'Knowing and Treating Kosaki/Penttinen syndrome' international collaborative consortium: recommendations for follow-up, natural history and a real-life observational study about safety and efficacy profile of tyrosine kinase inhibitors.

Background: 5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in . Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future.

Update on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review.

RASopathies are a diverse group of genetic conditions caused by hyperactivation of the RAS-MAPK signaling pathway, mainly inherited in an autosomal dominant manner. They present with variable features such as short stature, congenital heart defects, facial dysmorphisms, and neurodevelopmental delays. This study retrospectively analyzed 143 cases from 2003 to 2022, aiming to improve genotype-phenotype correlation knowledge for personalized care.

The wide phenotypic spectrum of thiamine metabolism dysfunction syndrome 5 and its treatment.

Thiamine metabolism dysfunction syndrome 5 (TMDS5) is a rare inborn error of metabolism caused by variants in TPK1, leading to reduced TPK levels. This enzyme is crucial for the production of thiamine pyrophosphate, the active form of thiamine, a vital coenzyme in numerous metabolic pathways. The clinical presentation exhibits a diverse range of manifestations.

Quantification of Lateralized Overgrowth and Genotype-Driven Tissue Composition.

Lateralized overgrowth (LO) is characterized by excessive growth of one side of the body compared to the other. LO can present as isolated (ILO) or within syndromes, like Beckwith-Wiedemann Spectrum (BWSp) and PIK3CA-related overgrowth spectrum (PROS). Currently, the diagnosis of LO relies on clinical evaluation and lacks a standardized method.

Novel PDGFRB Gene Fusions in Two Cases of Infantile Myofibromatosis.

Infantile myofibromatosis (IM) comprises a wide clinical spectrum, ranging from solitary or multicentric lesions to generalized life-threatening forms. IM is mostly linked to germline or somatic heterozygous mutations in the PDGFRβ tyrosine kinase, encoded by the PDGFRB gene. Treatments for IM range from wait and see approach to systemic chemotherapy, according to the clinical context.

Expanding the phenotypic spectrum of PROS: reclassifying isolated lateralised overgrowth.

Lateralised overgrowth (LO) is characterised by the asymmetric increase in the size of any part of the body exceeding 10% compared with the unaffected contralateral one. LO is a key feature in various syndromic overgrowth disorders, such as Beckwith-Wiedemann spectrum and -related overgrowth spectrum (PROS). However, it can also present as isolated (ILO).

Molecular and Clinical Features of Adrenocortical Tumors in Beckwith-Wiedemann Spectrum.

Background/objectives: Adrenocortical tumors (ACTs), including adrenocortical adenoma (ACA) and carcinoma (ACC), represent 0.3-0.4% of pediatric tumors.

Molecular Basis and Diagnostic Approach to Isolated and Syndromic Lateralized Overgrowth in Childhood.

Objective: To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics.

Study Design: We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum (PROS), vascular overgrowth, or isolated LO, based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA.

Exploring New Drug Repurposing Opportunities for MEK Inhibitors in RASopathies: A Comprehensive Review of Safety, Efficacy, and Future Perspectives of Trametinib and Selumetinib.

The RASopathies are a group of syndromes caused by genetic variants that affect the RAS-MAPK signaling pathway, which is essential for cell response to diverse stimuli. These variants functionally converge towards the overactivation of the pathway, leading to various constitutional and mosaic conditions. These syndromes show overlapping though distinct clinical presentations and share congenital heart defects, hypertrophic cardiomyopathy (HCM), and lymphatic dysplasia as major clinical features, with highly variable prevalence and severity.

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.

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.

Mulibrey nanism and immunological complications: a comprehensive case report and literature review.

Introduction: Mulibrey nanism (MUL) is a rare disorder caused by gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased risk of Wilms' tumor. Although immune system impairment has been documented in MUL, the underlying mechanisms remain poorly understood.

Methods: We present a case of MUL with progressive lymphopenia and review similar cases from the literature.

Epidemiology of the disorders of the Pik3ca-related overgrowth spectrum (Pros).

PIK3CA pathogenic variants are responsible for a group of overgrowth syndromes, collectively known as PIK3CA-Related Overgrowth Spectrum (PROS). These gain-of-function variants arise postzygotically, and, according to time of onset, kind of embryonal tissue affected and regional body extension, give rise to heterogeneous phenotypes. PROS rarity and heterogeneity hamper the correct estimation of its epidemiology.

Adult experiences in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth and epigenetic disorder caused by changes on chromosome 11p15. The primary features requiring management in childhood include macroglossia, omphalocele, lateralized overgrowth, hyperinsulinism, and embryonal tumors. Management guidelines have not been developed for adults with BWS and there have been few studies to assess the clinical needs of these patients.

Granulomatous inflammation in inborn errors of immunity.

Granulomas have been defined as inflammatory infiltrates formed by recruitment of macrophages and T cells. The three-dimensional spherical structure typically consists of a central core of tissue resident macrophages which may merge into multinucleated giant cells surrounded by T cells at the periphery. Granulomas may be triggered by infectious and non-infectious antigens.

Intestinal ultrasonography in pediatric population.

Bowel ultrasound (US) is a low-cost, non-invasive, bed side practice and a reproducible procedure that represents a high yield tool in clinical practice and in the diagnostic workup of a consistent group of acute and chronic gastrointestinal (GI) tract disease. Moreover, in case of GI diseases of neonatal and pediatric age, it allows an easier evaluation due to the small body size and scarce presence of fat tissue in the abdominal wall and peritoneal cavity and gas content. No particular preparation of the patient is needed, nevertheless a 3- to 5-hour fasting state improves the quality of the examination.

Spatial tuning of electrophysiological responses to multisensory stimuli reveals a primitive coding of the body boundaries in newborns.

The ability to identify our own body and its boundaries is crucial for survival. Ideally, the sooner we learn to discriminate external stimuli occurring close to our body from those occurring far from it, the better (and safer) we may interact with the sensory environment. However, when this mechanism emerges within ontogeny is unknown.

Chronic subdural hematoma: A previously unreported life-threatening complication in adult with Sotos syndrome.

Macrocephaly, defined as head circumference ≥ 2 SDs, is a cardinal feature of Sotos syndrome (SS) and generally persists in adulthood. Subdural fluid collection, typically associated with macrocephaly, is described in children due to anatomical conformation, and in adulthood due to brain atrophy and ex-vacuo hydrocephalus. On the other hand, a true, symptomatic, chronic subdural hematoma (CSH) is a previously unreported complication of SS in adulthood.

Phenotype evolution and health issues of adults with Beckwith-Wiedemann syndrome.

Background: Beckwith-Wiedemann syndrome (BWS) phenotype usually mitigates with age and data on adulthood are limited. Our study aims at reporting phenotype evolution and health issues in adulthood.

Methods: 34 patients (16 males), aged 18-58 years (mean 28.

NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype-phenotype correlations.

The pathogenic variants in the neuroblastoma-amplified sequence (NBAS) are associated with a clinical spectrum involving the hepatic, skeletal, ocular, and immune systems. Here, we report on two unrelated subjects with a complex phenotype solved by whole-exome sequencing, who shared a synonymous change in NBAS that was documented to affect the transcript processing and co-occurring with a truncating change. Starting from these two cases, we systematically assessed the clinical information available for all subjects with biallelic NBAS pathogenic variants (73 cases in total).

Transcription alterations of KCNQ1 associated with imprinted methylation defects in the Beckwith-Wiedemann locus.

Purpose: Beckwith-Wiedemann syndrome (BWS) is a developmental disorder caused by dysregulation of the imprinted gene cluster of chromosome 11p15.5 and often associated with loss of methylation (LOM) of the imprinting center 2 (IC2) located in KCNQ1 intron 10. To unravel the etiological mechanisms underlying these epimutations, we searched for genetic variants associated with IC2 LOM.