Caterina Luongo

High-normal fasting glucose levels are associated with increased prevalence of impaired glucose tolerance in obese children.

The natural history of impaired glucose tolerance (IGT) and Type 2 diabetes among obese children is not clear. Although the cut-off for impaired fasting glucose (IFG) has recently been changed from 110 (6.1 mmol/l) to 100 mg/dl (5.6 mmol/l), it does not seem a reliable way to find all subjects with impaired glucose homeostasis. The aim of our study was to determine whether high-normal fasting glucose level could predict the occurrence of IGT and metabolic syndrome. Three hundred and twenty-three Italian obese children and adolescents were included in the study (176 females, mean age 11±2.9 yr; mean body mass index z-score: 3±0.6). Waist circumference, serum glucose, insulin, triglyceride, cholesterol HDL, blood pressure were evaluated and an oral glucose tolerance test (OGTT) was performed. The prevalence of IFG and IGT were respectively 1.5% (5 subjects) and 5% (18 patients); no diabetic patients were found. Metabolic syndrome was diagnosed in 20% of patients. Fasting glycemia values <100 mg/dl (5.6 mmol/l) have been divided in quintiles. Metabolic syndrome prevalence increased across quintiles, although not in a statistically significantly manner, but it could depend on the selected diagnostic criteria as no univocal definition exists for metabolic syndrome in youths. Interestingly high-normal fasting plasma glucose levels constitute an independent risk factor for IGT among obese children and adolescents; therefore, this very easy-to-use parameter may help to identify obese patients at increased risk of diabetes or at least could suggest in which subjects to perform an OGTT.

Novel cAMP binding protein-BP (CREBBP) mutation in a girl with Rubinstein-Taybi syndrome, GH deficiency, Arnold Chiari malformation and pituitary hypoplasia

BackgroundRubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disorder (prevalence 1:125,000) characterised by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa and short stature. The known genetic causes are point mutations or deletions of the cAMP-response element binding protein-BP (CREBBP) (50-60% of the cases) and of the homologous gene E1A-binding protein (EP300) (5%).Case presentationWe describe, for the first time in literature, a RTS Caucasian girl, 14-year-old, with growth hormone (GH) deficiency, pituitary hypoplasia, Arnold Chiari malformation type 1, double syringomyelic cavity and a novel CREBBP mutation (c.3546insCC).ConclusionWe hypothesize that CREBBP mutation we have identified in this patient could be responsible also for RTS atypical features as GH deficiency and pituitary hypoplasia.

Brain magnetic resonance in the routine management of Rubinstein-Taybi syndrome (RTS) can prevent life-threatening events and neurological deficits.

Rubinstein-Taybi syndrome (RTS) is a rare syndrome with prevalence 1:125,000 births [Hennekam, 2006]. Distinctive characteristics are broad and sometimes laterally deviated thumbs and halluces, downslanting palpebral fissures, long eyelashes, higharched eyebrows, prominent nose with columella below the alae nasi, malpositioned ears with abnormal helices, high palate, and hypoplastic maxilla. These patients present withmoderate intellectual disability [Wiley et al., 2003]. Moreover, craniospinal and posterior fossa abnormalities have been commonly reported in the literature [Yamamoto et al., 2005; Kim et al., 2010; Wójcik et al., 2010; Parsley et al., 2011; Giussani et al., 2012; Marzuillo et al., 2013] including large foramen magnum, microcranium, spina bifida occulta, cervical hyperkyphosis, dens hypoplasia, cervical instability of C1–C2, cervical spondylolisthesis, and scoliosis. Symptoms that may be reported with these conditions are dysesthesias, paresthesias, anesthesias, recurrent sub-occipital headache, cervical pain, vertigo, tinnitus, aural fullness, and occasionally mild neurosensorial hearing loss. Ocular symptoms such as retro-orbital headache, diplopia, photopsia, blurred vision, and photophobiamay be also present. In very severe cases inwhich compression of the spinal cord ormedulla oblongata occurs, symptoms suggesting the involvement of motor or sensory pathways, as well as of lower cranial nervesmay appear. However, if these symptoms also occur, they are extremely rare in individuals with RTS. On the other hand, physical signs are represented by generalized hyperreflexia, spasticity, and Babinski reflex, mostly in the lower limbs; atrophy, weakness, fasciculations, and areflexia, mostly in the upper limbs; nystagmus, ataxia, and dysmetria. In 15–25% of the cases vocal cord paralysis, soft palate weakness, lingual atrophy, cricopharyngeal achalasia, facial hypoesthesia, and absent gag reflex suggest the involvement of the lower cranial nerves [Fernández et al., 2009] Point mutations or deletions of the cAMP-response element binding protein-BP (CREBBP) (50–60% of the cases) or of the homologous gene E1A-binding protein (EP300) (5%) are involved in RTS [Hennekam, 2006].

MKRN3 levels in girls with central precocious puberty and correlation with sexual hormone levels: a pilot study

PurposeRecently, mutations of makorin RING-finger protein 3 (MKRN3) have been described in familial central precocious puberty. Serum levels of this protein decline before the pubertal onset in healthy girls and boys. The aim of the study is to investigate MKRN3 circulating levels in patients with central precocious puberty.MethodsWe performed an observational cross-sectional study. We enrolled 17 patients with central precocious puberty aged 7 years (range: 2–8 years) and breast development onset <8 years; 17 prepubertal control age-matched patients aged 6.3 years (2–8.2); and 10 pubertal stage-matched control patients aged 11.4 years (9–14). Serum values of MKRN3, gonadotropins, (17)estradiol and Anti-Müllerian Hormone were evaluated and the MKRN3 genotyped in central precocious puberty patients.ResultsNo MKRN3 mutation was found among central precocious puberty patients. MKRN3 levels were lower in patients with central precocious puberty compared to prepubertal age-matched ones (p: 0.0004) and comparable to those matched for pubertal stage. MKRN3 levels were inversely correlated to Body Mass Index Standard Deviations (r:−0.35; p:0.02), Luteinizing Hormone (r:−0.35; p:0.03), FSH (r:−0.37; p:0.02), and (17)estradiol (r: −0.36; p:0.02).ConclusionsWe showed that girls with central precocious puberty had lower peripheral levels of MKRN3 compared to age-matched pairs and that they negatively correlated to gonadotropins, estrogen, and BMI. Our findings support the MKRN3 involvement in central precocious puberty also in absence of deleterious mutations, although our sample size is small.In addition our data suggest the role of MKRN3 in the complex mechanism controlling puberty onset and its interaction with other factors affecting puberty such as nutrition.

Basal levels of 17-hydroxyprogesterone can distinguish children with isolated precocious pubarche

BackgroundBasal levels of androgens, in particular 17-hydroxyprogesterone (17OHP), are widely debated as predictors of non-classical congenital adrenal hyperplasia (NCCAH) among patients with precocious pubarche (PP). Many authors have recommended the use of adrenocorticotropic hormone (ACTH) stimulation test in children with PP. The aim of our study was to identify clinical and biochemical predictors of NCCAH in children with PP.MethodsWe conducted a prospective study of 92 patients with PP undergoing an ACTH stimulation test. We tested the association of basal clinical and biochemical parameters with NCCAH diagnosis. Patients were suspected to have NCCAH if their stimulated 17OHP plasma levels were >10 ng/mL. In these patients, the diagnosis was confirmed by genetic test.ResultsSeven (7.6%) patients resulted having NCCAH. The best basal biochemical predictor for NCCAH was 17OHP level >2 ng/mL. In fact, a basal 17OHP level >2 ng/mL had 100% (95% confidence interval (CI), 59.04–100) sensitivity and 93% (95% CI, 85.3–97.37) specificity. The area under the receiver-operating characteristic curve for 17OHP was 0.99 (95% CI, 0.98–1.007).ConclusionsBasal 17OHP cut-off of 2 ng/mL was very effective in predicting NCCAH among our patients with PP. Assay-specific cut-off would probably be the best strategy to avoid unnecessary ACTH test.

MKRN3 Levels in Girls with Central Precocious Puberty during GnRHa Treatment: A Longitudinal Study

Background: Recently, mutations of makorin RING finger protein 3 (MKRN3) have been identified in familial central precocious puberty (CPP). Serum levels of this protein decline before the pubertal onset in healthy girls and boys and are lower in patients with CPP compared to prepubertal matched pairs. The aim of our study was to investigate longitudinal changes in circulating MKRN3 levels in patients with CPP before and during GnRH analogs (GnRHa) treatment. Methods: We performed a longitudinal prospective study. We enrolled 15 patients with CPP aged 7.2 years (range: 2–8) with age at breast development onset < 8 years and 12 control girls matched for the time from puberty onset (mean age 11.8 ± 1.2 years). Serum values of MKRN3, gonadotropins, and 17β-estradiol were evaluated before and during treatment with GnRHa (at 6 and 12 months). The MKRN3 gene was genotyped in CPP patients. In the girls from the control group, only basal levels were analyzed. Results: No MKRN3 mutations were found among CPP patients. MKRN3 levels declined significantly from baseline to 6 months of GnRHa treatment (p = 0.0007) and from 6 to 12 months of treatment (p = 0.003); MKRN3 levels at 6 months were significantly lower than in the control girls (p < 0.0001). Conclusions: We showed that girls with CPP had a decline in peripheral levels of MKRN3 during GnRHa treatment. Our data suggest a suppression of MKRN3 by continuous pharmacological administration of GnRHa.