Summary
Context
Central precocious puberty (CPP), treated or untreated, may have implications in adulthood.
Objective
To assess the reproductive outcome and social adjustment of former CPP women ...between the 3rd and 5th decades of life.
Design
Cross‐sectional study of an historical cohort.
Methods
Demographic data and gynaecological history of 214 CPP women aged 25–56 years 135 GnRH analogue (GnRHa)‐treated, 18 cyproterone acetate (CyA)‐treated, 61 untreated and of 446 controls with normal puberty, matched for age and year of birth, were recorded in a structured interview.
Results
Marital status, education and number of children were similar in CPP women and controls. Clinical hyperandrogenism (acne/hirsutism with oligomenorrhoea) was more frequently reported in CPP women than in controls: GnRHa‐treated 29·6% vs 17·4% (P = 0·006), CyA‐treated 50% vs 20·4% (P = 0·04), untreated 34·4% vs 17·2% (P = 0·003), with no significant difference between CPP groups. Spontaneous pregnancy was similarly achieved by treated CPP and controls: GnRHa‐treated 90·4% vs 93·4%, CyA‐treated 86·7% vs 90·2%. Assisted fertilization rate was higher in untreated CPP than treated CPP groups (P = 0·006) and controls (P = 0·03). Untreated CPP was the only parameter associated with clinical hyperandrogenism (OR=2·04, 95% CI, 1·0–4·16, P = 0·07) and fertility problems (OR=3·40, 95% CI, 1·15–10·0, P = 0·047). Course of pregnancy was uneventful in 90·2% of CPP women and 90·9% of controls.
Conclusions
The increased rate of clinical hyperandrogenism among CPP women implies that the underlying neuroendocrine dysfunction persists into adult life. Pubertal suppression treatment may have a protective effect as fertility problems were more prevalent only among untreated CPP women. Educational achievements and marital status were unaffected by CPP.
Abstract
Context
Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in ...dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants.
Objective
To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates.
Design
This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA.
Participants
A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program.
Results
Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters–adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%.
Conclusions
The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter–adjusted approach for NBS of classic CAH in NBS programs worldwide.
A strategy using cutoff levels adjusted for both GA and BW significantly reduced FP rates of NBS for CAH in 10 years' experience of the Israeli NBS program.
To describe clinical manifestations of SARS-CoV-2 infection in children, adolescents, and young adults with established type 1 diabetes and explore the effects of COVID-19 on glycemic control and ...disease course.
Observational study conducted at three pediatric diabetes clinics in Israel between mid-March-2020 and mid-March-2021. Included were young people with established type 1 diabetes, <30years, who tested positive for SARS-CoV-2 (qRT-PCR). Data was collected from medical files, diabetes devices, and COVID-19 questionnaire. Outcome measures were analyzed by presence/absence of clinical symptoms (symptomatic/asymptomatic) and by age group (pediatric, <19years/young adults, 19-30years).
Of 132 patients, mean age 16.9±5.3years, with COVID-19 confirmed infection, 103 (78%) had related symptoms; the most common were headaches, fatigue, fever and loss of sense of smell. All had mild disease course, but four required hospitalization and two cases were directly related to COVID-19 infection (pleuropneumonia in a patient with immunodeficiency syndrome, one case of diabetic-ketoacidosis). Logistic regression analysis showed that age (OR=1.11, 95%CI, 1.01, 1.23; P=0.033), elevated glucose levels (OR=5.23, 95%CI, 1.12, 24.41; P=0.035) and comorbidities (OR=8.21, 95%CI, 1.00, 67.51; P=0.050) were positively associated with symptomatic infection. Persistent symptoms occurred in 16.5% of the cohort over a median of 6.7 months; age (OR=1.14, 95%CI, 1.01, 1.29; P=0.030) and elevated glucose levels (OR=3.42, 95%CI, 1.12, 10.40; P=0.031) were positively associated with persistent symptoms. Usually, no change was reported in glucose levels (64%) except for a temporary deterioration in glycemic control during the short infection period.
Young people with established type 1 diabetes experience mild COVID-19 infection. Elevated glucose levels during COVID-19 infection and older age were associated with prolonged disease course.
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.
Display omitted
•Homozygous mutations in seven pancreatic transcription factors cause neonatal diabetes•Homozygous NKX2-2 and MNX1 mutations were found in five patients•Confirms NKX2-2 and MNX1 are critical for murine and human pancreas development•Similar phenotypes in mouse and man validate models for beta cell development
Analyzing a large collection of consanguineous patients with permanent neonatal diabetes, Flanagan et al. performed a comprehensive search for recessive mutations in transcription factors known to be critical for mouse pancreatic development. They identify seven pancreatic transcription factors that cause neonatal diabetes, including NKX2-2 and MNX1.
Patients with Turner syndrome (TS) are at increased risk for metabolic disorders. We aimed to delineate the occurrence and evolution of metabolic comorbidities in TS patients and to determine whether ...these differ in 45,X monosomy and other karyotypes.
A longitudinal and cross-sectional retrospective cohort study was conducted in a tertiary pediatric endocrine unit during 1980-2016. Ninety-eight TS patients, 30 with 45,X monosomy were followed from childhood to early adulthood. Outcome measures included weight status, blood pressure (BP), glucose metabolism, and lipid profile.
Longitudinal analysis showed a significant change in body mass index (BMI) percentiles over time
(3,115) = 4.8,
= 0.003. Age was associated with evolution of elevated BP systolic BP: odds ratio (OR) = 0.91,
= 0.003; diastolic BP: OR = 0.93,
= 0.023, impaired glucose metabolism (HbA1c: OR = 1.08,
= 0.029; impaired glucose tolerance: OR = 1.12,
= 0.029), and abnormal lipid profile (cholesterol: OR = 1.06,
= 0.01; low-density lipoprotein cholesterol: OR = 1.07,
= 0.041; high-density lipoprotein cholesterol: OR = 1.07,
= 0.033). The occurrence of metabolic comorbidities was similar in 45,X monosomy and other karyotypes. Coexistence of multiple metabolic comorbidities was significantly higher in 45,X monosomy
(1,72) = 4.81,
= 0.032. BMI percentiles were positively correlated with metabolic comorbidities (occurrence and number) in each patient (
= 0.35,
= 0.002 and
= 0.383,
= 0.001, respectively).
Our longitudinal study provides unique insights into the evolution of weight gain and metabolic disorders from childhood to early adulthood in TS patients. Since overweight and increasing age aggravate the risk for metabolic comorbidities, careful surveillance is warranted to prevent and control obesity already from childhood. The more prominent clustering of metabolic comorbidities in 45,X monosomy underscores the importance of a more vigorous intervention in this group.
Background
The occurrence of celiac disease (CD) in patients with type 1 diabetes (T1D) is increasing.
Objective
To determine the effect of CD on growth and glycemic control in patients with T1D, and ...the effects of adherence to gluten‐free diet (GFD) on these parameters.
Patients and methods
A longitudinal retrospective case–control design was used. The medical files of 68 patients with T1D and duodenal‐biopsy‐confirmed CD were reviewed for data on weight, height, hemoglobin A1c (HbA1c), frequency of diabetic ketoacidosis (DKA), and severe hypoglycemic events before and after diagnosis and treatment of CD. Findings were compared with 131 patients with T1D only matched for age, gender, and duration of diabetes.
Results
CD was diagnosed in 5.5% of all patients with T1D attending our center during the study period; 26% of the patients with CD were symptomatic. There were no significant differences in glycemic control or frequency of severe hypoglycemia or DKA events between the study and control groups. Body mass index‐standard deviation score (SDS), height‐SDS, and HbA1c values were marginally but not significantly higher in the control than the study group and similar in subjects with CD with good or fair/poor adherence to a GFD throughout follow‐up.
Conclusions
Patients with T1D and CD treated with GFD have growth and measures of metabolic control similar to those with T1D without CD. The decision whether asymptomatic celiac patients should be put on a GFD or only symptomatic patients has to be weighed against possible short‐ and long‐term consequences of no intervention, and should be based on more evidence from larger randomized studies.
Abstract
Context
Central precocious puberty (CPP) may be the first presentation of nonclassical congenital adrenal hyperplasia (NCCAH) in girls. Data on the prevalence and the clinical phenotype of ...CPP associated with NCCAH are sparse.
Objectives
To study the clinical and laboratory characteristics that could differentiate idiopathic CPP from CPP associated with NCCAH and to determine the prevalence of NCCAH among girls with CPP.
Design
Case-control study.
Setting
Tertiary pediatric endocrinology institute.
Participants and Methods
From 2008 to 2017, 147 girls who had undergone stimulation tests with gonadotropin-releasing hormone and ACTH were diagnosed with CPP; of these, seven (4.8%) were eventually diagnosed with NCCAH. These seven patients together with 30 girls who presented with CPP during 1984 to 2008 and were later diagnosed with NCCAH comprised the NCCAH group. Demographic, anthropometric, clinical, and laboratory data were compared between the NCCAH group and the 140 girls with idiopathic CPP (ICPP group).
Results
No between-group differences were found in height, weight, body mass index, bone age, and Tanner stage. Mean basal levels of androstenedione, dehydroepiandrosterone-sulphate, and 17-hydroxyprogesterone were significantly higher in the NCCAH group, although ranges overlapped between the groups, and stimulated cortisol level was higher in the ICPP group.
Conclusion
NCCAH was found in 4.8% of girls presenting with true CPP over 10 years, and no single parameter could differentiate between the diagnoses. Thus, in girls with true CPP from populations in which NCCAH is prevalent, assessment of adrenal androgens is required, and ACTH test should be considered.
Girls presenting with CPP underwent GnRH and ACTH tests. NCCAH was found in 4.8% of girls with CPP. No single parameter could differentiate between NCCAH and idiopathic CPP.
Aim
This study explored whether using the suggested diagnostic serum basal level of 17‐hydroxyprogesterone (6.0 nmol/L) would lead to underdiagnosis of nonclassical congenital adrenal hyperplasia.
...Methods
We retrospectively studied 123 patients with nonclassical congenital adrenal hyperplasia, defined as an adrenocorticotropic hormone‐stimulated 17‐hydroxyprogesterone level of more than 45 nmol/L. Of these 13 had basal 17‐hydroxyprogesterone levels of less than 6.0 nmol/L and 110 exceeded that level. The 42 controls had idiopathic premature pubarche. Clinical and laboratory data were reviewed and compared.
Results
There were no differences between patients with 17‐hydroxyprogesterone levels of <6.0 nmol/L or ≥6.0 nmol/L based on age at presentation, gender, anthropometric measurements, bone age advancement, age at glucocorticoid initiation and hydrocortisone dosage. Patients with basal 17‐hydroxyprogesterone <6.0 nmol/L had significantly lower stimulated 17‐hydroxyprogesterone levels (p = 0.02) and higher stimulated serum cortisol levels (p < 0.008). Children with nonclassical congenital adrenal hyperplasia and premature pubarche were clinically indistinguishable from controls with idiopathic premature pubarche. Androgen levels were significantly higher in the nonclassical congenital adrenal hyperplasia group.
Conclusion
A basal 17‐hydroxyprogesterone threshold of 6.0 nmol/L was not a sensitive predictive marker for diagnosing nonclassical congenital adrenal hyperplasia. Children whose clinical presentation suggests nonclassical congenital adrenal hyperplasia should undergo diagnostic adrenocorticotropic hormone stimulation testing.
Abstract Background/aim It is controversial whether the endocrine dysfunction in epilepsy patients is caused by the epilepsy itself, the antiepileptic therapy, or both. We prospectively evaluated the ...long-term impact of valproic acid monotherapy compared to other anti-epileptic drugs on anthropometric, metabolic, hormonal, and ultrasonographic parameters in girls with epilepsy. Methods Fifty-seven female patients with epilepsy who had started therapy at mean age of 11.5 ± 3.3 years, 42 with valproic acid (mean dose 13.1 ± 7.0 mg/kg/day and 15 with other anti-epileptic agents were followed for a mean of 3.2 years (range 1.0–8.5 years) in our center. Clinical, hormonal and transabdominal pelvic ultrasound data were collected at 3 time points: before and 6–12 months after onset of anti-epileptic drug treatment; and at the last visit while patients were still taking anti-epileptic drugs. Results There were no significant between-group differences regarding changes in height, body mass index standard deviation score, levels of glucose and insulin, or lipid and endocrine profile from first to last visits. Mean thyroid-stimulating hormone level increased significantly between first and last visit only in the valproic acid group ( p < 0.001), with no significant difference in free T4 level over time or between groups. The rate of clinical polycystic ovary syndrome for the valproic acid group (11%) was comparable to that reported in healthy controls (5–10%). Conclusions Administration of valproic acid had no adverse effect on body weight, metabolic status or endocrine function over an average follow-up of 3.2 years. Valproic acid appears to be safe for use in girls with epilepsy.
Objectives
Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes, diagnosed before age 6 months. We aimed to describe the clinical characteristics, molecular genetics, and long‐term ...follow‐up of NDM patients from a single pediatric endocrine center in Israel.
Methods
Retrospective study (1975–2020) of all patients diagnosed with diabetes before 6 months of age, who tested negative for pancreatic autoantibodies. Medical records were reviewed for demographic, familial and medical history, and clinical and biochemical features; a genetic analysis was performed.
Results
Of 24 patients, nine had transient neonatal diabetes (TNDM) and 15 permanent neonatal diabetes (PNDM), of whom five had rare syndromic causes. Genetic etiology was revealed in 87.5% of the NDM cohort, and the most common causes were ABCC8 mutations in TNDM and KCNJ11 and insulin gene mutations in PNDM. The switch from insulin to off‐label sulfonylurea therapy was successful for 5/9 (56%) of the qualifying candidates. Severe hypoglycemia and diabetic ketoacidosis developed in 2 (8%) patients, and chronic diabetes complications in 5 (21%) patients with more than 10 years NDM. At last follow‐up, weight and height of all but two syndromic PNDM patients were normal. The median height‐SDS of the TNDM subgroup was significantly taller and the mean weight‐SDS significantly heavier than those of the PNDM subgroup (−0.52 (−0.67, −0.09) vs. −0.9 (−1.42, −0.3) (p = 0.035) and 0.22 ± 0.69 vs. −0.89 ± 1.21 (p = 0.02), respectively). PNDM patients showed no incremental change in mean weight SDS over the time.
Conclusion
The Israeli NDM cohort has clinical and genetic characteristics comparable with other populations. Patients with TNDM were taller and heavier than those diagnosed with PNDM, although both show rapid catch‐up growth and reached normal growth parameters. Chronic diabetes complications developed in patients with long‐standing NDM.
PDF
