Linear growth of children with X-linked hypophosphatemia treated with burosumab: a real-life observational study.

To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6-15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1-4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3% after 12 months of treatment (p = 0.041). The RSS improved from 1.7 ± 1.0 at burosumab initiation to 0.5 ± 0.6 and 0.3 ± 0.6 after 12 and 24 months, respectively (p < 0.001). Both height z-score and weight z-score improved from burosumab initiation to the end of the study: from - 2.07 ± 1.05 to - 1.72 ± 1.04 (p < 0.001) and from - 0.51 ± 1.12 to - 0.11 ± 1.29 (p < 0.001), respectively. Eight children received growth hormone combined with burosumab treatment. Height z-score improved among those who received growth hormone (from - 2.33 ± 1.12 to - 1.94 ± 1.24, p = 0.042) and among those who did not (from - 2.01 ± 1.01 to - 1.66 ± 1.01, p = 0.001). CONCLUSION:  Burosumab treatment in a real-life setting improved phosphate homeostasis and rickets severity and enhanced linear growth. WHAT IS KNOWN: • Compared to conventional therapy, burosumab treatment has been shown to increase serum phosphate levels and reduce the severity of rickets. • The effect of burosumab on growth is still being study. WHAT IS NEW: • Height z-score improved between the start of burosumab treatment and the end of the study (-2.07 ± 1.05 vs. -1.72 ± 1.04, p < 0.001). • Eight children received burosumab combined with growth hormone treatment without side effects during the concomitant treatments.

Alarming increase in ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the first wave of the COVID-19 pandemic in Israel.

OBJECTIVE: To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. RESEARCH DESIGN AND METHODS: A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. RESULTS: During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002). CONCLUSIONS: The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

The natural history of congenital hypothyroidism with delayed TSH elevation in neonatal intensive care newborns.

OBJECTIVE: To assess the clinical and neurological outcomes in newborns with primary congenital hypothyroidism presented with delayed TSH elevation (dTSH), and to define parameters that may predict the evolution of transient vs. permanent hypothyroidism in these newborns. DESIGN AND PATIENTS: An observational study was performed of a cohort of 113 children with a history of dTSH. MEASUREMENTS: Birth parameters, thyroid screening results, thyroid gland imaging, levothyroxine dose and neurological outcome were compared between newborns with spontaneous recovery and children with a final diagnosis of either transient or permanent hypothyroidism. RESULTS: Of the children with a history of dTSH, 93% demonstrated recovery, either spontaneously or following levothyroxine treatment (transient hypothyroidism). Newborns with spontaneous recovery demonstrated milder thyroid dysfunction at the newborn screening compared to those who started levothyroxine treatment. Levothyroxine dose was lower in children with transient vs. permanent hypothyroidism only during the first 6 months of life; otherwise, these groups were similar in birth parameters, thyroid screening results and gland images. Seventeen out of 61 children (28%) that underwent neurological assessment demonstrated a developmental delay. Duration of treatment was highly variable in children with transient hypothyroidism. CONCLUSIONS: Thyroid dysfunction is transient in most cases of dTSH. No reliable parameters can predict a priori transient vs. permanent hypothyroidism.

Birth during the moderate weather seasons is associated with early onset of type 1 diabetes in the Mediterranean area.

AIM: To assess the association of seasonal and perinatal parameters with early age of type 1 diabetes (T1D) onset. METHODS: A cross-sectional review of all medical records of T1D patients born between the years 1990 and 2005, and diagnosed before/by the age of 10 years, from 13 university-affiliated paediatric medical centres in Israel, was performed. Data included: gender, ethnicity, seasons of birth and disease onset, birth gestational age and weight, and autoimmune diseases of the probands and their first-degree family members. Statistical analysis included the Chi-square test or Mann-Whitney test, as appropriate and multivariate regression analysis. RESULTS: Enrolled were 1571 T1D patients at a median age of T1D onset 6.9 years (IQR 4.4,8.4); 336 of them presented before 4 years of age. The median age of this group was 2.5 years (IQR 1.7,3.2), and of the 1235 patients who presented after 4 years of age, median presentation age was 7.5 years (IQR 6.1,8.8). Multivariate regression analysis demonstrated that a more recent birth year; OR = 1.06, 95% CI 1.02-1.1, P = 0.003, and birth during the moderate weather months (September, October, March, and April) were significantly associated with younger age at T1D onset; OR = 1.68, 95% CI 1.17-2.4, P = 0.005. CONCLUSIONS: Our novel finding demonstrates the association between younger than 4 years old age at presentation and birth during moderate weather months. The results also support previous reports, that there is a slight increase in the annual incidence of T1D in the youngest age groups.

Adrenal crises in children with adrenal insufficiency: epidemiology and risk factors.

The aim of the study was to assess the epidemiology and risk factors of adrenal crises (AC) in children with adrenal insufficiency (AI). Children diagnosed with AI between 1990 and 2017 at four Israeli pediatric endocrinology units were studied. Demographic and clinical data were retrieved retrospectively from their files. The study population consisted of 120 children (73 boys, 47 girls) and comprised 904 patient years. Median age at diagnosis was 0.3 years (0-17.5). Thirty-one AC events in 26 children occurred during the study period, accounting for a frequency of 3.4 crises/100 patient years. Fifty-two percent of AC events occurred at presentation. The significant risk factors for developing AC were the following: younger age at diagnosis (P = 0.003), primary AI vs. secondary AI (P = 0.016), specific diagnosis of autoimmune AI, adrenal hypoplasia congenita and salt wasting congenital adrenal hyperplasia (P < 0.001), mineralocorticoid treatment (P < 0.001), and recurrent hospital admissions (P > 0.001). After applying a stepwise logistic regression model, only the group of diagnoses, including salt wasting CAH, AHC, and Addison's disease, remained significant predictor of AC (OR 17.5, 95% CI 4.7-64.9, P < 0.001). There was no AC-associated mortality during the study period.Conclusions: Since significant percent of AC events occurred at presentation, measures to increase the awareness to signs and symptoms of AI among primary care physicians should be taken. Efforts to prevent AC should be focused on younger patients, especially those with primary AI. What Is Known: • Diagnosis and long-term management of pediatric patients with adrenal insufficiency (AI) remain a challenge. • Adrenal crises (AC) pose life-threatening emergencies in affected youngsters. Studies on the rate and risk factors of AC in children with AI are scarce, and they were done mainly on children with congenital adrenal hyperplasia (CAH). What Is New: • The rate of AC was relatively low and there was no AC-associated mortality during the study period. • Children with primary AI were at higher risk for AC than children with secondary AI. Specifically, children with salt wasting CAH, adrenal hypoplasia congenita, and Addison's disease at the highest risk.

Prevalence of early and late prematurity is similar among pediatric type 1 diabetes patients and the general population.

BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) has increased in recent decades, as has the incidence of preterm births (<37 weeks). We aimed to evaluate and compare the prevalence of prematurity and early prematurity (<34 weeks) and birth season variability among T1DM and non-T1DM children. METHODS: A nationwide cross-sectional study was conducted, with linkage of data from 13 paediatric diabetes centers and Israeli National Registries, including T1DM patients and general non-T1DM population, born during 2000 to 2013. Gathered data included ethnicity, gender, birth week, weight, and season. The prevalence of prematurity and birth season were compared with the general population birth registry using Pearson Chi-square test. RESULTS: The study population included 1452 T1DM patients, 52.7% males, and 2 138 668 subjects in the general non-T1DM population, 51.2% males. The prevalence of late and early prematurity was similar between groups (6.1% and 2.2% in the T1DM group vs 5.6% and 2.0% in the general non-T1DM group, P = 0.25 and P = 0.38, respectively). OR for prematurity among T1DM patients was 1.15 (0.95-1.39), P = 0.16. No difference in birth season was demonstrated between preterm and term, in T1DM and general non-T1DM populations. Ethiopian descent was more prevalent among T1DM patients compared with the non-T1DM population, in both term and preterm born. CONCLUSIONS: This is the largest population-based study, and the first in the Middle East geographical area, indicating that prematurity, including early prematurity, is not associated with T1DM during childhood. The study was registered at https://clinicaltrials.gov/: NCT02929953.

The proportion of familial cases of type 1 diabetes is increasing simultaneously with the disease incidence: Eighteen years of the Israeli Pediatric Diabetes Registry.

BACKGROUND: The global rise in incidence of type 1 diabetes (T1D) is too rapid to be attributed to susceptible genetic background, pinpointing a significant role for environmental factors. Unlike the theory that the need for genetic susceptibility has lessened over time, we hypothesized that the rise in T1D incidence is faster in a genetically susceptible population. SUBJECTS AND METHODS: The study population comprised of 5080 patients aged 0 to 17 years who were reported to the National Israel Diabetes Registry between 1997 and 2014. The patients were divided into familial cases (first-degree relative has T1D), and sporadic cases. Demographic and clinical data were retrieved from the registry. The change in annual percent (from the entire cohort) was computed separately for the sporadic and familial cohorts. RESULTS: The familial (n = 546; 10.7%) and sporadic (n = 4534; 89.3%) cases were comparable for gender, ethnicity, and age at diagnosis. Consanguinity was more common in the familial vs sporadic group (10% vs 6.1%; P = .001). The average annual percent change increased by 1.9% in the familial cases and decreased by 0.2% in the sporadic cases (P = .04). CONCLUSIONS: The rapid rise in the proportion of familial cases of T1D suggests that environmental factors impose higher diabetogenic pressure in patients with a susceptible genetic background.

Characteristics of Delayed Thyroid Stimulating Hormone Elevation in Neonatal Intensive Care Unit Newborns.

OBJECTIVES: To elucidate the incidence, clinical characteristics, and short-term outcome of delayed thyroid stimulating hormone (TSH) elevation (dTSH) in a large cohort of newborns admitted to the neonatal intensive care unit. STUDY DESIGN: Data were gathered from a cohort of 13 201 newborns admitted to the neonatal intensive care unit born between January 1, 2008, and October 31, 2014, who underwent TSH measurements because of low T4 levels on the second screen. The data from the newborn screening program included gestational age, birth weight (BW), T4 levels, and short-term outcome. RESULTS: Of 13 201 newborns, 333 (1:40) presented with dTSH (TSH >15 IU/L). dTSH had a peak proportion at gestational age of 37-39 weeks, and 66% of the patients had BW >1500 g. T4 levels in the 333 patients were negatively correlated with TSH levels (R = -0.505; P < .001), and significantly lower than levels in the other newborns: 5.9 ± 2.8 vs 7.6 ± 1.7 µg/dL; P < .001. TSH levels in dTSH newborns were already higher on the initial screen compared with the other newborns: 8.3 ± 5.2 vs 4.2 ± 3.7 IU/L; P < .001. Fifty-eight percent of 193 patients with dTSH were started on levothyroxine treatment. CONCLUSIONS: dTSH has a higher incidence than previously reported, especially among newborns with BW >1500 g. Relatively high TSH and low T4 levels on the initial and second screen respectively are predictors for dTSH. Levothyroxine treatment is required in most cases.

Homozygous deletion of TRMT10A as part of a contiguous gene deletion in a syndrome of failure to thrive, delayed puberty, intellectual disability and diabetes mellitus.

Two recent reports describe a new syndrome of intellectual disability, short stature, microcephaly, and young onset diabetes or disturbed glucose metabolism in association with inactivating mutations in the TRMT10A gene. We investigated the clinical spectrum presented by a 17-year-old female with a homozygous contiguous gene deletion involving the TRMT10A gene. From infancy, she presented with failure to thrive and microcephaly. Puberty was characterized by a slow and an inconsistent course of progression. Concomitantly, gonadotropin levels fluctuated between low and high levels which were compatible with gonadal failure. Unlike the previous reports, the patient had ketoacidosis at onset of diabetes and islet cell autoantibodies. Nevertheless, glycemic control was excellent (HbA1C 5.0%-6.2%). RT-PCR and Western blot analysis demonstrated a complete abolishment of TRMT10A mRNA and its translated protein. In order to elucidate the nature of diabetes in this patient, endogenous insulin secretion and glycemic control were evaluated by a glucagon stimulation test and continuous glucose monitoring both during insulin treatment and off therapy. Endogenous insulin secretion still persisted 22 months after onset of diabetes and relatively normal glucose levels were kept over 3 days without insulin treatment. The fluctuating course of puberty and diabetes may reflect intermittent apoptotic damages due to sensitization of the relevant cells to various stress agents in the absence of functional TRMT10A.

Glycerol Phenylbutyrate treatment of two patients with Monocarboxylate Transporter 8 deficiency.

CONTEXT: Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. OBJECTIVE: We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. METHODS: We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, Vital signs, anthropometric measurements and neurocognitive functions. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P321L mutation. The effects of GPB were compared to the effects of DITPA and TRIAC, thyromimetic medications that the patients received in the past. RESULTS: NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment reduced high T3 and increased low T4 levels. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, in hyperreflexia score and in cognitive functions. Serum metabolites did not exceed the toxic range but elevated liver transaminases were observed. CONCLUSIONS: In the first report of GPB treatment in MCT8 deficiency we found an improvement in TH profile and body-mass index, with minor neuro-developmental changes.

Novel Calcium-Sensing Receptor (CASR) Mutation in a Family with Autosomal Dominant Hypocalcemia Type 1 (ADH1): Genetic Study over Three Generations and Clinical Characteristics.

INTRODUCTION: Activating mutation of the calcium-sensing receptor gene (CASR) reduces parathyroid hormone secretion and renal tubular reabsorption of calcium, defined as autosomal dominant hypocalcemia type 1 (ADH1). Patients with ADH1 may present with hypocalcemia-induced seizures. Calcitriol and calcium supplementation in symptomatic patients may exacerbate hypercalciuria, leading to nephrocalcinosis, nephrolithiasis, and compromised renal function. METHODS: We report on a family with seven members over three generations with ADH1 due to a novel heterozygous mutation in exon 4 of CASR: c.416T>C. RESULTS: This mutation leads to substitution of isoleucine with threonine in the ligand-binding domain of CASR. HEK293T cells transfected with wild type or mutant cDNAs demonstrated that p.Ile139Thr substitution led to increased sensitivity of the CASR to activation by extracellular calcium relative to the wild-type CASR (EC50 of 0.88 ± 0.02 mM vs. 1.1 ± 0.23 mM, respectively, p < 0.005). Clinical characteristics included seizures (2 patients), nephrocalcinosis and nephrolithiasis (3 patients), and early lens opacity (2 patients). In 3 of the patients, serum calcium and urinary calcium-to-creatinine ratio levels obtained simultaneously over 49 patient-years were highly correlated. Using the age-specific maximal-normal levels of calcium-to-creatinine ratio in the correlation equation, we obtained age-adjusted serum calcium levels that are high enough to reduce hypocalcemia-induced seizures and low enough to reduce hypercalciuria. CONCLUSION: We report on a novel CASR mutation in a three-generation kindred. Comprehensive clinical data enabled us to suggest age-specific upper limit of serum calcium levels, considering the association between serum calcium and renal calcium excretion.

Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects.

Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

Increase in the incidence of type 1 diabetes in Israeli children following the Second Lebanon War.

BACKGROUND: Type 1 diabetes is an autoimmune disease occurring in genetically susceptible individuals. The precipitating cause is unclear. Recently, the Second Lebanon War exposed a large civilian population in northern Israel to significant psychological stress in the form of repeated barrages of missile attacks. HYPOTHESIS: We hypothesized that trends in regional incidence of type 1 diabetes before and after the war would reflect an association with stress. METHODS: All type 1 diabetes patients aged 0-17 yr who were reported to the Israel Juvenile Diabetes Register (n = 1822) in the four pre-war (2002-2005) and two post-war years (2006-2007) were included in the study. The patients were stratified by gender, age, ethnicity, family history of type 1 diabetes, season at diagnosis, and region of residency, namely, those who lived in the northern regions that were attacked and those in other regions. RESULTS: The post-war incidence of type 1 diabetes was increased in the northern regions (rate ratio, RR = 1.27; p = 0.037), with no change in the other regions. This change was more prominent in males (RR = 1.55; p = 0.005) but similar in summer and winter, in different ages, and in different ethnic groups. There was no change in the proportion of new patients with a family history of the disease. CONCLUSIONS: For the first time in a large population, we found a positive association between the trauma of war and an increase in the incidence of type 1 diabetes in children and adolescents. The increase in incidence was not associated with genetic susceptibility to the disease.

Lack of association between seroconversion and catch-up growth in children with celiac disease.

OBJECTIVE: To assess the association between seroconversion and catch-up growth during the first year of a gluten-free diet (GFD) program in children with celiac disease (CD). METHODS: All prepubertal and biopsy-proven children diagnosed with CD between January 1999 and August 2009 were included in a retrospective study (n=55). Growth parameters and celiac antibodies were documented before and after 6 (period 1) and 12 months (period 2) of GFD, respectively. RESULTS: Mean height velocity-standard deviation score (SDS) was significantly higher in period 1 compared with that in period 2 (2.90 +/- 3.20 vs. 0.20 +/- 2.08, p<0.001) irrespective of the serology status, with marginal difference in mean weight-SDS gain (p=0.074). Mean levels of height velocity-SDS and the weight-SDS gain were similar in the seropositive and seronegative groups in both periods of the study. Mean height-SDS and weight-SDS levels after 6 months were higher than those in baseline levels, both in seropositive (-0.47 +/- 0.91 vs. -0.82 +/- 0.82, p<0.001 and -0.59 +/- 1.17 vs. -1.11 +/- 1.33, p<0.001, respectively) and seronegative patients (-1.02 +/- 1.14 vs. -1.50 +/- 1.12, p<0.001 and -1.19 +/- 1.27 vs. -1.45 +/- 1.40, p=0.048, respectively). These growth parameters were higher at the end compared with the beginning of period 2, but only in seropositive patients. CONCLUSIONS: The most remarkable catch-up growth in children with CD can be expected during the first 6 months of GFD, irrespective of the serology status.

Embryonic pig pancreatic tissue for the treatment of diabetes in a nonhuman primate model.

Xenotransplantation of pig tissues has great potential to overcome the shortage of organ donors. One approach to address the vigorous immune rejection associated with xenotransplants is the use of embryonic precursor tissue, which induces and utilizes host vasculature upon its growth and development. Recently, we showed in mice that embryonic pig pancreatic tissue from embryonic day 42 (E42) exhibits optimal properties as a beta cell replacement therapy. We now demonstrate the proof of concept in 2 diabetic Cynomolgus monkeys, followed for 393 and 280 days, respectively. A marked reduction of exogenous insulin requirement was noted by the fourth month after transplantation, reaching complete independence from exogenous insulin during the fifth month after transplantation, with full physiological control of blood glucose levels. The porcine origin of insulin was documented by a radioimmunoassay specific for porcine C-peptide. Furthermore, the growing tissue was found to be predominantly vascularized with host blood vessels, thereby evading hyperacute or acute rejection, which could potentially be mediated by preexisting anti-pig antibodies. Durable graft protection was achieved, and most of the late complications could be attributed to the immunosuppressive protocol. While fine tuning of immune suppression, tissue dose, and implantation techniques are still required, our results demonstrate that porcine E-42 embryonic pancreatic tissue can normalize blood glucose levels in primates. Its long-term proliferative capacity, its revascularization by host endothelium, and its reduced immunogenicity, strongly suggest that this approach could offer an attractive replacement therapy for diabetes.

Reproducibility and Refinement of Urinary LH in the Screening of Progressive Puberty in Girls.

CONTEXT: First-voided urinary LH (FVU-LH) has been suggested as an alternative to GnRH stimulation test for detection of precocious puberty. OBJECTIVE: To evaluate the reproducibility of FVU-LH, its correlation with basal and GnRH-stimulated gonadotropins, and its diagnostic value for differentiating progressive from nonprogressive puberty. DESIGN AND PARTICIPANTS: Clinical and endocrine data were obtained from the medical records of 95 girls with suspected progressive puberty who underwent 2 consecutive FVU-LH tests. In 55 of these participants, GnRH stimulation test was performed close to the FVU-LH test. The reported cutoff levels of 5 IU/L and 1.16 IU/L for GnRH-stimulated LH and FVU-LH, respectively, were used as markers of progressive puberty, clinically defined as bone age advancement of ≥1 year and/or growth velocity SD score ≥2, in addition to thelarche. RESULTS: The 2 consecutive measurements of FVU-LH were highly correlated (r = 0.830; P < 0.001). The higher of the 2 results was better correlated with basal gonadotropins and GnRH-stimulated LH. Furthermore, it aligned better with the clinical outcome of girls with early thelarche, which supports the approach of double tests of FVU-LH to distinguish progressive from nonprogressive puberty. By comparison to GnRH-stimulated LH, the higher FVU-LH value had better sensitivity (68%), whereas peak LH had better specificity (91%) for the diagnosis of progressive puberty. Both tests had high positive predictive value and poor negative predictive value. CONCLUSIONS: The higher value of paired FVU-LH tests can be used to screen girls with suspected progressive puberty and can reduce the need for GnRH stimulation test.

MODY type 2 in Greig cephalopolysyndactyly syndrome (GCPS) as part of a contiguous gene deletion syndrome.

Maturity-onset diabetes of the young type 2 (MODY2) is a form of monogenic diabetes, characterized by mild fasting hyperglycemia. MODY2 is caused by heterozygous mutations in the GCK gene that encodes the glucokinase enzyme. We describe the clinical features and the underlying genetic defect of MODY2 in a patient with atypical Greig cephalopolysyndactyly syndrome (GCPS). The patient presented with the limb formation and the craniofacial developmental abnormalities typical to GCPS, in addition to mental retardation and epilepsy (assigned as atypical syndrome). Fasting hyperglycemia in the diabetic range, impaired glucose tolerance, and lack of diabetes autoantibodies were compatible with MODY2. In order to delineate the genetic aberrations relevant both to MODY2 and Greig syndrome in this patient, we performed cytogenetic analysis, real-time PCR of the GCK gene, and comparative genomic hybridization (CGH) array. Cytogenetic study has shown a microscopic detectable deletion in the 7p13-15 chromosomal region. Real-time PCR demonstrated a deletion of the GCK gene in the patient but not her parents, and CGH array revealed a deleted region of approximately 12 Mb in the 7p13-15 region. This deleted region included GLI3 and GCK genes (where heterozygous mutations cause GCPS and MODY2, respectively), and many other contiguous genes. Our patient manifests a unique form of MODY2, where GCK gene deletion is part of a large deleted segment in the 7p13-15 chromosomal region.

Inhaled fluticasone causes iatrogenic cushing's syndrome in patients treated with Ritonavir.

INTRODUCTION: Ritonavir, a protease inhibitor (PI), is commonly used in the treatment of HIV-1 infection. It is a potent inhibitor of the hepatic cytochrome P450 superfamily. Therefore, its usage with other PI medications leads to significant increases in the levels of the latter PI, which allows a reduction in pill burden. Intranasal and inhaled corticosteroids are widely used for the treatment of allergic rhinitis and asthma. Inhaled steroids do not usually lead to systemic adverse events, since their plasma concentrations are quite low due to extensive first-pass metabolism and clearance by CYP3A4. However, the coadministration of Ritonavir with inhaled (or intranasal) corticosteroids may result in an increase in the plasma corticosteroid levels due to the potent CYP3A4 inhibition by Ritonavir. This may cause Cushing's syndrome (laboratory and clinical) with adrenal suppression. METHODS: Plasma cortisol and urinary-free cortisol levels were determined using immunoassays. In the Synacthen test, plasma cortisol levels were measured at time 0 as well as at times 60, 120, and 150 minutes following an intramuscular injection of 0.25 mg Synacthen. RESULTS: We present here three HIV-1 female patients aged 12, 55 and 65 years who developed iatrogenic Cushing's syndrome with adrenal suppression following the coadministration of Ritonavir and inhaled Fluticasone, both at the standard recommended doses. CONCLUSIONS: The coadministration of Ritonavir and Fluticasone at the recommended doses caused, in our three patients, iatrogenic Cushing's syndrome with adrenal suppression. We suggest that this adverse event is underdiagnosed and high clinical suspicion is needed for early diagnosis and prenention of Addisonian crises. Thus, Fluticasone treatment should be avoided in patients who are treated with Ritonavir. Alternative therapeutic options for asthma control such as oral Montelukast or bronchodilators alone should be considered.

Adrenal cortisol secretion capacity in children and adolescents with new-onset, mild Crohn's disease.

OBJECTIVES: To evaluate the integrity of the hypothalamic-pituitary-adrenal axis in active Crohn's disease (CD) among children and adolescents. STUDY DESIGN: We retrieved data on patients with CD who participated in a prospective study where budesonide treatment was evaluated. Basal and adrenocorticotropic hormone and corticotropin-stimulated cortisol levels in 52 children and adolescents with CD were compared with levels obtained in 52 age-matched control subjects. Correlations of cortisol levels with pediatric CD activity index and C-reactive protein (CRP) as an inflammatory marker were also assessed. RESULTS: Both basal and stimulated cortisol levels in CD were significantly higher than in control subjects: 364 +/- 173 versus 290 +/- 122 nmol/L (P = .029) and 865 +/- 236 versus 738 +/- 148 nmol/L (P < or = .001), respectively. Cortisol levels were correlated with CRP but not with pediatric CD activity index. Unlike in the control group, stimulated cortisol levels in patients with CD were not correlated with basal levels but rather with CRP (positive correlation) and age at diagnosis (negative correlation). CONCLUSIONS: Contrary to previous reports suggesting that dysregulation of the hypothalamic-pituitary-adrenal axis is implicated in the susceptibility to and severity of CD and other chronic inflammatory diseases, we demonstrated an adequate response of this axis in pediatric CD, in proportion to the inflammation severity.

Neonatal hyperthyrotropinemia: population characteristics, diagnosis, management and outcome after cessation of therapy.

INTRODUCTION: Neonatal hyperthyrotropinaemia (HT), defined by elevated TSH and normal T(4), is either transient or persistent. The eventual outcome of neonatal HT is unpredictable and the management of HT patients is controversial. We assessed perinatal parameters and diagnostic measures that may distinguish between transient and persistent HT, compared with congenital hypothyroidism (CH). We also aimed to recommend optimal treatment in these forms of thyroid impairment. DESIGN AND PATIENTS: A multi-centre, retrospective study was conducted in six paediatric endocrinology units. Forty-three HT patients and 83 CH patients were included in the study. Measurements We evaluated differences in birth weight (BW), gestational age (GA), modes of diagnosis, screening and confirmatory T(4) and TSH levels, thyroid imaging results and optimal thyroxine doses between HT and CH and between the two forms of HT. RESULTS: Newborns with HT had lower BW and GA than those with CH. Transient (n = 18) and persistent HT (n = 25) patients were indistinguishable by most parameters, but those with persistent HT had a higher prevalence of abnormal thyroid imaging (69%vs 8%; P = 0.005). During treatment, 79% and 55% of transient and persistent HT patients respectively experienced elevated levels of free T(4.) Although most HT patients were reevaluated after 2.5 years, six transient HT patients stopped therapy and showed full recovery within the first year of life. CONCLUSIONS: We recommend obtaining thyroid imaging to distinguish between the two forms of HT. Adherence to recommended doses of thyroxine and probably early cessation of therapy in transient HT can prevent iatrogenic hyperthyroidism in these patients.