Maturity onset diabetes of the young and fibrin-related thrombosis risk.

BACKGROUND: Fibrin network characteristics determine predisposition to cardiovascular disease (CVD). Individuals with type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have higher risk of CVD and display deranged fibrin network structure. Those with maturity onset diabetes of the young (MODY) may also be at increased risk but their fibrin clot properties have not been studied. METHODS: Plasma clots properties from 13 individuals with HNF1A-MODY, 12 matched-individuals with T2DM and 12 with T1DM were studied using a validated turbidimetric assay and confocal microscopy. Plasma levels of fibrinogen, plasminogen activator inhibitor-1, complement C3 and C-reactive protein were also measured. RESULTS: MODY clot maximum absorbance was 0.37 ± 0.03 AU, similar to T1DM (0.32 ± 0.03 AU; p = 0.26), but lower than T2DM (0.49 ± 0.03 AU; p = 0.02), with confocal microscopy confirming structural differences. Clot lysis time in MODY was similar to T1DM (456 ± 50 and 402 ± 20 s, respectively; p = 0.09) but shorter than T2DM (588 ± 58 s; p = 0.006). Comparing inflammatory/thrombotic proteins in HNF1A-MODY and T2DM, C3 levels were lower in MODY than T2DM (0.58 ± 0.09 and 0.80 ± 0.1 mg/ml, respectively; p < 0.01). CONCLUSIONS: HNF1A-MODY fibrin network alterations are at least as pronounced as in T1DM but less thrombotic than T2DM clots. Differences in fibrin clot characteristics comparing HNF1A-MODY and T2DM may, in part, relate to lower C3 levels.

Atypical phenotype associated with reported GCK exon 10 deletions: Clinical judgement is needed alongside appropriate genetic investigations.

BACKGROUND: Maturity-onset diabetes of the young (MODY) caused by heterozygous mutations in the glucokinase (GCK) gene typically presents with lifelong, stable, mild fasting hyperglycaemia. With the exception of pregnancy, patients with GCK-MODY usually do not require pharmacological therapy. We report two unrelated patients whose initial genetic test results indicated a deletion of GCK exon 10, but whose clinical phenotypes were not typical of GCK-MODY. CASE REPORTS: In case 1, the patient was hyperglycaemic at diagnosis (glucose > 30 mmol/l) and elevated glucose levels > 10 mmol/l persisted after withdrawal of insulin therapy. The patient in case 2 was also hyperglycaemic at diagnosis [HbA1c > 86 mmol/mol (10%)], which improved with the introduction of oral hypoglycaemic agents. These clinical features were not consistent with GCK-MODY. Both patients had a single nucleotide variant that prevented multiplex ligation-dependent probe analysis, which generated a false positive result of a GCK exon 10 deletion. CONCLUSION: False positive genetic results in these two unrelated cases were attributable to the presence of a rare single nucleotide variant that prevented ligation of the probe in the multiplex ligation-dependent probe analysis kit used and falsely indicated deletion of exon 10 within GCK. Both cases had clinical features that did not tally with the typical GCK-MODY phenotype. These cases emphasize the need to interpret the results of definitive genetic tests within the specific clinical context. Increased medical sequencing is likely to lead to more reports of novel mutations of uncertain significance. If genetic investigations do not agree with the clinical picture, clinicians should exercise caution when making therapeutic changes based on these results.

A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes.

AIMS/HYPOTHESIS: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. METHODS: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A)-MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve-derived C-statistic. RESULTS: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 × 10(-105)). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 × 10(-5)). High-sensitivity CRP values between assays were strongly correlated (r (2) ≥ 0.91, p ≤ 1 × 10(-5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. CONCLUSIONS/INTERPRETATION: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A-MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes.

Nonsurgical cerebrospinal fluid rhinorrhea in invasive macroprolactinoma: incidence, radiological, and clinicopathological features.

CONTEXT: Macroprolactinomas (MPRLs) may result in nonsurgical (spontaneous or dopamine agonist induced) cerebrospinal fluid (CSF) rhinorrhea; however, the incidence of and mechanisms underlying this phenomenon are poorly understood. OBJECTIVE: The objective of the study was to determine the incidence of nonsurgical rhinorrhea and identify biochemical, radiological, and histopathological factors associated with leakage. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of MPRL patients (n = 114) was compared with patients with nonfunctioning pituitary adenoma (NFA) (n = 181) seen over a 19-yr period (1985-2004). MAIN OUTCOME MEASURES: Incidence of CSF rhinorrhea, factors predictive of leakage, and differential expression of candidate markers of invasiveness were measured. RESULTS: Nonsurgical CSF rhinorrhea occurred in 8.7% of MPRLs (10 of 114) [2.6% spontaneous (three of 114), 6.1% dopamine agonist induced (seven of 114)], whereas no NFAs developed nonsurgical rhinorrhea. There was a clear male preponderance in MPRLs with nonsurgical rhinorrhea (males to females, 9:1, P = 0.008). Dopamine agonist resistance was more frequent in MPRLs with rhinorrhea than with MPRLs without rhinorrhea [30% (n = 10) vs. 5% (n = 104) P = 0.003]. Baseline prolactin levels, rate of prolactin decline in response to dopamine agonists, and tumor volume at diagnosis did not predict CSF leakage. Candidate markers of invasiveness, specifically the protease-activated receptor 1 and e-cadherin expression scores and tumor macrophage density, were not significantly different between groups; MPRL+CSF rhinorrhea (n = 6), MPRL without CSF rhinorrhea (n = 9), and NFAs (n = 9). CONCLUSIONS: The incidence of nonsurgical CSF rhinorrhea in MPRL patients (8.7%) is higher than expected. Dopamine agonist resistance is more common in MPRLs with CSF rhinorrhea; however, whether this is a mechanistic relationship requires further study. Protease-activated receptor 1 expression, e-cadherin expression, and macrophage infiltration rates do not distinguish tumors with from those without CSF rhinorrhea.