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Aims To define the reproducibility of vibration perception thresholds (VPTs) and the possible associated factors, as an early index of peripheral diabetic neuropathy (PDN) in type 1 diabetes mellitus (T1DM) children and adolescents. Methods A single examiner studied 118 T1DM subjects (aged 13.5±3.4 years) and 79 controls (aged 12.0±3.07 years). Glycaemic control was assessed with HbA1c levels. VPT was measured twice on upper and lower limbs, using a Biothesiometer. Concordance between the two VPT measurements was evaluated using the Cohen's Weighted Kappa statistic (Kappa=0.41–0.60→moderate concordance, Kappa=0.61–0.80→substantial concordance). Results T1DM children had significantly higher VPTs than controls at all sites ( p =0.001), but with lower Kappa values (0.64–0.70). VPT values increased in parallel with HbA1c ( a . b . 8–9.5%, c .>9.5%) and T1DM duration ( a . b .5.1–10, c .>10 years). However, Kappa values were lower in the groups with the poorest control (HbA1c>9.5%) (Kappa=0.54–0.76) or the longest T1DM duration (>10 years) (Kappa=0.49–0.71). Although VPTs increased with stature and male gender, no effect on VPT reproducibility was observed. However, obesity was associated with lower VPT values and poorer concordance. Conclusions These findings suggest that the reproducibility of VPTs is lower in the high-risk patients for early subclinical PDN development, who need a regular follow-up.

Denys-Drash and Frasier syndromes are rare human disorders that associate nephropathy with gonadal and genital abnormalities. In DDS there is a predisposition to Wilms' tumor. Heterozygous point mutations in the Wilms' tumor, type1 gene (WT1), particularly those altering the zinc finger (ZF) encoding exons, have been reported in most DDS patients, while mutations in intron 9 of the same gene cause FS. This paper describes two cases of DDS, one FS and one patient with Wilm's tumor and intersex genitalia, in which mutations were searched by sequencing the exons 8 and 9 of WT1 gene. Patient 1 carried a missense point mutation in exon 8 (ZF2), converting a CGA-Arg codon to a TGA-stop codon. Patient 2 presented a single nucleotide deletion within exon 9 (ZF3) introducing a premature chain termination at codon 398. Patients 3 and 4 had a C-->T transition at position +4 of the second alternative splice donor site of exon 9 (this mutation was detected in peripheral blood and in tumor derived DNA of patient 3). However, patient 3 had previously developed a Wilms' tumor. This is the first case of Wilms' tumor development in a phenotypically and genetically confirmed case of FS.

Type 1 diabetes mellitus (T1DM) is characterized by selective autoimmune destruction of pancreatic b-cells, resulting in insulin deficiency. Associated autoimmune disorders, such as celiac disease, autoimmune thyroiditis, and gastritis, can coexist in patients with T1DM. These disorders are characterized by the presence of antibodies against tissue transglutaminase (anti-tTG-IgA), thyroglobulin, and thyroid peroxidase (anti-TG, anti-TPO), as well as antibodies against gastric parietal cells. Children with T1DM may also develop organ-specific multiple autoimmunity, with the coexistence of one or more autoimmune disorders. Furthermore, there is a lot of controversy regarding the role of thyroid autoimmunity in the pathogenesis of thyroid cancer. We present a child with T1DM and multiple autoimmunity including autoimmune Hashimoto's thyroiditis (HT), who developed thyroid cancer. The literature on the prevalence of associated autoimmunity in children with T1DM and the prevalence, pathogenesis, and timely diagnosis of thyroid cancer among patients with HT is also reviewed.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing syndrome in children, often occurring in association with Carney complex. We report a case of Cushing syndrome due to isolated non-familial PPNAD. The child presented with typical clinical characteristics, growth retardation and obesity. Liddle's test was positive but micronodular appearance was not evident on CT scan and MRI; selective venous sampling revealed higher cortisol concentrations in the right adrenal vein. The patient underwent a laparoscopic right adrenalectomy. Postoperatively, hypercortisolism signs disappeared but after the second year a slight increase in urinary cortisol was noted and the patient developed osteopenia. Although significant catch-up growth occurred postoperatively, height did not normalize over the next 2 years. When she entered puberty, treatment with a luteinizing-hormone-releasing hormone agonist was initiated and growth hormone was added. Almost 5 years later a left adrenalectomy was also performed. Thereafter, complete disease remission was observed, the patient's growth accelerated and her osteopenia reversed.

There have been considerable advances concerning understanding of the early and later stages of ovarian development; a number of genes have been implicated and their mutations have been associated with developmental abnormalities. The most important genes controlling the initial phase of gonadal development, identical in females and males, are Wilms' tumor suppressor 1 (WT1) and steroidogenic factor 1 (SF1). Four genes are likely to be involved in the subsequent stages of ovarian development (WNT4, DAX1, FOXL2 and RSPO1), but none is yet proven to be the ovarian determining factor. Changes in nomenclature and classification were recently proposed in order to incorporate genetic advances and substitute gender-based diagnostic labels in terminology. The term "disorders of sex development" (DSD) is proposed to substitute the previous term "intersex disorders". Three main categories have been used to describe DSD in the 46,XX individual: 1) disorders of gonadal (ovarian) development: ovotesticular DSD, previously named true hermaphroditism, testicular DSD, previously named XX males, and gonadal dysgenesis; 2) disorders related to androgen excess (congenital adrenal hyperplasia, aromatase deficiency and P450 oxidoreductase deficiency); and 3) other rare disorders. In this mini-review, recent advances concerning development of the genital system in 46,XX individuals and related abnormalities are discussed. Basic embryology of the ovary and molecular pathways determining ovarian development are reviewed, focusing on mutations disrupting normal ovarian development. Disorders of sex development according to the revised nomenclature and classification in 46,XX individuals are summarized, including genetic progress in the field.

Aims Our aim was to determine in children with T1DM the prevalence of positive antibodies against tissue transglutaminase (anti-tTG IgA) as indices of coeliac disease (CD), as well as its clinical presentation, its determinants and its association with thyroid (anti-TG, anti-TPO) and pancreatic b-cell autoimmunity (anti-GAD). Methods The study included 105 children and adolescents with T1DM, aged (mean ± SD) 12.44 ± 4.76 years, with a T1DM duration of 4.41 ± 3.70 years. Results Fifty of our patients (47.6%) were positive for anti-GAD, 9/105 (8.6%) for anti-tTG IgA and 21/105(20%) for anti-thyroid antibodies. The anti-tTG IgA (+) children, in comparison with the rest of the study population, were of younger age (9.31 vs. 12.74 years, p = 0.038), shorter diabetes duration (2.16 vs. 4.62 years, p = 0.056) and had mild growth impairment (height SDS: −0.55 vs. +0.20, p = 0.055). Univariate logistic regression analysis revealed that the presence of anti-tTG IgA (+) was associated with younger age and shorter T1DM duration. Only 5/9 (55.6%) children with high titres of anti-tTG IgA developed mild gastrointestinal symptoms or growth retardation and had histological findings typical of CD. Conclusions The prevalence of anti-tTG IgA positivity among T1DM children was 8.6% and its occurrence was associated with younger age and short diabetes duration. Since CD presents in T1DM patients asymptomatically or with non-specific symptoms, periodic autoantibody screening is necessary for its early diagnosis.

Childhood obesity is a common and complex problem that may persist in adulthood. It may present as a component of genetic syndromes associated with dysmorphic features, developmental abnormalities, mental retardation and/or learning disabilities and often neuroendocrine dysfunction. Although the chromosomal abnormalities of these rare syndromes are already known, the specific genetic and pathophysiological mechanisms leading to the distinct phenotypes and obesity still remain unclarified. New exciting genetic pathways contributing to syndrome phenotype and leading to obesity have recently been identified. Prader-Willi syndrome is caused by loss of expression of the C/D box HBII-84 cluster of snoRNAs. Dysfunction of the primary cilium, thought to have important signalling functions, may contribute to disease phenotype and obesity in Bardet-Biedl, Alstrom and Carpenter syndromes. In this mini-review current knowledge of clinical and genetic characteristics is summarized as well as the pathogenesis of these syndromes with special emphasis on the pathogenesis of obesity.

Objective To establish the diagnosis of complete androgen insensitivity syndrome (CAIS) in two patients with characteristic clinical and hormonal findings, relative family history in one of them, and unusual Mullerian remnants in the other. Design Case report. Setting Research laboratory in the Department of Medical Genetics at a university children's hospital. Patient(s) Two patients with 46,XY sex reversal and two maternal aunts of the first patient with the same clinical condition were tested. Intervention(s) Bilateral gonadectomy was performed on both patients. Main Outcome Measure(s) Genetic counseling, cancer prophylaxis, hormone substitution therapy. Result(s) Molecular analysis revealed two novel mutations, a frameshift familial (c.2494delA) in patient 1 and a missense sporadic (c.T3004C) in patient 2. The c.2494delA mutation was also detected in two of the three affected maternal aunts of patient 1. Patient 2 presents an unusual persistence of Mullerian structures. Conclusion(s) Genetic counseling of potential women carriers of androgen receptor (AR) mutations is crucial for the early diagnosis of the affected offspring. The presence of Mullerian remnants, although rare, should not exclude the diagnosis of CAIS. Both identified mutations are novel and provide further evidence for the correlation between specific AR mutations and phenotype.

Autoimmune polyglandular syndrome (APs) type 2 is characterized by the presence of Addison's disease, in association with autoimmune thyroid disease and/or type 1 diabetes mellitus and is rare in children. A 12.5 yr old prepubertal boy presented with symptoms related to Addison's disease and a large goiter. He was euthyroid with positive thyroid antibodies, low cortisol, aldosterone and very high adrenocorticotropin (ActH) and renin levels. Growth hormone (GH) secretion and an MrI scan of the pituitary were normal. He was started on hydrocortisone, fludrocortisone and subsequently on L thyroxine. Eighteen months later, decreased growth rate was noted and GH deficiency was detected, apparently secondary to autoimmune hypophysitis. Interestingly, he did not develop any other pituitary hormone deficiencies. He was started on GH therapy and had a good treatment response in the next 3 years. the combination of adrenal and thyroid insufficiencies with autoimmune hypophysitis is a very rare manifestation of APs-type 2. GH deficiency as the only symptom of lymphocytic hypophysitis is extremely rare. In children with autoimmune polyendocrine disorders, careful monitoring of growth is needed. In the case of low growth rate, GH should be evaluated by dynamic tests and, if GH deficiency is detected, treatment with hGH must be initiated.

The term precocious puberty encompasses a group of heterogeneous conditions that range from variants of normal to slowly progressive and rapidly progressive maturation of both sexes. It is defined as the appearance of secondary sex characteristics before the age of 8 in girls and 9 in boys. The clinician who is evaluating a child with precocious puberty should be aware of the normal events of puberty, the ages at which pubertal milestones are achieved and the tempo of pubertal progression. The mechanisms involved in the onset and progression of normal puberty are briefly discussed in this article. The diverse etiology of precocious puberty, the diagnostic evaluation of the patient including clinical, laboratory and radiological investigation as well as problems associated with precocious puberty and indications for treatment and treatment modalities are further discussed in the article.

OBJECTIVE: Our goal was to investigate the effect of body weight on bone age (BA) and hormonal features in children with benign premature adrenarche. METHODS: We studied 221 children (175 girls, 46 boys) with premature adrenarche (pubic and/or axillary hair at 95th percentile). Children with late-onset congenital adrenal hyperplasia were excluded from study. RESULTS: Mean CA of adrenarche was 6.3 years (girls) and 7.1 years (boys). The percentages of overweight and obese children was significantly higher than those reported in the general population of children in Greece. Obese children had significantly more advanced BA compared with overweight and normal-weight children. Higher levels of DHEA-S and Δ4-A were observed in overweight and obese girls compared with normal-weight girls, whereas higher levels of DHEA-S, testosterone, and IFG-I were observed in overweight and obese boys (Table 1). No statistically significant difference was observed between the 3 groups in the levels of 17-hydroxyprogesterone, estradiol, cholesterol, triglycerides, or high- and low-density lipoprotein cholesterol. CONCLUSIONS: A higher frequency of obesity and advanced BA was observed in children with benign premature adrenarche, with a strong correlation between BA and degree of obesity. Furthermore, obese children were characterized by higher levels of adrenal androgens compared with normal-weight children. TABLE 1.Levels of Adrenal Androgens in Normal-Weight and Obese ChildrenNormal Weight Mean (Range)Overweight Mean (Range)Obese Mean (Range) P a Girls Testosterone, ng/mL0.11 (0.06–0.20)0.14 (0.10–0.21)0.16 (0.09–0.24).112 DHEAS, μg/mL0.71 (0.41–1.10)0.85 (0.61–1.15)0.88 (0.57–1.21)b.081 Δ 4-A, ng/mL0.4 (0.2–0.8)b0.6 (0.4–1.1)b0.6 (0.4–0.8)b