning and outdoor sunbathing were used to categorize UV exposure. We calculated odds ratios (OR) and 95% confidence intervals (CIs) using unconditional multivariate logistic regression in the full sample and in women only. Results There was no statistically significant association between lifetime alcohol intake and early-onset BCC overall [above median intake vs. no regular alcohol intake (OR 1·10, 95% CI 0·69–1·73)] or in women only (OR 1·21, 95% CI 0·73–2·01). Similarly, intake of red wine, white wine, beer or spirits and mixed drinks was not associated with early-onset BCC. In exploratory analyses, we saw limited evidence for an interaction (Pinteraction = 0·003), with highest risk for high alcohol and high UV exposures, especially in women, but subgroup risk estimates had wide and overlapping CIs. Conclusions Overall, we did not observe any clear association between lifetime alcohol intake and early-onset BCC.

While next-generation genome sequencing can successfully guide cancer therapy, it can also reveal significant incidental findings that patients, families, and physicians may not be prepared to handle and may not want to know.

Thoracic aortic aneurysm (TAA) is a lethal disease, with a natural history of enlarging progressively until dissection or rupture occurs. Since the discovery almost 20 years ago that ascending TAAs are highly familial, our understanding of the genetics of thoracic aortic aneurysm and dissection (TAAD) has increased exponentially. At least 29 genes have been shown to be associated with the development of TAAD, the majority of which encode proteins involved in the extracellular matrix, smooth muscle cell contraction or metabolism, or the transforming growth factor-β signaling pathway. Almost one-quarter of TAAD patients have a mutation in one of these genes. In this review, we provide a summary of TAAD-associated genes, associated clinical features of the vasculature, and implications for surgical treatment of TAAD. With the widespread use of next-generation sequencing and development of novel functional assays, the future of the genetics of TAAD is bright, as both novel TAAD genes and variants within the genes will continue to be identified.

Background— With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. Methods and Results— We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels ( P =0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. Conclusions— Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.

SummaryHereditary mixed polyposis is a genetically heterogeneous, autosomal dominant condition with adenomatous, hyperplastic and juvenile polyps. We conducted a comprehensive clinical evaluation of a large Ashkenazi Jewish family with this phenotype and performed extensive genetic testing. As seen in one previous report, a 40 kb duplication upstream of GREM1 segregated with the polyposis/colon cancer phenotype in this kindred. Our study confirms the association of GREM1 with mixed polyposis and further defines the phenotype seen with this mutation. This gene should be included in the test panel for all Jewish patients with mixed polyposis and may be considered in any Ashkenazi patient with unexplained hereditary colon cancer when mutations in other hereditary colon cancer genes have been ruled out.

Introduction: Venous thromboembolism (VTE), defined as deep venous thrombosis (DVT) and pulmonary embolism (PE), is a cause of significant morbidity and mortality worldwide, with an overall incidence of about 10,000,000 cases per year. The majority of VTEs are believed to be attributable to genetic factors. Yet, the five established heritable thrombophilias of factor V Leiden (FVL), prothrombin (PT) gene mutation, antithrombin (AT) deficiency, protein C (PC) deficiency, and protein S (PS) deficiency comprise only a small portion of VTEs, suggesting that further genetic factors contributing to VTE risk are unrecognized. In our previously published study, we performed whole exome sequencing (WES) in 64 patients with VTE and developed a 55-gene extended thrombophilia panel which identified 40 pathogenic or likely pathogenic variants or variants of uncertain significance (VUS) involving 22 different genes. Here, we present updated data from an expanded patient cohort. Methods: Blood was obtained from 101 patients with VTE. Genomic DNA was extracted and WES performed; mean coverage of the exome was 100x with 98% of the exome covered >/= 20 times. Variants were filtered for an allele frequency of 7% in the GnomAD database. A targeted analysis of the 55 genes in the extended thrombophilia panel was then performed. Variants in these genes were classified according to ACGM criteria as pathogenic, likely pathogenic, VUS, benign or likely benign. The number of patients with pathogenic or likely pathogenic variants and VUS in VTE patients was compared to a control population of 237 patients who had WES performed for reason other than VTE. The results of WES were also compared to those of traditional laboratory-based thrombophilia testing. Further, 17 VUS underwent in silico protein modeling to evaluate structural modifications. Results: Of the 101-patient study population, 46 were men and 55 women; 62% were Caucasian, 22% African American and 5% Hispanic; 15% had unprovoked VTE, 71% had provoked, 12% had both; and 55% had first degree family members with VTE. WES and extended thrombophilia testing identified a pathogenic or likely pathogenic variant or VUS in 69/101 (68%) VTE patients compared to 6/237 (2.5%) controls, a statistically significant difference (p-value A total of 72 genetic variants (26 previously published and 46 novel) were identified in 30 genes in the extended thrombophilia panel. 18 variants were categorized as pathogenic or likely pathogenic and 54 as VUS. 32 patients had pathogenic or likely pathogenic variants in one or more of the major thrombophilia genes, with FVL being the most common, and AT and PS deficiency being more common than PT gene mutation (FVL, n=15; PT gene mutation, n=3; AT deficiency, n=5; PC deficiency, n=3; PS deficiency, n=6). Of pathogenic variants in major thrombophilia genes, 15 were previously reported in literature, while 13 were novel. Of the 52 VUS, 17 were subjected to in silico analysis, including protein modeling, which suggested impaired protein folding in 14 variants. Conclusions: WES and extended thrombophilia testing reveal a high frequency of pathogenic or likely pathogenic variants or VUS in VTE patients compared to controls. These variants demonstrate good concordance with traditional laboratory-based thrombophilia testing. Several novel pathogenic or likely pathogenic variants were identified. In silico studies and protein modeling suggest that many VUS identified by this approach are likely to be deleterious to protein function. The results may underlie a strong genetic component to VTE. Next steps include further characterization of VUS using protein modeling, biochemical analysis, and epidemiological and familial studies to understand potential roles these variants may play in thrombosis. Table. Table. Disclosures Camire: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy.

Nevus sebaceus (NS) is a congenital skin hamartoma that presents in childhood. Tumors may arise within these lesions over time. Mutations in the PTCH gene have been associated with both NS and some of the developing tumors. Only nine documented cases of basal cell carcinoma arising in nevus sebaceus in childhood are available. We present a case of an 8-year-old male with nevus sebaceus who developed a basal cell carcinoma. Evaluation for constitutional PTCH gene mutation and loss of heterozygosity (LOH) from the BCC within the NS did not reveal an underlying mutation. We further discuss the literature regarding prophylactic excision of NS.

We assessed the association between the single-nucleotide polymorphism (SNP) rs58542926 in the transmembrane 6 superfamily member 2 (TM6SF2) gene and fatty liver disease in obese youth. We genotyped the TM6SF2 rs58542926 SNP in a multiethnic cohort of 957 obese children and adolescents (42% Caucasians, 28% African Americans, 30% Hispanics). All underwent an oral glucose tolerance test, a liver panel, and a lipid profile. Of them, 454 children underwent a magnetic resonance imaging study to assess hepatic fat content and 11 underwent liver biopsy to assess the degree of disease severity. The minor allele of the rs58542926 SNP was associated with high hepatic fat content in Caucasians and African Americans (all P

BackgroundBasal cell carcinoma (BCC) is the most common malignancy in the US. Body mass index (BMI) and height have been associated with a variety of cancer types, yet the evidence regarding BCC is limited. Therefore, we evaluated BMI and height in relation to early- onset BCC and explored the potential role of ultraviolet (UV) radiation exposure as well as estrogen-related exposures in the BMI-BCC relationship.MethodsBCC cases (n=377) diagnosed under age 40 were identified through a central dermatopathology facility in Connecticut. Control subjects (n=389) were randomly sampled from the same database and frequency matched to cases on age, gender, and biopsy site. Participants reported weight (usual adult and at age 18), adult height, sociodemographic, phenotypic, and medical characteristics, and prior UV exposures. We calculated multivariate odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression models.ResultsAdult BMI was inversely associated with early-onset BCC (obese vs. normal OR=0.43, 95% CI=0.26-0.71). A similar inverse association was present for BMI at age 18 (OR=0.54, 95% CI=0.34-0.85). Excluding UV exposures from the BMI models and including estrogen-related exposures among females only did not alter the association between BMI and BCC, indicating limited mediation or confounding. We did not observe an association between adult height and BCC (OR per cm=1.00, 95% CI=0.98-1.02).ConclusionWe found a significant inverse association between BMI and early-onset BCC, but no association between height and BCC. This association was not explained by UV exposures in this population or estrogen-related exposures among only the females

Author(s): Cartmel, Brenda; Mayne, Susan T; Bale, Allen E; Gelernter, Joel; DeWan, Andrew; Leffell, David J; Pagoto, Sherry; Spain, Peter; Ferrucci, Leah M | Abstract: Growing evidence suggests some individuals may exhibit dependence to ultraviolet light, a known carcinogen; however, few studies have investigated predictors of tanning dependence (TD).A sub-set of early-onset basal cell carcinoma case-control study participants completed an online survey. The modified-Cut down, Annoyed, Guilty, Eye-opener (mCAGE) and a questionnaire based on the addiction criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (mDSM-IV-TR) were used to classify participants having‘Symptoms of TD’ if they met criteria for TD on both questionnaires, ‘Tendency for TD’ if met criteria on only one questionnaire, or ‘Not TD’. We also assessed lifetime alcohol dependence, nicotine dependence, seasonal affective disorder (SAD), ‘exercise addiction,’ and depression. We compared TD groups with multivariate logistic regression.499 individuals reported volitional tanning and 24.4% were classified as having ‘Symptoms of TD’ and 24.4% as having a ‘Tendency for TD’. Women were more likely to have ‘Symptoms of TD’ (odds ratio (OR)=6.93; 95% Confidence Interval (95% CI)=(3.36-14.27)) or a ‘Tendency for TD’ (OR=2.82; 95% CI=1.59-4.98) than men. Alcohol dependence (OR=6.55; 95% CI=3.19-13.42), alcohol abuse (OR=3.16; 95% CI=1.81-5.51), risk of ‘exercise addiction’ (OR=5.47; 95%=1.15-26.06) and SAD (OR=2.77; 95% CI=1.26-6.09) were all significant predictors for ‘Symptoms of TD’. Alcohol dependence (OR=3.66; 95% CI=1.84-7.31) and alcohol abuse (OR=2.60; 95% CI=1.53-4.41) were significant predictors for ‘Tendency for TD.’Knowledge of associations between TD and gender, alcohol dependence/abuse, SAD, and ‘exercise addiction’ may be helpful to practitioners in treating TD and for targeting skin cancer preventive interventions for those with TD.

Background As a marker of genetic susceptibility and shared lifestyle characteristics, family history of cancer is often used to evaluate an individual's risk for developing a particular malignancy. With comprehensive data on pigment characteristics, lifestyle factors, and melanocortin 1 receptor ( MC1R ) gene sequence, we sought to clarify the role of family history of skin cancer in early-onset basal cell carcinoma (BCC). Materials and methods Early onset BCC cases ( n =376) and controls with benign skin conditions ( n =383) under age 40 were identified through Yale dermatopathology. Self-report data on family history of skin cancer (melanoma and non-melanoma skin cancer), including age of onset in relatives, was available from a structured interview. Participants also provided saliva samples for sequencing of MC1R . Results A family history of skin cancer was associated with an increased risk of early-onset BCC (OR 2.49, 95% CI 1.80–3.45). In multivariate models, family history remained a strong risk factor for early-onset BCC after adjustment for pigment characteristics, UV exposure, and MC1R genotype (OR 2.41, 95% CI 1.74–3.35). Conclusions Risk for BCC varied based upon the type and age of onset of skin cancer among affected relatives; individuals with a first-degree relative diagnosed with skin cancer prior to age 50 were at highest risk for BCC (OR 4.79, 95% CI 2.90–7.90). Even after taking into account potential confounding effects of MC1R genotype and various lifestyle factors that close relatives may share, family history of skin cancer remained strongly associated with early-onset BCC.

Nonmelanoma skin cancers (NMSCs) are the most common cancers in white populations in the world (1). Basal cell carcinoma (BCC), which accounts for 70%–80% of NMSCs (2, 3), has increased dramatically in recent decades, notably among young women (1, 4–6). BCC is treatable and unlikely to result in death; however, it can be associated with both significant morbidity and health-care costs (2, 7). The ability to identify those at highest risk of early-onset BCC could focus public health efforts and mitigate the imminent epidemic. There are few BCC risk prediction models (8, 9), yet several exist for melanoma (8–16) that typically evaluate demographic, phenotypic, and clinical factors. The melanocortin 1 receptor gene, MC1R, has been consistently associated with high-risk skin cancer phenotypes, including red hair and fair skin; however, common variants of MC1R are also now recognized as contributing to the risk of melanoma (9, 11, 17, 18) and NMSC (9, 19, 20) independent of phenotype. Consequently, the MC1R genotype has improved prediction in several melanoma (8, 9, 11, 12) and NMSC (8, 9) models. Indoor tanning has recently emerged as an important risk factor for both melanoma (21, 22) and NMSC (23) and seems particularly relevant for skin cancer in younger populations (24–26). Of the 3 published prediction models that evaluated the additive prediction of indoor tanning (8, 11, 12), only 1 model, for melanoma, observed increased predictive ability (12). Given the increase in indoor tanning in young populations and the high incidence of BCC, we were interested in evaluating whether MC1R and indoor tanning added to the predictive ability of BCC risk models, as seen in some melanoma risk models. Thus, we examined the utility of 2 existing skin cancer risk prediction models that included MC1R and indoor tanning in the setting of early-onset BCC. We then built a novel risk prediction model in the same early-onset BCC case-control population, with careful consideration of the additive prediction of indoor tanning and the MC1R genotype.

Objective: To explore the role of MTNR1B rs10830963 and G6PC2 rs560887 variants in the pathogenesis of impaired fasting glucose (IFG) in obese adolescents. Methods: A total of 346 Caucasians, 218 African-Americans, and 217 Hispanics obese children and adolescents underwent an oral glucose tolerance test (OGTT) and 518 underwent the evaluation of insulin secretion by the oral minimal model (OMM). Also, 274 subjects underwent a second OGTT after 3.0 -/+ 2.1years. Results: The MTNR1B rs10830963 variant was associated with higher fasting glucose levels and lower dynamic beta-cell response in Caucasians and Hispanics (P 0.10). Conclusions: It has been shown for the first time in obese youth that the MTNR1B variant is associated with an increased risk of IFG. (Less)

Purpose: Based on results of diagnostic MEN1 testing, we have attempted to further define the mutational spectrum of the MEN1 gene and the clinical features most frequently associated with MEN1 mutations. Methods: Mutation testing was performed on blood samples by PCR amplification and sequencing of exons 2 to 10 of the MEN1 gene and the corresponding intron-exon junctions. Pedigree phenotypic information was obtained by written questionnaire. Results: Among 288 presumably unrelated pedigrees, 73 independent mutations were found in 89 families. Five mutations were found in 2 pedigrees, and 4 mutations were seen in more than 2 pedigrees. There were 17 nonsense mutations (23.3%), 2 in-frame deletions (2.7%), 18 frameshift-deletion mutations (24.7%), 10 frameshift-insertion or -duplication mutations (13.7%), 13 splice-site mutations (17.8%), and 13 presumptive missense mutations (17.8%). Thirty-nine of 56 pedigrees with parathyroid and pancreatic islet neoplasia tested positive, compared with 4/24 and 8/32 pedigrees affected with hyperparathyroidism or hyperparathyroidism and pituitary tumors. MEN1 mutations were found in 6/20 sporadic patients, all of whom had both parathyroid and pancreatic neoplasms. Of 14 mutation-negative sporadic patients, 10 exhibited hyperparathyroidism and pituitary tumors without islet cell neoplasia. Somatic mosaicism was detected in 1 sporadic patient. Conclusion: Patients from pedigrees with hyperparathyroidism and pancreatic islet tumors are most likely to test positive for MEN1 mutations. Mutations are less often detected in patients from pedigrees with hyperparathyroidism alone or in combination with pituitary tumors without pancreatic islet neoplasia. Sporadic cases are less likely to test positive than familial cases, in part due to somatic mosaicism.

Purpose The prevalence of BRCA-associated breast carcinoma in the Korean population has not been evaluated extensively. Methods Sixty Korean women who developed breast cancer by age 40 years were studied. Lymphocyte specimens from peripheral blood were processed for BRCA1 and BRCA2 by complete sequencing. Family history through three generations was obtained. Available paraffin-embedded tissue blocks were processed for immunohistochemical staining. Results In the cohort of 60 patients, nine patients with 11 deleterious mutations (six in BRCA1 and five in BRCA2) and seven missense mutations of unknown significance were found. Two patients had deleterious mutations in both BRCA1 and BRCA2 (double mutant). One half of the mutations were novel, and no founder mutations were observed in this cohort. Most of the BRCA-associated patients had no family history of breast and/or ovarian cancer. The expression of HER-2/neu, cyclin D1, and hormone receptors was less common, and p53 overexpression was more common in BRCA-associated tumors. Conclusion The prevalence of BRCA1 and BRCA2 mutations in Korean women with breast cancer at a young age was high. However, the penetrance, as evidenced by the low frequency of breast and ovarian cancers in family members, appears to be low. These data suggest that there may be different genetic and etiologic factors affecting transmission and penetrance of the BRCA genes in Korean patients with breast cancer diagnosed at a young age.

Conservatively treated premenopausal breast cancer has a higher rate of local relapse as well as an increased genetic predisposition to cancer. The current study's purpose was to evaluate the interactions between BRCA-1/2 status and molecular biologic markers in a cohort of conservatively managed breast cancer patients. Seventy-six premenopausal women treated with breast-conserving surgery and radiation therapy were this study's focus. All patients were treated with wide local excision with or without axillary dissection, followed by radiation to the intact breast. Systemic therapy was administered as clinically indicated. All patients in this study had an available paraffin block from the primary tumor and agreed to undergo complete sequencing of the BRCA-1 and BRCA-2 genes. The primary breast tumor tissue from each patient was immunohistochemically stained for estrogen receptor (ER), progesterone receptor (PR), p53, HER-2/neu, and Proliferating Cell Nuclear Antigen (PCNA). Of the 76 patients tested for BRCA, 50 patients had wild-type BRCA-1 and BRCA-2, 15 had variants of unclear significance, 6 had deleterious mutations in BRCA-1, and 5 had deleterious mutations in BRCA-2. p53 positivity correlated with deleterious mutations in BRCA-1 (p = 0.023), but not in BRCA-2. Though not significant, there was a trend for ER and PR negativity to correlate with BRCA-1 mutation (p = 0.087 and 0.054, respectively); there were no correlations between ER, PR, and BRCA-2. Though not significant, all 11 tumors with BRCA mutations were HER-2/neu negative. Patients with BRCA mutations have a unique molecular profile. These data can be helpful in understanding differences in the biologic behavior of patients with familial breast cancers.

Immunosuppressive medications are common in the management of numerous conditions, such as organ transplantation, allergies, and respiratory disorders [1]. In some patients with conditions, such as organ transplantation, that require long-term, high-dose immunosuppression, immunosuppressives increase risk for squamous cell carcinoma of the skin (SCC) (60–250 fold increase), and to a lesser extent for basal cell carcinoma (BCC) (10 fold increase) [2–10]. An increased risk of non-melanoma skin cancer (NMSC) has also been associated with immunosuppressives among rheumatoid arthritis and inflammatory bowel disease patients [11–13]. With widespread use of low-potency, low-dose immunosuppressives, particularly glucocorticoids, for allergic and inflammatory conditions, there is interest in whether these low-level exposures increase NMSC risk. Glucocorticoids and NMSC have been evaluated in three studies [14–17]. A US case-control study found a two-fold increased risk of SCC with oral glucocorticoids, but only a suggestive non-significant association for BCC [16]. A Danish cohort study using national prescription data found a 16% increase in BCC with injected or oral glucocorticoids, with greater risk with more prescriptions [17]. A case-control study in the same Danish population found a 15% increase in BCC with oral glucocorticoids and increased risk with longer duration [15]. There was one positive [17] and one null finding [15] for SCC in the Danish studies. Finally, a US prospective study found no association between oral prednisone and BCC or SCC in adults with prior NMSC [14]. While short-term steroid use is not known to have any lasting impact on immune function, transient immune suppression from systemic steroid use could impact BCC risk, especially in those with high ultraviolet radiation exposure, which may itself induce local immune suppression [18]. To address the paucity of research on systemic glucocorticoids and NMSC, we evaluated this relationship in a case-control study of early-onset BCC.

OBJECTIVE Paralleling the rise of pediatric obesity, the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes (T2D) is increasing among youth. In this study, we asked whether the co-occurrence of risk alleles in or near five genes modulating insulin secretion (TCF7L2 rs7903146, IGF2BP2 rs4402960, CDKAL1 rs7754840, HHEX rs1111875, and HNF1A rs1169288) is associated with a higher risk of IGT/T2D in obese children and adolescents. RESEARCH DESIGN AND METHODS We studied 714 obese subjects (290 boys and 424 girls; mean age 13.6 ± 3.1 years; mean z score BMI 2.2 ± 0.4) and evaluated the insulin secretion by using the oral minimal model and, in a subgroup of 37 subjects, the hyperglycemic clamp. Also, 203 subjects were followed up for a mean of 2.1 years. RESULTS We observed that the increase of risk alleles was associated with a progressive worsening of insulin secretion (P < 0.001) mainly due to an impairment of the dynamic phase of insulin secretion (P = 0.004); the higher the number of the risk alleles, the higher the chance of progression from normal glucose tolerance (NGT) to IGT/T2D (P = 0.022). Also, for those who were IGT at baseline, a higher risk score was associated with a lower odds to revert to NGT (P = 0.026). CONCLUSIONS Obese children and adolescents developing IGT/T2D have a higher genetic predisposition than those who do not show these diseases, and this predisposition is mainly related to gene variants modulating the early phase of insulin secretion. Although these data are very interesting, they need to be replicated in other cohorts.

Many genes originally identified because of their role in embryonic development are also important in control of cell growth and differentiation postnatally. Mutations in some of these genes have been shown to contribute to carcinogenesis. The nevoid basal cell carcinoma syndrome is an autosomal dominant disorder that predisposes to basal cell carcinomas of the skin as well as widespread developmental defects. The gene for this disorder, NBCCS, maps to chromosome 9q22.3, and loss of heterozygosity at this site in both sporadic and hereditary basal cell carcinomas suggests that it functions as a tumor suppressor. NBCCS was positionally cloned and shown to be the human homologue of the Drosophila gene, patched. Drosophila patched is part of the hedgehog signaling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. That mutations in human patched result in dysregulation of several genes known to play a role in both organogenesis and carcinogenesis may explain both the birth defects and the cancer predisposition seen in the nevoid basal cell carcinoma syndrome.

Purpose: We report that patients with nevoid basal cell carcinoma syndrome (Gorlin syndrome) are at risk for developing neoplasms, especially basal cell carcinomas and rarely medul-loblastoma. Methods: A case report is presented of a 5-year-old child with medulloblastoma and multiple basal cell carcinomas who was diagnosed with nevoid basal cell carcinoma syndrome. Genetic analyses were performed on tumor DNA from the patient's medulloblastoma and basal cell carcinomas as well as germline DNA from the patient and unaffected family members. Results: After radiation therapy for medulloblastoma, the patient developed thousands of additional basal cell carcinomas. Analysis of tumor DNA revealed the characteristic defect of nevoid basal cell carcinoma syndrome, loss of heterozygosity at 9q22. Photodynamic therapy was successfully used to control the majority of her cutaneous tumors. Conclusion: DNA analysis confirmed the presence of the distinctive genetic lesion of nevoid basal cell carcinoma syndrome in both medulloblastoma and basal cell carcinoma. Omitting or limiting radiation therapy for children with nevoid basal cell carcinoma syndrome and medulloblastoma should be considered.

Individuals who have had basal cell carcinoma (BCC) are at high risk of subsequent BCCs and melanoma.1 Indoor tanning is an established risk factor for BCC, squamous cell carcinoma and melanoma.2 As such, continuing to tan indoors after a BCC diagnosis may elevate one’s risk for future skin cancers. Skin cancer survivors have sun protection behaviors that are similar to those of the general population,3 but little is known about their indoor tanning behavior. Notably, research suggests some individuals develop tanning dependence, analogous to substance dependence,4 which could be related to continued indoor tanning. To understand better the patterns of and reasons for indoor tanning after BCC diagnosis, we assessed indoor tanning and symptoms of tanning dependence in people who had at least one BCC before age 40.

Background Despite educational and public health campaigns to convey the risks of indoor tanning, many individuals around the world continue to engage in this behavior. Few descriptive studies of indoor tanning have collected information pertaining to the lifetime history of indoor tanning, thereby limiting our ability to understand indoor tanning patterns and potentially target interventions for individuals who not only initiate, but continue to persistently engage in indoor tanning. Methods In-person interviews elicited detailed retrospective information on lifetime history of indoor tanning among white individuals (n = 401) under age 40 seen by a dermatologist for a minor benign skin condition. These individuals were controls in a case-control study of early-onset basal cell carcinoma. Outcomes of interest included ever indoor tanning in both males and females, as well as persistent indoor tanning in females - defined as females over age 31 who tanned indoors at least once in the last three or all four of four specified age periods (ages 11-15, 16-20, 21-30 and 31 or older). Multivariate logistic regression was used to identify sociodemographic and lifestyle correlates of ever and persistent indoor tanning in females. Results Approximately three-quarters (73.3%) of females and 38.3% of males ever tanned indoors, with a median age of initiation of 17.0 and 21.5, respectively. Among indoor tanners, 39.3% of females and 21.7% of males reported being burned while indoor tanning. Female ever indoor tanners were younger, had darker color eyes, and sunbathed more frequently than females who never tanned indoors. Using unique lifetime exposure data, 24.7% of female indoor tanners 31 and older persistently tanned indoors starting as teenagers. Female persistent indoor tanners drank significantly more alcohol, were less educated, had skin that tanned with prolonged sun exposure, and sunbathed outdoors more frequently than non-persistent tanners. Conclusions Indoor tanning was strikingly common in this population, especially among females. Persistent indoor tanners had other high-risk behaviors (alcohol, sunbathing), suggesting that multi-faceted behavioral interventions aimed at health promotion/disease prevention may be needed in this population.

Pancreatic islet tumors are relatively rare in the general population but occur frequently in patients with MEN 1. Delineation of the genetic events leading to neoplastic transformation of islet cells is at an early stage; but based on tumor deletion studies, it appears that inactivation of the MEN 1 gene is an early step in carcinogenesis for both sporadic and MEN 1-related tumors. Limited data also suggested a role for other tumor suppressors including the retinoblastoma, adenomatous polyposis coli, and Gorlin syndrome genes. Activation of oncogenes has not been identified in pancreatic islet tumors.

Despite an increase in incidence of basal cell carcinoma (BCC) among young people and the ubiquity of indoor tanning in this population, few epidemiologic studies have investigated this exposure-disease relationship.We sought to evaluate the association between indoor tanning and early-onset BCC.Patients with BCC (n = 376) and control subjects with minor benign skin conditions (n = 390) who were younger than 40 years of age were identified through Yale Dermatopathology. Participants provided information on ever indoor tanning, age of initiation, frequency, duration, burns while tanning, and type of tanning device during an in-person interview. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariate logistic regression with never indoor tanners as the referent group.Ever indoor tanning was associated with a 69% increased risk of early-onset BCC (95% CI 1.15-2.48). This association was stronger among females (OR 2.14, 95% CI 1.31-3.47), for multiple BCCs (OR 2.16, 95% CI 1.26-3.70), and for BCCs on the trunk and extremities (OR 2.81, 95% CI 1.57-5.02). Risk increased dose dependently with years using regular indoor tanning devices (P trend = .003), number of overall burns (P trend.001), and burns to biopsy site (P trend.001) from indoor tanning. Approximately one quarter (27%) of early-onset BCCs (or 43% among women) could be prevented if individuals never tanned indoors.Potential recall bias of indoor tanning by patients and generalizability of the control population suggest replication in other studies is warranted.Indoor tanning was a strong risk factor for early-onset BCC, particularly among females. Indoor tanning should continue to be targeted by both policy-based and behavioral interventions, as the impact on BCC-associated morbidity may be substantial.

Introduction: Venous thromboembolism (VTE) occurs with an incidence of 1-2 per 1000 individuals per year. Approximately 10-20% of patients with VTE have a heritable thrombophilia involving one of five known genes: Factor V, prothrombin (PT), antithrombin (AT), protein C (PC), and protein S (PS). Significant variability of laboratory functional assays as well as fluctuating plasma levels of AT, PC and PS lead not only to delay in initial thrombophilia screening but also to multiple rounds of costly testing. Whole exome sequencing (WES) is a potentially useful diagnostic tool for inherited thrombophilias as it avoids dependence on laboratory and situational variation in protein levels. We compiled a panel of 33 genes involved in thrombosis with a goal of investigating the diagnostic yield and cost of WES in comparison to traditional thrombophilia testing. Methods: Since January of 2014, we have been performing WES in patients with a personal and family history of VTE seen at Yale New Haven Hospital. Thus far, 18 such patients have had a complete WES analysis. Data regarding patient demographics, number and type of VTE events, family/surgical history, medical co-morbidities, and traditional laboratory testing for inherited thrombophilias was recorded. Costs of each test were determined based on the amount billed to insurance. WES focusing on 33 genes involved in thrombosis was performed and analyzed by the DNA Diagnostic Lab at the Yale School of Medicine. Positive WES testing was defined as identification of a pathogenic variant in a gene known to be associated with thrombophilia, found at a frequency consistent with frequency of the disease, and with evidence that the variant predisposes to thrombosis. Positive laboratory testing was defined as any test that led to an unequivocal diagnosis of Factor V Leiden, PT mutation, homozygous MTHFR mutation with hyperhomocysteinemia, or a deficiency in AT, PC, or PS. Results: All 18 patients (7 male, 11 female) were included in the final analysis. Median age at first VTE was 35.5 years (range, 14-78 years); median number of independent VTE events was 2 (range, 1-9). WES with our 33-gene thrombophilia panel was positive in 11 of 18 (61.1%) patients, while traditional laboratory testing was positive in only 2 of 16 (12.5%) cases (Table 1). There were no statistically significant differences in clinical characteristics between those patients with positive findings on WES versus those without. Identified variants included those in genes with well known roles in thrombosis (SERPINC1, PROS1, F5), and in genes with emerging data regarding thrombosis (HABP2, SERPINA10, SERPIND1). Two patients identified on WES as having PS deficiency, one with AT deficiency, and one with a non-Leiden Factor V mutation had laboratory testing that was either normal or uninterpretable. The total cost of WES at our institution was $1935.00; by comparison, among 16 patients who underwent laboratory testing, median cost of laboratory testing was $2892.70 (range, $406.90-$11419.80), and the cost of laboratory testing exceeded WES in 13 patients. Conclusions: WES using our 33-gene thrombophilia panel has higher diagnostic yield and is more cost effective than traditional thrombophilia testing. With increasing availability and declining cost, this thrombophilia gene panel has the potential to truly transform thrombophilia testing. Further investigation of the diagnostic power and phenotypic correlation of identified mutations is in progress. | Gender | Age (yrs) | Lab testing result | WES result | | ------ | --------- | ------------------------- | --------------------------------------------------------- | | M | 40 | Negative | SERPINA10 (Q384R) heterozygous | | M | 67 | Negative | SERPINC1 (S426W) heterozygous | | M | 30 | Negative | PROS1 (Y234C) heterozygous | | F | 34 | Negative | HABP2 (G508E) heterozygous | | F | 56 | APC resistance | F5 (R506Q) heterozygous | | F | 27 | F2 20210 G>A heterozygous | F2 20210G>A heterozygous; vWF P2063S heterozygous | | F | 37 | Negative | SERPIND1 (R468C) heterozygous | | F | 48 | Negative | F5 (T915S) heterozygous | | M | 20 | Negative | PROS1 (P76L) heterozygous | | M | 55 | Negative | SERPINA10 (21_23delCCT ) heterozygous | | F | 78 | Negative | HABP2 (G534E) heterozygous | | F | 49 | Negative | Negative | | F | 41 | Negative | Negative | | M | 32 | Negative | Negative | | F | 64 | Negative | Negative | | M | 42 | Negative | Negative | | F | 51 | Negative | Negative | | F | 28 | Negative | Negative | Table 1. Mutations detected by the 33 gene thrombophilia panel Disclosures No relevant conflicts of interest to declare.

Background: The incidence of basal cell carcinoma (BCC), which accounts for the majority of non-melanoma skin cancer (NMSC), is increasing, particularly in young people. While BCC is treatable, it can be associated with significant morbidity and health care costs. The ability to identify individuals at the highest risk of early-onset BCC could help focus public health efforts and mitigate the increasing incidence. However, to date, few risk prediction models exist for BCC. To identify individuals at risk of BCC at young ages, we assessed the utility of existing skin cancer risk prediction models (for melanoma or overall skin cancer) in the setting of early-onset BCC and built a novel risk prediction model, with a focus on indoor tanning and melanocortin 1 receptor (MC1R) genotype. Methods: We evaluated unconditional multivariate logistic regression models among 759 (376 cases, 383 controls) non-Hispanic whites from the Yale Study of Skin Health, a case-control study of early-onset BCC conducted in Connecticut among individuals under age 40. BCC cases and randomly sampled controls with minor benign skin conditions diagnosed between July 2006 and September 2010 were identified through Yale University's Dermatopathology database. Participants completed a structured in-person interview, self-administered questionnaires, and provided a saliva sample. We gathered self-reported eye color, skin color (inner upper arm), hair color (natural color), freckling on the arms (based on images), number of moles on the back ≥ 5 mm (clear acetate size template), mole removal, skin reaction to sunlight for the first time in the summer for one hour without sunscreen, skin reaction after repeated and prolonged exposure to sunlight, family history of melanoma and NMSC, and indoor and outdoor ultraviolet (UV) radiation exposure. We assessed the predictive performance of our novel risk prediction model and two models in the literature via summary measures of calibration, misclassification, and discrimination. We employed bootstrapping to better reflect the area under the receiver operating characteristic curve (AUC) expected when the model is tested on an independent, but similar set of patients. To investigate if indoor tanning and MC1R improved prediction performance over our early-onset BCC base model, we evaluated the regression coefficients for the markers in the expanded risk model and the corresponding likelihood ratio test statistic. All statistical tests were two-sided and analyses were performed in the statistical software R (Version 3.0.2). Results: An existing model by Han et al. (2006) included seven MC1R variants and in our data the bootstrapped AUC for this model was 0.72 (95% CI, 0.66-0.78). Another existing model by Smith et al. (2012) with MC1R and indoor tanning resulted in a bootstrapped AUC of 0.69 (95% CI 0.63-0.75) in our population. Our base model, which included hair color, skin color, skin reaction with prolonged sun exposure, education, freckles on arm, family history of NMSC, and outdoor sun exposure in warm months, had greater predictive ability (bootstrapped AUC=0.75, 95% CI=0.72-0.79) than the existing models we evaluated. We also found that our model was significantly improved when we added ever indoor tanning, burns from indoor tanning, and the R151C MC1R variant (bootstrapped AUC=0.77, 95% CI, 0.74-0.81). Conclusions: Our risk prediction model incorporating both MC1R and indoor tanning in the risk of early-onset BCC, validates and extends the work of other skin cancer risk prediction models and emphasizes the value of considering both genotype and indoor tanning in skin cancer risk prediction in young people. Therefore, in addition to the typical skin cancer characteristics clinicians rely on, assessing and counseling young people to reduce both indoor and outdoor UV exposure is needed to reduce BCC risk. Citation Format: Annette M. Molinaro, Leah M. Ferrucci, Brenda Cartmel, Erikka Loftfield, David J. Leffell, Allen E. Bale, Susan T. Mayne. Impact of indoor tanning and MC1R genotype on basal cell carcinoma risk in young people. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A50.

Background A 5-year-old year girl with a medical history of mental retardation, physical abnormalities and a known interstitial deletion of chromosome 9q22–q32 presented with a palpable suprapubic mass. During ultrasound investigation, a left renal mass was also detected. The patient underwent surgical removal of both neoplasms, which were diagnosed as a rhabdomyosarcoma and a Wilms tumor. Seven years later, she presented with macroglossia and a benign mandibular cyst. Investigations Physical examination, karyotyping, abdominal and pelvic ultrasound, brain CT scan, anatomic pathology analysis with immunohistochemistry, and typing of polymorphic markers in the patched (PTCH) gene region. Diagnosis Gorlin syndrome with synchronous rhabdomyosarcoma and Wilms tumor. Management Left nephrectomy, excision of paravesical tumor, excision of mandibular cysts, chemotherapy, and radiotherapy.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by the predisposition to develop both peptic ulcer disease and a wide variety of endocrine tumors usually in adolescence and adulthood. Specifically, hyperplasia and/or tumors (most often adenomas) of the parathyroid, pancreatic islet cells, anterior pituitary, and adrenal cortical glands are classically described in affected individuals who have MEN1 (1,2). MEN1 is a highly penetrant disorder whose onset is generally during adult life with the occurrence of at least one, but most often more than one, of the aforementioned tumors. The age-related penetrance of this disorder based on analysis in 63 unrelated kindreds is 7, 52, 87, 98, 99, and 100% by 10, 20, 30, 40, 50, and 60 yr, respectively (3). The disorder is estimated to occur in approx 1 in 30,000 to 1 in 50,000 individuals. Most cases are associated with a positive family history of the disorder, but new germline mutations have been identified in a small percentage of individuals having a negative family history of the disorder but classic features of MEN1 (3-7).

Summary Background Management of early-stage breast cancer in young women with mutations in BRCA1 or BRCA2 remains controversial. This study assessed the long-term risks of ipsilateral and contralateral breast cancer in a cohort of young women who underwent breast-conserving surgery followed by radiotherapy. Methods Between 1975 and 1998, 290 women with breast cancer diagnosed at age 42 years or younger underwent lumpectomy followed by radiotherapy at our hospital. We recruited 127 of these women for complete sequencing of BRCA1 and BRCA2. Demographic, clinical, pathological, and outcome data were recorded. The primary endpoints were rates of ipsilateral and contralateral breast cancer, in relation to germline BRCA1/2 status. Findings 105 women were classified as having sporadic disease (94 with wild-type or known polymorphisms and 11 with variants of unclear significance) and 22 as having genetic predisposition (deleterious mutations in BRCA1 [15] or BRCA2 [seven]). At 12 years of follow-up, the genetic group had significantly higher rates of ipsilateral (49% vs 21%, p=0·007) and contralateral events (42% vs 9%, p=0·001) than the sporadic group. The majority of events were classified as second primary tumours. No patient in the genetic group had undergone oophorectomy or was taking prophylactic agents such as tamoxifen. Interpretation Patients with germline mutations in BRCA1 or BRCA2 have a high risk of developing late ipsilateral and contralateral second primary tumours. With breast-conserving therapy, chemoprophylaxis or other interventions to reduce the rate of second cancers may be valuable. Alternatively, bilateral mastectomy may be considered, to minimise the risk of second tumours in the breasts.

To note that a thyrotropin (TSH)-secreting macroadenoma may be part of the multiple endocrine neoplasia-1 (MEN-1) syndrome and to report the use of octreotide-LAR (OCT-LAR) to treat a TSH-secreting macroadenoma in a patient with MEN-1 with previous surgery for hyperparathyroidism and gastrinoma.We present a patient with a TSH-secreting pituitary macroadenoma and report the results of her endocrine, genetic, radiologic, and nuclear medicine testing and her response to treatment with octreotide (OCT), octreotide-LAR, and estrogen.This patient's TSH-induced hyperthyroidism responded to octreotide for 5 months and octreotide-LAR for more than 11 months. Her hypercalcemia normalized while she was taking estrogen. Her genetic testing is reported to show a genetic defect that is typical of patients with MEN-1.This report describes: (1) The use of octreotide-LAR to treat both a TSH-secreting pituitary tumor and a gastrinoma over 12 months; (2) the importance of including these tumors into the MEN-1 syndrome with its attendant implications; and (3) a genetic defect, typical of patients with MEN-1, associated with this tumor.

Two kindreds with familial medullary thyroid carcinoma (MTC) are described in which affected family members had variable clinical and pathologic manifestations. Genetic testing in 2 children from one kindred revealed a mutation in exon 10, codon 618 (TGC to AGC) in the extracellular cysteine-rich region of the RET gene. In this kindred an 11-year-old had microscopic evidence of MTC; however, a 17-year-old had no evidence of pathology on thyroidectomy. In a second kindred a rare mutation in exon 14, codon 804 (GTG to TTG) of the intracellular tyrosine kinase region of the RET gene was detected. In this kindred MTC has occurred in the 4th to 5th decades of life, with a clinical spectrum in mutation-positive family members ranging from no disease and C-cell hyperplasia to carcinoma with lymph node metastasis; a 7-year-old with the mutation and a normal response to provocative testing was also identified. Management recommendations in children from families with clearly defined familial MTC may be individualized to reflect emerging genotype-phenotype correlations.