Novel PHEX gene mutation associated with X linked hypophosphatemic rickets.

INTRODUCTION: X-linked hypophosphatemia (XLH) is characterized by renal phosphate wasting with hypophosphatemia, short stature, and rachitic manifestations. CLINICAL PICTURE: We describe a novel nonsense mutation in exon 3 of the PHEX gene (Glu(96)X (c.286G>T) causing XLH in a mother and daughter of Indian ancestry. The mother was noted to have concomitant vitamin D insufficiency. CONCLUSION: Our report identifies a novel nonsense mutation in the PHEX gene causing XLH. It also highlights the fact that the presence of concomitant vitamin D insufficiency should not preclude the diagnosis of familial forms of hypophosphatemic rickets, especially if more than one family member is affected.

Microarray analysis of multiple candidate genes and associated plasma proteins for nephropathy secondary to type 2 diabetes among Chinese individuals.

AIMS/HYPOTHESIS: Evolving research suggests that common and rare alleles jointly constitute the genetic landscape of complex disease. We studied the association between 43 pathway-related candidate genes with 'intermediate phenotype' (i.e. corresponding plasma protein) and diabetic nephropathy in a customised microarray of 1,536 SNPs. METHODS: In this case-control study of type 2 diabetic Chinese individuals with and without diabetic nephropathy, cases (n = 545) were defined on the basis of a spot urinary albumin/creatinine ratio (ACR) > 113 mg/mmol; the value for controls (n = 503) was ACR < 3.3 mg/mmol. Genotyping was performed using Illumina GoldenGate assay. RESULTS: No single nucleotide polymorphism (SNP) remained significant in single locus analysis after correction for multiple testing. Therefore, we explored the best approximately 1% SNPs. Of these 13 SNPs, four clustered to a 5' end NADPH oxidase homologue 4 (NOX4) haplotype (GGCC frequency = 0.776) with estimated OR for diabetic nephropathy of 2.05 (95% CI 1.04-4.06) (heterozygous) and 2.48 (1.27-4.83) (homozygous) (p = 0.0055). The haplotype was correlated with plasma Cu/Zn superoxide dismutase (SOD) concentration, suggesting increased oxidative burden. Endothelin-1 SNP (rs1476046G>A, frequency = 0.252) was correlated with plasma C-terminal pro-endothelin-1 concentrations with an estimated OR for diabetic nephropathy of (heterozygous) 1.26 (0.96-1.66) and (homozygous) 1.87 (1.13-3.12) (p = 0.0072). Nitric oxide synthase 1 (NOS1) 5' haplotype (TGTC frequency = 0.38) also revealed a suggestive association with diabetic nephropathy: heterozygous 1.26 (0.95-1.67), homozygous 1.57 (1.04-2.35) (p = 0.0073). A rare NADPH oxidase homologue 1 (NOX1)-coding non-synonymous SNP (Arg315His, frequency = 0.006) was found exclusively among cases. CONCLUSIONS/INTERPRETATION: Our preliminary observations suggest that common haplotypes from NOX4 and endothelin-1 SNP correlated with plasma Cu/Zn SOD and C-terminal pro-endothelin-1 concentrations, respectively, and might have conferred diabetic nephropathy susceptibility. Common NOS1 and rare NOX1 variants also revealed a suggestive association with diabetic nephropathy. Future studies to validate our observation are needed.

Ministry of Health Clinical Practice Guidelines: Diabetes Mellitus.

The Ministry of Health (MOH) have updated the clinical practice guidelines on Diabetes Mellitus to provide doctors and patients in Singapore with evidence-based treatment for diabetes mellitus. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Diabetes Mellitus, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Oncogenic osteomalacia -- hypophosphataemic spectrum from "benignancy" to "malignancy".

Though case reports and case series about oncogenic osteomalacia due to benign mesenchymal tumours and much more rarely, secondary to malignant ones exist in the literature, there has not been any series reported from a single department spanning the gamut of causes from benign to malignant. We present 3 patients who were seen at the department of endocrinology of our hospital between 2010 and 2012 with hypophosphataemia and severe skeletal complications. All of them were found to have oncogenic osteomalacia otherwise known as tumour induced osteomalacia (TIO) - a paraneoplastic syndrome characterised by renal phosphate wasting and severe hypophosphataemia. The implicating tumours in our patients ranged from a subcutaneous mesenchymal tumour in the heel to a mixed connective tissue variant within the nasal cavity to metastatic prostate cancer. All our patients had protracted periods before the diagnosis was made, during which time the burden of their metabolic and skeletal pathology had increased. A timely recognition of the clinical features and biochemical findings of this rare but potentially debilitating disease is critical. Physicians should be cognizant of the presence of the disease and its localising and treatment strategies.

Novel association of thymic carcinoid with a germline mutation in a kindred with multiple endocrine neoplasia 1 (MEN1).

Multiple endocrine neoplasia 1 (MEN1) is an autosomal dominant syndrome characterized by a triad of endocrine (parathyroid, enteropancreatic and pituitary) tumors. Familial MEN1 is defined by one first-degree relative having at least one of these 3 main tumors, and is associated with germline mutations in the MEN1 gene on 11q13 in a large proportion of cases. MEN1 patients may also develop non-endocrine tumors, notably thymic carcinoid. These are rare tumors found predominantly in men, and are a major cause of death in MEN1 due to their insidious nature, lack of effective treatment and unpredictable recurrence. Prophylactic thymectomy has been advocated for prevention but continued surveillance for recurrence is necessary. Although genotype-phenotype correlation in MEN1-related thymic carcinoid is inconsistent, there is a high prevalence of truncating mutations in this condition. We describe a father and son with MEN1, associated with thymic carcinoid (father) and the truncating mutation R29X (son), which was not previously reported in MEN1-related thymic carcinoid, and review the literature about thymic carcinoids in MEN1. Our cases illustrate the importance of a high index of suspicion for early diagnosis and lifelong surveillance in MEN1, and the utility of genetic analysis in defining surveillance for MEN1-related thymic carcinoid.

Point-of-care blood ketone testing: screening for diabetic ketoacidosis at the emergency department.

INTRODUCTION: We piloted the use of a blood beta-hydroxybutyrate meter as a point-of-care testing in an emergency department (ED) to establish its role in distinguishing ketosis/ketoacidosis from simple hyperglycaemia, and develop guidelines for its use in the ED. METHODS: 111 consecutive patients presenting with capillary glucose levels exceeding 14 mmol/L had a simultaneous blood ketone measurement at triage. This was correlated with clinical diagnosis, venous bicarbonate levels and urine ketone testing. RESULTS: The median beta-hydroxybutyrate levels was 5.7 (range 4.3-6.0) mmol/L for patients with diabetic ketoacidosis (DKA) and 0.1 (0.0-3.2) mmol/L for the remaining patients. Only 47.7 percent could provide urine samples in the ED. A blood ketone result of 3.5 mmol/L yielded 100 percent specificity and sensitivity for the diagnosis of DKA. CONCLUSION: This is a useful tool that allows clinicians to immediately distinguish between simple hyperglycaemia and potentially life-threatening ketotic states. We formulated simple guidelines for its utilisation in an ED setting.