Transient generalized glucocorticoid hypersensitivity.

BACKGROUND: Transient generalized glucocorticoid hypersensitivity is a rare disorder characterized by increased tissue sensitivity to glucocorticoids and compensatory hypo-activation of the hypothalamic-pituitary-adrenal axis. The condition itself and the underlying molecular mechanisms have not been elucidated. OBJECTIVE: To present the clinical manifestations, endocrinologic evaluation and transcriptomic profile in a patient with transient generalized glucocorticoid hypersensitivity. DESIGN AND RESULTS: A 9-year-old girl presented with an 8-month history of clinical manifestations suggestive of Cushing syndrome. Endocrinologic evaluation revealed undetectable 08:00 h ACTH (<1 pg/mL) and cortisol (0·025 µg/dL) concentrations, which remained decreased throughout the 24-h period and did not respond to stimulation with ovine CRH. The disease gradually resolved spontaneously over the ensuing 3 months. Sequencing of the human glucocorticoid receptor gene revealed no mutations or polymorphisms. Western blot analysis in peripheral blood mononuclear cells revealed equal protein expression of hGRα of the patient in the disease and postresolution phases compared with a control subject. Transcriptomic analysis in peripheral blood mononuclear cells in the disease and postresolution phases identified 903 differentially expressed genes. Of these, 106 genes were up-regulated and 797 were down-regulated in the disease compared with the resolution phase. Bioinformatics analysis on the differentially expressed gene networks revealed Nuclear Factor-κB as the predominant transcription factor influencing the expression of the majority of differentially expressed genes. CONCLUSIONS: Our findings indicate that a transient postreceptor defect, or a virus- or bacterium-encoded molecule, may have enhanced glucocorticoid signal transduction, leading to transient generalized glucocorticoid hypersensitivity and hypo-activation of the HPA axis.

Neurophysiologic evaluation of infants with congenital hypothyroidism before and after treatment.

We performed a systematic neurophysiological evaluation of newborns-infants newly diagnosed with congenital hypothyroidism and started on replacement therapy, in order to document the maturation of visual, auditory and somesthetic pathways and to evaluate the influence of treatment. Twenty-one patients (9 boys, 12 girls) were studied. They underwent neurophysiological evaluation consisting of visual, auditory, and somatosensory evoked potentials at diagnosis, as well as 6 and 12 months after initiation of treatment. At the time of diagnosis, 47.61 % of the patients had abnormal evoked potentials, with visual evoked potentials being most commonly abnormal. Twelve months after the onset of treatment, abnormal evoked potentials were detected in 33.3 % of the patients. In newly diagnosed infants with congenital hypothyroidism there is a high relevance of abnormal evoked potentials (47.61 %) at the time of diagnosis, declining with time and not correlating with the severity of the disease at diagnosis, the time of diagnosis or the initial dose of thyroxine.

Fok-I gene polymorphism of vitamin D receptor in patients with beta-thalassemia major and its effect on vitamin D status.

Most of the biological actions of vitamin D are mediated by an intracellular receptor (VDR) in which several single nucleotide gene polymorphisms have been identified. Vitamin D deficiency is increasingly identified among thalassemic patients and recent evidence links it with myocardial iron accumulation. The aim of this work was to assess the distribution of the Fok-I polymorphism of the VDR gene among Greek children and young adults with beta-thalassemia major and to investigate its association with 25(OH)D(3) and 1,25(OH)(2)D(3) serum levels. Sixty-nine thalassemic patients (35 females and 34 males), with a mean age of 23·05±6·07 years, participated in the study. Genotype frequencies of Fok-I were similar to those previously reported for other populations; 44·9% of the patients were homozygotes for F allele, 43·5% were heterozygotes and 11·6% were homozygotes for the f allele. Low levels of serum 25(OH)D(3) were recorded, as 41 patients (59·4%) were below the cut-off limit of 50 nmol/l that determines deficiency, whereas, levels of 1,25(OH)(2)D(3) showed wide variability ranging from deficiency (≤50 pmol/l) in 34 patients (49·3%) to excess (≥125 pmol/l) in 13 patients (18·8%). When stratifying patients according to serum 1,25(OH)(2) D(3) concentrations, a higher prevalence of the f allele was observed in the deficiency group (P = 0·03). A comparison of the serum concentrations of the two vitamin D metabolites produced a trend towards a negative correlation (r = -0·204, P = 0·09). Further studies are required to assess the genetic contribution to the regulation of vitamin D metabolites in the serum of patients with beta-thalassemia major.

Elevated serum parathormone levels are associated with myocardial iron overload in patients with beta-thalassaemia major.

OBJECTIVES: Despite advances in conventional treatment, iron-induced cardiomyopathy is still the most frequent cause of death among patients with beta-thalassaemia major. Recent studies have correlated increased myocardial iron content to decreased levels of vitamin D in thalassaemic patients. The aim of this study was to measure parathormone (PTH) and metabolites of vitamin D and consequently to investigate whether these parameters predispose to myocardial iron overload in patients with beta-thalassaemia major. METHODS: In 62 patients (29 M and 33 F, mean age: 22.79 +/- 6.18 yr) with beta-thalassaemia major levels of intact parathormone (iPTH) and vitamin D metabolites [25(OmicronH)D(3) and 1,25(OmicronH)(2)D(3)] were measured in serum. Additionally, estimation of myocardial iron content was performed by magnetic resonance imaging, whereas mean serum ferritin concentrations were calculated for 1 yr prior to the study. RESULTS: Results showed markedly decreased levels of serum 25(OH)D(3) in 37 patients (60%), whereas 7 patients (11%) had borderline 25(OH)D(3) levels (between 50 and 75 nmol/L). Serum iPTH levels were significantly higher in patients having increased myocardial iron compared to those having normal myocardial iron (44.04 +/- 22.09 pg/mL vs. 31.39 +/- 14.30 pg/mL, P = 0.017). Multivariant regression analysis identified PTH levels as the major predictor of increased myocardial iron.

Reference values for quantitative ultrasonography (QUS) of radius and tibia in healthy greek pediatric population: clinical correlations.

The aim of this study was to provide reference standards for measurements of quantitative ultrasonography (QUS) of radius and tibia in normative Greek pediatric population. Analysis was performed in 1549 healthy subjects (814 girls and 735 boys) with a mean decimal age of 11.41+/-3.52 yr (range: 3.78-18.33 yr). Results showed a gradual increase of absolute values of radial and tibial speed of sound (SOS), with aging and with pubertal progressing, in both girls and boys. Gender comparison showed significantly increased SOS values measured both at radius and at tibia in girls more than 13 yr of age compared with aged-matched boys. Significant but mild correlation was noted between standard deviation scores (SDS) of SOS at radius and at tibia (r = 0.259, p < 0.001). Additionally, tibial SOS SDS were significantly negatively correlated with body mass index (BMI) SDS (r = -0.230, p < 0.001). Finally, subjects that spend more than 3h of daily "screen time" (television and personal computer) showed significantly decreased SOS values measured both at radius and at tibia. On the contrary, no correlation was observed between SOS values and the amount of physical activity reported.

Sonographic assessment of uterine and ovarian development in normal girls aged 1 to 12 years.

PURPOSE: To provide normal references of sonographic uterine and ovarian size in girls aged 1-12 years. METHOD: Ninety-nine girls were enrolled in the study (mean age +/- SD, 6.9 +/- 2.4 years [range, 1-12 years]). Pubertal status was classified according to Tanner staging, whereas for height and weight assessment a standard stadiometer and weight scale were employed. All subjects underwent pelvic sonographic examination for the measurement of uterine length, volume, ratio of anteroposterior diameter at the fundus divided by the anteroposterior diameter at the cervix (fundal-cervical [F/C] ratio), and ovarian volume and morphology. RESULTS: A gradual increase with age was observed in all uterine and ovarian measurements. Cubic model analysis provided the best curve estimation for uterine length, uterine volume, and ovarian volume in relation to age. Uterine length, uterine volume, ovarian volume and F/C ratio were significantly correlated to both age and height. With respect to ovarian morphology, there was a gradual decrease in frequency of the homogeneous and the paucicystic appearances with increasing age. The macrocystic appearance was observed after the age of 6 years, and its frequency increased gradually with age. CONCLUSION: There is a continuous increase in size of internal female genitalia from early childhood until the onset of puberty. We have provided reference percentile charts of normal uterine length, uterine volume, and ovarian volume in girls aged 1-12 years.

Normal lumbar bone mineral density in optimally treated children and young adolescents with beta-thalassaemia major.

OBJECTIVE: Osteopenia/osteoporosis of multi-factorial pathogenetic mechanism is reported to be a significant cause of morbidity in adult patients with beta-thalassaemia major. Even in young patients, decreased Bone Mineral Density (BMD) values are a consistent finding in the literature. This study was performed in order to assess BMD in children and young adults with beta-thalassaemia major, regularly transfused and sufficiently chelated, along with auxological, clinical and laboratory parameters. DESIGN: Thirty-five young thalassaemic patients (19 F, 16 M, aged 5-20 yr) were studied. Lumbar BMD was assessed by dual X-ray absorptiometry (DXA) and Z-scores were calculated according to bone density values using age- and sex-matched normal population. None of the patients presented with clinical or laboratory signs of endocrinopathy and none was receiving hormonal replacement therapy. RESULTS: All BMD Z-scores were within normal range, with a mean Z-score of 0.42 for girls and -0.41 for boys (statistically significant gender difference, p=0.018). When correlated with age, a decline in Z-scores was observed, indicating a delay in bone mass acquisition with advancing age in the thalassaemic group compared to controls. CONCLUSIONS: Optimal conventional treatment prevents the manifestation of osteopenia/osteoporosis during the first two decades of life in patients with beta-thalassaemia major. However, close surveillance with regular screening, preventive intervention and early management of possible endocrine complications are essential in order to secure normal bone health during adulthood and improve quality of life in the thalassaemic population.

Bone age estimation and prediction of final height in patients with beta-thalassaemia major: a comparison between the two most common methods.

BACKGROUND: Thalassaemic patients are in need of frequent assessment of bone age because of growth failure and pubertal disorders. OBJECTIVE: To compare the "rapid" Greulich and Pyle (G&P) method with the third edition of the Tanner and Whitehouse (TW3) method for determining skeletal maturity and predicting final height in thalassaemic patients. MATERIALS AND METHODS: A total of 191 radiographs from 58 patients (28 male, 30 female) were retrospectively evaluated by two investigators, one for each method. In 47 radiographs from 15 patients having attained their adult height, predicted final height was calculated according to each method. RESULTS: The mean bone ages determined by both the G&P and TW3 methods were lower than mean chronological age, although the differences were not statistically significant (10.04 +/- 3.69 years and 9.98 +/- 3.39 years vs. 10.78 +/- 3.96 years, respectively). Both methods had a tendency to over-estimate final height. Overall, the TW3 method seemed to be more accurate than the G&P method (mean absolute error 3.21 +/- 2.51 years vs. 3.99 +/- 2.99 years, respectively, P=0.048). CONCLUSIONS: The same method should be used when serial assessments are performed, as both methods provide similarly reliable, although not equivalent, results. The TW3 height prediction method seemed to be more accurate in patients with beta-thalassaemia major than the G&P method, albeit with a large confidence interval.

Thelarche variant in a girl with Angelman syndrome.

A case of Angelman syndrome (AS) with thelarche variant in a 4.5-year-old girl is presented. Clinical suspicion of AS was raised at the age of 15 months when she presented with mental retardation and epilepsy, absence of speech, ataxic gait with jerky movements, hyperactivity and paroxysmal episodes of laughter. Moreover, she had facial dysmorphic features such as microbrachycephaly, mid-facial hypoplasia, macrostomia and prominent mandible. Dinucleotide repeat polymorphism (DNRP) analysis, identified absence of maternal alleles at D15S543, D15S113 and GABRB3 loci, findings consistent with AS. Studies on CYP19 locus (outside the 15q11-13 region) revealed the presence of two different alleles, thus excluding the possibility of paternal isodisomy of chromosome 15 in this patient. Breast development at the age of 4.5 years, accompanied by accelerated growth velocity and bone age suggested the diagnosis of variant thelarche. This is the second case of AS with sexual precocity reported and whether this combination is a coincidence or not remains to be clarified.

Familial moyamoya disease in a Greek family.

Moyamoya disease (M-M) is characterized by progressive obstruction of the supraclinoid portion of internal carotid arteries and the proximal middle, anterior and posterior cerebral arteries, associated with the formation of a characteristic net of collateral vessels in the basal ganglia region. Clinical manifestations in childhood include transient ischaemic attacks, seizures and multiple infarcts. Approximately 7% of M-M cases are familial. We report two affected Greek siblings with typical clinical and neuroradiological findings of M-M. Linkage analysis of the whole family was consistent with linkage to the region 3p24-26, as previously reported in other familial Japanese M-M cases.