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ObjectiveAim of this paper is to illustrate the methodology, design, and development of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to patients with the Periodic Fever, Aphthous stomatitis, Pharyngitis, and cervical Adenitis (PFAPA) syndrome.MethodsThis is a physician-driven, non-population- and electronic-based registry proposed to gather real-world demographics, clinical, laboratory, instrumental and socioeconomic data from PFAPA patients. Data recruitment is realized through the on-line Research Electronic Data Capture (REDCap) tool. This registry is thought to collect standardized information for clinical research leading to solid real-life evidence. The international scope and the flexibility of the registry will facilitate the realization of cutting-edge study projects through the constant updating of variables and the possible merging and transfer of data between current and future PFAPA registries.ResultsA total of 112 centers have already been involved from 23 countries and 4 continents starting from August 24th, 2021, to April 6th, 2022. In total 56/112 have already obtained the formal approval from their local Ethics Committees. The platform counts 321 users (113 principal investigators, 203 site investigators, two lead investigators, and three data managers). The registry collects retrospective and prospective data using 3,856 fields organized into 25 instruments, including PFAPA patient's demographics, medical histories, symptoms, triggers/risk factors, therapies, and impact on the healthcare systems.ConclusionsThe development of the AIDA International Registry for PFAPA patients will enable the on-line collection of standardized data prompting real-life studies through the connection of worldwide groups of physicians and researchers. This project can be found on https://clinicaltrials.gov NCT 05200715.

ObjectiveThe aim of this paper is to present the AutoInflammatory Disease Alliance (AIDA) international Registry dedicated to Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome, describing its design, construction, and modalities of dissemination.MethodsThis Registry is a clinical, physician-driven, population- and electronic-based instrument designed for the retrospective and prospective collection of real-life data. Data gathering is based on the Research Electronic Data Capture (REDCap) tool and is intended to obtain real-world evidence for daily patients' management. The Registry may potentially communicate with other on-line tools dedicated to VEXAS syndrome, thus enhancing international collaboration and data sharing for research purposes. The Registry is practical enough to be easily modified to meet future needs regarding VEXAS syndrome.ResultsTo date (April 22nd, 2022), 113 Centers from 23 Countries in 4 continents have been involved; 324 users (114 Principal Investigators, 205 Site Investigators, 2 Lead Investigators, and 3 data managers) are currently able to access the registry for data entry (or data sharing) and collection. The Registry includes 4,952 fields organized into 18 instruments designed to fully describe patient's details about demographics, clinical manifestations, symptoms, histologic details about skin and bone marrow biopsies and aspirate, laboratory features, complications, comorbidities, therapies, and healthcare access.ConclusionThis international Registry for patients with VEXAS syndrome will allow the achievement of a comprehensive knowledge about this new disease, with the final goal to obtain real-world evidence for daily clinical practice, especially in relation to the comprehension of this disease about the natural history and the possible therapeutic approaches. This Project can be found on https://clinicaltrials.gov NCT05200715.

Objective The objective of this study was to use real-world data to evaluate the effectiveness and safety of canakinumab in Italian patients with systemic JIA (sJIA). Methods A retrospective multicentre study of children with sJIA was performed. Clinical features, laboratory parameters and adverse events were collected at baseline, and 6 and 12 months after starting canakinumab. The primary outcome measure of effectiveness was clinically inactive disease (CID) off glucocorticoids (GCs) treatment at 6 months. Results A total of 80 children from 15 Italian centres were analysed. Of the 12 patients who started canakinumab in CID while receiving anakinra, all maintained CID. Of the 68 with active disease at baseline, 57.4% achieved CID off GCs at 6 months and 63.8% at 12 months. In univariate analysis, the variables significantly related to non-response were number of active joints (NAJs) ≥5, history of macrophage activation syndrome (MAS) and disease duration. Multivariate analysis confirmed the association between non-response and NAJs ≥5 [odds ratio (OR) 6.37 (95% CI: 1.69, 24.02), P = 0.006] and between non-response and history of MAS [OR 3.53 (95% CI: 1.06, 11.70), P = 0.039]. No serious adverse events were recorded in this series. There were two cases of MAS during canakinumab, leading to a rate of 2.9 episodes per 100 patient years. Conclusion We have confirmed, using real-world data, the efficacy of canakinumab in sJIA in a multicentric cohort. History of MAS and higher NAJ were associated with lower probability of achieving CID.

Familial Mediterranean fever (FMF) is characterized by self limited episodes of fever and polyserositis.1 MEFV gene en codes for a protein named Pyrin, which plays a pivotal role in the activation and secretion of IL-1.2 Daily colchicine is highly effective in preventing attacks in this disorder in a dose-related fashion.3 Many definitions of colchicine resistance are available in the literature. The European League Against Rheumatism (EULAR) guidelines defined resistance as one or more attacks per month in compliant patients who had been receiving the maxi mally tolerated dose for at least 6 months.4 A similar definition was confirmed by a recent consensus among experts.5 In the present national multicentric longitudinal study, we analyze the impact of colchicine treatment on disease activity and quality of life in real life in pediatric and adult patients with FMF.

Complessivamente 12 sono i saggi che compongono questa raccolta dedicata alla riflessione antica e moderna sulla crescita e sviluppo delle forme di vita. Ogni saggio rappresenta un vero e proprio viaggio che attraversa diverse regioni del sapere: i classici antichi, greci e latini, sono in effetti quantitativamente predominanti, e questo a ragione dei prevalenti interessi scientifici dei curatori, i quali però si sono ben guardati dall’isolare il ‘classico’ nella sua idiosincratica prospettiva ante litteram, ma hanno cercato e trovato la collaborazione con altri settori della ricerca scientifica. Il che si traduce nella partecipazione al progetto editoriale e scientifico anche di antropologi del mondo antico, di biologi e genetisti, di filosofi e storici del pensiero filosofico e scientifico. Altogether 12 are the essays that make up this collection dedicated to ancient and modern reflection on the growth and development of forms of life. Each essay represents a real journey that crosses different regions of knowledge: the ancient Greek and Latin classics are in quantitatively predominant effects, and this due to the prevalent ones scientific interests of the curators, who, however, have been careful not to isolate the 'classic' in its idiosyncratic perspective ante litteram, but have sought and found collaboration with other sectors of scientific research. This translates into the participation in the editorial and scientific project of anthropologists of the ancient world, biologists and geneticists, of philosophers and historians of philosophical and scientific thought.

C'è una grande confusione nela valutare il ruolo che le piante aliene invasive giocano nel ridurre la biodiversità. Vengono chiariti alcuni concetti spesso oggetto di mistificazioni.

Dopo un inquadramento terminologico atto a presentare le più comuni radici che esprimono in greco antico i concetti di crescita e di sviluppo del vivente, l’attenzione è rivolta alle modalità con cui in testi di varia natura e datazione (da Omero sino al Corpus ippocratico) si descrive la crescita dell’essere umano a partire dal costante confronto con il mondo vegetale, in modo che dal configurarsi delle teorie possano risaltare le più o meno implicite mentalità. Attraverso il massiccio ricorso al ragionamento analogico, le fonti considerate permettono di farsi un’idea non solo del processo di crescita in sé, ma anche del ruolo assegnato nella cultura e nel pensiero della Grecia antica alla madre nel suo rapporto con la prole. After a terminological framework aimed at presenting the most common roots that express the concepts of growth and development of the living being in ancient Greek, the attention is turned to the ways in which texts of various kinds and dating (from Homer to the Hippocratic Corpus) the growth of the human being is described starting from the constant confrontation with the vegetable world, so that the more or less implicit mentalities can emerge from the configuration of the theories. Through the massive use of analogical reasoning, the sources considered allow us to get an idea not only of the growth process itself, but also of the role assigned in the culture and thought of ancient Greece to the mother in her relationship with the offspring.

Background and Objective: Only a few studies have reported long-term efficacy of interleukin (IL)-1 inhibition in systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still disease (AOSD). Herein we report on the effectiveness of anakinra (ANA), expressed in terms of drug retention rate (DRR), and evaluate the predictive factors of drug survival in a cohort of patients with sJIA and AOSD. Patients and Methods: This is a multicenter study reviewing retrospectively the medical records from 61 patients with sJIA and 76 with AOSD, all treated with ANA in 25 Italian tertiary referral centers. Results: The cumulative retention rate of ANA at 12-, 24-, 48-, and 60-month of follow-up was 74.3%, 62.9%, 49.4%, and 49.4%, respectively, without any significant differences between sJIA and AOSD patients (p = 0.164), and between patients treated in monotherapy compared with the subgroup coadministered with conventional diseasemodifying antirheumatic drugs (cDMARDs) (p = 0.473). On the other hand, a significant difference in DRR was found between biologic-naïve patients and those previously treated with biotechnologic drugs (p = 0.009), which persisted even after adjustment for pathology (p = 0.013). In the regression analysis, patients experiencing adverse events (AEs) {hazards ratio (HR) = 3.029 [confidence interval (CI) 1.750–5.242], p < 0.0001} and those previously treated with other biologic agents [HR = 1.818 (CI 1.007–3.282), p = 0.047] were associated with a higher HR of ANA discontinuation. The median treatment delay was significantly higher among patients discontinuing ANA (p < 0.0001). Significant corticosteroid-sparing (p = 0.033) and cDMARD-sparing effects (p < 0.0001) were also recorded. Less than one-third of our cohort developed AEs, and 85% were deemed mild in nature, with 70% of them involving the skin. Conclusions: Our findings display an overall excellent DRR of ANA on the long run for both sJIA and AOSD, that may be further optimized by closely monitoring patient’s safety issues and employing this IL-1 inhibitor as a first-line biologic as early as possible. Moreover, ANA allowed a significant drug-sparing effect and showed an overall good safety profile.

Introduction: The advent of biologic agents has revolutionized therapeutic approaches in systemic juvenile idiopatic arthritis (sJIA) as their introduction has been shown to modify disease course and improve overall outcomes, particularly when initiated early. Few studies have reported the drug retention rate (DRR) of biologic drugs in JIA, and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on sJIA. Objectives: The primary aim of the study was to examine the overall DRR of IL-1 blockers in sJIA patients. Secondary aims of our study were to: (i) explore the influence of biologic line of treatment, adverse events (AEs), type of anti-IL-1 agent and the concomitant use of conventional disease modifying anti-rheumatic drugs (cDMARDs) on DRR; (ii) find eventual predictive factors associated with events leading to drug discontinuation. The corticosteroid sparing effect and the impact of disease duration and treatment delay on survival constituted ancillary aims. Methods: sJIA patients – diagnosed according to the revised International League of Association for Rheumatology (ILAR) criteria – treated with anakinra (ANA) and canakinumab (CAN) were enrolled in 15 Italian tertiary referral centers. Demographic, clinical and therapeutic data collected from medical records were retrospectively collected and statistically analyzed. Results: Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN (p = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors (p = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs (p = 0.038) and when distinguishing according to AEs occurrence (p = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341–8.406], p = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186–7.435], p = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors (p = 0.0002). Conclusion: Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.

Background Behçet’s disease is a rare multi-systemic inflammatory disease with unknown etiology which involves principally oral and genital mucosa, skin and eyes. Average age at onset of the disease is about 25-30 years, but it may be diagnosed before the age of 16. It is not very rare in Italy, even though there are limited data concerning epidemiology. Aim of this study is to describe the baseline data of an Italian cohort of patients with as having BD or probable BD. Methods We described the baseline data of the first national epidemiological study on children coming from 16 Italian Pediatric Rheumatologic Centers diagnosed by the treating physicians as having Behçet’s Disease. Data on demographic characteristics, clinical features and therapy were collected. We then compared our findings to those of international pediatric cohort studies and also retrospectively evaluated the ability to diagnose BD using ISG, ICBD and, for the first time, the new PEDBD criteria. Results The study included 110 patients (62 M, 48F). Average age at onset was 8.34±4.11 years. The frequencies of signs/symptoms were: recurrent oral aphtosis 94.5%, genital ulcers 33.6%, ocular 43.6%, gastrointestinal 42.7%, musculoskeletal 42.7%, neurological 30.9% and vascular involvement 10%. Thirty-two patients (29.1%) fulfilled ISG, 78 (70.9%) ICBD, 50 (45.5%) PEDBD criteria and 31 (28%) didn’t fulfill any of them. The most frequently used treatments were colchicine and corticosteroids followed by immunosuppressants. Four patients received biologic therapy (anti TNF-α and anti-IL-1) to treat severe organ involvement. Conclusions Recurrent oral aphtosis was the most frequent clinical manifestation, followed by ocular involvement. Gastrointestinal lesions were more frequent in Italy than in non-European countries as opposed to genital ulcers. Skin, ocular and vascular manifestations had a higher frequency in males and genital ulcers in females. Constitutional symptoms were present in 44.5% and recurrent fever in one third of our population.

OBJECTIVE: Aim of this study is to report on basal clinical phenotype and follow up after diagnosis, of patients with 17beta-hydroxysteroid-dehydrogenase type 3 (17beta-HSD3) deficiency in Italy. SETTING: Pediatric Endocrine Departments, University Hospitals. PATIENTS: The cases of 5 Italian subjects affected by 17beta-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/ Delta4-androstenedione ratio) were informative. Two girls were homozygous for 17beta-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: 17betaHSD3 deficiency may present from pregnancy to puberty for different clinical issues. Albeit testosterone/Delta4-androstenedione ratio represents the most accurate endocrine marker to diagnose the disorder, hCGstimulation is mandatory in pre-puberty. Molecular analysis of 17beta-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.

ipoplasia emisferica, DDMS, dilatazione ventricolare

The coexistence of mutations in more than one gene, linked to Autoinflammatory Diesases, can confuse and make difficult the diagnosis and management of these patients, especially in childhood, when the clinical history is still brief.

INTRODUCTION: Defects of prokineticin pathway affect the neuroendocrine control of reproduction, but their role in the pathogenesis of central hypogonadism remains undefined, and the functional impact of the missense PROKR2 variants has been incompletely characterized. MATERIAL AND METHODS: In a series of 246 idiopathic central hypogonadism patients, we found three novel (p.V158I, p.V334M, and p.N15TfsX30) and six already known (p.L173R, p.T260M, p.R268C, p.V274D, p.V331M, and p.H20MfsX23) germline variants in the PROKR2 gene. We evaluated the effects of seven missense alterations on two different prokineticin receptor 2 (PROKR2)-dependent pathways: inositol phosphate-Ca(2+) (Gq coupling) and cAMP (Gs coupling). RESULTS: PROKR2 variants were found in 16 patients (6.5%). Expression levels of variants p.V158I and p.V331M were moderately reduced, whereas they were markedly impaired in the remaining cases, except p.V334M, which was significantly overexpressed. The variants p.T260M, p.R268C, and p.V331M showed no remarkable changes in cAMP response (EC50) whereas the IP signaling appeared more profoundly affected. In contrast, cAMP accumulation cannot be stimulated through the p.L173R and p.V274D, but IP EC50 was similar to wt inp.L173R and increased by 10-fold in p.V274D. The variant p.V334M led to a 3-fold increase of EC50 for both cAMP and IP. CONCLUSION: Our study shows that single PROKR2 missense allelic variants can either affect both signaling pathways differently or selectively. Thus, the integrity of both PROKR2-dependent cAMP and IP signals should be evaluated for a complete functional testing of novel identified allelic variants.

The advent of biologic medications has considerably increased the potential for treatment benefit in juvenile idiopathic arthritis (JIA), with clinical remission being now achievable in a substantial proportion of patients.

Acute hemorrhagic edema of infancy (AHEI) was considered a rare form of Henoch-Schönlein purpura; however, it is now regarded as an independent disease typically involving patients aged 4-24 months. The authors describe the clinical case of a toddler aged 8 months, with skin erythematous pomphoid lesions, treated at home with topical steroids without benefits. The appearance of new lesions and the worsening of the previous skin signs induced the parents to drive the child to the hospital. The medical history revealed the administration of a vaccine dose 2 months before.

Background/Aim: Combined growth hormone (GH) and insulin therapy is rarely prescribed by pediatric endocrinologists. We investigated the attitude of Italian physicians to prescribing that therapy in the case of short stature and type-1 diabetes (T1DM). Methods: A questionnaire was sent and if a patient was identified, data on growth and diabetes management were collected. Results: Data from 42 centers (84%) were obtained. Of these, 29 centers reported that the use of combined therapy was usually avoided. A total of 17 patients were treated in 13 centers (GH was started before T1DM onset in 9 patients and after the onset of T1DM in 8). Height SDS patterns during GH therapy in the 11 patients affected by GH deficiency ranged from -0.3 to +3.1 SDS. In the 8 diabetic patients in whom GH was added subsequently, mean insulin dose increased during the first 6 months of therapy from 0.7 ± 0.2 to 1.0 ± 0.2 U/kg (p = 0.004). HbA1c was unchanged during the first 6 months of combined therapy. Conclusions: Most Italian physicians do not consider prescribing the combined GH-insulin therapy in diabetic children with growth problems. However, the results of the 17 patients identified would confirm that the combined therapy was feasible and only caused mild insulin resistance. GH therapy was effective in promoting growth in most patients and did not affect diabetes metabolic control.

We present an adolescent with Metaphyseal acroscyphodysplasia (Bellini disease), characterized by severe short stature with accelerated bone maturation, micromelia predominating in the lower limbs, knee flexion, severe brachydactyly, very short hands and feet, metaphyseal changes and specific radiologic features, cup-shaped distal femoral metaphysis with cone-shaped epiphyses, short hands and feet, dental malocclusion. She presented chronic respiratory infections, with secondary bronchiectasis in the course of the follow up. This is the first case reported in literature of a patient with this extremely rare metaphyseal dysplasia, the Bellini disease, associated with bronchiectasis.

Introduction:There is a lack of data investigating the effects of physical activity (PA) on adolescent and young adultsurvivors of child- hoods’leukemia, moreover some authors suggest that children with diagnosis of leukemia (LK) are showing decreased level of fitness and a moderate risk for developing neuromuscular and musculoskeletal complications.We aim to verify if, in children involved in an individualized physical exercise program, the above-mentionedlow fitness level may be prevented or at least reduced. Subjects and methods:We assessed the level of physical fitness on children with diagnosis of leukemia during the post-chemotherapy period. We evaluated the fitness in 9 children (8.3 ± 2.7 yrs), off-therapy by ≥ 6 months (group GOT) at the end of a physical activity program (13 weekslength).Few validated fitness tests(Ruiz et al., 2011)wereadoptedandthen administered three times in 2 weeks: standing broad jump, 4 x 10 m shuttle test, sit-up test and handgrip strength test. The tests were also administered to a sedentary control group (CG) of 32 children (8.12 ± 1.56 yrs) with no diagnosis of neoplasia.The scores from the performances were used for statistical purposes. Re- sults:Standing broad jump results showed112.55 ± 32.80 cm in GOT and 124.18 ± 22.19 cm in CG, without remarkable differences (p = 0.11). An interesting findingcomes from 4 x 10 m shuttle run test with GOT that revealed 16.27±0.83 seconds, whileCG performed the same test in 14.02±0.25 seconds(p = 0.001). No differences were found when comparing sit-up performances (0.25) and handgrip per- formances (0.08 left arm and 0.15 right arm). Conclusions:After 13 weeks of properly PA program, the level of GOT’s physical fitness appears to be in line with control group results. These preliminary findings are confirming the eligibility of GOT to start a specific exercise program in order to reduce cardiovascular and muscular complications and improve their quality of life. The only concern is about the agility test (4 x 10 SRT) that showedvery high significant differences, (∆=2s). The sample is not adequate to make conclusions. More data coming from a bigger sample size of GOT are necessary to confirm this pilot. References Gohar, S.F., Comito, M., Price, J., and Marchese, V. (2011). Feasibility and parent satisfaction of a physical therapy intervention program for children with acute lymphoblastic leukemia in the first 6 months of medical treatment. Pediatr Blood Cancer 56, 799-804. Ruiz, J.R., Espana Romero, V., Castro Pinero, J., Artero, E.G., Ortega, F.B., Cuenca Garcia, M., Jimenez Pavon, D., Chillon, P., Girela Rejon, M.J., Mora, J., et al.(2011). [ALPHA-fitness test battery: health- related field-based fitness tests assessment in children and adolescents]. Nutr Hosp 26, 1210-1214.

Introduction: Children with diagnosis of leukemia are at risk for developing neuromuscular and musculoskeletal complications such as decreased muscle strength, impaired gross and fine motor performance, decreased energy expenditure, osteonecrosis, and osteoporosis. These secondary complications due to the medical interventions may lead to activity limitations and participation restrictions in daily life experiences. However, few Authors suggest that if children participate in an individualized physical therapy exercise program, these limitations may be prevented or at least reduced. We evaluated the level of physical fitness on children with diagnosis of leukemia (C-LK) during the post-chemotherapy period. Subjects and methods: Nine (8,3±2,7 yrs) C-LK of both sex participated to the study with the consents of their parents. We also recruited a group of thirty-two healthy children of both sex with similar age (8,12±1,56 yrs) as control group (GC). In order to assess the fitness level of the experimental sample we used few fitness tests already validated by scientific papers. Standing broad jump, 4 x 10 m shuttle run test, sit up test and handgrip strength test were administered three times in a period of two weeks during the period of May 2012. Exclusion criteria for C-LK were at least six months of therapy stopped and for CG no regularly physical activity participation. The scores coming from the best performances were used for statistical purpose. Results: Preliminary results shown no differences in standing broad jump performances. C-LK reported a mean value of 112,55±32,80 cm, while CG reported 124,18±22,19 cm, p = 0.11. An interesting findings is coming from 4 x 10 m shuttle run test. The C-LK group performed the test in a mean value of 16.27±0.83 seconds, while the control performed the same test in 14.02±0.25 seconds, p = 0.001. No differences between groups were found when comparing sit-up performances (0.25) and handgrip performances (0.08 left arm and 0.15 right arm), respectively. Conclusions: The level of physical fitness of C-LK group seems to be in line with control group results. These preliminary data are confirming the eligibility of C-LK to start with specific exercise programs in order to reduce cardiovascular and muscular complications and improve quality of life. The only concern is about the agility test (4 x 10 SRT) who shown a very high significant differences, 2 seconds in 40 mt sprint. To date, the sample size is not adequate to make conclusions. More data coming from C-LK groups are necessary to better understand this topic.

Background/Aims: Mutations of the short stature homeobox-containing (SHOX) gene on the pseudoautosomal region of the sex chromosomes cause short stature. GH treatment has been recently proposed to improve height in short patients with SHOX deficiency. The aim of this study was to evaluate GH secretion and analyze growth and safety of recombinant human GH (rhGH) therapy in short children and adolescents with SHOX deficiency. Patients and Design: We studied 16 patients (10 females; 9.7 ± 2.9 years old; height –2.46 ± 0.82 standard deviation score, SDS) with SHOX deficiency. All subjects underwent auxological evaluations, biochemical investigations, and were treated with rhGH (0.273 ± 0.053 mg/kg/week). Results: Impaired GH secretion was present in 37.5% of the studied subjects. Comparing baseline data with those at the last visit, we found that rhGH treatment improved growth velocity SDS (from –1.03 ± 1.44 to 2.77 ± 1.95; p = 0.001), height SDS (from –2.41 ± 0.71 to –1.81 ± 0.87; p < 0.001), and IGF-1 values (from –0.57 ± 1.23 to 0.63 ± 1.63 SDS, p = 0.010) without affecting body mass index SDS. Height SDS measured at the last visit was significantly correlated with chronological age (r = –0.618, p = 0.032), bone age (r = –0.582, p = 0.047) and height SDS (r = 0.938, p < 0.001) at the beginning of treatment. No adverse events were reported on rhGH therapy which was never discontinued. Conclusion: These data showed that impaired GH secretion is not uncommon in SHOX deficiency subjects, and that rhGH therapy may be effective in increasing height in most of these patients independent of their GH secretory status, without causing any adverse events of concern.

The effects of sexual hormones secretion in children with precocious puberty induce significant somatic and psychological changes, with systemic implications on several organs and tissues. Besides immune system and blood cells are involved in these changes. Recent studies on mice lymphocytes have demonstrated a protection of estrogens against apoptosis Fas-FasL pathway. These data could partially elucidate why autoimmune diseases are more frequent in females adolescents, whereas males have higher mortality associated with infectious diseases. We studied ten girls (age: 4-7 years) affected by idiopathic precocious puberty, with pubertal stage B3-PH3-4. All presented increased bone age/chronological age, increased growth velocity, echographic signs of ovarian and uterine maturation, enhanced FSH, LH and 17-β-estradiol levels. In all the patients pituitary MNR was normal. We also evaluated 10 control girls matched for age, with pubertal stage B1PH1. We studied apoptosis of peripheral lymphocytes, using the technique of stratification on Ficoll. Lymphocytes sensitization to apoptotic death mediated by receptors CD95 and TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) was induced. Lymphocytes were incubated for 24 hours with 11 [mu]g/ml of PHA and for 4 days with 25U/ml of IL-2. Therefore 2x10^5 lymphocytes were cultured in 96-well plates and incubated for 24 hours with 200 ng/ml of CD95, 800 ng/ml of TRAIL and with negative control medium alone. Apoptotic death was detected by MTT and lecture by Orange Acridine. We relieved a reduced lymphocytes apoptosis in girls with precocious puberty versus lymphocytes of control subjects both with CD95 and with TRAIL. Our results support the role of pubertal activation by sex hormones on the immune response and the potential incidence of autoimmune diseases in children with precocious puberty, linked to estrogens protection of lymphocytes against apoptosis.