Liat de Vries

Analysis of Transcription Factors Key for Mouse Pancreatic Development Establishes NKX2-2 and MNX1 Mutations as Causes of Neonatal Diabetes in Man

Summary Understanding transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes. Current knowledge of key transcriptional regulators has predominantly come from mouse studies, with rare, naturally occurring mutations establishing their relevance in man. This study used a combination of homozygosity analysis and Sanger sequencing in 37 consanguineous patients with permanent neonatal diabetes to search for homozygous mutations in 29 transcription factor genes important for murine pancreatic development. We identified homozygous mutations in 7 different genes in 11 unrelated patients and show that NKX2-2 and MNX1 are etiological genes for neonatal diabetes, thus confirming their key role in development of the human pancreas. The similar phenotype of the patients with recessive mutations and mice with inactivation of a transcription factor gene support there being common steps critical for pancreatic development and validate the use of rodent models for beta cell development.

Endocrine Effects of Valproate in Adolescent Girls with Epilepsy

Summary:  Purpose: To investigate the effect of epilepsy and/or valproate (VPA) monotherapy on physical growth, weight gain, pubertal development, and hormonal status in adolescent girls with epilepsy.

Factors associated with increased risk of insulin pump discontinuation in pediatric patients with type 1 diabetes.

de Vries L, Grushka Y, Lebenthal Y, Shalitin S, Phillip M. Factors associated with increased risk of insulin pump discontinuation in pediatric patients with type 1 diabetes.

Prepubertal and pubertal growth, timing and duration of puberty and attained adult height in patients with congenital hypothyroidism (CH) detected by the neonatal screening programme for CH — a longitudinal study

We have evaluated parameters of growth, the pubertal process and attained adult height in patients with congenital hypothyroidism (CH) of various aetiologies, diagnosed by the neonatal screening programme, and followed up longitudinally. To the best of our knowledge, no such data are available in the published literature. Our aim was to define the most important factors affecting these parameters.

Exome Sequencing Reveals SYCE1 Mutation Associated With Autosomal Recessive Primary Ovarian Insufficiency

CONTEXT Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early menopause. Genes involved in essential steps in chromosome synapsis and recombination during meiosis, such as synaptonemal complex central element 1 (SYCE1), have been shown to cause POI in animal models. We describe for the first time a homozygous mutation in SYCE1 in humans. OBJECTIVE To identify the genetic cause of POI in an Israeli Arab family with a consanguineous pedigree. SETTING AND DESIGN A family-based genetic study conducted at a tertiary medical center. PATIENTS Two daughters of consanguineous parents (first cousins) from a 13-member family were diagnosed with POI. Genotyping was performed in the index patients, their parents, and four unaffected siblings. INTERVENTION DNA from the affected sisters was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of the additional family members were determined by Sanger sequencing. Genotyping was also performed in 90 ethnically matched control individuals. RESULTS A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation. The mutation was not identified in the DNA samples from the 90 control subjects. CONCLUSIONS Given the known function of the SYCE1 gene, we suggest that the nonsense mutation identified accounts for the POI phenotype. These results highlight the importance of the synaptonemal complex and meiosis in ovarian function.

Premature Thelarche: Age at Presentation Affects Clinical Course but Not Clinical Characteristics or Risk to Progress to Precocious Puberty

OBJECTIVES To determine whether age at premature thelarche (PT) onset affects the clinical characteristics, course, and risk of progression to precocious puberty (PP). STUDY DESIGN Data regarding course of growth and puberty were retrieved from the medical files of 139 girls with PT followed up from 1995 to 2005. Analysis was based on age at PT appearance (birth, 1-24 months, and 2-8 years); course was categorized as regressive, persistent, progressive, or cyclic. RESULTS At diagnosis, height standard deviation score, bone age-chronological age ratio, and hormonal values were comparable in the 3 age groups. PT regressed in 50.8%, persisted in 36.3%, progressed in 3.2% and had a cyclic course in 9.7%. A progressive or cyclic course was significantly more prevalent among girls presenting after 2 years (52.6%) compared with girls presenting at birth (13.0%) or at 1 to 24 months (3.8%) (P < .001). PP occurred in 13% irrespective of age at PT presentation or clinical course. CONCLUSIONS Clinical and anthropometric characteristics at admission and risk of PP were similar in all girls with PT, regardless of age at onset. There are currently no clinical or laboratory tests that can predict the risk of progression to PP at presentation.

Growth and metabolic control in patients with type 1 diabetes and celiac disease: a longitudinal observational case–control study

The occurrence of celiac disease (CD) in patients with type 1 diabetes (T1D) is increasing.

Treated and untreated women with idiopathic precocious puberty: long-term follow-up and reproductive outcome between the third and fifth decades

Central precocious puberty (CPP), treated or untreated, may have implications in adulthood.

Clinical characterization of a newly described neonatal diabetes syndrome caused by RFX6 mutations

Mutations in the RFX6 gene were recently described to underlie a distinct autosomal recessive syndrome of neonatal diabetes comprising intestinal atresia and hepatobiliary abnormalities. Until now, only six patients harboring RFX6 mutations have been reported. We report on a new case due to a novel homozygous splice site mutation and update on the clinical outcome of a previously reported patient. In addition we review the clinical and molecular features of all RFX6 mutated cases to better characterize the syndrome. Our results suggest that despite the early postnatal fulminant course, patients who survive may expect a relatively favorable prognosis.

Treated and Untreated Women With Idiopathic Precocious Puberty: BMI Evolution, Metabolic Outcome, and General Health Between Third and Fifth Decades

CONTEXT Central precocious puberty (CPP) may have clinical implications in adulthood. OBJECTIVE To assess the prevalence of obesity, metabolic outcome (hyperlipidemia, diabetes, and hypertension), and malignancy rate of former CPP women between the third and fifth decades of life. DESIGN This was a case control study of a historical cohort using the computerized database of a health management organization. SETTING The setting was the Institute for Endocrinology and Diabetes, Schneider Childrens Medical Center of Israel, and Clalit Health Services. PARTICIPANTS The study group comprised of 142 CPP women aged 27-50 years [100 GnRH analog (GnRHa) treated; 42 untreated]. The control group comprised of 413 women randomly matched for age, year of birth, and community clinic (283 for the GnRHa treated; 130 for the untreated). METHODS Extracted from the database were demographic data, medical history, medications dispensed, recorded anthropometric measurements, vital signs, and laboratory data. RESULTS At young adulthood, body mass index (percentile and distribution) of treated and untreated former CPP women was comparable to that of their respective controls. Elevated body mass index at presentation was a risk factor for obesity in adulthood in the GnRHa-treated group (r = 0.257; P = .01). The prevalence of metabolic comorbidities (16 vs 13.4%; 21.4 vs 24.6%) and malignancy rate (1.0 vs 1.5%; 4.8 vs 1.5%) were similar in the former CPP women and their controls, with no significant difference between CPP groups. CONCLUSION CPP (treated or untreated) is not associated with increased risk of obesity, metabolic derangements, or cancer morbidities in young adulthood. The finding that the health status of former CPP women is similar to that of the general population is reassuring.