Novel PTH Gene Mutations Causing Isolated Hypoparathyroidism.

CONTEXT: Parathyroid hormone (PTH) gene mutations represent a rare cause of familial isolated hypoparathyroidism (FIH). These defects can cause hypoparathyroidism with increased or decreased serum levels of PTH through 1) impaired PTH synthesis; 2) induction of parathyroid cell apoptosis; or 3) secretion of bioinactive PTH molecules. Eight pathogenic mutations of this gene have been described previously. OBJECTIVE: Through describing 2 novel mutations of the PTH gene, we aim to extend the molecular basis for FIH and further refine the proposed mechanisms by which PTH mutations cause hypoparathyroidism. METHODS: Proband case reports were compiled with extended family analysis. The probands in both kindreds presented before age 10 days with hypocalcemia and elevated phosphate levels. Proband A had low PTH levels, whereas these levels were elevated in Proband B. Proband B was initially diagnosed with pseudohypoparathyroidism. Methylation analysis was performed of CpG dinucleotides within 3 GNAS differentially methylated regions; whole-genome sequencing; and PTH infusion with analysis of nephrogenous 3',5'-cyclic adenosine 5'-monophosphate. RESULTS: Proband A had a novel heterozygous sequence change in exon 2 of the PTH gene, c.46_47delinsAA (p.Ala16Lys), and proband B had a novel homozygous nucleotide transition in PTH exon 3 (c.128G > A; p.G43E) that led to replacement of glycine by glutamic acid at position 12 of PTH 1-84. PTH 1-34 infusion demonstrated that renal responsiveness to PTH was intact and not antagonized by circulating bioinactive PTH. CONCLUSION: PTH gene mutations are uncommon causes of hypoparathyroidism, but can be misdiagnosed as disorders of gland development or receptor function if PTH levels are decreased or elevated, respectively. Genetic testing should be considered early in the diagnostic approach to these presentations.

Creation of the Web-based University of Chicago Monogenic Diabetes Registry: using technology to facilitate longitudinal study of rare subtypes of diabetes.

BACKGROUND: Monogenic diabetes is a group of disorders caused by mutations in any one of a number of genes. Although a monogenic diagnosis--estimated to represent as much as 2% of all diabetes patients--can have a transformational impact on treatment, the majority of monogenic cases remain unidentified and little is known about their natural history. We thus created the first United States Monogenic Diabetes Registry (http://www.kovlerdiabetescenter.org/registry/) for individuals with either neonatal diabetes diagnosed before 1 year of age or with a phenotype suggestive of maturity-onset diabetes of the young. METHODS: Inclusion criteria and consent documents are viewable on our Web site, which allows secure collection of contact information to facilitate telephone consent and enrollment. Relevant medical, family, and historical data are collected longitudinally from a variety of sources and stored in our Web-accessible secure database. RESULTS: We have enrolled well over 700 subjects in the registry so far, with steady recruitment of those diagnosed under 1 year of age and increasing enrollment of those diagnosed later in life. Initially, participants were mostly self-referred but are increasingly being referred by their physicians. Comprehensive survey and medical records data are collected at enrollment, with ongoing collection of longitudinal data. Associated private Facebook and email discussion groups that we established have already fostered active participation. CONCLUSIONS: Our early success with the Monogenic Diabetes Registry demonstrates the effectiveness of low-cost Web-based tools, including surveys, the Research Electronic Data Capture database program, and discussion groups, for efficient enrollment and support of rare patients, and collection and maintenance of their data.

Neonatal diabetes mellitus: a model for personalized medicine.

Neonatal diabetes mellitus occurs in approximately 1 out of every 100,000 live births. It can be either permanent or transient, and recent studies indicate that is likely to have an underlying genetic cause, particularly when diagnosed before 6 months of age. Permanent neonatal diabetes is most commonly due to activating mutations in either of the genes encoding the two subunits of the ATP-sensitive potassium channel. In most of these patients, switching from insulin to oral sulfonylurea therapy leads to improved metabolic control, as well as possible amelioration of occasional associated neurodevelopmental disabilities. It remains to be determined what is the most appropriate treatment of other causes. The diagnosis and treatment of neonatal diabetes, therefore, represents a model for personalized medicine.

Update in neonatal diabetes.

PURPOSE OF REVIEW: Here we give context to new data on neonatal diabetes mellitus, a rare group of insulin-requiring monogenic forms of diabetes presenting at birth or shortly thereafter. Genetic studies are critical in the diagnosis and treatment of these patients. The most common causes of neonatal diabetes are activating mutations in the two protein subunits of the ATP-sensitive potassium channel. These are responsible for about half of all cases of permanent neonatal diabetes and some cases of transient neonatal diabetes. Identification of these mutations allows patients treated with insulin to be transferred to sulfonylureas, but associated conditions and other causes must be considered. RECENT FINDINGS: Recent data suggest that neonatal diabetes is more common than previously thought, with variable presentations. Continued studies provide further evidence for amelioration of developmental and neurological dysfunction exhibited by a significant proportion of patients. Abnormalities of chromosome 6q24 remain the most common cause of transient neonatal diabetes. Other causes of neonatal diabetes being studied include mutations in proinsulin, FOXP3 mutations in immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, homozygous glucokinase mutations, and Wolcott-Rallinson/EIF2AK3 diabetes. SUMMARY: We still have much to learn about the different forms of neonatal diabetes, their associated clinical features, and the optimization of therapy using a growing number of available therapeutic agents.