Do Rare Genetic Conditions Exhibit a Specific Phonotype? A Comprehensive Description of the Vocal Traits Associated with Crisponi/Cold-Induced Sweating Syndrome Type 1.

: Perceptual analysis has highlighted that the voice characteristics of patients with rare congenital genetic syndromes differ from those of normophonic subjects. In this paper, we describe the voice phenotype, also called the phonotype, of patients with Crisponi/cold-induced sweating syndrome type 1 (CS/CISS1). : We conducted an observational study at the Department of Life Sciences and Public Health, Rome.

Real-world experience with selumetinib in children with neurofibromatosis type 1: a multicentric retrospective study.

Purpose: Selumetinib is a MEK inhibitor indicated for pediatric patients with neurofibromatosis type 1 (NF1) and symptomatic inoperable plexiform neurofibromas (PNs).

Methods: This retrospective study collected data from 70 patients (aged 3 - 18 years) with NF1 and symptomatic inoperable PNs treated with selumetinib as part of compassionate use at 11 Italian centers between October 2018 and October 2024. Assessments included the clinical benefit rate (CBR) after 24 months and at the last observation.

Safety findings from the phase 1/2 MOSAIC study of miransertib for patients with PIK3CA-related overgrowth spectrum or Proteus syndrome.

Background: PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome are associated with mosaic tissue overgrowth of varying severity that commonly presents in childhood. The multicenter, open-label, phase 1/2 MOSAIC study (NCT03094832) was designed to evaluate the clinical efficacy and safety of the selective pan-AKT inhibitor miransertib for participants with PROS or Proteus syndrome.

Methods: Participants ≥ 2 years of age with PROS with documented somatic PIK3CA mutations or Proteus syndrome with documented somatic AKT1 mutations were enrolled to receive oral miransertib at a starting dose of 15 mg/m every day for the first 3 cycles (1 cycle = 28 days) and miransertib 25 mg/m every day thereafter, provided no clinically significant drug-related toxicities were observed.

Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort.

Introduction: Cardiofaciocutaneous syndrome (CFCS) is a rare syndromic disorder caused by germline mutations affecting the RAS/MAPK pathway. It is characterized by distinctive craniofacial dysmorphism, congenital heart defects, skin abnormalities, gastrointestinal dysfunction, neurocognitive impairment, and epilepsy. Emerging evidence suggests an association with hypogammaglobulinemia, but a comprehensive characterization of immunological abnormalities in CFCS is lacking.

Integrating vosoritide therapy with limb surgery in paediatric patients with achondroplasia: real-life experiences.

Background: Achondroplasia is the most common form of disproportionate short stature and can lead to serious medical complications, including foramen magnum and spinal stenosis. Until 2021, there were no precision treatments available, and in some countries, elective surgery was considered a standard approach to increase height, improve body proportions, enhance functionality, and correct deformities in a selected group of patients. Recently, C-type natriuretic peptide (CNP) has been explored as a potential treatment, aiming to counteract the molecular activity driven by FGFR3.

Multi-OMICs analysis on tridimensional fibroblast spheroids to model vascular Ehlers-Danlos syndrome pathogenesis.

Three-dimensional (3D) spheroids are an innovative cellular model mimicking tissue-like properties for a more effective replication of physiological cellular environment. Vascular Ehlers-Danlos syndrome (vEDS) is a rare hereditary connective tissue disorder caused by heterozygous deleterious variants in COL3A1. Affected individuals are at increased risk of early death due to ruptures of arteries, large intestine, and gravid uterus.

Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in and Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy.

Background: Macrocephaly can be a component manifestation of several monogenic conditions, in association with intellectual disability/developmental delay (ID/DD) behaviour abnormalities, including autism spectrum disorders (ASD), and variable additional features. On the other hand, idiopathic ASD can present with developmental delay and macrocephaly.

Methods: We carried out a retrospective analysis of a cohort of 78 patients who were tested from February 2017 to December 2024 by high-throughput sequencing of a panel of 27 genes (, , , , , , , , , , , , , , , , , , , , , , , , , and ) because of neurodevelopmental impairment, including ID/DD, ASD/behaviour abnormalities associated with macrocephaly, mimicking to a large extent idiopathic ASD.

Costello Syndrome and Ophthalmologic Issues: Unveiling the Unseen.

Costello syndrome (CS) is an ultra-rare condition belonging to the RASopathies, a group of disorders characterized by aberrant RAS/MAPK pathway signaling, which is involved in ocular development and in some eye pathologies. However, only a few studies assessing the ophthalmic features of individuals with CS are available. In this article, we describe the main ophthalmic anomalies and MRI findings in a large cohort of CS patients and compare our data with theliterature.

Expanding the mutational spectrum of ReNU syndrome: insights into 5' Stem-loop variants.

A narrow spectrum of heterozygous variants in RNU4-2, encoding the small nuclear RNA (snRNA) U4, underlies ReNU syndrome, a neurodevelopmental disorder (NDD) characterized by moderate to severe developmental delay (DD), intellectual disability (ID), a distinctive facial gestalt, and multisystem involvement. Pathogenic variants have primarily been reported within an 18-nt critical region contributing to stabilizing the U4/U6 snRNA duplex and proper spliceosome assembly. By combining whole genome sequencing reanalysis and targeted direct sequencing in 190 molecularly unexplained NDD cases, we report on five affected individuals carrying pathogenic/putative pathogenic RNU4-2 variants (2.

The Arg99Gln Substitution in HNRNPC Is Associated with a Distinctive Clinical Phenotype Characterized by Facial Dysmorphism and Ocular and Cochlear Anomalies.

Heterozygous variants in the heterogeneous nuclear ribonucleoprotein C gene () have recently been reported to cause intellectual developmental disorder-74 (MRD74), a neurodevelopmental disorder with no recurrent diagnostic handles. Affected individuals show variable, non-specific, and subtle dysmorphic features. The degree of developmental delay (DD)/intellectual disability (ID) is also wide, ranging from mild to severe.

Clinically interpretable multiclass neural network for discriminating cardiac diseases.

Background: Deep-learning applications in cardiology typically perform trivial binary classification and are able to discriminate between subjects affected or not affected by a specific cardiac disease. However, this working scenario is very different from the real one, where clinicians are required to recognize the occurrence of one cardiac disease among the several possible ones, performing a multiclass classification. The present work aims to create a new interpretable deep-learning tool able to perform a multiclass classification and, thus, discriminate among several different cardiac diseases.

Relationship Between Loss of Y Chromosome and Urologic Cancers: New Future Perspectives.

The Y chromosome (ChrY) is essential for male sex determination and spermatogenesis. However, recent studies have revealed its broader role in various physiological processes and disease susceptibility, including cancer. A comprehensive literature review was conducted using databases like MEDLINE, Scopus, Web of Science, and Google Scholar.

Value-based healthcare in management of chronic back pain: A multidisciplinary- and lean-based approach.

Background: Chronic back pain stands as the most common musculoskeletal disorder and a primary cause of disability in people under 45 years old. Multidisciplinary consultation offers an efficient approach to chronic back pain management compared to traditional therapeutic-rehabilitative paths. This paper aims to show the benefit of a diagnostic-therapeutic multidisciplinary program pathway for patients with chronic back pain.

Parenting Stress Index in Caregivers of Individuals With Noonan Syndrome.

Medical professionals frequently underestimate stress level of parents/caregivers of patients with rare disorders as RASopathies, the latter might experience elevated stress levels, with their own health frequently overlooked despite significant responsibilities and hurdles encountered. The aim of this study is to assess the stress experienced by parents of individuals with Noonan syndrome and related conditions. Forty-eight parents (20 fathers; 28 mothers), among the 31 recruited families, completed the Italian version of the Parenting Stress Index-Short Form.

Dominantly acting variants in ATP6V1C1 and ATP6V1B2 cause a multisystem phenotypic spectrum by altering lysosomal and/or autophagosome function.

The vacuolar H-ATPase (V-ATPase) is a functionally conserved multimeric complex localized at the membranes of many organelles where its proton-pumping action is required for proper lumen acidification. The V-ATPase complex is composed of several subunits, some of which have been linked to human disease. We and others previously reported pathogenic dominantly acting variants in ATP6V1B2, the gene encoding the V1B2 subunit, as underlying a clinically variable phenotypic spectrum including dominant deafness-onychodystrophy (DDOD) syndrome, Zimmermann-Laband syndrome (ZLS), and deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures (DOORS) syndrome.

Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules.

Purpose: Pathogenic LZTR1 variants cause schwannomatosis and dominant/recessive Noonan syndrome (NS). We aim to establish an association between heterozygous loss-of-function LZTR1 alleles and isolated multiple café-au-lait macules (CaLMs).

Methods: A total of 849 unrelated participants with multiple CaLMs, lacking pathogenic/likely pathogenic NF1 and SPRED1 variants, underwent RASopathy gene panel sequencing.

Loss-of-function variants in ERF are associated with a Noonan syndrome-like phenotype with or without craniosynostosis.

Pathogenic, largely truncating variants in the ETS2 repressor factor (ERF) gene, encoding a transcriptional regulator negatively controlling RAS-MAPK signaling, have been associated with syndromic craniosynostosis involving various cranial sutures and Chitayat syndrome, an ultrarare condition with respiratory distress, skeletal anomalies, and facial dysmorphism. Recently, a single patient with craniosynostosis and a phenotype resembling Noonan syndrome (NS), the most common disorder among the RASopathies, was reported to carry a de novo loss-of-function variant in ERF. Here, we clinically profile 26 individuals from 15 unrelated families carrying different germline heterozygous variants in ERF and showing a phenotype reminiscent of NS.

Defining the variant-phenotype correlation in patients affected by Noonan syndrome with the RAF1:c.770C>T p.(Ser257Leu) variant.

Hypertrophic cardiomyopathy (HCM) is the major contributor to morbidity and mortality in Noonan syndrome (NS). Gain-of-function variants in RAF1 are associated with high prevalence of HCM. Among these, NM_002880.

Trisomy 22 Mosaicism from Prenatal to Postnatal Findings: A Case Series and Systematic Review of the Literature.

Background: Among aneuploidies compatible with life, trisomy 22 mosaicism is extremely rare, and only about 25 postnatal and 18 prenatal cases have been described in the literature so far. The condition is mainly characterized by facial and body asymmetry, cardiac heart defects, facial dysmorphisms, growth failure, delayed puberty, and variable degrees of neurodevelopmental delay.

Problem: The scattered information regarding the condition and the dearth of data on its natural history and developmental outcomes restrict genetic counseling, particularly in prenatal settings.

Ligamentous laxity in children with achondroplasia: Prevalence, joint involvement, and implications for early intervention strategies.

Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia. Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories.

Work-Up and Treatment Strategies for Individuals with -Related Disorders: A Consensus of Experts from the Scientific Committee of the Italian Macrodactyly and PROS Association.

-related disorders encompass many rare and ultra-rare conditions caused by somatic genetic variants that hyperactivate the PI3K-AKT-mTOR signaling pathway, which is essential for cell cycle control. -related disorders include -related overgrowth spectrum (PROS), -related vascular malformations and -related non-vascular lesions. Phenotypes are extremely heterogeneous and overlapping.

The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications.

Cardiofaciocutaneous (CFC) syndrome is one of the rarest RASopathies characterized by multiple congenital ectodermal, cardiac and craniofacial abnormalities with a mild to severe ocular, gastrointestinal and neurological involvement. It is an autosomal dominant syndrome, with complete penetrance, caused by heterozygous pathogenic variants in the genes , , , or, rarely, , all part of the RAS-MAPK pathway. This pathway is a signal transduction cascade that plays a crucial role in normal cellular processes such as cell growth, proliferation, differentiation, survival, metabolism and migration.

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1.