Usmani-Riazuddin syndrome can have a recognizable phenotype: Report of a novel AP1G1 variant.

Usmani-Riazuddin syndrome (USRISR, MIM# 619548; USRISD, MIM#619467) is a very rare genetic condition. recently associated with deleterious variants in AP1G1 (MIM* 603533). It is characterized by multisystemic involvement including intellectual disability, speech and developmental delay, behavioral anomalies, muscular tone disorders, seizures, limb defects, and unspecified facial gestalt. In this report, we describe this syndrome for the second time, in association to a novel AP1G1 variant identified in a toddler with multisystemic involvement including intellectual disability, speech and developmental delay, behavioral anomalies, arrhythmias, hearing loss, skin changes, and limb defects. Next generation sequencing (NGS) analysis through clinical exome disclosed AP1G1: c.1969C>G (p.Leu657Val), de novo, likely pathogenic variant, according to ACMG classification criteria. Proband's facial features resembled the spectrum of chromatinopathies. Clinical pictures were analyzed and a clinical overlap was supported by DeepGestalt analysis (www.face2gene.com). The system identified 6 chromatin disorders out of 30 possible diagnoses. The remaining 24 included 9 miscellaneous cryptic chromosomal abnormalities (excluded due to normal microarray study). To the best of our knowledge, this is the first description of likely distinctive facial features in a patient with Usmani-Riazuddin syndrome. Further multicentric analyses are needed for a better definition of this aspect.

Use of an Orthodontic and Otolaryngological Approach in an Infant with Holoprosencephaly.

Holoprosencephaly is a complex human brain malformation resulting from incomplete cleavage of the prosencephalon into both hemispheres. Congenital nasal pyriform aperture stenosis (CNPAS) is sometimes found in patients with mild forms of holoprosencephaly. Surgical treatment is required. Low-invasive surgical approaches involve balloon dilation of the pyriform opening. We present the case of an 8-day-old girl diagnosed with holoprosencephaly, CNPAS, and the presence of a solitary median maxillary central incisor. Once examined by neonatologist, geneticist, pneumologist, otolaryngologist, and pediatric dentist, a combined otolaryngological-orthodontic approach was used. The obstruction of the right nasal cavity was treated by widening the nasal cavities and stabilizing them with a balloon dilation technique. After surgery, the respiratory space was increased by applying a neonatal palatal expander plate (NPEP) considering the palatal deformity: ogival shaped, anterior vertex growth direction, reduction of transverse diameters. The NPEP promoted distraction of the median palatine suture and assisted the nasal dilation. Therefore, after the insertion of NPEP, the physiological sucking-swallowing mechanism was activated. In infants with CNPAS, NPEP can be useful to ensure the safe stability of nasal dilation. A multidisciplinary approach is fundamental. In our experience, the close collaboration between an otolaryngologist and orthodontist is essential for the management of the patient with CNPAS.

Congenital Heart Defects in Patients with Molecularly Confirmed Sotos Syndrome.

Sotos syndrome is an autosomal dominant condition characterized by overgrowth with advanced bone age, macrodolicocephaly, motor developmental delays and learning difficulties, and characteristic facial features caused by heterozygous pathogenetic variants in the NSD1 gene located on chromosome 5q35. The prevalence of heart defects (HDs) in individuals with Sotos syndrome is estimated to be around 15-40%. Septal defects and patent ductus arteriosus are the most commonly diagnosed malformations, but complex defects have also been reported. The aim of our study was to analyze the prevalence of HD, the anatomic types, and the genetic characteristics of 45 patients with Sotos syndrome carrying pathogenetic variants of NSD1 or a 5q35 deletion encompassing NSD1, who were followed at Bambino Gesù Children's Hospital in Rome. Thirty-nine of the forty-five patients (86.7%) had a mutation in NSD1, while six of the forty-five (13.3%) had a deletion. Most of the patients (62.2%, 28/45) were male, with a mean age of 14 ± 7 years (range 0.2-37 years). A total of 27/45 (60.0%) of the patients had heart defects, isolated or combined with other defects, including septal defects (12 patients), aortic anomalies (9 patients), mitral valve and/or tricuspid valve dysplasia/insufficiency (1 patient), patent ductus arteriosus (3 patients), left ventricular non-compaction/hypertrabeculated left ventricle (LV) (4 patients), aortic coarctation (1 patient), aortopulmonary window (1 patient), and pulmonary valve anomalies (3 patients). The prevalences of HD in the two subgroups (deletion versus intragenic mutation) were similar (66.7% (4/6) in the deletion group versus 58.91% (23/39) in the intragenic variant group). Our results showed a higher prevalence of HD in patients with Sotos syndrome in comparison to that described in the literature, with similar distributions of patients with mutated and deleted genes. An accurate and detailed echocardiogram should be performed in patients with Sotos syndrome at diagnosis, and a specific cardiological follow-up program is needed.

Unique Features of Cardiovascular Involvement and Progression in Children with Marfan Syndrome Justify Dedicated Multidisciplinary Care.

Marfan syndrome (MIM: # 154700; MFS) is an autosomal dominant disease representing the most common form of heritable connective tissue disorder. The condition presents variable multiorgan expression, typically involving a triad of cardiovascular, eye, and skeletal manifestations. Other multisystemic features are often underdiagnosed. Moreover, the disease is characterized by age related penetrance. Diagnosis and management of MFS in the adult population are well-described in literature. Few studies are focused on MFS in the pediatric population, making the clinical approach (cardiac and multiorgan) to these cases challenging both in terms of diagnosis and serial follow-up. In this review, we provide an overview of MFS manifestations in children, with extensive revision of major organ involvement (cardiovascular ocular and skeletal). We attempt to shed light on minor aspects of MFS that can have a significant progressive impact on the health of affected children. MFS is an example of a syndrome where an early personalized approach to address a dynamic, genetically determined condition can make a difference in outcome. Applying an early multidisciplinary clinical approach to MFS cases can prevent acute and chronic complications, offer tailored management, and improve the quality of life of patients.

Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology.

INTRODUCTION: CTNNB1 gene loss-of-function variants cause Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, OMIM 615075). Although motor impairment represents a core feature of this condition, the motor phenotype remains poorly described. We systematically assessed a cohort of 14 patients with disease-causing CTNNB1 variants to better characterize the movement disorder phenotype. METHODS: patients were enrolled at Bambino Gesù Children's Hospital in Rome, Italy, between January 2019 and February 2024. 14 participants were included and underwent extensive genetic and neurologic examination. Clinical features, neuroimaging and neurophysiological investigations were retrospectively analyzed from medical charts and video recordings. RESULTS: 13 out of 14 patients showed motor disorders (one only showing mild coordination difficulties). 12 presented abnormal gait (11 patients with broad-based gait, one with narrow-based in-toeing gait, one with broad-based gait with unilateral intoeing). One did not achieve walking ability. 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13). Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients. CONCLUSIONS: CTNNB1-syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia.

Work-Up and Treatment Strategies for Individuals with PIK3CA-Related Disorders: A Consensus of Experts from the Scientific Committee of the Italian Macrodactyly and PROS Association.

PIK3CA-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. PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations and PIK3CA-related non-vascular lesions. Phenotypes are extremely heterogeneous and overlapping. Therefore, diagnosis and management frequently involve various health specialists. Given the rarity of these disorders and the limited number of centers offering optimal care, the Scientific Committee of the Italian Macrodactyly and PROS Association has proposed a revision of the most recent recommendations for the diagnosis, molecular testing, clinical management, follow-up, and treatment strategies. These recommendations give insight on molecular diagnosis, eligible samples, preferable sequencing, and validation methods and management of negative results. The purpose of this paper is to promote collaboration between health care centers and clinicians with a joint shared approach. Finally, we suggest the direction of present and future research studies, including new systemic target therapies, which are currently under evaluation in several clinical trials, such as specific inhibitors that can be employed to downregulate the signaling pathway.

Exploiting in silico structural analysis to introduce emerging genotype-phenotype correlations in DHCR24-related sterol biosynthesis disorder: a case study.

Desmosterolosis is a rare sterol biosynthesis disorder characterized by multiple congenital anomalies, failure to thrive, severe developmental delay, progressive epileptic encephalopathy, and elevated levels of desmosterol caused by biallelic mutations of DHCR24 encoding 3-ß-hydroxysterol Δ-24-reductase. DHCR24 is regarded as the key enzyme of cholesterol synthesis in the metabolism of brain cholesterol as it catalyzes the reduction of the Δ-24 double bond of sterol intermediates during cholesterol biosynthesis. To date, 15 DHCR24 variants, detected in 2 related and 14 unrelated patients, have been associated with the desmosterolosis disorder. Here, we describe a proband harboring the never-described DHCR24 homozygous missense variant NM_014762.4:c.506T>C, NP_055577.1:p.M169T, whose functional validation was confirmed through biochemical assay. By using molecular dynamics simulation techniques, we investigated the impact of this variant on the protein stability and interaction network with the flavin adenine dinucleotide cofactor, thereby providing a preliminary assessment of its mechanistic role in comparison to all known pathogenic variants, the wild-type protein, and a known benign DHCR24 variant. This report expands the clinical and molecular spectra of the DHCR24-related disorder, reports on a novel DHCR24 deleterious variant associated with desmosterolosis, and gives new insights into genotype-phenotype correlations.