Information Survey on the Use of Complementary and Alternative Medicine.

Background and Objectives: Complementary and alternative medicines (CAMs) are generally considered non-scientific and poor effective therapies. Nevertheless, CAMs are extensively used in common clinical practice in Western countries. We decided to promote a Delphi consensus to intercept the opinion of Italian physicians on CAM use in clinical practice. Materials and Methods: We run a Delphi-based consensus, interviewing anonymously 97 physicians. Of these, only 78 participate to the questionnaire. Results: Consensus about agreement and disagreement have been reached in several topics, including indication, as well as safety issues concerning CAMs. Conclusions: The use of CAMs in clinical practice still lacks evidence. Experts agree about the possibility to safely use CAMs in combination with conventional medicines to treat non-critical medical conditions.

Vitamin D and Cardiovascular Risk: which Implications in Children?

Vitamin D (25OHD) pleiotropic effects are widely recognized and studied. Recently, vitamin D cardiovascular effects are gaining interest, especially in children, although the studies present conflicting data. Some randomized controlled trials (RCTs) have demonstrated that cardiovascular risk markers, such as lipid parameters, inflammation markers, blood pressure, and arterial stiffness, are unaffected by vitamin D supplementation. By contrast, other studies show that low vitamin D levels are associated with higher risk of cardiovascular disease (CVD) and mortality, and support that increased risk of these diseases occurs primarily in people with vitamin D deficiency. An update on these points in pediatric patients is certainly of interest to focus on possible benefits of its supplementation.

Vitamin D effects and endocrine diseases.

A lack of vitamin D has been linked to autoimmune diseases including type 1 diabetes, autoimmune thyroiditis and to obesity. The prevalence of vitamin D deficiency is higher in diabetic or obese children and patients with thyroiditis compared to healthy controls. Moreover, low vitamin D values seem to be associated with major complications and poor glycemic control, in particular in obese children. Supplementation with vitamin D, which has immune-regulatory properties, may support our therapies and improve the outcomes in different diseases. Although some studies suggest a possible role of vitamin D in the etiology of autoimmune diseases and obesity, data on supplementation benefits are inconclusive and further studies are needed. In this paper, we focus on the current evidence regarding vitamin D function in endocrine diseases and possible benefits of its supplementation in pediatric age.

Developmental and behavioral profile in a domestic adoptees sample: a new challenge for the pediatrician.

BACKGROUND: The aim of this study is to investigate the changes of developmental and behavioral profile in a domestic adoptees sample. METHODS: Thirty-six domestic adoptive families were recruited, resulting in a sample of 39 children. Families were sent a general questionnaire for collecting data related to the children demographic variables, infant's background (time spent in institutional care, age at adoption), children's health status and anthropometric measures at T0, T1, T2, and T3. Moreover, the Infant Behavior Questionnaire-Revised Very Short Form and a modified version of parent-report of Child Behavior Checklist were used to assess temperament and to detect behavioral problems. RESULTS: As regards the psychopathological evaluation, behavior problems were more common in older children, especially among girls. In particular they exhibited a higher frequency of internalizing problems versus externalizing. CONCLUSIONS: Children in foster care suffer discontinuity of care that negatively affects their emotional and physical development. It is important for pediatricians to be aware of the special needs of adopted children, providing adequate support to adoptive families.

Food security and the nutritional status of children in foster care: new horizons in the protection of a fragile population.

BACKGROUND: The nutritional status of foster children, the quality of daily menus in group homes and the Food Security inside these organizations have been poorly studied and this study means to investigate them. METHODS: A sample of 125 children, ranging in age from 0-17 years, among seven group homes (group A) was compared with 121 children of the general population we (group B). To evaluate nutritional status, BMI percentiles were used. Mean percentiles of both groups were compared through statistical analysis. Both nutritional and caloric daily distributions in each organization were obtained using the 24-hour recall method. A specific questionnaire was administered to evaluate Food Security. RESULTS: From the analysis of mean BMI-for-age (or height-for-length) percentiles, did not observe statistically significant differences between group A and group B. The average daily nutrient and calorie distribution in group homes proves to be nearly optimal with the exception of a slight excess in proteins and a slight deficiency in PUFAs. Moreover, a low intake of iron and calcium was revealed. All organizations obtained a "High Food Security" profile. CONCLUSIONS: Nutritional conditions of foster children are no worse than that of children of the general population. Foster care provides the necessary conditions to support their growth.

Mutation-specific therapies and drug repositioning in cystic fibrosis.

Cystic fibrosis (CF) is an inherited, prematurely lethal rare disease affecting more than 85,000 people worldwide. CF is caused by more than 2000 loss-of-function mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). This review summarizes recent advances in the etiological therapies of CF that aim at repairing the functional defect of CFTR by means of CFTR modulators. We will discuss the state of art of the mutation-specific treatments that are designed to target different steps of the CFTR biogenesis perturbed by mutations in CFTR gene. Moreover, we will discuss how drug repositioning, namely the use of drugs already approved for the treatment of other human diseases, may be repurposed in CF patients to circumvent CFTR dysfunction. Finally, we highlight how the combined use of two or more compounds acting on different disease mechanisms is required to achieve clinical benefit in CF population.

Inhaled medications in cystic fibrosis beyond antibiotics.

Structural lung disease begins very early in children with cystic fibrosis (CF), often in the first three months of life. Inhaled medications represent an attractive therapeutic approach in CF that are routinely used as early intervention strategies. Two aerosolized solutions, hypertonic saline and dornase alfa, have significant potential benefits by improving mucociliary clearance, with minimal associated side-effects. In particular, they favor rehydration of airway surface liquid and cleavage of extracellular DNA in the airways, respectively, consequently reducing rate of pulmonary disease exacerbations. Indirect anti-inflammatory effects have been documented for both drugs, addressing each of the three interrelated elements in the vicious cycle of lung disease in CF: airway obstruction, inflammation and infection. This short review aimed to summarize the main papers that support potential clinical impact of inhaled solutions on pulmonary disease in CF.

Personalization of therapies in rare diseases: a translational approach for the treatment of cystic fibrosis.

High variability in the response rates to treatments can make the interpretation of data from clinical trials very difficult, particularly in rare genetic diseases in which the enrolment of thousands of patients is problematic. Personalized medicine largely depends on the establishment of appropriate early detectors of drug efficacy that may guide the administration (or discontinuation) of specific treatments. Such biomarkers should be capable of predicting the therapeutic response of individual patients and of monitoring early benefits of candidate drugs before late clinical benefits become evident. The identification of these biomarkers implies a rigorous stepwise process of translation from preclinical evaluation in cultured cells, suitable animal models or patient-derived freshly isolated cells to clinical application. In this review, we will discuss how a process of research translation can lead to the implementation of functional and mechanistic disease-relevant biomarkers. Moreover, we will address how preclinical data can be translated into the clinic in a personalized medical approach that can provide the right drug to the right patient within the right timeframe.

Improving clinical diagnosis in SHOX deficiency: the importance of growth velocity.

BackgroundThe aim of this study was to estimate the prevalence of haploinsufficiency of short stature homeobox containing gene (SHOX) deficiency (SHOXD) in a population of short-statured children, and to analyze their phenotype and the performance of clinical scores.MethodsScreening for SHOXD was performed in 281 children with short stature by direct sequencing and multiplex ligation probe-dependent amplification. Subjects with SHOXD were compared with 117 matched short patients without SHOXD. We calculated the cutoff of growth velocity associated with the highest sensitivity and specificity as a screening test for SHOXD by receiver operating characteristic curves.ResultsThe prevalence of SHOXD was 6.8%. Subjects with SHOXD showed a lower growth velocity (P<0.05) and a higher prevalence of dysmorphic signs. The best cutoff for growth velocity was -1.5 standard deviation score (SDS) both in the whole population and in subjects with a Rappold score <7 and <4 points. Growth velocity was ≤-1.5 SDS or Rappold score was >7/>4 points in 17/17 of 19 children with SHOXD and in 49/65 of 117 subjects without SHOX mutations.ConclusionsGrowth rate ≤-1.5 SDS, even with negative Rappold score, may be useful to detect precociously children with SHOXD. Selecting children deserving the genetic test by using growth velocity or the Rappold score significantly increases the sensitivity in detecting mutations and decreases the specificity.

Unacylated ghrelin and obestatin: promising biomarkers of protein energy wasting in children with chronic kidney disease.

BACKGROUND: Impairment in orexigenic/anorexigenic hormone balance may be key in the pathogenesis of protein energy wasting in children with chronic kidney disease (CKD). Measurement of ghrelin and obestatin concentrations in children with CKD would help assess the potential contribution of these hormones to uremic protein energy wasting. METHODS: This was a cross-sectional case-control study. Acylated and unacylated ghrelin and obestatin were measured in 42 children on conservative treatment (CT), 20 children on hemodialysis, 48 pediatric renal transplant (RTx) recipients and 43 controls (CTR) (mean age 11.9, range 5-20 years). Weight, height and bicipital, tricipital, subscapular and suprailiac folds were measured, and the body mass index-standard deviation score (BMI-SDS), percentage of fat mass and fat-free mass were calculated. Urea and creatinine were measured and the glomerular filtration rate (GFR) calculated. RESULTS: Unacylated ghrelin level was higher in patients than controls (p = 0.0001), with the highest levels found in hemodialysis patients (p = 0.001 vs. CKD-CT, p = 0.0001 vs. RTx, p < 0.0001 vs. CTR). Obestatin level was significantly higher in patients on hemodialysis than those on conservative treatment, RTx recipients and controls (p < 0.0001 in each case). Unacylated ghrelin negatively correlated with weight-SDS (p < 0.0001), BMI-SDS (p = 0.0005) and percentage fat mass (p = 0.004) and positively correlated with percentage fat-free mass (p = 0.004). Obestatin concentration negatively correlated with weight-SDS (p = 0.007). Unacylated ghrelin and obestatin concentrations positively correlated with creatinine and urea and inversely with eGFR, even after adjustments for gender, age, puberty and BMI-SDS (p < 0.0001 for each model). CONCLUSIONS: Unacylated ghrelin and obestatin, negatively related to renal function, seem to be promising inverse indicators of nutritional status in children with CKD. Potential therapeutic implications in terms of optimization of their removal in patients on hemodialysis could be hypothesized.

Italian multicentre study found infectious and vaccine-preventable diseases in children adopted from Africa and recommends prompt medical screening.

AIM: This study evaluated the prevalence of infectious diseases and immunisation status of children adopted from Africa. METHODS: We studied 762 African children referred to 11 Italian paediatric centres in 2009-2015. Clinical and laboratory data were retrospectively collected and analysed. RESULTS: The median age of the children (60.3% males) was 3 years and 6 months, 52.6% came from Ethiopia and 50.1% had at least one infectious disease. Parasitic infections accounted for the majority of the infectious diseases (409 of 715), and the most common were Giardia lamblia (n = 239), Toxocara canis (n = 65) and skin infections (n = 205), notably Tinea capitis/corporis (n = 134) and Molluscum contagiosum (n = 56) Active tuberculosis (TB) was diagnosed in nine children (1.2%). Latent TB infections were diagnosed in 52 (6.8%) children, and only 23 had concordant positive tuberculin skin tests and Quantiferon Gold In-Tube results. Discordant results were associated with Bacille de Calmette-Guérin vaccinations (odd ratio 6.30 and 95% confidence interval of 1.01-39.20, p = 0.011). Nonprotective antitetanus or antihepatitis B antibody titres were documented in 266 (34.9%) and 396 (51.9%) of the 762 children. CONCLUSION: The prevalence of infectious conditions and not-protective titres for vaccine-preventable diseases observed in our population underlines the need for prompt and complete medical screening of children adopted from Africa.

[Teething: from symptomatology to practical approach].

Scopo della presente trattazione è promuovere la consapevolezza del pediatra nei confronti della sintomatologia legata alla dentizione nei bambini con il supporto delle evidenze più significative reperibili nella letteratura scientifica. Dopo la caratterizzazione dei disturbi più comuni, con la relativa incidenza e durata nella popolazione pediatrica, e del ruolo dell'infiammazione saranno definiti i limiti delle terapie attualmente disponibili. Saranno quindi illustrate le prerogative di un medicinale omeopatico, Camilia® (Boiron, Francia), che interviene sull'infiammazione locale e sistemica e sulla composita fenomenologia correlata al processo di dentizione, con il vantaggio di un'azione multifunzionale ed efficace e l'assenza di effetti indesiderati o rischi di interazione con altri farmaci.

Comparison of neurally-adjusted ventilator assist in infants before and after extubation.

BACKGROUND: To compare invasive (iNAVA) and non-invasive (nivNAVA) neurally adjusted ventilatory assist in infants, respect to gas exchange, breathing pattern, respiratory drive, infant-ventilator interaction and synchrony, vital parameters and required sedation. METHODS: Ten consecutive intubated term infants admitted for respiratory failure of different etiology underwent to 2-hour not-randomized trials of iNAVA and, after extubation, nivNAVA, the latter with unchanged ventilator settings and with air-leaks compensating software. Arterialized capillary blood was sampled at the end of each trial. We computed: 1) the minimum (EAdimin) and peak (EAdipeak) values of the diaphragm electrical activity; 2) ventilator (RRmec) and own patients' (RRneu) respiratory rates; 3) inspiratory (delayTR-insp) and expiratory trigger delays (delayTR-exp) and the time of synchrony between patient's effort and ventilator assistance (Timesynch/Tineu); 4) the asynchrony index. Vital parameters and required sedation were also recorded. RESULTS: iNAVA and nivNAVA did not differ between in terms of gas exchange (pH (7.35 [7.31-7.41] vs. 7.36 [7.30-7.40], P=0.745), PcCO2 (38.4 [34.8-42.6] vs. 36.9 [33.9-41.6] mmHg, P=0.469) and PcO2/FiO2 (211 [168-323] vs. 214 [189-282], P=0.195), respectively). EAdimin, EAdipeak, RRmec and RRneu were similar before and after extubation. Both modes confirmed an optimal infant-ventilator interaction (i.e. delayTR-insp, delayTR-exp and Timesynch/Tineu), irrespective of the interface, and no patients showed clinical relevant asynchronies. A low requirement of sedation with fentanyl was recorded during both trials, without differences between. CONCLUSIONS: We found iNAVA and nivNAVA to be characterized by similar gas exchange, breathing pattern, respiratory drive, infant-ventilator interaction and synchrony, vital parameters and required sedation.

Persistence of immunity after vaccination with a capsular group B meningococcal vaccine in 3 different toddler schedules.

BACKGROUND: One schedule for the capsular group B meningococcal vaccine 4CMenB is 2 doses that are administered 2 months apart for children aged 12-23 months, with a booster dose 12-24 months later. Our objective was to provide data on persistence of human serum bactericidal antibody (hSBA) titres in children up to 4 years of age after initial doses at 12-24 months, and immunogenicity of a booster dose at 48 months of age compared with vaccine-naive children. METHODS: Children previously immunized, as part of a randomized controlled trial, with 2 doses of 4CMenB vaccine at 12-24 months of age received a booster at 4 years of age. Vaccine-naive age-matched toddlers received 2 doses of 4CMenB. Human serum bactericidal antibody titres against reference strains H44/76, 5/99, NZ98/254 and M10713 were evaluated before and after innoculation with 4CMenB vaccine in 4-year-old children. RESULTS: Of 332 children in the study, 123 had previously received 4CMenB and 209 were vaccine-naive controls. Before the booster, the proportions of participants (previously vaccinated groups compared with controls) with hSBA titres of 1:5 or more were as follows: 9%-11% v. 1% (H44/76), 84%-100% v. 4% (5/99), 0%-18% v. 0% (NZ98/254) and 59%-60% v. 60% (M10713). After 1 dose of 4CMenB in previously immunized children, the proportions of participants achieving hSBA titres of 1:5 or more were 100% (H44/76 and 5/99), 70%-100% (NZ98/254) and 90%-100% (M10713). INTERPRETATION: We found that waning of hSBA titres by 4 years of age occurred after 2 doses of 4CMenB vaccine administered at 12-24 months, and doses at 12-24 months have a priming effect on the immune system. A booster may be necessary to maintain hSBA titres of 1:5 or more among those children with increased disease risk. Trial registration: ClinicalTrials.gov, no. NCT01717638.

Nonrandomised interventional study showed that early aggressive nutrition was effective in reducing postnatal growth restriction in preterm infants.

AIM: This study evaluated whether an early aggressive nutrition (EAN) strategy could limit extrauterine growth restriction (EUGR) in a cohort of preterm infants. METHODS: This prospective nonrandomised interventional study was carried out in the neonatal intensive care unit of an Italian hospital from January 2013 to December 2015. The prevalence of EUGR was assessed in 100 infants with a gestational age of ≤34 weeks, 50 after the introduction of an EAN regimen in October 2014 and 50 before. RESULTS: The prevalence of EUGR at discharge was significantly lower after the introduction of EAN than before for weight (34% vs. 66%), head circumference (22% vs. 42%) and length at discharge (20% vs. 48%). The Z-scores for all measurements were significantly higher after the introduction of EAN. In the EAN group, weight velocity was significantly higher and maximum weight loss and negative changes in the Z-scores from birth to discharge for weight were lower than in the pre-intervention controls. In extremely low birthweight subjects, the weight Z-score and weight velocity were significantly higher in the EAN group than the control group. CONCLUSION: The use of EAN at a very early age reduced EUGR and improved auxological outcomes in preterm infants.

Influence of Ultraviolet Radiation on the Association between 25-Hydroxy Vitamin D Levels and Cardiovascular Risk Factors in Obesity.

OBJECTIVE: To establish if the correction with estimates of ultraviolet (UV) exposure influences the association between 25-OH-vitamin D (25OHD) levels and metabolic variables. STUDY DESIGN: A cross-sectional study was performed in 575 obese children and adolescents (>6 years of age) in a tertiary referral center. Cardiovascular risk factors were measured. The estimate of UV exposure was evaluated by 3 methods: (1) season; (2) mean of UV radiation (UVR); and (3) mean of UV index (UVI). UVR and UVI were considered at 1 (UVR 1 month prior to testing [UVR1], UVI 1 month prior to testing [UVI1]) or 3 (UVR 3 months prior to testing [UVR3], UVI 3 months prior to testing [UVI3]) months prior to testing. All analyses were corrected for confounders (sex, age, puberty, body mass index, waist circumference, the inclusion and exclusion of estimates of UV exposure). RESULTS: The 25OHD levels were associated with seasons, UVR1, UVR3, UVI1, and UVI3, and best associations with UVR3 and UVI3. In all models, total cholesterol, low-density lipoprotein cholesterol and triglycerides were negatively associated with 25OHD levels. The strength of the association increased with no correction, correction for seasons, UVR, and UVI. UVR3 and UVI3 performed better than UVR1 and UVI3. CONCLUSIONS: Higher lipid concentrations were associated with low 25OHD levels in obese children and adolescents with the power of the association dependent on the estimates of UVR. As the mean values 3 months prior to testing for both UVR and UVI determined the best associations, the interval of the steady state time of 25OHD levels could be preferentially used in the metabolic studies. Controlling for an estimate of UVR is important to decrease the heterogeneity of studies.

Variations in the high-mobility group-A2 gene (HMGA2) are associated with idiopathic short stature.

BACKGROUND: Several association studies confirmed high-mobility group-A2 gene (HMGA2) polymorphisms as the most relevant variants contributing to height variability. Animal models and deletions in humans suggest that alterations of HMGA2 might be relevant in causing short stature. Together, these observations led us to investigate the involvement of HMGA2 in idiopathic short stature (ISS) through an association study and a mutation screening. METHODS: We conducted an association study (155 ISS patients and 318 normal stature controls) with three HMGA2 single-nucleotide polymorphisms (SNPs) (SNPs rs1042725, rs7968682, and rs7968902) using a TaqMan-based assay. The patients were then analyzed by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect point mutations and genomic micro-rearrangements. RESULTS: Considering a recessive model, an OR value >1 was observed for genotypes rs7968682 TT (Odds ratio (OR) = 1.72, confidence interval (CI): 1.14-2.58) and rs1042725 TT (OR = 1.51, CI: 1.00-2.28) in accordance to the effect exhibited by the single alleles in the general population. None of the patients carried possibly causative HMGA2 mutations. CONCLUSION: Besides the already known role in determining variability in human height, HMGA2 polymorphisms also contribute to susceptibility to ISS. Moreover, we here report the first mutation screening performed in ISS concluding that HMGA2 has not a significant impact on the monogenic form of ISS.

The Association of Bifidobacterium breve BR03 and B632 is Effective to Prevent Colics in Bottle-fed Infants: A Pilot, Controlled, Randomized, and Double-Blind Study.

GOALS: To assess the effectiveness of Bifidobacterium breve B632 and BR03 association in the reduction of infants crying over time. The second endpoint was to observe the effect of the same strains on daily evacuations and on the number of regurgitations and vomits. BACKGROUND: Infant colics represent a clinical condition in childhood, characterized by an uncontrollable crying that occurs without any apparent organic cause. An altered intestinal microbiota composition in the very first months may induce intestinal colics in infants. Thus far, no treatment is really effective for this problem, but recent literature shows an increasing attention toward probiotics. STUDY: A total of 83 subjects were enrolled, 60 breastfed infants and 23 bottle-fed infants. Sixty of them carried out the study: 29 infants were given probiotics, whereas 31 placebo. During the 90 days of the study, parents were asked to give 5 drops of active product (10 viable cells/strain) or placebo and to daily take note of: minutes of crying, number, color, and consistency of evacuations, and number of regurgitations or vomits. RESULTS: No significant differences were detected in the infants treated with probiotics, compared with placebo group (P=0.75). The analysis of the 3 months of treatment demonstrated that during the third month, the probiotic group cried 12.14 minutes on average and the placebo cried 46.65 minutes. This difference is statistically significant (P=0.016). CONCLUSIONS: The evidence of the usefulness of some probiotic strains in the treatment and prevention of infant colics is growing, and therefore their use in clinical practice is spreading.

Hemolytic uremic syndrome in children.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by thrombocytopenia, non-immune microangiopathic hemolytic anemia and acute renal failure. HUS is typically classified into two primary types: 1) HUS due to infections, often associated with diarrhea (D+HUS, Shiga toxin-producing Escherichia Coli-HUS), with the rare exception of HUS due to a severe disseminated infection caused by Streptococcus; 2) HUS related to complement, such HUS is also known as "atypical HUS" and is not diarrhea associated (D-HUS, aHUS); but recent studies have shown other forms of HUS, that can occur in the course of systemic diseases or physiopathological conditions such as pregnancy, after transplantation or after drug assumption. Moreover, new studies have shown that the complement system is an important factor also in the typical HUS, in which the infection could highlight an underlying dysregulation of complement factors. Clinical signs and symptoms may overlap among the different forms of HUS. Shiga toxin-producing Escherichia Coli (STEC) infection cause a spectrum of clinical sings ranging from asymptomatic carriage to non-bloody diarrhea, hemorrhagic colitis, HUS and death. The average interval between ingestion of STEC and illness manifestation is approximately 3 days, although this can vary between 2 and 12 days. Patients with pneumococcal HUS usually have a severe clinical picture with microangiopathic hemolytic anemia, respiratory distress, neurological involvement. The atypical HUS, in contrast to STEC-HUS which tends to occur as a single event, is a chronic condition and involves a poorer prognosis. Early diagnosis and identification of underlying pathogenic mechanism allow instating specific support measures and therapies. Typical management of STEC-HUS patients relies on supportive care of electrolyte and water imbalance, anemia, hypertension and renal failure. For the aHUS the initial management is supportive and similar to the approach for STEC-HUS; currently we have moved from the historic plasma therapy to new therapeutic approaches, first of all eculizumab, a monoclonal antibody that blocks the C5 cascade. This drug has shown an improvement in platelet count, cessation of hemolysis, improvement of renal function within a few days after the treatment. In patients with end-stage renal disease (ESRD) renal transplantation from a non-related donor and prophylactic administration of eculizumab to prevent recurrent disease in the allograft could be considered.

Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort.

OBJECTIVE: Combined pituitary hormonal deficiency (CPHD) can result from mutations within genes that encode transcription factors. This study evaluated the frequency of mutations in these genes in a cohort of 144 unrelated Italian patients with CPHD and estimated the overall prevalence of mutations across different populations using a systematic literature review. MATERIAL AND METHODS: A multicentre study of adult and paediatric patients with CPHD was performed. The PROP1, POU1F1, HESX1, LHX3 and LHX4 genes were analysed for the presence of mutations using direct sequencing. We systematically searched PubMed with no date restrictions for studies that reported genetic screening of CPHD cohorts. We only considered genetic screenings with at least 10 individuals. Data extraction was conducted in accordance with the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). RESULTS: Global mutation frequency in Italian patients with CPHD was 2·9% (4/136) in sporadic cases and 12·5% (1/8) in familial cases. The worldwide mutation frequency for the five genes calculated from 21 studies was 12·4%, which ranged from 11·2% in sporadic to 63% in familial cases. PROP1 was the most frequently mutated gene in sporadic (6·7%) and familial cases (48·5%). CONCLUSION: The frequency of defects in genes encoding pituitary transcription factors is quite low in Italian patients with CPHD and other western European countries, especially in sporadic patients. The decision of which genes should be tested and in which order should be guided by hormonal and imaging phenotype, the presence of extrapituitary abnormalities and the frequency of mutation for each gene in the patient-referring population.