Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53.

Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid and other cancers. Germline mutations in phosphatase and tensin homolog (PTEN) have been recently reported in 23% of a large series of classic CS. Here, we validated our small (n = 10) pilot study in a large patient series that germline variations in succinate dehydrogenase genes (SDHx) occur in 8% (49/608) of PTEN mutation-negative CS and CS-like (CSL) individuals (SDH(var+)). None of these SDHx variants was found in 700 population controls (P < 0.0001). We then found that SDHx variants also occur in 6% (26/444) of PTEN mutation-positive (PTEN(mut+)) CS/CSL individuals (PTEN(mut+)/SDH(var+)). Of 22 PTEN(mut+)/SDH(var+) females, 17 had breast cancers compared with 34/105 PTEN(mut+) (P < 0.001) or 27/47 SDH(var+) patients (P = 0.06). Notably, individuals with SDH(var+) alone had the highest thyroid cancer prevalence (24/47) compared with PTEN(mut+) patients (27/105, P = 0.002) or PTEN(mut+)/SDH(var+) carriers (6/22, P = 0.038). Patient-derived SDH(var+) lymphoblastoid cells had elevated cellular reactive oxygen species, highest in PTEN(mut+)/SDH(var+) cells, correlating with apoptosis resistance. SDH(var+) cells showed stabilized and hyperactivated hypoxia inducible factor (HIF)1α signaling. Most interestingly, we also observed the loss of steady-state p53 in the majority of SDH(var+) cells. This loss of p53 was regulated by MDM2-independent NADH quinone oxidoreductase 1-mediated protein degradation, likely due to the imbalance of flavin adenine dinucleotide/nicotinamide adenine dinucleotide in SDH(var+) cells. Our data suggest the potential regulation of HIF1α, p53 and PTEN signaling by mitochondrial metabolism in CS/CSL tumorigenesis. Together, our findings suggest the importance of considering SDHx as candidate predisposing and modifier genes for CS/CSL-related malignancy risks, and a mechanism which suggests ways of therapeutic reversal or prevention.

Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps.

BACKGROUND & AIMS: Gastrointestinal polyposis is a common clinical problem, yet there is no consensus on how to best manage patients with moderate-load polyposis. Identifying genetic features of this disorder could improve management and especially surveillance of these patients. We sought to determine the prevalence of hamartomatous polyposis-associated mutations in the susceptibility genes PTEN, BMPR1A, SMAD4, ENG, and STK11 in individuals with ≥5 gastrointestinal polyps, including at least 1 hamartomatous or hyperplastic/serrated polyp. METHODS: We performed a prospective, referral-based study of 603 patients (median age: 51 years; range, 2-89 years) enrolled from June 2006 through January 2012. Genomic DNA was extracted from peripheral lymphocytes and analyzed for specific mutations and large rearrangements in PTEN, BMPR1A, SMAD4, and STK11, as well as mutations in ENG. Recursive partitioning analysis was used to determine cutoffs for continuous variables. The prevalence of mutations was compared using Fisher's exact test. Logistic regression analyses were used to determine univariate and multivariate risk factors. RESULTS: Of 603 patients, 119 (20%) had a personal history of colorectal cancer and most (n = 461 [76%]) had <30 polyps. Seventy-seven patients (13%) were found to have polyposis-associated mutations, including 11 in ENG (1.8%), 13 in PTEN (2.2%), 13 in STK11 (2.2%), 20 in BMPR1A (3.3%), and 21 in SMAD4 (3.5%). Univariate clinical predictors for risk of having these mutations included age at presentation younger than 40 years (19% vs 10%; P = .008), a polyp burden of ≥30 (19% vs 11%; P = .014), and male sex (16% vs 10%; P = .03). Patients who had ≥1 ganglioneuroma (29% vs 2%; P < .001) or presented with polyps of ≥3 histologic types (20% vs 2%; P = .003) were more likely to have germline mutations in PTEN. CONCLUSIONS: Age younger than 40 years, male sex, and specific polyp histologies are significantly associated with risk of germline mutations in hamartomatous-polyposis associated genes. These associations could guide clinical decision making and further investigations.

Implementation of tumor testing for lynch syndrome in endometrial cancers at a large academic medical center.

OBJECTIVES: Lynch syndrome (LS) is a hereditary condition that increases the risk for endometrial and other cancers. Recognizing women at risk for LS based on personal/family history is burdensome and imprecise. Tumor testing using microsatellite instability (MSI) testing and immunohistochemistry (IHC) for mismatch repair protein expression can be an effective strategy for identifying potential LS in patients presenting with colorectal or endometrial cancer. Here we describe our experience implementing a screening program for endometrial cancers. METHODS: Endometrial cancers diagnosed ≤50 years or those with suspicious personal history or histopathologic features were screened with MSI/IHC, June 2009-June 2011. Criteria were later (July 2011-July 2012) expanded to patients diagnosed <60 years, or at any age with suspicious features, and finally (after August 2012) universal screening was implemented. Screening techniques began with both MSI and IHC for every tumor, and later converted to IHC for two proteins, and MLH1 promoter methylation analysis when indicated. A genetic counselor contacted patients directly to offer genetic counseling appointments. RESULTS: Two hundred and forty-five endometrial cancers (average age, 57 years) were screened. Sixty-two patients (25%) had abnormal results, and 42 patients were referred for genetic counseling. Of the 42 patients, 34 underwent genetic counseling, 28 pursued genetic testing, and 11 were diagnosed with LS. When age and pathology criteria were used, 27 eligible cases were overlooked for screening and 3 cases of LS were found only because a clinician requested screening. CONCLUSIONS: Universal screening of endometrial cancers for LS is practical and successfully implemented with collaboration among genetic counselors, gynecologic oncologists, and pathologists.

A time study of cancer genetic counselors using a genetic counselor-only patient care model versus a traditional combined genetic counselor plus medical geneticist care model.

Analyses of time-based effort have determined that clinical genetic services are labor-intensive, although these data derive primarily from studying geneticists' efforts in the pediatric model. No studies have investigated the time and patient care activities of cancer genetic counselors (GCs) in traditional clinics with a medical geneticist (GC/MD) compared with genetic counselor-only (GCO) appointments. In this study, 6 GCs prospectively tracked time spent in patient care activities in both clinical settings. The authors found that overall, GCs' time spent per patient was lower for GCO versus GC/MD visits. No differences were seen in time spent on results disclosure, but differences were noted in case preparation, face-to-face, and follow-up times. Furthermore, no differences were seen in number of case preparation activities or topics covered during a session. These data suggest that GCO visits result in better use of GCs' time, without a trade-off in number of patient-related activities.

Elevated plasma succinate in PTEN, SDHB, and SDHD mutation-positive individuals.

PURPOSE: Cowden syndrome results from germline mutations in the gene for phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and from variants in succinate dehydrogenase B and D subunits. We hypothesized that succinate accumulation may be common among individuals with SDH variants/mutations and those with PTEN mutations. METHODS: Urine and blood were collected from individuals meeting full or partial Cowden syndrome diagnostic criteria or those with paraganglioma (PGL) or a known susceptibility paraganglioma-associated gene mutation, and succinate was measured. PTEN, SDHB, SDHC, and SDHD genes were sequenced from genomic DNA. RESULTS: Elevated plasma succinate was observed in 13/21 (62%) individuals with germline PTEN, SDHB, or SDHD mutations as compared with 5/32 (16%) controls (P < 0.001), in 10/15 (67%) individuals with pathogenic PTEN mutations but in <20% of mutation-negative individuals meeting identical criteria, and in individuals with mutations in SDHB (1/1, 100%) and SDHD (2/5, 40%). CONCLUSION: Our data suggest that mutations in PTEN, SDHB, and SDHD reduce catalytic activity of succinate dehydrogenase, resulting in succinate accumulation, and identify a common biochemical alteration in these two patient populations (PTEN and SDHx mutation positive individuals). Plasma organic acid analysis may provide an effective and inexpensive screening method to determine when more expensive gene sequencing of PTEN and SDH genes is warranted.

Multiple endocrine neoplasia type 2: an overview.

Multiple endocrine neoplasia type 2 is historically composed of three clinical subtypes, all of which are associated with germline mutations in the RET proto-oncogene. Multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and multiple endocrine neoplasia type 2B are collectively associated with a 70-100% risk of medullary thyroid carcinoma by age 70 years. Pheochromocytomas are identified in 50% of individuals with multiple endocrine neoplasia type 2A and multiple endocrine neoplasia type 2B. Furthermore, those with multiple endocrine neoplasia type 2A have a 20-30% risk for primary hyperparathyroidism. Individuals with multiple endocrine neoplasia type 2B often have distinct physical features including mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, ganglioneuromatosis of the gastrointestinal tract, distinctive facies with enlarged lips, and a "Marfanoid" body habitus. Clinical recognition and accurate diagnosis of individuals and families who are at risk of harboring a germline RET mutation is critical for the prevention and management of potentially life-threatening neoplasms. This overview summarizes the clinical description of multiple endocrine neoplasia type 2, diagnosis and testing strategies, management and surveillance, and differential diagnosis for other related syndromes.

Distinctive phenotype in 9 patients with deletion of chromosome 1q24-q25.

Reports of individuals with deletions of 1q24→q25 share common features of prenatal onset growth deficiency, microcephaly, small hands and feet, dysmorphic face and severe cognitive deficits. We report nine individuals with 1q24q25 deletions, who show distinctive features of a clinically recognizable 1q24q25 microdeletion syndrome: prenatal-onset microcephaly and proportionate growth deficiency, severe cognitive disability, small hands and feet with distinctive brachydactyly, single transverse palmar flexion creases, fifth finger clinodactyly and distinctive facial features: upper eyelid fullness, small ears, short nose with bulbous nasal tip, tented upper lip, and micrognathia. Radiographs demonstrate disharmonic osseous maturation with markedly delayed bone age. Occasional features include cleft lip and/or palate, cryptorchidism, brain and spinal cord defects, and seizures. Using oligonucleotide-based array comparative genomic hybridization, we defined the critical deletion region as 1.9 Mb at 1q24.3q25.1 (chr1: 170,135,865-172,099,327, hg18 coordinates), containing 13 genes and including CENPL, which encodes centromeric protein L, a protein essential for proper kinetochore function and mitotic progression. The growth deficiency in this syndrome is similar to what is seen in other types of primordial short stature with microcephaly, such as Majewski osteodysplastic primordial dwarfism, type II (MOPD2) and Seckel syndrome, which result from loss-of-function mutations in genes coding for centrosomal proteins. DNM3 is also in the deleted region and expressed in the brain, where it participates in the Shank-Homer complex and increases synaptic strength. Therefore, DNM3 is a candidate for the cognitive disability, and CENPL is a candidate for growth deficiency in this 1q24q25 microdeletion syndrome.

The association of serotonin transporter genotypes and selective serotonin reuptake inhibitor (SSRI)-associated sexual side effects: possible relationship to oral contraceptives.

OBJECTIVE: To study the relationship between functional variants in the serotonin transporter gene (SLC6A4) and selective serotonin reuptake inhibitor (SSRI)-associated sexual dysfunction. METHODS: One hundred fifteen subjects aged 18-40 years and currently being treated with an SSRI for depression were assessed for clinical variables known to affect sexual well-being. SSRI-associated sexual difficulties were assessed with the Changes in Sexual Functioning Questionnaire (CSFQ). Subjects were subsequently genotyped for the SLC6A4 promoter region (5HTTLPR) insertion/deletion variant and a variable number of tandem repeats (VNTR) in the second intron. RESULTS: The 5HTTLPR insertion/deletion variant was associated with sexual dysfunction in this study sample [odds ratio (OR) = 2.7; 95% confidence interval (CI) 1.2, 6.4; p = 0.02]. The relationship between promoter genotypes and sexual well-being differed in males and females and was related to whether females were taking an oral contraceptive (OC) medication. Females with the ll genotype were nearly eight times more likely to be categorized as having sexual dysfunction if they were taking OCs, while no relationship was observed in those not taking OCs. CONCLUSIONS: These results suggest that a functional variant in the serotonin transporter gene is associated with sexual difficulties in persons taking an SSRI for depression. This relationship may differ by sex and be dependent on OC status in females.

Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C variants.

INTRODUCTION: The metabolic syndrome and insulin resistance represent growing concerns related to atypical antipsychotic (AAP) use as their incidence in the schizophrenia population is two-to-four-fold higher than the general population. Reduced methylenetetrahydrofolate reductase (MTHFR) activity, resulting in aberrant folate metabolism and hyperhomocysteinemia, has been linked to cardiovascular disease and is unstudied in relation to AAP associated metabolic complications. PURPOSE: To examine the relationship between MTHFR, metabolic syndrome, and insulin resistance in schizophrenia subjects receiving AAPs for >or=12 months. METHODS: Fifty-eight subjects were included in this cross-sectional analysis and screened for the metabolic syndrome, insulin resistance and MTHFR 677C/T and 1298A/C genotype. RESULTS: Overall, 23 subjects (40%) met metabolic syndrome criteria. There were no differences in age, gender, race, or AAP exposure between genotype groups. For the 677 T allele carriers, 53% met metabolic syndrome criteria, compared to 23% in the CC genotype group, giving an OR=3.7, (95% CI=1.24-12.66, p=0.02). Thus, for T allele subjects, the risk was almost four times greater, despite similar antipsychotic exposure. Both waist circumference and MTHFR genotype significantly predicted insulin resistance (F=8.35, df=5, 51, p<0.0001), with these two terms interacting (F=8.6, df=2, p=0.0006) suggesting that TT subjects are at greater risk for insulin resistance with increasing central adiposity, which is independent of age, gender, BMI, or metabolic syndrome diagnosis. CONCLUSION: Results should be taken cautiously due to the small sample size, but suggest the MTHFR 677C/T variant may predispose patients to AAP metabolic complications.

Serotonin 2A -1438 G/A and G-protein Beta3 subunit C825T polymorphisms in patients with depression and SSRI-associated sexual side-effects.

The occurrence of sexual side-effects from antidepressants is thought to be mediated through serotonin 2A (5HT2A) receptors. It is currently unknown if functional polymorphisms in the 5HT2A receptor or its G-protein second messenger complex are related to sexual dysfunction in patients taking an selective serotonin reuptake inhibitor (SSRI) for depression. The purpose of this study was to determine the relationship of the 5HT2A -1438 G/A and GNB3 C825T single nucleotide polymorphisms with overall sexual well-being and individual components of sexual health as measured by the Changes in Sexual Functioning Questionnaire (CSFQ). We evaluated 89 outpatients (18-40 years of age) at low risk for other causes of sexual dysfunction who were being treated for depression with an SSRI and did not have sexual difficulties before taking the antidepressant. Outcome measures were stratified by 5HT2A and GNB3 genotypes. After controlling for age, gender, anxiety scale scores, and depression scale scores, persons with a GG genotype of the 5HT2A -1438 single nucleotide polymorphisms (SNP) were significantly more likely to be categorized as having sexual dysfunction than persons with a GA or AA genotype (OR=3.6; 95% CI 1.03, 12.6; p=0.046). Furthermore, the 5HT2A -1438 GG genotype was a significant predictor of lower arousal scores (p=0.022) after accounting for other measures. There was no significant relationship between any outcome measure and GNB3 genotype.

Association between the polymorphic GRM3 gene and negative symptom improvement during olanzapine treatment.

PURPOSE: The excitatory neurotransmitter glutamate has become an important area of focus for schizophrenia researchers. Polymorphisms in the type-three metabotropic glutamate receptor gene (GRM3) have been associated with the pathogenesis of schizophrenia. The purpose of this study was to determine whether a pharmacogenetic relationship exists between six polymorphisms of GRM3 and clinical improvement during olanzapine treatment in persons with schizophrenia. METHOD: Forty-two subjects meeting DSM-IV criteria for schizophrenia started olanzapine and were titrated to a fixed dose of 7.5-20 mg/day for 6 weeks. The Brief Psychiatric Rating Scale (BPRS) total score and the Scale for Assessment of Negative Symptoms (SANS) were completed at baseline and then weekly to assess psychopathology. RESULTS: The principle finding of this study is that GRM3 polymorphisms were collectively significant predictors of negative symptom improvement in persons with schizophrenia treated with the atypical antipsychotic olanzapine. After controlling for baseline SANS scores, the genotypes as a whole were significant predictors of negative symptom improvement, accounting for approximately 28% of the variance in scores (F = 16.30, df = 29, p < 0.001). The single nucleotide polymorphism SNP1 (rs274622), located in a potential promoter region, had the most significant influence on SANS scores, but the effects of this locus could not be fully separated from the other polymorphisms. The mean decrease in SANS scores was 21% vs. 51% for SNP1 T/T + T/C and SNP1C/C subjects, respectively. CONCLUSION: These data suggest that polymorphisms in the GRM3 gene may be useful as predictors of negative symptom improvement in persons with schizophrenia treated with olanzapine.

Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice.

CONTEXT: Germline mutations in genes coding succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified in familial paragangliomas (PGLs)/pheochromocytomas (PHEOs) and other tumors. We described a GH-secreting pituitary adenoma (PA) caused by SDHD mutation in a patient with familial PGLs. Additional patients with PAs and SDHx defects have since been reported. DESIGN: We studied 168 patients with unselected sporadic PA and with the association of PAs, PGLs, and/or pheochromocytomas, a condition we named the 3P association (3PAs) for SDHx germline mutations. We also studied the pituitary gland and hormonal profile of Sdhb(+/-) mice and their wild-type littermates at different ages. RESULTS: No SDHx mutations were detected among sporadic PA, whereas three of four familial cases were positive for a mutation (75%). Most of the SDHx-deficient PAs were either prolactinomas or somatotropinomas. Pituitaries of Sdhb(+/-) mice older than 12 months had an increased number mainly of prolactin-secreting cells and several ultrastructural abnormalities such as intranuclear inclusions, altered chromatin nuclear pattern, and abnormal mitochondria. Igf-1 levels of mutant mice tended to be higher across age groups, whereas Prl and Gh levels varied according to age and sex. CONCLUSION: The present study confirms the existence of a new association that we termed 3PAs. It is due mostly to germline SDHx defects, although sporadic cases of 3PAs without SDHx defects also exist. Using Sdhb(+/-) mice, we provide evidence that pituitary hyperplasia in SDHx-deficient cells may be the initial abnormality in the cascade of events leading to PA formation.

Immunohistochemistry for annexin A10 can distinguish sporadic from Lynch syndrome-associated microsatellite-unstable colorectal carcinoma.

Differentiating sporadic microsatellite-unstable colorectal carcinoma due to MLH1 promoter hypermethylation from Lynch syndrome (LS)-associated tumors due to mutations in mismatch-repair proteins is time consuming, cost intensive, and requires advanced laboratory testing. A mutation in BRAF has been shown to be highly specific for sporadic tumors; however, a significant proportion of sporadic microsatellite-unstable tumors lack BRAF mutations. MLH1 promoter methylation analysis is subsequently used to differentiate LS and sporadic tumors, but both tests require specialized laboratories and are costly. Through previous gene expression profiling of serrated polyps, we identified annexin A10 as a protein highly expressed in sessile serrated adenomas/polyps. As these polyps give rise to the majority of sporadic microsatellite-unstable tumors, we evaluated the ability of annexin A10 expression to discriminate between LS and sporadic tumors. A marked increase in annexin A10 mRNA was observed in sporadic microsatellite-unstable tumors compared with LS tumors (378-fold increase, P<0.001). Using immunohistochemistry, annexin A10 was expressed in 23/53 (43%) BRAF-mutated and 9/22 (41%) BRAF wild-type sporadic tumors. In contrast, only 3/56 (5%) LS tumors were positive for annexin A10 (P<0.0001). One patient had a deleterious MSH2 mutation, and another had a variant of uncertain significance in MSH6. These 2 tumors could be easily distinguished from sporadic tumors using mismatch-repair protein immunohistochemistry. Only 1/28 (4%) LS tumors with loss of MLH1 was positive for annexin A10. This patient did not have a deleterious MLH1 mutation but rather germline promoter hypermethylation of MLH1. On the basis of these results, immunohistochemistry for annexin A10 may be a useful marker to distinguish sporadic from LS-associated microsatellite-unstable colon cancer.

10 rare tumors that warrant a genetics referral.

The number of described cancer susceptibility syndromes continues to grow, as does our knowledge on how to manage these syndromes with the aim of early detection and cancer prevention. Oncologists now have greater responsibility to recognize patterns of cancer that warrant referral for a genetics consultation. While some patterns of common cancers are easy to recognize as related to hereditary cancer syndromes, there are a number of rare tumors that are highly associated with cancer syndromes yet are often overlooked given their infrequency. We present a review of ten rare tumors that are strongly associated with hereditary cancer predisposition syndromes: adrenocortical carcinoma, carcinoid tumors, diffuse gastric cancer, fallopian tube/primary peritoneal cancer, leiomyosarcoma, medullary thyroid cancer, paraganglioma/pheochromocytoma, renal cell carcinoma of chromophobe, hybrid oncocytoic, or oncocytoma histology, sebaceous carcinoma, and sex cord tumors with annular tubules. This review will serve as a guide for oncologists to assist in the recognition of rare tumors that warrant referral for a genetic consultation.

Implementation of universal microsatellite instability and immunohistochemistry screening for diagnosing lynch syndrome in a large academic medical center.

PURPOSE: In 2009, the Evaluation of Genomic Applications in Practice and Prevention recommended that all colorectal cancers (CRCs) be screened for Lynch syndrome (LS) through microsatellite instability (MSI) or immunohistochemistry (IHC). No studies report how this process is implemented on a health system-wide basis. METHODS: Since 2004, Cleveland Clinic has screened CRC specimens with MSI/IHC. Between January 2004 and July 2007, MSI/IHC results went only to the colorectal surgeon (approach 1). Between August 2007 and June 2008, colorectal surgeons and a genetic counselor received the MSI/IHC results, and the counselor e-mailed the colorectal surgeon regarding appropriate patients for genetic counseling (GC) referral (approach 2). After July 2008, the colorectal surgeon and counselor received MSI/IHC results, but the counselor contacted the patient to facilitate referral (approach 3). In approaches 2 and 3, patients were presumed to have sporadic CRC if the tumor lacked MLH1 expression and was also BRAF mutated or if the patient was diagnosed at age greater than 72 years and had no cancer family history. RESULTS: Abnormal MSI/IHC results occurred in 178 (16%) of 1,108 patients. In approach 1, 21 (55%) of 38 patients with abnormal MSI/IHC were referred for GC, 12 (32%) of 38 underwent GC, and 10 (26%) of 38 underwent genetic testing (GT). In approach 2, nine (82%) of 11 patients were referred for GC, seven (64%) of 11 underwent GC, and five (45%) of 11 underwent GT. In approach 3, 56 (100%) of 56 patients were referred for GC, 40 (71%) of 56 underwent GC, and 37 (66%) of 56 underwent GT. Time from referral to GC was 10-fold quicker in approach 3 than approach 1. CONCLUSION: Implementation of universal MSI/IHC with GC/GT, along with effective multidisciplinary communication and plans of responsibility for patient contact, resulted in increased identification of patients with LS.

Pharmacogenetics of glutamate system genes and SSRI-associated sexual dysfunction.

We examined whether polymorphisms in the GRIK2, GRIA3 and GRIA1 genes were associated with selective serotonin reuptake inhibitor (SSRI)-associated sexual dysfunction in 114 participants treated for depression. One polymorphism in GRIA1 (rs1994862) was associated with arousal dysfunction, providing further evidence for the role of GRIA1 in mechanisms underlying SSRI-associated sexual side effects.

Evil lurks in the heart of man: cardiac paraganglioma presenting as recurrent dyspnoea and chronic cough.

A man in his 60s presents with chronic dyspnoea and cough for 3 years. EKG and nuclear stress test were not diagnostic. An echocardiogram revealed moderate pericardial effusion. His symptoms improved with ibuprofen temporarily and a repeat echocardiogram showed resolution of the effusion. However, when his symptoms recurred, re-imaging showed a large intracardiac tumour causing right ventricular outflow obstruction. Subsequent histological examination revealed metastatic paraganglioma. He was found to carry a germline mutation in the SDHB gene which is associated with higher malignant risk. Knowledge of his underlying mutation allowed the patient and his family to receive appropriate gene-specific counselling and surveillance.

Variants of the dopamine D2 receptor gene and risperidone-induced hyperprolactinemia in children and adolescents.

OBJECTIVE: To investigate the association between hyperprolactinemia and variants of the dopamine D2 receptor (DRD2) gene in children and adolescents in long-term treatment with risperidone. METHODS: Medically healthy 7 to 17-year-old patients chronically treated with risperidone but receiving no other antipsychotics were recruited in a cross-sectional study. Four DRD2 variants were genotyped and prolactin concentration was measured. Medication history was obtained from the medical records. The effect of the TaqIA variants of the DRD2 on the risk of risperidone-induced hyperprolactinemia was the primary outcome measure. RESULTS: Hyperprolactinemia was present in 50% of 107 patients (87% males) treated with risperidone for an average of 2.9 years. Age, stage of sexual development, and the dose of risperidone independently predicted a higher prolactin concentration, whereas the dose of psychostimulants was negatively correlated with it. However, these four predictors became nonsignificant when risperidone serum concentration was entered into the model. Adverse events potentially related to hyperprolactinemia were more common in participants with elevated prolactin concentration and in girls (45%) compared with boys (10%). After controlling for risperidone concentration and the dose of psychostimulants, the TaqIA A1 and the A-241G alleles were associated with higher prolactin concentration, whereas the -141C Ins/Del and C957T variants had no significant effect. In addition, adverse events potentially related to hyperprolactinemia were four times more common in TaqIA A1 allele carriers. CONCLUSION: Prolactin concentration is closely related to central DRD2 blockade, as reflected by risperidone serum concentration. Furthermore, the TaqIA and A-241G variants of the DRD2 gene could be useful in predicting the emergence of hyperprolactinemia and its potential adverse events.