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Background: Investigating copy number variations (CNVs) such as microdeletions or microduplications can significantly contribute to discover the aetiology of neurodevelopmental disorders. 15q11.2 genomic region, including NIPA1 and NIPA2 genes, contains a recurrent but rare CNV, flanked by the break points BP1 and BP2. Both BP1–BP2 microdeletion and microduplication have been associated with intellectual disability (ID), neuropsychiatric/behavioural disturbances and mild clinical features, even if with incomplete penetrance and variable expressivity. The pathogenic role of this CNV is quite unclear though. Unknown variants in other DNA regions and parent‐of‐origin effect (POE) are some of the mechanisms that have been proposed as an explanation of the wide phenotypic variability. As NIPA1 and NIPA2 encode for proteins that mediate magnesium (Mg2+) metabolism, it has been suggested that urinary Mg2+ levels could potentially represent informative and affordable biomarkers for a rapid screening of 15q11.2 duplications or deletions. Furthermore, magnesium supplementation has been proposed as possible therapeutic strategy. Methods: Thirty one children with ID and/or other neurodevelopmental disorders carrying either a duplication or a deletion in 15q11.2 BP1–BP2 region have been recruited. When available, blood samples from parents have been analysed to identify the CNV origin. All participants underwent family and medical data collection, physical examination and neuropsychiatric assessment. Electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) scan were performed in 15 children. In addition, 11 families agreed to participate to the assessment of blood and urinary Mg2+ levels. Results: We observed a highly variable phenotypic spectrum of developmental issues encompassing ID in most subjects as well as a variety of behavioural disorders such as autism and attention‐deficit disorder/attention‐deficit hyperactivity disorder. Dysmorphic traits and malformations were detected only in a minority of the participants, and no clear association with growth anomalies was found. Abnormal brain MRI and/or EEG were reported respectively in 64% and 92% of the subjects. Inheritance assessment highlighted an excess of duplication of maternal origin, while cardiac alterations were detected only in children with 15q11.2 CNV inherited from the father. We found great variability in Mg2+ urinary values, without correlation with 15q11.2 copy numbers. However, the variance of urinary Mg2+ levels largely increases in individuals with 15q11.2 deletion/duplication. Conclusions: This study provides further evidence that 15q11.2 BP1–BP2 CNV is associated with a broad spectrum of neurodevelopmental disorders and POE might be an explanation for clinical variability. However, some issues may question the real impact of 15q11.2 CNV on the phenotype in the carriers: DNA sequencing could be useful to exclude other pathogenic gene mutations. Our results do not support the possibility that urinary Mg2+ levels can be used as biomarkers to screen children with neurodevelopmental disorders for 15q11.2 duplication/deletion. However, there are evidences of correlations between 15q11.2 BP1–BP2 CNV and Mg2+ metabolism and future studies may pave the way to new therapeutic options. [ABSTRACT FROM AUTHOR]

Abstract Background Hypospadias is a congenital displacement of the urethral meatus in male newborns, being either an isolated defect at birth or a sign of sexual development disorders. The aim of this study was to assess the prevalence rate of hypospadias in different Districts of Italy, in order to make a comparison with other countries all over the world. Methods We reviewed all the newborns file records (years 2001–2004) in 15 Italian Hospitals. Results We found an overall hypospadias prevalence rate of 3.066 ± 0.99 per 1000 live births (82.48% mild hypospadias, 17.52% moderate-severe). In newborns Small for Gestational Age (birthweight < 10th percentile) of any gestational age the prevalence rate of hypospadias was 6.25 per 1000 live births. Performing multivariate logistic regression analysis for different degrees of hypospadias according to severity, being born SGA remained the only risk factor for moderate-severe hypospadias (p = 0.00898) but not for mild forms (p > 0.1). Conclusion In our sample the prevalence of hypospadias results as high as reported in previous European and American studies (3–4 per 1000 live births). Pathogenesis of isolated hypospadias is multifactorial (genetic, endocrine and environmental factors): however, the prevalence rate of hypospadias is higher in infants born small for gestational age than in newborns with normal birth weight.

Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder associated with variants in the HUWE1 gene on chromosome Xp11. The condition is characterized by variable phenotypes, including global developmental delay, intellectual disability, and distinctive facial dysmorphisms, with inheritance patterns ranging from X-linked recessive to de novo mutations in females. Here, we describe five probands in two families, highlighting their clinical features and genetic findings. Trio whole-exome sequencing identified a de novo variant in HUWE1 in the proband in one family and a maternally inherited hemizygous variant in three boys in a second family. A comprehensive review of HUWE1-associated cases from the literature assisted genotype-phenotype correlations, revealing consistent features such as intellectual disability, skeletal anomalies, and facial dysmorphisms as well as instances of intrafamilial variability. Our findings confirm the phenotypic variability of MRXST and underscore the significance of the HUWE1 gene product in neurodevelopment. We propose a baseline monitoring protocol to aid in diagnosis and management, contributing to the development of specific guidelines for patient follow-up., (© 2024 Wiley Periodicals LLC.)

Background/Objectives : The pathogenetic role of 15q11.2 Copy Number Variations (CNVs) remains contentious in the scientific community, as microdeletions and microduplications in this region are linked to neurodevelopmental disorders with variable expressivity. This study aims to explore the diagnostic utility of Exome Sequencing (ES) in a cohort of pediatric patients with 15q11.2 CNVs. Methods : We enrolled 35 probands with 15q11.2 microdeletions or microduplications from two genetic centers between January 2021 and January 2023. Chromosomal Microarray Analysis (CMA) and ES were performed with written consent obtained from all parents. Pathogenic variants were classified according to ACMG guidelines. Results : CMA identified additional pathogenic CNVs in 3 of 35 children (9%). Subsequent ES revealed likely pathogenic or pathogenic variants in 11 of 32 children (34%). Notably, a higher percentage of isolated autism spectrum disorder (ASD) diagnoses was observed in patients without other CNVs or point mutations ( p = 0.019). Conclusions : The ES analysis provided a diagnostic yield of 34% in this pediatric cohort with 15q11.2 CNVs. While the study does not dismiss the contribution of the CNV to the clinical phenotype, the findings suggest that ES may uncover the underlying causes of neurodevelopmental disorders. Continuous monitoring and further genetic testing are recommended for all 15q11.2 CNV carriers to optimize clinical management and familial counseling., Competing Interests: The authors declare no conflicts of interest.

Background: Silver-Russell Syndrome (SRS, MIM #180860) is a clinically and genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation; SRS is also accompanied by dysmorphic features such as triangular facial appearance, broad forehead, body asymmetry and significant feeding difficulties. The incidence is unknown but estimated at 1:30,000-100,000 live births. The diagnosis of SRS is guided by specific criteria described in the Netchine-Harbison clinical scoring system (NH-CSS)., Case Presentation: Hereby we describe four patients with syndromic short stature in whom, despite fitting the criteria for SRS genetic analysis (and one on them even meeting the clinical criteria for SRS), molecular analysis actually diagnosed a different syndrome. Some additional features such as hypotonia, microcephaly, developmental delay and/or intellectual disability, and family history of growth failure, were actually discordant with SRS in our cohort., Conclusions: The clinical resemblance of other short stature syndromes with SRS poses a risk of diagnostic failure, in particular when clinical SRS only criteria are met, allowing SRS diagnosis in the absence of a positive result of a genetic test. The presence of additional features atypical for SRS diagnosis becomes a red flag for a more extensive and thorough analysis. The signs relevant to the differential diagnosis should be valued as much as possible since a correct diagnosis of these patients is the only way to provide the appropriate care pathway, a thorough genetic counselling, prognosis definition, follow up setting, appropriate monitoring and care of possible medical problems., (© 2024. The Author(s).)

Background: Some chromatinopathies may present with common clinical findings (intellectual disability, brain and limb malformation, facial dysmorphism). Furthermore, one of their cardinal shared features is growth dysregulation.We aimed to assess and deepen this resemblance in three specific conditions, namely Wiedemann-Steiner (WDSTS), Kleefstra (KLEFS1) and Coffin-Siris syndrome (CSS1), with a particular focus on possible metabolic roots., Methods: Eleven patients were enrolled, three with WDSTS, five with KLEFS1 and three with CSS1, referring to Fondazione IRCCS Ca' Granda Ospedale Maggiore, Milan, Italy. We performed both a physical examination with detailed anthropometric measurements and an evaluation of the patients' REE (rest energy expenditure) by indirect calorimetry, comparing the results with age- and sex-matched healthy controls., Results: We observed new clinical features and overlap between these conditions suggesting that different disturbances of epigenetic machinery genes can converge on a common effect, leading to overlapping clinical phenotypes.
The REE was not distinguishable between the three conditions and healthy controls., Conclusions: Epigenetic machinery plays an essential role both in growth regulation and in neurodevelopment; we recommend evaluating skeletal [craniovertebral junction abnormalities (CVJ) polydactyly], otolaryngological [obstructive sleep apnea syndrome (OSAs), recurrent otitis media], dental [tooth agenesis, talon cusps], and central nervous system (CNS) [olfactory bulbs and cerebellum anomalies] features. These features could be included in monitoring guidelines. Further studies are needed to deepen the knowledge about energy metabolism., (© 2024. The Author(s).)

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes ( CREBBP , EP300 ) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP ; RTS2: EP300 ), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

SATB1 (MIM #602075) is a relatively new gene reported only in recent years in association with neurodevelopmental disorders characterized by variable facial dysmorphisms, global developmental delay, poor or absent speech, altered electroencephalogram (EEG), and brain abnormalities on imaging. To date about thirty variants in forty-four patients/children have been described, with a heterogeneous spectrum of clinical manifestations. In the present study, we describe a new patient affected by mild intellectual disability, speech disorder, and non-specific abnormalities on EEG and neuroimaging. Family studies identified a new de novo frameshift variant c.1818delG (p.(Gln606Hisfs*101)) in SATB1 . To better define genotype-phenotype associations in the different types of reported SATB1 variants, we reviewed clinical data from our patient and from the literature and compared manifestations (epileptic activity, EEG abnormalities and abnormal brain imaging) due to missense variants versus those attributable to loss-of-function/premature termination variants. Our analyses showed that the latter variants are associated with less severe, non-specific clinical features when compared with the more severe phenotypes due to missense variants. These findings provide new insights into SATB1 -related disorders.

We report the case of a 12-year-old girl and her father who both had marked postnatal tall stature, camptodactyly and clinodactyly, scoliosis and juvenile-onset hearing loss. The CATSHL (CAmptodactyly - Tall stature - Scoliosis - Hearing Loss syndrome) syndrome was suspected, and molecular analysis revealed a hitherto unreported, monoallelic variant c.1861C>T (p.Arg621Cys) in FGFR3. This variant affects the same residue, but is different than, the variant p.Arg621His reported in the two families with dominant CATSHL described so far. Interestingly, peg-shaped incisors were observed in the proband, a feature never reported in CATSHL but typical of another FGFR3-related condition, LADD (Lacrimo - Auricolo - Dento - Digital) syndrome. The FGFR3 p.Arg621Cys variant seems to be a newly identified cause of CATSHL syndrome with some phenotypic overlap with the LADD syndrome., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: The recent guidelines suggest the use of genome-wide analyses, such as whole exome sequencing (WES), at the beginning of the diagnostic approach for cases with suspected genetic conditions. However, in many realities it still provides for the execution of a multi-step pathway, thus requiring several genetic tests to end the so-called 'diagnostic odyssey'., Methods: We reported the results of GENE Project (Genomic analysis Evaluation NEtwork): a multicentre prospective cohort study on 125 paediatric outpatients with a suspected genetic disease in which we performed first-tier trio-WES, including exome-based copy number variation analysis, in parallel to a 'traditional approach' of two/three sequential genetic tests., Results: First-tier trio-WES detected a conclusive diagnosis in 41.6% of patients, way above what was found with routine genetic testing (25%), with a time-to-result of about 50 days. Notably, the study showed that 44% of WES-reached diagnoses would be missed with the traditional approach. The diagnostic rate (DR) of the two approaches varied in relation to the phenotypic class of referral and to the proportion of cases with a defined diagnostic suspect, proving the major difference for neurodevelopmental disorders. Moreover, trio-WES analysis detected variants in candidate genes of unknown significance (EPHA4, DTNA, SYNCRIP, NCOR1, TFDP1, SPRED3, EDA2R, PHF12, PPP1R12A, WDR91, CDC42BPG, CSNK1D, EIF3H, TMEM63B, RIPPLY3) in 19.4% of undiagnosed cases., Conclusion: Our findings represent real-practice evidence of how first-tier genome-wide sequencing tests significantly improve the DR for paediatric outpatients with a suspected underlying genetic aetiology, thereby allowing a time-saving setting of the correct management, follow-up and family planning., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objective: We describe the prenatal ultrasound findings and autopsy of three fetuses with multiple congenital anomalies (MCA) whose diagnostic workup suggested the same genetic etiology. We conducted a literature review to corroborate the molecular results and find evidence that the identified variants are responsible for the phenotype seen., Methods: Trio-based Exome Sequencing (ES) analysis was performed on chorionic villus samples. We reviewed available reports dealing with prenatal manifestations of genes involved in the Glycosylphosphatidylinositols (GPI) biosynthesis defects (GPIBDs)., Results: Prenatal findings shared by all the three pregnancies included facial dysmorphisms, brain malformations of the posterior fossa, skeletal and genitourinary anomalies. ES analysis identified homozygous variants of uncertain significance in PIGW in the three fetuses. Prenatal findings of the three pregnancies overlapped with those previously described for PIGW variants and with those associated with PIGN, PIGV and PIGA variants., Conclusion: Based on the phenotypic overlap between the prenatal findings in our three cases and other cases with pathogenic variants in other genes involved in GPIBDs, we speculate that the variants identified in the three fetuses are likely causal of their phenotype and that the PIGWclinical spectrum might extend to MCA, mainly involving brain, skeletal and genitourinary systems. Moreover, we suggest that also PIGW could be involved in Fryns/Fryns-like phenotypes., (© 2022 John Wiley & Sons Ltd.)

Objective: To assess autoimmune regulator (AIRE) gene mutations, class II HLA haplotypes, and organ- or non-organ-specific autoantibodies in patients with chronic hypoparathyroidism (CH) without associated Addison's disease (AD) or chronic candidiasis (CC)., Design, Patients and Measurements: Twenty-four patients who had CH without AD or CC were included in the study. AIRE gene mutations in all 14 exons were studied using PCR in 24 patients, 105 healthy controls and 15 first-degree relatives of CH patients with AIRE mutations. Human leucocyte antigens (HLA) were determined for all 24 patients and 105 healthy controls. Autoantibodies to a range of antigens including NACHT leucine-rich-repeat protein-5 (NALP5) and interferon omega (IFNω) were tested in all 24 patients., Results: AIRE gene mutations were found in 6 of 24 (25%) patients, all females, and this was significantly higher (P < 0·001) compared with AIRE mutations found in healthy controls (2/105). Three patients (12·5%) had homozygous AIRE mutations characteristic of Autoimmune-Poly-Endocrinopathy-Candidiasis-Ectodermal-Dystrophy and all three were also positive for IFNω-autoantibodies. Three patients (12·5%) had heterozygous AIRE mutations; two of these were novel mutations. One of the patients with heterozygous AIRE mutations was positive for both NACHT leucine-rich-repeat protein 5 and IFNω autoantibodies. Heterozygous AIRE mutations were found in 10 of 15 first-degree relatives of CH patients with AIRE mutations, although none was affected by CH. Class II HLA haplotypes were not statistically different in patients with CH compared to healthy controls., Conclusions: Analysis of AIRE gene mutations together with serum autoantibody profile should be helpful in the assessment of patients with CH, in particular young women with associated autoimmune diseases., (© 2010 Blackwell Publishing Ltd.)

The potential health consequences of human exposure to environmental estrogen disrupters are not known. Because many chemical compounds are environmentally persistent, toxic and estrogen-active, they can dysregulate the hypothalamic-pituitary-gonadal axis, potentially inducing reproductive disorders such as central precocious puberty (CPP). We performed a multi-center analysis of CPP distribution in northwest Tuscany (NWT), an area of 5990 km2 with 1,280,895 inhabitants. Study criteria consisted of recorded CPP diagnoses and prescriptions of gonadotropin-releasing hormone analogs from January 1, 1998 to December 1, 2003. Although similar CPP prevalences were found in four major cities of NWT (Livorno, Lucca, Massa and Pisa) (mean 30.4 per 100,000 children, standard deviation 18.6; p > 0.05), Viareggio area (< 300 km2) with 19,219 child inhabitants (0-14 years of age) had the highest CPP prevalence: more than 161 CPP cases per 100,000 children. Living in Viareggio area significantly increased the risk of CPP (relative risk (RR) 5.73, 95% confidence interval (CI) 3.5-9.3; rate/risk difference 0.133%, p < 0.05). Annual CPP incidence in the Viareggio area was relatively constant and significantly higher than in other NWT areas (RR 5.04, 95% CI 2.3-11.2; rate/risk difference 0.03%, p < 0.05). Indeed, 47% of total NWT cases were distributed in the countryside (300?km2) surrounding Viareggio. Specifically, three villages - Camaiore, Pietrasanta and Stazzema - in Viareggio presented the highest CPP frequency: 216.1, 393.5 and 274.0 CPP cases per 100,000 children, respectively (RR 9.59, 95% CI 1.71-16.6; rate/risk difference 0.26%, p < 0.05). Owing to the definite geographic distribution of CPP and because increasing distance (km) from Pietrasanta rarefied CPP frequency, we suggest environmental factors (e.g. estrogen disrupter pollution) as major CPP determinants in NWT.

Many advances characterize the research into the diagnosis of short stature in children. Increasing evidence shows a continuous spectrum of growth hormone (GH) output among GH-deficient patients and short normal children. Although biosynthetic human GH could theoretically offer the chance of treating most slowly growing children, it is not certain that all short normal children with a poor height velocity could benefit from therapy. Indeed, besides auxological findings, the assessment of GH secretion remains essential in selecting candidates for therapy. In this respect the evaluation of GH secretion by means of tests that can explore the physiological pathways involved in the hormone output appears important. Moreover some clinical evidence suggests that pharmacological stimuli cause the pituitary release of stored GH perhaps unavailable in physiological conditions. Among the classical physiological tests, the exercise test, the standardization of which has been debated, is commonly used in clinical practice. The sleep test, i.e. the evaluation of sleep-associated GH secretion, is the most important. It has no side effects and does not require the administration of exogenous stimuli. Several studies have demonstrated its reliability in diagnosing growth disorders in childhood, mainly if performed with EEG monitoring. Among the new physiological diagnostic approaches the most reliable test is the evaluation of 24-hour GH secretion. Knowledge of the integrated hormone concentrations appears particularly important in studying children who may have more subtle disturbances in GH secretion. These cases show normal GH response to provocative stimuli but show a reduced hormone output over 24 h. Indeed they respond well to human GH treatment.