A Novel Homozygous Loss-of-Function Variant in Causes Autosomal Recessive Noonan-like Syndrome.

Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic cardiomyopathy. In 2001, was identified as the first Noonan syndrome gene and is responsible for the majority of Noonan syndrome cases. Over the years, several other genes involved in Noonan syndrome (, , , , , , , and ) have been identified, acting at different levels of the RAS-mitogen-activated protein kinase pathway.

An atypical Aymé-Gripp phenotype detected by exome sequencing.

Aymé-Gripp Syndrome (AGS) is an ultra-rare syndrome characterized by peculiar facial traits combined with early bilateral cataracts, sensorineural hearing loss, and variable neurodevelopmental abnormalities. Only a few cases carrying a pathogenic variant in MAF have been described to date. A significant effort is then required to expand the genotypic and phenotypic spectrum of this condition.

Whole-Exome and Transcriptome Sequencing Expands the Genotype of Majewski Osteodysplastic Primordial Dwarfism Type II.

Microcephalic Osteodysplastic Primordial Dwarfism type II (MOPDII) represents the most common form of primordial dwarfism. MOPD clinical features include severe prenatal and postnatal growth retardation, postnatal severe microcephaly, hypotonia, and an increased risk for cerebrovascular disease and insulin resistance. Autosomal recessive biallelic loss-of-function genomic variants in the centrosomal pericentrin (PCNT) gene on chromosome 21q22 cause MOPDII.

A Novel Homozygous Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect.

Glycosylphosphatidylinositol biosynthesis defect 15 is a rare autosomal recessive disorder due to biallelic loss of function of GPAA1. At the moment, less than twenty patients have been reported, usually compound heterozygous for GPAA1 variants. The main clinical features are intellectual disability, hypotonia, seizures, and cerebellar atrophy.

The management of achondroplasia in Italy: results from a Delphi panel based on real-world experience.

Background: Achondroplasia is a rare genetic disorder caused by a mutation in the gene, leading to skeletal changes and other systemic complications that greatly impact the patient's quality of life. There currently are differences in achondroplasia patients' management among countries and centers within the same country.

Method: A group of Italian experts discussed the best practice and the current unmet needs in the management of patients with achondroplasia though a two-round Delphi panel, between September and November 2022.

Early prenatal diagnosis of a recurrent case of short-rib thoracic dysplasia 3 due to compound heterozygosity for variations in the DYNC2H1 gene: an "ultrasound first" approach.

Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias associated with homozygous or compound heterozygous mutations of DYNC2H1. We describe the case of a couple with two consecutive therapeutic abortions due to a diagnosis of short-rib thoracic dysplasia mutations. In the first pregnancy, the diagnosis has been made at 21 weeks.

Genotype-phenotype spectrum and correlations in Xia-Gibbs syndrome: Report of five novel cases and literature review.

Background: Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA-binding motif-containing 1 gene (AHDC1), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. AHDC1 variants possibly act through a dominant-negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N-terminal are thought to determine a milder phenotype with better cognitive performances.

Cardiovascular Involvement in mtDNA Disease: Diagnosis, Management, and Therapeutic Options.

Mitochondrial diseases (MD) include an heterogenous group of systemic disorders caused by sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA), causing impairment of oxidative phosphorylation system. Hypertrophic cardiomyopathy is the dominant pattern of cardiomyopathy in all forms of mtDNA disease, being observed in almost 40% of the patients. Dilated cardiomyopathy, left ventricular noncompaction, and conduction system disturbances have been also reported.

Diagnosis and Management of Cardiovascular Involvement in Friedreich Ataxia.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a homozygous GAA triplet repeat expansion in the frataxin gene. Cardiac involvement, usually manifesting as hypertrophic cardiomyopathy, can range from asymptomatic cases to severe cardiomyopathy with progressive deterioration of the left ventricular ejection fraction and chronic heart failure. The management of cardiac involvement is directed to prevent disease progression and cardiovascular complications.

The Heart Muscle and Valve Involvement in Marfan Syndrome, Loeys-Dietz Syndromes, and Collagenopathies.

The inherited connective tissue disorders (Marfan syndrome, Loeys-Dietz syndrome [LDS], and Ehlers-Danlos syndrome [EDS]) involve connective tissue of various organ systems. These pathologies share many common features, nonetheless compared to Marfan syndrome, LDS' cardiovascular manifestations tend to be more severe. In contrast, no association is reported between LDS and the presence of ectopia lentis.

De Novo Inverted Duplication Deletion of 4p in a 14-Week-Old Male Fetus Aborted Due to Multiple Anomalies.

Inverted duplications deletions are rare, complex, and nonrecurrent chromosomal rearrangements associated with a variable phenotype. In this case report, we described the phenotype and genotype of a 14-week-old male fetus, who was aborted after discovery of multiple anomalies (septal cystic hygroma, open abdominal wall, and a nonidentifiable lower limb). At autopsy, fluorescence in situ hybridization and array comparative genomic hybridization identified an inverted duplication with terminal deletion of 4p [46,XY,der(4)del(p16.

Clinical heterogeneity of Kabuki syndrome in a cohort of Italian patients and review of the literature.

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones.

Clinical Characterization of a 6-Year-Old Patient with Autism and Two Adjacent Duplications on 10q11.22q11.23. A Case Report.

Autism is a neurodevelopmental disorder presenting in the first 3 years of life. Deficits occur in the core areas of social communication and interaction and restricted, repetitive patterns of behavior, interests or activities. The causes of autism are unknown, but clinical genetic studies show strong evidence in favor of the involvement of genetic factors in etiology.

Diagnostic issues faced by a rare disease healthcare network during Covid-19 outbreak: data from the Campania Rare Disease Registry.

Background: The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period.

Methods: To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period.

Delineation of MidXq28-duplication syndrome distal to MECP2 and proximal to RAB39B genes.

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features.

Small 4p16.3 deletions: Three additional patients and review of the literature.

Wolf-Hirschhorn syndrome is a well-defined disorder due to 4p16.3 deletion, characterized by distinct facial features, intellectual disability, prenatal and postnatal growth retardation, and seizures. Genotype-phenotype correlations based on differently sized deletions have been attempted, and some candidate genes have been suggested.

Phenotype and genotype of 87 patients with Mowat-Wilson syndrome and recommendations for care.

Purpose: Mowat-Wilson syndrome (MWS) is a rare intellectual disability/multiple congenital anomalies syndrome caused by heterozygous mutation of the ZEB2 gene. It is generally underestimated because its rarity and phenotypic variability sometimes make it difficult to recognize. Here, we aimed to better delineate the phenotype, natural history, and genotype-phenotype correlations of MWS.

Congenital Anomalies in Contaminated Sites: A Multisite Study in Italy.

The health impact on populations residing in industrially contaminated sites (CSs) is recognized as a public health concern especially in relation to more vulnerable population subgroups. The aim of this study was to estimate the risk of congenital anomalies (CAs) in Italian CSs. Thirteen CSs covered by regional CA registries were investigated in an ecological study.

Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.

Purpose: Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability, and congenital malformations, including Hirschsprung disease, genital and eye anomalies, and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.

Methods: Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations.

First evidence of Smith-Magenis syndrome in mother and daughter due to a novel RAI mutation.

Smith-Magenis syndrome (SMS) is a complex genetic disorder caused by interstitial 17p11.2 deletions encompassing multiple genes, including the retinoic acid induced 1 gene-RAI1-or mutations in RAI1 itself. The clinical spectrum includes developmental delay, cognitive impairment, and behavioral abnormalities, with distinctive physical features that become more evident with age.

Prevalence of maternal preconception risk factors: an Italian multicenter survey.

Objectives: Adequate preconception maternal health care is essential to reduce the risk of unwanted pregnancy outcomes and complications. Still, many women are exposed to a number of unhealthy risk factors both before and early in pregnancy. This study aimed to estimate the prevalence of a number of important preconception risk factors using data from a recent multicenter study in Italy.

Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review.

Background: Arterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection. During infancy, children frequently present the involvement of the pulmonary arteries (elongation, tortuosity, stenosis) with dyspnea and cyanosis. Other CTD signs of ATS are dysmorphisms, abdominal hernias, joint hypermobility, skeletal abnormalities, and keratoconus.