The Effect of the Testis on the Ovary: Structure-Function Relationships in a Neonate with a Unilateral Ovotestis (Ovotesticular Disorder of Sex Development) .

Aims: To evaluate gonadal function in a newborn with suspected ovotesticular disorder of sex development (DSD).

Methods: Gonadal function was evaluated at baseline and after gonadotropin-releasing hormone agonist (GnRHag) stimulation testing.

Results: A full-term 46,XX neonate with genital ambiguity produced serum testosterone and anti-Müllerian hormone (AMH) levels appropriate for males within days, while serum estradiol remained prepubertal, both spontaneously and in response to GnRHag stimulation testing.

Preservation of Reduced Numbers of Insulin-Positive Cells in Sulfonylurea-Unresponsive KCNJ11-Related Diabetes.

Context: The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls.

GCK-MODY in the US National Monogenic Diabetes Registry: frequently misdiagnosed and unnecessarily treated.

Aims: GCK-MODY leads to mildly elevated blood glucose typically not requiring therapy. It has been described in all ethnicities, but mainly in Caucasian Europeans. Here we describe our US cohort of GCK-MODY.

An online monogenic diabetes discussion group: supporting families and fueling new research.

Many online support groups are available for patients with rare disorders, but scant evidence is available on how effectively such groups provide useful information or valuable psychosocial support to their participants. It is also unclear to what extent physicians and researchers may learn more about these disorders by participating in such groups. To formally assess the utility of the Kovler Monogenic Diabetes Registry online discussion group for patients and families affected by KATP channel-related monogenic neonatal diabetes in providing psychosocial and informational support and in identifying concerns unique to patients with this rare form of diabetes.

Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.

Background: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus.

Methods: Clinical and functional characterisation of a novel homozygous intronic mutation (c.

Age at the time of sulfonylurea initiation influences treatment outcomes in KCNJ11-related neonatal diabetes.

Aims/hypothesis: Individuals with heterozygous activating mutations of the KCNJ11 gene encoding a subunit of the ATP-sensitive potassium channel (KATP) can usually be treated with oral sulfonylurea (SU) pills in lieu of insulin injections. The aim of this study was to test our hypothesis that younger age at the time of initiation of SU therapy is correlated with lower required doses of SU therapy, shorter transition time and decreased likelihood of requiring additional diabetes medications.

Methods: We performed a retrospective cohort study using data on 58 individuals with neonatal diabetes due to KCNJ11 mutations identified through the University of Chicago Monogenic Diabetes Registry ( http://monogenicdiabetes.

Commentary: Launch of a quality improvement network for evidence-based management of uncommon pediatric endocrine disorders: Turner syndrome as a prototype.

Background: Traditional, hypothesis-oriented research approaches have thus far failed to generate sufficient evidence to achieve consensus about the management of children with many endocrine disorders, partly because of the rarity of these disorders and because of regulatory burdens unique to research in children.

Objective: The Pediatric Endocrine Society is launching a quality improvement network in spring 2015 for the management of pediatric endocrine disorders that are relatively uncommon in any single practice and/or for which there is no consensus on management.

Design: The first of the quality improvement programs to be implemented seeks to improve the care of 11- to 17-year-old girls with Turner syndrome who require initiation of estrogen replacement therapy by providing a standardized clinical assessment and management plan (SCAMP) for transdermal estradiol treatment to induce pubertal development.

Sulfonylurea treatment before genetic testing in neonatal diabetes: pros and cons.

Context: Diabetes in neonates nearly always has a monogenic etiology. Earlier sulfonylurea therapy can improve glycemic control and potential neurodevelopmental outcomes in children with KCNJ11 or ABCC8 mutations, the most common gene causes.

Objective: Assess the risks and benefits of initiating sulfonylurea therapy before genetic testing results become available.

Hyperinsulinism in a neonate.

A male patient was born small for gestational age (SGA) at 33 weeks with a birth weight of 1,663 grams (< 10th percentile) and length 43 cm (10th percentile) to a 38-year-old G5P4 mother by cesarean section due to non-reassuring fetal heart tones. Prior to delivery, his mother experienced decreased fetal movement and decelerations. At birth, he was initially well-appearing and vigorous, with Apgar scores of 7 and 8 at 1 and 5 minutes, respectively.

Microcephaly, epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder.

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures.

Cost-effectiveness of MODY genetic testing: translating genomic advances into practical health applications.

OBJECTIVE To evaluate the cost-effectiveness of a genetic testing policy for HNF1A-, HNF4A-, and GCK-MODY in a hypothetical cohort of type 2 diabetic patients 25-40 years old with a MODY prevalence of 2%. RESEARCH DESIGN AND METHODS We used a simulation model of type 2 diabetes complications based on UK Prospective Diabetes Study data, modified to account for the natural history of disease by genetic subtype to compare a policy of genetic testing at diabetes diagnosis versus a policy of no testing. Under the screening policy, successful sulfonylurea treatment of HNF1A-MODY and HNF4A-MODY was modeled to produce a glycosylated hemoglobin reduction of -1.

Neonatal diabetes, gallbladder agenesis, duodenal atresia, and intestinal malrotation caused by a novel homozygous mutation in RFX6.

Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446 mg/dL) within 24 h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation.

Gain-of-function mutations in the K(ATP) channel (KCNJ11) impair coordinated hand-eye tracking.

Background: Gain-of-function mutations in the ATP-sensitive potassium channel can cause permanent neonatal diabetes mellitus (PNDM) or neonatal diabetes accompanied by a constellation of neurological symptoms (iDEND syndrome). Studies of a mouse model of iDEND syndrome revealed that cerebellar Purkinje cell electrical activity was impaired and that the mice exhibited poor motor coordination. In this study, we probed the hand-eye coordination of PNDM and iDEND patients using visual tracking tasks to see if poor motor coordination is also a feature of the human disease.

Visuomotor performance in KCNJ11-related neonatal diabetes is impaired in children with DEND-associated mutations and may be improved by early treatment with sulfonylureas.

Objective: To assess performance on an age-standardized neuromotor coordination task among sulfonylurea-treated KCNJ11-related neonatal diabetic patients.

Research Design And Methods: Nineteen children carrying KCNJ11 mutations associated with isolated diabetes (R201H; n = 8), diabetes with neurodevelopmental impairment (V59M or V59A [V59M/A]; n = 8), or diabetes not consistently associated with neurodevelopmental disability (Y330C, E322K, or R201C; n = 3) were studied using the age-standardized Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI).

Results: Although R201H subjects tested in the normal range (median standard score = 107), children with V59M/A mutations had significantly lower than expected VMI standard scores (median = 49).

Neonatal diabetes: an expanding list of genes allows for improved diagnosis and treatment.

There has been major progress in recent years uncovering the genetic causes of diabetes presenting in the first year of life. Twenty genes have been identified to date. The most common causes accounting for the majority of cases are mutations in the genes encoding the two subunits of the ATP-sensitive potassium channel (K(ATP)), KCNJ11 and ABCC8, and the insulin gene (INS), as well as abnormalities in chromosome 6q24.

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.

Genetics and pathophysiology of neonatal diabetes mellitus.

Neonatal diabetes mellitus (NDM) is the term commonly used to describe diabetes with onset before 6 months-of-age. It occurs in approximately one out of every 100,000-300,000 live births. Although this term encompasses diabetes of any etiology, it is recognized that NDM diagnosed before 6 months-of-age is most often monogenic in nature.

Onset features and subsequent clinical evolution of childhood diabetes over several years.

Aim: To explore whether it is possible to predict a child's eventual diabetes phenotype using characteristics at initial presentation, we reassessed 111 young patients on average 7.8 ± 4.2 (2.

HLA-DQ haplotypes differ by ethnicity in patients with childhood-onset diabetes.

Aim: To understand the etiology of childhood-onset diabetes, we examined genetic risk markers, autoantibodies, and β-cell function in a mixed race group of young patients.

Methods: One hundred and forty-five patients aged 0-17 at diagnosis (54% African American, 22% Caucasian, 16% Latino, 8% mixed-other) were studied at mean duration 6.9 ± 5.

The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes.

Objective: Neonatal diabetes mellitus is a rare form of diabetes diagnosed in infancy. Nearly half of patients with permanent neonatal diabetes have mutations in the genes for the ATP-sensitive potassium channel (KCNJ11 and ABCC8) that allow switching from insulin to sulfonylurea therapy. Although treatment conversion has dramatic benefits, the cost-effectiveness of routine genetic testing is unknown.