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Background/Aims: Skeletal maturation is considered a reliable variable in evaluating the ‘tempo’ of growth. It is important in the diagnosis of endocrinological diseases, in chronic diseases, in hormonal therapy follow-up and in computing height prediction for prognostic and therapeutic purposes. It is also used when chronological age is not available for minors without known birth dates. There are different methods to evaluate skeletal maturation and height prediction. The Tanner-Whitehouse (TW) method 2 (TW2) has been considered to be the most useful method so far, and has recently been updated with modified height prediction equations (TW2-Mark II). TW3 is the newest method. The aim of this study is to evaluate whether TW3 is more accurate in the assessment of height prediction than TW2-Mark II in a sample of healthy north Italian subjects. Methods: Anthropometrical data were collected as part of a survey in 1977–1978 in Turin. The sample involved 1,384 healthy children. The children, now adults, have been traced and recalled to measure their final height in order to test height prediction reliability. At present, we have collected 118 adult heights. Results: According to the TW2 method 40% of the males had a height prediction error larger than ± residual SD (4.1 cm), and with TW3 this was 32.9%. The female height prediction error with TW2 was larger than ± residual SD (3.6 cm) in 29.2% of girls, and the same value was found with TW3. Conclusion: According to our preliminary data, TW3 does not represent any real progress. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A peroxidase-antiperoxidase (PAP) technique was used to detect Clostridium chauvoei in tissue sections from sheep inoculated intramuscularly with a pure culture of this microorganism. Samples of various tissues were taken for bacteriology, histopathology and immunohistochemistry. A primary antiserum against C. chauvoei for use in the PAP technique was produced in rabbits. Formalin-fixed, paraffin-embedded sections of muscle samples were positively and specifically stained by the PAP technique. The results were consistent with those obtained by bacteriology, but the PAP test was simpler, quicker and less expensive than the bacteriological procedures. The use of the PAP technique would be appropriate for detecting clostridial infections without the constraints of conventional identification methods, especially where laboratory conditions for anaerobic procedures are not readily available. [ABSTRACT FROM AUTHOR]

The successful introduction of medical devices (MDs) in real-world settings hinges on designing service processes that cater to stakeholders' needs. While human-centered design (HCD) approaches have been widely applied to service process innovation, the literature lacks a methodology that leverages MDs' key features to design service processes that meet stakeholders' needs. This study aims to fill this gap by developing a framework for the HCD of service processes enabled by MDs. The proposed framework mixes and adapts methodological elements from HCD and technology-enabled design approaches and proposes four new tools. The five-phase framework was applied to the design of a new Parkinson's disease diagnosis and treatment process (PD-DTP) enabled by two wearable MDs for the detection of motor symptoms. The case study lasted five months and involved 42 stakeholders in 21 meetings (interviews, focus groups, etc.). Thanks to the case study, the framework was tested, and a new PD-DTP that could benefit all stakeholders involved was identified. This study provides a framework that, in addition to contributing to theory, could assist MDs developers and healthcare managers in designing service processes that cater to stakeholders' needs by leveraging MDs' key features.

Objective: This Italian survey aims to evaluate real-life long-term efficacy and safety of recombinant human growth hormone (rhGH) therapy in children with short stature homeobox-containing gene deficiency disorders (SHOX-D) and to identify potential predictive factors influencing response to rhGH therapy., Design and Methods: This is a national retrospective observational study collecting anamnestic, anthropometric, clinical, instrumental and therapeutic data in children and adolescents with a genetic confirmation of SHOX-D treated on rhGH. Data were collected at the beginning of rhGH therapy (T0), yearly during the first 4 years of rhGH therapy (T1, T2, T3 and T4) and at near-final height (nFH) (T5), when available., Results: One hundred and seventeen SHOX-D children started rhGH therapy (initial dose 0.23 ± 0.04 mg/kg/week) at a mean age of 8.67 ± 3.33 years (74% prepubertal), 99 completed the first year of treatment and 46 reached nFH. During rhGH therapy, growth velocity (GV), standard deviation score (SDS) and height (H) SDS improved significantly. Mean H SDS gain from T0 was +1.14 ± 0.58 at T4 and +0.80 ± 0.98 at T5. Both patients carrying mutations involving intragenic SHOX region (group A) and ones with regulatory region defects (group B) experienced a similar beneficial therapeutic effect. The multiple regression analysis identified the age at the start of rhGH treatment (β = -0.31, P = 0.030) and the GV during the first year of rhGH treatment (β = 0.45, P = 0.008) as main independent predictor factors of height gain. During rhGH therapy, no adverse event of concern was reported., Conclusions: Our data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless the wide variety of genotype., Significance Statement: Among children with idiopathic short stature, the prevalence of SHOX-D is near to 1/1000-2000 (1.1-15%) with a wide phenotypic spectrum. Current guidelines support rhGH therapy in SHOX-D children, but long-term data are still few. Our real-life data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless of the wide variety of genotypes. Moreover, rhGH therapy seems to blunt the SHOX-D phenotype. The response to rhGH in the first year of treatment and the age when rhGH was started significantly impact the height gain.

Background: SHOX enhancer CNVs, affecting one or more of the seven recognized evolutionary conserved non-coding elements (CNEs) represent one of the most frequent cause of SHOX-haploinsufficiency. During the diagnostic workflow deletions/duplications have been identified downstream SHOX not including any of the these CNEs., Methods: Fine tiling aCGH and breakpoint PCR were used to characterize the critical interval and to search for novel alterations in a cohort of selected patients., Results: Screening of 252 controls provided evidence that duplications in this area represent likely benign variants whereas none of the deletions were detected. These findings suggested that other alterations relevant for SHOX-haploinsufficiency might be missed by the standard diagnostic methods. To identify such undisclosed elements, the aCGH was used to reanalyze 52 unresolved cases with clinical features strongly suggestive of SHOX-haploinsufficiency. This analysis followed by the screening of 210 patients detected two partially overlapping small deletions of ~12 and ~8 kb in four unrelated individuals, approximately 15 kb downstream SHOX, that were absent in 720 normal stature individuals., Conclusion: Our results strengthen the hypothesis that alterations of yet unidentified cis-regulatory elements residing outside those investigated through conventional methods, might explain the phenotype in ISS/LWD patients thus enlarging the spectrum of variants contributing to SHOX-haploinsufficiency., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objectives: Growth impairment is a common manifestation in Noonan syndrome (NS). Recombinant human GH (rhGH) treatment has been shown to increase growth and adult height (AH) in a few studies. We aimed to evaluate the growth trajectory towards the AH, and the effects of rhGH treatment in a large cohort of NS children., Methods: Retrospective, multicenter, cohort study including subjects with genetic diagnosis of NS. A total of 228 NS patients, 154 with PTPN11 mutations, 94 who reached AH, were recruited. Auxological data were collected at 2, 5, and 10 years, at pubertal onset, at AH. Sixty-eight NS subjects affected with GH deficiency (GHD) were treated with rhGH at a mean dose of 0.24 mg/kg per week until AH achievement., Results: ANOVA analysis showed a significant difference between birth length and height standard deviation scores (HSDS) at the different key ages ( p<0.001 ), while no significant differences were found between HSDS measurements at 2, 5, and 10 years, at pubertal onset, and at AH. HSDS increased from -3.10 ± 0.84 to -2.31 ± 0.99 during rhGH treatment, with a total height gain of 0.79 ± 0.74, and no significant difference between untreated and treated NS at AH., Conclusions: rhGH treatment at the standard dose used for children with GH idiopathic deficiency is effective in improving growth and AH in NS with GHD. Further studies are needed to assess genotype-specific response to rhGH treatment in the different pathogenic variants of PTPN11 gene and in the less common genotypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Libraro, D’Ascanio, Cappa, Chiarito, Digilio, Einaudi, Grandone, Maghnie, Mazzanti, Mussa, Patti, Scarano, Spinuzza, Vannelli, Wasniewska, Ferrero and Faienza.)

Background: The phenotypic features of SHOX deficiency (SHOX-D) are highly variable and can be very mild, especially in young children. The aim of this retrospective study was to evaluate auxological and radiological indicators that could be predictive of SHOX-D in children., Methods: Molecular analysis of the SHOX gene was performed in 296 subjects with growth impairment or skeletal disproportion, without alternative diagnosis. Auxological variables and radiographs of the hand, wrist and forearm were evaluated., Results: SHOX mutations (88% inherited, 12% de novo) were identified in 52 subjects. The most predictive auxological indicators of SHOX-D were an increased sitting height/height ratio and a decreased arm span/height ratio. The convexity of distal radial metaphysis at X-ray, not yet reported in literature, was also found to be predictive of SHOX-D. In young children, stratification of data by bone age also highlighted ulnar tilt, lucency of the ulnar border of the distal radius and enlarged radius as the radiological signs most related to SHOX-D ., Conclusions: In this study, the analysis of auxological and radiological indicators in SHOX-D children allowed to identify an additional early radiological sign and underlines the importance of family auxological evaluation.

Preterm infant growth is a major health indicator and needs to be monitored with an appropriate growth curve to achieve the best developmental and growth potential while avoiding excessive caloric intake that is linked to metabolic syndrome and hypertension later in life. New international standards for size at birth and postnatal growth for preterm infants are available and need implementation in clinical practice. A prospective, single center observational study was conducted to evaluate the in-hospital and long-term growth of 80 preterm infants with a mean gestational age of 33.3 ± 2.2 weeks, 57% males. Size at birth and at discharge were assessed using the INTERGROWTH-21 ST standards, at preschool age with World Health Organization (WHO) child growth standards. The employment of INTERGROWTH-21 ST Preterm Postnatal longitudinal standards during the in-hospital follow-up significantly reduced the diagnosis of short term extrauterine growth restriction when compared to commonly used cross sectional neonatal charts, with significant lower loss of percentiles between birth and term corrected age ( p < 0.0001). The implementation of a package of standards at birth, preterm postnatal growth standards and WHO child growth standards proved to be consistent, with correlation between centile at birth and at follow-up, and therefore effective in monitoring growth in a moderate and late preterm infant cohort without chronic or major morbidities. Infants identified as small for gestational age at birth showed significantly more frequently a need for auxological referral.

Context: Up to 20% of children with neurofibromatosis type 1 (NF1) develop low-grade optic pathway gliomas (OPGs) that can result in endocrine dysfunction. Data on prevalence and type of endocrine disorders in NF1-related OPGs are scarce., Objectives: The aim of the study was to determine the prevalence of endocrine dysfunctions in patients with NF1 and OPGs and to investigate predictive factors before oncological treatment., Design: Multicenter retrospective study., Settings and Patients: Records were reviewed for 116 children (64 females, 52 males) with NF1 and OPGs followed at 4 Italian centers., Main Outcome Measures: We evaluated endocrine function and reviewed brain imaging at the time of OPG diagnosis before radio- and chemotherapy and/or surgery. OPGs were classified according to the modified Dodge classification., Results: Thirty-two children (27.6%) with a median age of 7.8 years had endocrine dysfunctions including central precocious puberty in 23 (71.9%), growth hormone deficiency in 3 (9.4%), diencephalic syndrome in 4 (12.5%), and growth hormone hypersecretion in 2 (6.2%). In a multivariate cox regression analysis, hypothalamic involvement was the only independent predictor of endocrine dysfunctions (hazard ratio 5.02 [1.802-13.983]; P = .002)., Conclusions: Endocrine disorders were found in approximately one-third of patients with Neurofibromatosis type 1 and OPGs before any oncological treatment, central precocious puberty being the most prevalent. Sign of diencephalic syndrome and growth hormone hypersecretion, although rare, could be predictive of optic pathway gliomas in NF1. Tumor location was the most important predictor of endocrine disorders, particularly hypothalamic involvement., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Jaffe-Campanacci syndrome is characterized by multiple non-ossifying fibromas, café-au-lait macules and giant cell granulomas of the jaw. Even if the association between all these peculiar features and neurofibromatosis type 1 have been described, it has not yet been clarified whether Jaffe-Campanacci syndrome represents a distinct entity or it can be regarded as a neurofibromatosis type 1 subtype., Case Presentation: The patient here described is a young boy, who fulfilled the clinical diagnostic criteria for both syndromes. He had a complex clinical history with café-au-lait macules, axillary and inguinal freckling, multiple non-ossifying fibromas, giant-cell granuloma of the jaw, neurofibromas, plexiform fibroma, ocular Lisch nodules, optic chiasmatic- hypothalamic glioma, pseudarthrosis, scoliosis, short stature, vascular anomalies, seizures. Molecular analysis of the NF1 gene both on blood cells and non-ossifying fibroma's biopsy tissue allowed the detection of a novel variant within the coding region, NM&#95;000267.3:c.2789&#95;2791delATC(p.Tyr930&#95;Pro931delinsSer), with loss of heterozygosity (second hit mutation) in the non-ossifying fibroma., Conclusion: This result indicates that every patient with clinical features of Jaffe-Campanacci syndrome should be further evaluated to detect features related to neurofibromatosis type 1 and genetically investigated for mutations in the NF1 gene, since this could lead to a definite diagnosis, but also could clarify and quantify the real genotype-phenotype overlap between neurofibromatosis type 1 and Jaffe-Campanacci syndrome.

The GHEP-ISFG organized a collaborative study to estimate mutation rates for the markers included in the Investigator Argus X-12 QS kit Qiagen. A total of 16 laboratories gathered data from 1,612 father/mother/daughter trios, which were used to estimate both maternal and paternal mutation rates, when pooled together with other already published data. Data on fathers and mothers' age at the time of birth of the daughter were also available for ∼93 % of the cases. Population analyses were computed considering the genetic information of a subset of 1,327 unrelated daughters, corresponding to 2,654 haplotypes from residents in several regions of five countries: Argentina, Brazil, Ecuador, Portugal and Spain. Genetic differentiation analyses between the population samples from the same country did not reveal signs of significant stratification, although results from Hardy-Weinberg and linkage disequilibrium tests indicated the need of larger studies for Ecuador and Brazilian populations. The high genetic diversity of the markers resulted in a large number of haplotype combinations, showing the need of huge databases for reliable estimates of their frequencies. It should also be noted the high number of new alleles found, many of them not included in the allelic ladders provided with the kit, as very diverse populations were analyzed. The overall estimates for locus specific average mutation rates varied between 7.5E-04 (for DXS7423) and 1.1E-02 (for DXS10135), the latter being a troublesome figure for kinship analyses. Most of the found mutations (∼92 %) are compatible with the gain or loss of a single repeat. Paternal mutation rates showed to be 5.2 times higher than maternal ones. We also found that older fathers were more prone to transmit mutated alleles, having this trend not been observed in the case of the mothers., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Leri-Weill dyschondrosteosis is a pseudoautosomal dominantly-inherited skeletal dysplasia ascribed to haploinsufficiency of the SHOX gene caused by deletions, point mutations, or partial duplications of the gene, or to heterozygous deletions upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements that show enhancer activity. Recently, two SHOX conserved non-coding element duplications, one upstream and one downstream, were reported in patients referred with idiopathic short stature. To further evaluate the role of these duplications in SHOX-related disorders, we describe seven patients (five with Leri-Weill dyschondrosteosis and two with short stature) all of whom have duplications of part of the upstream or downstream conserved non-coding element regions, identified by multiplex ligation-dependent probe amplification. In addition, we show data from 32 patients with an apparently identical downstream duplication that includes a proposed putative regulatory element (identified by multiplex ligation-dependent probe amplification or array comparative genome hybridization), which results in a variable phenotype from normal to mild Leri-Weill dyschondrosteosis. These additional data provide further evidence that duplications of upstream and downstream long range cis-regulatory DNA elements can result in a SHOX-related phenotype., (© 2015 Wiley Periodicals, Inc.)

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.

Aim: The neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disease. In 40-70% of cases are described signal hyperintensity on MRI, called unidentified bright objects (UBO). Their correlation with clinical disorders is still debated. The present study investigated the correlation between the UBOs and neuropsychiatric outcomes overall, observes the long-term through the comparison of MRI brain and considers the utility of including MRI early in the investigation of NF1., Methods: We included 100 patients (age 2-18 years) with NF1. The parents were given a medical questionnaire to fill, a clinical neurologic examination (Touwen) was performed and brain MRI were analyzed during the years., Results: In 72% of cases were detected UBO's last MRI. It was observed that the UBO's tend to shrink over time and in some cases to disappear in pre-adolescent. There were significant correlations between UBOs and minor disturbances in motor function (P=0.004) and between UBO's and cognitive deficits (P=0.016). The 79.62% of the patients is followed by a specialist in neuropsychiatry, as correlated significantly (P=0.027) with changes on MRI., Conclusions: Given the correlation between UBO's, neurological disorders, cognitive and behavioral, suggest be included in the diagnostic protocol MRI brain areas as T2H can be considered predictive for a neuropsychiatric disorder.

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disorder characterized by high penetrance, widely variable expressivity and occurrence of specific skeletal changes such as tibial osteopathy (TO). We collected data on patients referred to the Italian Neurofibromatosis Study Group in order to compare clinical features between 49 NF1 patients with TO, and 98 age-matched NF1 patients without TO, and to determine whether the presence of TO is associated with a different risk of developing the typical NF1 complications. We assessed both groups for: age at diagnosis of NF1, gender distribution, family history, gender inheritance, presence of scoliosis, sphenoid wing osteopathy, other skeletal abnormalities, macrocrania, hydrocephalus, plexiform neurofibromas, tumors, optic pathway gliomas, T2H (high-signal intensity areas on T2 weighted brain MRI), epilepsy, headache, mental retardation, cardiovascular malformations, and Noonan phenotype. Patients of both groups were subdivided by gender and re-evaluated for these items. Statistical comparison was carried out between the two groups of patients for each feature. We collected data on type of treatment and on the clinical conditions of NF1-TO patients after follow-up. Patient's age at NF1 diagnosis was significantly younger in NF1-TO subjects compared with NF1 subjects without TO, and the incidence of T2H was significantly reduced in NF1-TO males compared with NF1 males without TO. The presence of TO does not imply that there is an increased risk of developing typical complications of NF1 (e.g., optic pathway glioma, plexiform neurofibroma, etc.), however, it does allow us to make an earlier diagnosis of NF1., (Copyright © 2012 Wiley Periodicals, Inc.)

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., (Copyright © 2012 S. Karger AG, Basel.)

In scientific papers, skeletal maturation-expressed as bone maturity scores or bone age-is often used as a quantifiable variable similar to height or weight. This paper discusses whether this approach is appropriate. The questions addressed are whether skeletal maturation can be measured on a quantitative scale, whether its use is appropriate in computing, and what the 'numbers' used represent. Reference will be made mainly to the Tanner-Whitehouse method, which, in the opinion of the authors, has been the most reliable method of assessment to date. Many of the remarks made in this paper may be extended to other methods of assessment, and have been stressed by Tanner himself. The authors are aware that, in the future, some of the remarks could be made redundant by the development of more detailed definitions of bone maturation. This is becoming feasible with the advent of expert systems for the automatic recognition of different stages of bone maturation.

Although growth hormone (GH) deficiency is a very common cause of short stature, many cases are still diagnosed as idiopathic. Magnetic Resonance Imaging (MRI), more clearly than CT, reveals the anatomy of the hypothalamic-hypophyseal region and of the possible alterations (pituitary hypoplasia, interruption of the stalk) causing hormonal deficit. Twenty-nine patients with short stature underwent MRI examinations of the hypothalamic-pituitary region to assess the significance of the correlation between hormonal test and MR patterns. Five patients had normal variants of short stature (NVSS), 7 had multiple pituitary hormone defects (MPHD) and 17 had isolated growth hormone deficiency (IGHD). In patients with MPHD or with severe isolated growth hormone deficit MRI shows interruption of the pituitary stalk with ectopy of the neurohypophysis or a mass. In patients with less severe IGHD and in NVSS, MRI demonstrates a normal pituitary region or a slightly hypoplastic gland, the neurohypophysis being normally situated. MRI may provide an ethiological classification in short stature patients. Typical MR patterns can be demonstrated in cases of dwarfism secondary to a mass in the hypothalamic-pituitary region or to morphological changes of the pituitary stalk, while in transient GH deficit no anatomical abnormalities are observed.