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Purpose: 25OHD levels in patients with Prader-Willi Syndrome (PWS), the most frequent cause of genetic obesity with a peculiar fat mass distribution, are still debated. Insulin resistance (IR), Body Mass Index-SDS (BMI-SDS), Growth Hormone Therapy (GHT), and puberty onset seem to interact with 25OHD levels. The objectives of the study are: (1) To analyze 25OHD levels in pediatric PWS patients in comparison with a control group (CNT) (2) To evaluate a possible correlation between BMI-SDS, HOMA-IR, puberty, GHT, and 25OHD levels. Methods: This is a retrospective case–control, multicenter study. Data were collected among 8 different Italian Hospitals (outpatient clinics), over a period of four years (2016–2020). We included 192 genetically confirmed PWS and 192 CNT patients, aged 3–18 years, matched 1:1 for age, gender, BMI-SDS, Tanner stage, sun exposure, and month of recruitment. Results: No statistically significant differences in 25OHD levels were observed between the PWS population and the CNT (PWS 24.0 ng/mL vs CNT 22.5 ng/mL, p> 0.05), OR = 0.89 (95% CI 0.58–1.35). We observed a slight, although non-significant, reduction in 25OHD levels comparing NW and OB populations. HOMA-IR, puberty onset, genotype and GHT (previous or ongoing) did not show statistically significant correlation with 25OHD levels. Conclusions: Our findings could be useful for clinicians to optimize the therapeutic management as well as to increase awareness of PWS.

Purpose: Early institution of GH therapy in children with Prader–Willi syndrome (PWS) yields beneficial effects on their phenotype and is associated with a persistent improvement of body composition, both in the transition age and in adulthood. Reports from GH stimulation testing in PWS adults, however, suggest that GH deficiency (GHD) is not a universal feature of the syndrome, and the current Consensus Guidelines suggest to perform a reassessment of persistent GHD so as to continue GH therapy after reaching adult height. Few data about GH responsiveness to stimulation testing throughout the transitional period in PWS are available to date.Thus, we investigated the prevalence of GHD in a large cohort of patients with PWS during the transition phase. Patients and methods: One hundred forty-one PWS patients, 72 females and 69 males, aged 15.4–24.9 years, were evaluated by dynamic testing with growth hormone‐releasing hormone (GHRH) plus arginine (GHRH + ARG). To define GHD, both BMI-dependent and BMI-independent diagnostic cut-off limits were considered. Results: According to BMI‐dependent criteria, 10.7% of normal weight (NW), 18.5% of overweight and 22.1% of obese PWS maintained a status of GHD. Similar results were obtained by adopting a cut-off limit specific for the adult age (26.2%), as well as criteria for the transition phase in NW subjects (25%). Conclusion: Our study shows that about 20% of patients with PWS fulfilled the criteria for GHD during the transitional age, suggesting the need of an integrated analysis of GH/IGF-I axis, in the context of the general clinical picture and other endocrine abnormalities, in all subjects after attainment of final stature.

Growth retardation is a common complication of chronic kidney disease (CKD) in children. Treatment with recombinant human growth hormone (rhGH) has been used to help short children with CKD to attain a height more in keeping with their age group, but the scientific evidence regarding the effect of rhGH on final height is scarce. Final heights of children with CKD receiving rhGH treatment (cases) were compared with final heights of a matched cohort of children with CKD that did not receive rhGH therapy (controls). Sixty-eight rhGH-treated cases (44 boys) were compared with 92 untreated controls (60 boys). Mean duration of rhGH therapy was 4.2 ± 0.9 years; rhGH dose was 0.3 ± 0.07 mg/kg/week. Height SDS at baseline was lower in rhGH-treated patients than in controls (−2.00 ± 1.02 versus −0.96 ± 1.11, p< 0.001). Baseline height SDS was significantly lower than target height SDS in both groups. Height SDS significantly improved from baseline to final height attainment in rhGH-treated patients, while it slightly decreased in controls (mean SDS variation 0.69 ± 1.05 in rhGH-treated cases versus −0.15 ± 1.2 in controls). Final height SDS was −1.25 ± 1.06 in rhGH-treated cases and −1.06 ± 1.17 in controls (p= 0.29). Target adjusted final height SDS was −0.91 ± 1.03 in rhGH-treated cases and −0.61 ± 1.17 in controls (p= 0.1). Long-term rhGH therapy is able to reduce the linear growth deceleration of children with CKD, and ultimately to improve their final height, reducing the difference with target height.

Atopic dermatitis (AD) is a public health problem, with an increasing prevalence worldwide. AD is a chronic inflammatory disease characterised by skin lesions and severe itching. Immunologically, AD has two forms, IgE-mediated and cell-mediated, but it may also be idiopathic. In the pathogenesis of AD, the gene mutations for filaggrin, a filament-aggregating protein present in the epidermis, are of pivotal importance, but other genetic factors are also operating, including those linked to family atopy.

There are conflicting data regarding the potential impact of chronic glucocorticoid (GC) therapy on the bone mineral density of patients with congenital adrenal hyperplasia (CAH). Previous studies performed by dual-energy X-ray absorptiometry reported conflicting results. The purpose of this study was to assess the impact of chronic GC replacement treatment in children with classical and non classical CAH due to 21-hydroxylase deficiency (21-OHD) by quantitative ultrasonometry (QUS), an easy, cheap, and radiation-free technique. The study population consisted of nineteen 21-OHD patients (nine males) on lifelong GC treatment. Anthropometric, hormonal, and treatment data were recorded for each patient, and bone quality was assessed by QUS measurements. QUS findings (amplitude-dependent speed of sound and bone transmission time) were normal in 21-OHD patients and did not correlate with duration of treatment, daily, total, and yearly hydrocortisone dose. Furthermore, no significant correlation was found between QUS findings and 17α-hydroxy progesterone, Δ4-androstenedione, and testosterone levels. In conclusion, our results provide reassurance that currently used replacement doses of GC do not have a major impact on bone in patients with CAH. QUS seems to be a reliable tool for screening of bone health in children with 21-OHD.

Objective: Scanty data are available about the thyroid function in childhood acute lymphoblastic leukemia (ALL) off-therapy patients treated only with chemotherapy. We aimed to assess the prevalence of thyroid autoimmunity and thyroid dysfunction in such patients. Design: Case-control cross-sectional study. Methods: Eighty-four patients diagnosed with ALL and treated only with chemotherapy. Mean age at diagnosis 5.9±3.6 yr, at recruitment 12.1±4.3 yr. The treatment had been stopped 4.3±3.2 yr before recruitment. A control group of 60 subjects was recruited. Free T4, TSH, anti-thyroperoxidase, and anti-thyroglobulin antibodies were measured. Results: Anti-thyroglobulin and anti-thyroperoxidase antibodies were negative in all patients. TSH was increased in 7 patients (8.3%) and 3 controls (5.0%). Free T4was within the normal limits in all patients and controls. Mean TSH and free T4levels did not statistically differ between controls and ALL off-therapy patients. TSH was negatively correlated with the age at the diagnosis (p=0.01) and the age at the end of therapy (p=0.008). Anti-thyroglobulin and/or anti-thyroperoxidase antibodies were detected in 3 controls (5%; vsstudy group: p=0.038), 1 of them with increased TSH. Conclusions: Some patients present hyperthyrotropinemia, without anti-thyroid antibodies, with a prevalence comparable to the control group. The thyroid gland seems more prone to be damaged by chemotherapy at a younger age. We think that a thyroid follow-up in ALL off-therapy patients may be advisable and should be differentiated on the basis of the age at the end of treatment, with more frequent tests for younger patients.

Background: Thalassemia majoris an inherited hemoglobin disorder characterized by chronic anemia and iron overload due to transfusion therapy and gastrointestinal absorption. Iron overload causes most of the associated mortality and morbidity and frequently involves the endocrine glands. Aim: To review the most pertinent literature on the topic. Methods: One hundred and twenty-three papers were evaluated. Results: Disproportionate short stature is frequent and becomes more evident at puberty because of the lack of growth spurt. Later on, partial height recovery may occur. Long-term treatment with recombinant human GH seems ineffective to improve final height. Pubertal development is characterized by a clinical spectrum ranging from hypogonadism to a simple delay in starting and developing of puberty. Hormonal replacement is mandatory in cases of absent or arrested puberty. Pancreatic β-cells function may be impaired during adolescence or later on. Its impairment ranges from hyperinsulinemia, secondary to insulin resistance, with normal glucose tolerance to β-cells failure with insulindependent diabetes mellitus. Primary hypothyroidism may affect thalassemic patients from the second decade of life. The thyroid dysfunction may be reversible (if an intensive chelation therapy regimen is started in the precocious phase), stationary, or slowly progressive. Central hypothyroidism is less common and autoimmune thyroiditis absent. Conclusion: Despite the improvement of the treatment, the involvement of the endocrine system still burdens the life of these patients. Further therapeutic improvement would reasonably reduce morbidity and, hopefully, mortality of thalassemic patients and make the endocrine disorders easier to treat.

Objective: Aim of this study is to report on basal clinical phenotype and follow up after diagnosis, of patients with 17β-hydroxysteroid-dehydrogenase type 3 (17β-HSD3) deficiency in Italy. Setting: Pediatric Endocrine Departments, University Hospitals. Patients: The cases of 5 Italian subjects affected by 17β-HSD3 deficiency are presented in this study. Interventions: Laboratory and genetic assessment. Gonadectomy and female sex assignment (4 patients) or GnRH analog therapy to regress puberty and gender identity disorder (1 patient). Results: Presentation lasted from pregnancy (pre-natal diagnosis of a 46,XY fetus with female external genitalia) to infancy (inguinal hernia containing testes/clitoromegaly) and adolescence (virilisation). All subjects but one (subject 1, Central-Northern Italy) were from small areas of Southern Italy. Endocrine data (baseline and/or stimulated testosterone/A4-androstenedione ratio) were informative. Two girls were homozygous for 17β-HSD3 gene mutations (G289S/G289S; R80W/R80W), while the others were compound heterozygous (IVS325+4 A>T/A203V; L212Q/M235V; R80W/A235E). Four patients were confirmed as females and were well-adjusted with assigned sex; gender identity disorder improved during treatment with GnRH analog in the last subject. Conclusions: 17βHSD3 deficiency may present from pregnancy to puberty for different clinical issues. Albeit testosterone/A4-androstenedione ratio represents the most accurate endocrine marker to diagnose the disorder, hCG-stimulation is mandatory in pre-puberty. Molecular analysis of 17β-HSD3 gene should be performed to confirm the diagnosis. Temporary GnRH analog treatment may regress gender identity disorder and provide time to confirm or change the birth sex assignment. Female individuals seems to be compliant with their sex, providing that virilisation does not occur. In Italy, the disorder seems to be more prevalent in the Southern regions and shows genetic heterogeneity.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and T-lymphocytes dysfunction. Autoimmune diseases are frequent. A 10.7-yr-old female, diagnosed with CVID when 7 yr old, was referred because of short stature. She was pre-pubertal and short (height−2.86 SD score) with delayed bone age. Her intestinal absorption, routine biochemistry, heart, renal, liver, and thyroid functions were normal. Two stimulation tests for GH showed a maximum peak of 1.9 ng/ml (IGF-1: 154 ng/ml, 147–832). When the patient was 13 yr old (height −4.23 SD score, telarche and pubarche stage 2, bone age 6.25 yr), GH treatment was initiated. Despite poor compliance, the growth velocity showed improvement. Anti-thyrogobulin, anti-thyroperoxidase, anti-21-hydroxylase, and anti-tyrosine-phosphate antibodies were negative while anti-pituitary antibodies (APA) were positive. For the first time, the presence of APA (previously associated with GH deficiency in non-CVID subjects) is reported in a CVID patient. The possibility of an autoimmune involvement of the pituitary gland was previously debated for CVID patients, but had never been demonstrated. This case suggests that in CVID, the pituitary gland can be targeted by autoantibodies and thus a more comprehensive follow-up of these patients should be performed.

Background: Few papers focus on exercise-related blood glucose (BG) in patients on continuous sc insulin infusion (CSII) or multiple daily injections (MDI) with glargine. Aim: The main objective was to evaluate the degree of glycemic control in Type 1 diabetes mellitus adolescents on CSII doing physical activity with pump switched on or off. These findings were also compared with a small group of patients on MDI with glargine. Subjects and methods: Eight patients on CSII (basal rate continued or turned off in alternating sessions) and 5 on MDI joined 4 sessions of moderate-severe exercise. Results: Post-exercise BG significantly increased with the pump off and was unchanged/decreased with the pump on and MDI groups vsbaseline. The hypoglycemia rate was not different among the 3 groups at any time. Pump on: hypoglycemias more frequent both at bed-time (p=0.031) and at awakening (p<0.001) than before dinner and at awakening than at bed-time (p=0.044). Pump off: hypoglycemias more frequent both at bed-time (p=0.010) and at awakening (p=0.031) than before dinner. MDI: no differences. Conclusions: Glargine is safe and reducing the prelunch insulin is unnecessary. Subjects on insulin pump should not stop the basal rate. If they stop the pump, some actions are advisable: pre-exercise insulin bolus, pre-sleeping snack rich in carbohydrates, slight reduction of the overnight basal rate. On the other hand, if the basal rate is unmodified, the ingestion of sugary drinks during the exercise, the reduction of the overnight basal rate, a reduction of the pre-dinner insulin bolus and/or a pre-sleeping snack should be considered.

The 17β-hydroxysteroid dehydrogenases (17βHSD) gene family comprises different enzymes involved in the biosynthesis of active steroid hormones. The 17βHSD type 3 (17βHSD3) isoenzyme catalyzes the reductive conversion of the inactive C19-steroid, Δ4-androstenedione (Δ4- A), into the biologically active androgen, testosterone (T), in the Leydig cells of the testis. It is encoded by the 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) gene, which maps to chromosome 9q22. Mutations in the HSD17B3 gene are associated with a rare form of 46,XY disorder of sex development referred to as 17βHSD3 deficiency (or as 17-ketosteroid reductase deficiency), due to impaired testicular conversion of Δ4-A into T. 46,XY patients with 17βHSD3 deficiency are usually classified as female at birth, raised as such, but develop secondary male features at puberty. Diagnosis, and consequently early treatment, is difficult because clinical signs from birth until puberty may be mild or absent. Biochemical diagnosis of 17βHSD3 deficiency requires measurement of serum T/Δ4-A ratio after hCG stimulation test in pre-pubertal subjects, while baseline values seem to be informative in early infancy and adolescence. However, low basal T/Δ4-A ratio is not specific for 17βHSD3 deficiency, being sometimes also found in patients with other defects in T synthesis or with Leydig cells hypoplasia. Mutational analysis of the 17HSDB3 gene is useful in confirming the clinical diagnosis of 17βHSD3 deficiency. This review describes clinical findings, diagnosis, and molecular basis of this rare disease.

We measured the final height (FH) of 25 short polytransfused thalassemia major (Th) patients (18 males) with a reduced GH reserve treated for 3.3±1.2 yr with recombinant GH (rhGH), 0.2 mg/kg/week sc. At baseline, all patients were clinically prepubertal; their chronological (CA) and bone ages (BA) were 13.6±2.0 and 11.4±1.6 yr, respectively. In 9 out of 18 males and 5 out of 7 females, the onset of puberty occurred spontaneously during the treatment. At the end of the rhGH administration, the height of the enrolled children was not significantly increased when calculated for CA (HxCA), while it was significantly decreased (p=0.004) when calculated for BA (HxBA); the BA increase (3.29±1.65 yr) was significantly higher (p<0.001 ) than the height age increase (2.16±0.98 yr). The FHxCA showed a significant increase (p=0.001) compared to both baseline and the end of therapy, while the FHxBA was significantly decreased (p<0.001) compared with the corresponding value at baseline. At the end of therapy, both HxCA and HxBA resulted positively related to the BA at baseline (r=0.50 and 0.42, p=0.012 and 0.034, respectively). FH was positively correlated with CA (r=0.63, p=0.001), BA (r=0.68, p<0.001) and HxBA (r=0.59, p=0.002) evaluated at baseline, and with both HxCA and HxBA (r=0.82 and 0.74, respectively, p<0.001), evaluated at the end of treatment. A negative correlation was found between FH and the length of treatment (r=−0.56, p=0.004). Our data seem to exclude that prolonged rhGH therapy could improve FH in Th patients; on the contrary, a negative effect may be hypothesized.

OBJECTIVE: To evaluate in a cohort of infants with congenital hypothyroidism (CH): (a) the frequency of bone maturation (BM) retardation at birth and (b) whether BM delay at birth may be considered as a tool to make a prognosis of psychomotor status at the age of 1 Year, irrespective of other variables related to treatment. DESIGN: BM at birth, CH severity and developmental quotient (DQ) at the age of 1 Year were retrospectively evaluated in 192 CH infants selected by the following inclusion criteria: (a) gestation age ranging between 38 and 42 weeks; (b) onset of therapy within the first Month of life; (c) initial thyroxine (l-T(4)) dosage ranging from 10 to 12 microg/kg/day; (d) normalization of serum thyrotropin (TSH) levels before the age of 3 Months; (e) Monthly adjustments of l-T(4) dose during the first Year of life with serum TSH levels ranging from 0.5 to 4 mIU/l; (f) no major diseases and/or physical handicaps associated with CH; (g) availability of both thyroid scanning and knee X-rays at the time of treatment initiation; (h) availability of DQ assessment at an average age of 12 Months. METHODS: BM was considered normal if the distal femur bony nucleus diameter exceeded 3 mm (group A) or retarded if either this nucleus was absent (subgroup B1) or its diameter was <3 mm (subgroup B2). DQ was evaluated with the Brunet-Lezine test. RESULTS: In 44.3% of cases BM was either delayed (23.5%) or severely delayed (20.8%). The risk of BM retardation was higher in the patients with athyreosis than in the remaining patients (41/57 vs 44/135, chi(2)=25.13, P<0.005). BM-retarded infants showed a more severe biochemical picture of CH at birth and a lower DQ at the age of one Year compared with the group A patients. If compared with infants of subgroup B2 those of subgroup B1 exhibited significantly lower T(4) levels at birth and a more frequent association with athyreosis (70.0 vs 30.0%; chi(2)=7.49, P<0.01), whereas DQ was superimposable in both subgroups. CONCLUSIONS: (a) BM at birth is delayed in almost half of CH patients and (b) CH severity per se can affect DQ at the age of 1 Year irrespective of other variables related to therapy.

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BACKGROUND Several reports showed decreased cortisol response to adreno-corticotropic hormone in preterms developing chronic lung disease (CLD). Administration of prophylactic low-dose hydrocortisone (HC) may allow for beneficial effects, particularly in infants with histologic chorioamnionitis. However, there are concerns regarding short and long-term effects of corticosteroid therapy in preterms.OBJECTIVE Evaluation of effectiveness and safety of prophylactic HC in improving survival without CLD in preterms.METHODS Double blind randomised placebo-controlled trial in 2 centres. After parental consent mechanically ventilated infants (birth weight 500-1249) were entered within 48 hours of life and randomized to receive treatment (HC: 0,5 mg/Kg/12 hrs for 9 days, then 0,5 mg/Kg/ 24 hrs for 3 days) or placebo for 12 days. The major outcome was assessed as survival without CLD (oxygen dependency at 36 weeks of postmenstrual age). The protocol was approved by Ethical Committee at each institution and notified to the National Observatory on Human Drug Experimentation.RESULTS 41 patients were enrolled since April 2003. Birth weight, gestational age, chorioamnionitis, CRIB and FiO2 requirements at entry were similar between the two groups. Survival without CLD was 61% in HC group versus 30% in controls (p<0.05). Mortality rate was 22% in HC group vs. 43% in controls (p=ns). Chorioamnionitis occurred in 51% of patients. In chorioamnionitis group survival without CLD was 42% in HC group vs. 16% in controls (p=ns). Incidence of sepsis, IVH, PVL, NEC, ROP, PDA, hyperglycaemia, hypertension, gastrointestinal perforation, head circumference and weight at 36 weeks were similar between the two groups. Hyperkalemia in the HC group was significantly higher.DISCUSSION HC prophylaxis improved survival without CLD in our population, without important short term effects. Neurodevelopmental outcomes will be assessed at 2 years.

Preterm newborns frequently have a slow postnatal growth and a close relationship between growth and both energy and protein intake has been demonstrated. The evaluation of the protein content of breast milk after a preterm delivery, using a quick and simple method, could be very useful to decide how to reach preterm nutritional needs. To evaluate the protein content of preterm breast milk by turbidimetric method. From April 2003 to March 2005 we collected breast milk from mothers who delivered preterm (G.A.24.8–35wks). The protein content (PC) in colostrum, transition milk (3 days after the beginning of lactation), and mature milk (1 week after the beginning of lactation) was measured. Maternal age, parity, diet, social status, as well as the cause of premature delivery, the mode of delivery, and gemellarity have been recorded. Milk was stored in plastic bottles at 4 C (max 12 hours) or at -20 C. PC was measured by a modified turbidimetric Kingsbury method (Milk screen, Callegari, Italy). 97 milk samples were collected. PC was 1.39–2.13 g/dl in colostrum, 1.23–2.04 g/dl in transition milk and 1.26–2.01 g/dl in mature milk. These results are consistent with published data using a spectrophotometric method, a technique neither simple nor easily available. PC gradually diminished from the beginning of lactation until mature milk: colostrum PC was higher compared to both transition milk (p =0.014) and mature milk (p=0.0001); similarly, transition milk PC was higher compared to mature milk (p==.001). A positive correlation has also been found between colostrum and transition milk PC. No correlations have been found between breast milk PC with other factors considered.

Breast fed newborns had significant larger thymus compared to that standard formula fed. We report for the first time a double blind study on healthy term newborns evaluating the effect of human milk versus a standard formula and versus a fermented formula (bifidobacterium c50 and Streptococcus thermophilus 065) on thymus index and stool pH. 90 newborns were enrolled in the study. 30 newborns, were exclusively breast feeded, and the other 60 were randomly assigned to receive, a fermented formula, and a standard formula,with the same nutritional composition. All newborns were matched for sex birth weight and gestational age. The newborns were evaluated at third day of life, at first, second, third and fourth month of age. Weight, length, head circumference, stool pH, and ultrasound measurement of thymus size were recorded. Results are shown in table like mean and standard deviation.*vs SF feed p < 0.001; *vs FF feed p < 0.036; vs SF feed p < 0.042; **vs Breast feed and FF feed p < 0.001.Fermented formula resembles the breast fed pattern concerning thymus size and faecal pH while no difference was demonstrated in the growth parameters. These effects may be linked to the bifidogenic effects of fermentation products and their interactions with the intestinal immune system leading to a general involvement of the immune system. Further studies are needed to understand these relationships and to asses the role of colostrum in increasing thymus size.