Secondary Prevention of Diabetes Type 1 with Oral Calcitriol and Analogs, the PRECAL Study.

Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3-6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1-4 mcg × 1-3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5-10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32-1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1-4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month-2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.

A Mixed-Longitudinal Study of Height Velocity of Greek Schoolchildren and the Milestones of the Adolescent Growth Spurt.

Height velocity (HV) growth charts constructed from longitudinal studies are scarce as they have inherent difficulties, e.g., time, and costs. These difficulties can be partly overcome by a mixed-longitudinal study that covers the entire age range within 3-6 years. To construct HV charts of Greek children and to estimate the milestones of the adolescent growth spurt (AGS), i.e., the onset of AGS (take-off), peak HV, and total pubertal growth (TPG), we performed a mixed longitudinal study in 1514 Greek schoolchildren (6-18 years) with height measurements every 6 months during three schoolyears. We constructed HV charts for boys and girls. Take-off occurs earlier in girls, and, in both sexes, it precedes by 1-1.5 years the appearance of physical signs of puberty. PHV in boys occurs at 12.61 years and in girls at 10.93 years. At take-off, boys are 5 cm taller than girls and TPG for boys is 35.8 cm and for girls 27.3 cm. We constructed HV charts plotted by age, irrespective of pubertal status, and presented data on the milestones of AGS. Furthermore, we suggest that the gradual increase in IGF-1 and E2 that occurs after 5 to 6 years of age triggers the onset of AGS, which precedes physical signs of puberty.

Lessons from Wolfram Syndrome: Initiation of DDAVP Therapy Causes Renal Salt Wasting Due to Elevated ANP/BNP Levels, Rescued by Fludrocortisone Treatment.

Initiation of desmopressin acetate (DDAVP) for untreated diabetes insipidus (DI) in Wolfram syndrome (WS) causes abrupt volume expansion resulting in particularly high secretion of Atrial Natriuretic Peptide (ANP) and/or Brain Natriuretic Peptide (BNP), which in turn blocks all stimulators of zona glomerulosa steroidogenesis, resulting in secondary mineralocorticoid deficiency and acute hyponatremia, causing renal salt wasting (RSW). Two sisters, a 19-y-old girl (A) and a 7-y-old girl (B) with WS, presented with severe polyuria-polydipsia due to never treated DI. Both had neurogenic bladder and "B" had severe hydronephrosis secondary to untreated grade III bilateral vesicoureteral reflux. They initiated therapy with oral melt DDAVP which resulted in RSW. ANP was found ×50 and BNP ×2-4 fold elevated. Fludrocortisone 100-200 × 2 µg/d controlled natriuresis and restored electrolytes to normal within 48 h. Fludrocortisone treatment rescues otherwise potentially life-threatening hyponatremia due to RSW and the secondary mineralocorticoid deficiency driven by elevated ANP and/or BNP, caused by sudden volume expansion following DDAVP initiation.

Hypoprolactinemia as a Clue to Diagnosis of Mild Central Hypothyroidism due to IGSF1 Deficiency

Loss-of-function mutations of IGSF1 are an X-linked cause of central hypothyroidism (CeH) and hypoprolactinemia. A boy who is now 15.2 years old presented at the age of 7.69 years for evaluation of obesity. Previous thyroid function evaluation suggested CeH [FT4 0.6 ng/mL, thyroid-stimulating hormone (TSH) 2.2 mIU/L] but his physician took no action. At presentation he was clinically and biochemically euthyroid, prepubertal and obese. Serum prolactin (PRL) was undetectable. Biochemistry was normal except for mild hypercholesterolemia, total cholesterol 198 mg/dL. Subsequently FT4 and TSH levels fluctuated between 0.72-0.95 ng/dL (normal 0.8-2.0) and 1.94-5.77 mIU/L (normal 0.3-5.0), respectively. Sequencing of IGSF1 gene revealed a novel genetic change c.3805C>T in exon 19; substitution of amino acid Arginine at position 1269 with a premature «stop¼ codon resulting in an altered protein product. The patient additionally presented delayed adrenarche, low height velocity that resolved spontaneously and normal pubertal onset associated with increased FSH levels. At 14 years-of-age, while the patient was at Tanner stage 4, PRL levels became detectable, rising gradually to 2.3 ng/mL at last examination. Thyroxine replacement therapy resulted in decrease in total cholesterol 103 mg/dL. A high index of suspicion for the disorder is needed since several measurements of thyroid function may be required for CeH to be disclosed. The patient's normal FT4 levels and normal intelligence would have resulted in a missed diagnosis if the serum PRL levels had not been measured. This case highlights the importance of measuring PRL in a boy with low normal FT4 and normal TSH levels.

A novel detrimental homozygous mutation in the WFS1 gene in two sisters from nonconsanguineous parents with untreated diabetes insipidus.

Given the limited lifespan and with the recent progress in experimental treatments for WS, timely diagnosis and multidisciplinary treatment for DI/DM, hydronephrosis, and visual/psychiatric status-maintaining quality of life-are of crucial importance.

Successful Treatment of Severe Atopic Dermatitis with Calcitriol and Paricalcitol in an 8-Year-Old Girl.

Atopic dermatitis (AD) is a chronic inflammatory disease affecting children and adolescence. The traditional therapeutic options for AD, including emollients topically and immune modulatory agents systemically focusing on reducing skin inflammation and restoring the function of the epidermal barrier, are proven ineffective in many cases. Several studies have linked vitamin D supplementation with either a decreased risk to develop AD or a clinical improvement of the symptoms of AD patients. In this report, we present a girl with severe AD who under adequate supplementation with cholecalciferol was treated with calcitriol and subsequently with paricalcitol. She had significant improvement-almost healing of her skin lesions within 2 months, a result sustained for more than 3 years now. Because of hypercalciuria as a side effect from calcitriol therapy, treatment was continued with paricalcitol, a vitamin D analogue used in secondary hyperparathyroidism in chronic kidney disease. Calcitriol therapy may be considered as a safe and efficacious treatment option for patients with severe AD, particularly for those with refractory AD, under monitoring for possible side effects. Treatment with paricalcitol resolves hypercalciuria, is safe, and should be further investigated as an alternative treatment of atopic dermatitis and possibly other diseases of autoimmune origin.

Overweight and obesity decreased in Greek schoolchildren from 2009 to 2012 during the early phase of the economic crisis.

AIM: We examined the weight status of Greek schoolchildren from November 2009 to May 2012, shortly before, and during the early years, of the Greek economic crisis. METHODS: This was a mixed longitudinal study that formed part of the West Attica Growth Study and followed children at the ages of 6-7, 9-10, 12-13 and 15-16 years every six months for 2.5 years. Each child's height and weight were measured and their body mass index calculated. We were able to determine the weight status of 1327 children (53% boys) based on their first and last measurements. Overweight, obesity and underweight were defined using the International Obesity Task Force criteria. RESULTS: During the 2.5-year study period, there was a decrease in the total prevalence of overweight and obesity, which reached a statistical significance for both sexes. It decreased from 43% to 37.3% (p = 0.02) in boys and from 33.4% to 26.9% (p = 0.0056) in girls. There was also a statistically significant increase in normal weight children and a slight but insignificant increase in underweight children of both sexes. CONCLUSION: During the initial years of the Greek economic crisis, there was a statistically significant reduction in overweight and obesity in children from six to 16 years of age.

A Greek girl with 11ß-hydroxylase deficiency due to compound heterozygosity for two novel mutations in CYP11B1 gene.

UNLABELLED: 11ß-hydroxylase deficiency (11ß-OHD), an autosomal recessive inherited disorder, accounts for 5-8% of congenital adrenal hyperplasia. In Greece, no cases of 11ß-OHD have been described so far. The patient presented at the age of 13 months with mild virilization of external genitalia and pubic hair development since the age of 3 months. Hormonal profile showed elevated 11-deoxycortisol, adrenal androgens and ACTH levels. ACTH stimulation test was compatible with 11ß-OHD. DNA of the proband and her parents was isolated and genotyped for CYP11B1 gene coding cytochrome P450c11. The girl was found to be compound heterozygous for two CYP11B1 novel mutations, p.Ala386Glu (exon 7), inherited from the father and p.Leu471Argin (exon 9) from the mother. Hydrocortisone supplementation therapy was initiated. Four years after presentation she remains normotensive, her growth pattern is normal and the bone age remains advanced despite adequate suppression of adrenal androgens. LEARNING POINTS: 11ß-hydroxylase (CYP11B1) deficiency (11OHD; OMIM +202010) is the second most common cause of CAH accounting for approximately 5-8% of cases with an incidence of 1:100 000-1:200 000 live births in non-consanguineous populations.Two CYP11B1 inactivating novel mutations, p.Ala386Glu and p.Leu471Arg are reportedRegarding newborn females, in utero androgen excess results in ambiguous genitalia, whereas in the male newborn diagnosis may go undetected. In infancy and childhood adrenal androgen overproduction results in peripheral precocious puberty in boys and various degrees of virilization in girls.Accumulation of 11-deoxycorticosterone and its metabolites causes hypertension in about two thirds of patients.Diagnosis lies upon elevated 11-deoxycortisol and DOC plus upstream precursors, such as 17α-hydroxyprogesterone and Δ4-androstenedione.The established treatment of steroid 11ß-OHD is similar to that of steroid 21-hydroxylase deficiency and consists of glucocorticoid administration in order to reduce ACTH-driven DOC overproduction resulting in hypertension remission and improvement of the virilization symptoms.

L-Dopa Stimulates Cortisol Secretion through Adrenocorticotropic Hormone Release in Short Children.

BACKGROUND/AIMS: We recently showed that L-Dopa administration is a potent stimulator of cortisol secretion in children with short stature. Herein, we examined whether adrenocorticotropic hormone (ACTH) is implicated in the mechanism by which cortisol is stimulated during the L-Dopa test. METHODS: Nineteen children with short stature who fulfilled the auxological criteria for growth hormone (GH) deficiency and had a subnormal GH response to glucagon stimulation underwent a second GH stimulation test (L-Dopa test). Serum GH, cortisol and plasma ACTH were determined at baseline and every 30 min up to 120 min after oral L-Dopa administration. Peak values of GH >10 ng/ml, cortisol >18 µg/dl and ACTH >52 pg/ml were considered as normal response. RESULTS: Normal response rates were 10.5% (2/19) for GH, 94.7% (18/19) for cortisol and 68.4% (13/19) for ACTH. Among the children with a normal response in ACTH, its concentration increased from a basal value (mean ± standard deviation) of 23.3 ± 9.6 to 290.3 ± 221 pg/ml, almost always 90-120 min after L-Dopa administration. Mean peak cortisol was 36.2 ± 9.1 µg/dl, and it peaked almost simultaneously with ACTH. CONCLUSION: Our data suggest a stimulatory effect of the dopaminergic system on the hypothalamic-pituitary-adrenal axis.

Characteristics of the short children referred to an academic paediatric endocrine clinic in Greece.

AIM: To describe the characteristics of short children in relation to gender and the various diagnoses. METHODS: All new patients of Greek origin that were referred to our institution in the years 2007 and 2008 for evaluation of short stature were included in the study. Children were categorized according to the severity of their short stature in those with height standard deviation score (HSDS) ≤ -3 and HSDS > -3. RESULTS: Two hundred ninety-five children (162 boys and 133 girls, ratio 1.2) were referred. HSDS of boys was -2.3 (0.6) and of girls -2.1 (0.5), P= 0.004. Girls had shorter parents, and the predicted adult HSDS was also shorter for girls -1.7 (0.8) than for boys -1.35 (0.76), P= 0.003. Seventy per cent of the children of both sexes had familial short stature (FSS), constitutional delay of growth or a combination of the two conditions. About 10% presented the auxological and biochemical criteria for growth hormone deficiency (GHD). In addition, 11.8% had a HSDS ≤ -3, the most common diagnosis being GHD (36.1%); the less severely short children most commonly presented FSS (41.2%). CONCLUSIONS: There is no gender bias in referrals for short stature in Greece. About 70% of children of both sexes presented FSS or constitutional delay of growth or a combination of the two conditions, whereas GHD was diagnosed in about 10% of the children. Normal variants of growth were present in about 80% of children with HSDS > -3, but in only 40% when HSDS was ≤ -3.

Pubertal maturation of contemporary Greek boys: no evidence of a secular trend.

PURPOSE: To examine pubertal status of contemporary Greek boys and compare the data with those of a previous study we performed in the year 1996. METHODS: We performed a cross-sectional study of 932 healthy boys, aged from 8.05 to 16.05 years. Development of the genitalia (G) and pubic hair was assessed by the method of Tanner and testicular volume (TV) was determined with a Prader orchidometer. Genitalia stage 2 (G2) was assessed by probit analysis. RESULTS: Median (95% confidence interval [CI]) age at G2, defined as TV 4 mL, was 11.3 (10.9-11.6) years, almost the same age as in our study performed in 1996, which was 11.4 (10.7-11.7) years (p = .21). When G2 was defined as change in scrotum texture and TV2 mL, median (95% CI) age at onset of puberty was 10.9 (10.5-11.3) years, again similar to the study performed in 1996 which was 11.0 (10.7-11.4) (p = .32). Median (95% CI) age of pubic hair development was 11.2 (10.8-11.6) years versus 11.5 (11.1-12.0) years in 1996, p = .015. CONCLUSIONS: Our data provide no evidence of a secular trend for gonadarche in Greek boys, although such a trend was evident for pubarche.