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. This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children. A total of 33 children (mean age 6.4 ± 3.2 years; age range 1-12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the FGFR3 gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers. Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females. Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood. The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients' follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility.

Status epilepticus in BRAF-related cardio-facio-cutaneous syndrome: Focus on neuroimaging clues to physiopathology.

OBJECTIVE: Cardio-facio-cutaneous syndrome (CFC) is a genetic disorder due to variants affecting genes coding key proteins of the Ras/MAPK signaling pathway. Among the different features of CFC, neurological involvement, including cerebral malformations and epilepsy, represents a common and clinically relevant aspect. Status epilepticus (SE) is a recurrent feature, especially in a specific subgroup of CFC patients with developmental and epileptic encephalopathy (DEE) and history of severe pharmacoresistant epilepsy. Here we dissect the features of SE in CFC patients with a particular focus on longitudinal magnetic resonance imaging (MRI) findings to identify clinical-radiological patterns and discuss the underlying physiopathology. METHODS: We retrospectively analyzed clinical, electroencephalogram (EEG), and MRI data collected in a single center from a cohort of 23 patients with CFC carrying pathogenic BRAF variants who experienced SE during a 5-year period. RESULTS: Seven episodes of SE were documented in 5 CFC patients who underwent EEG and MRI at baseline. MRI was performed during SE/within 72 hours from SE termination in 5/7 events. Acute/early post-ictal MRI findings showed heterogenous abnormalities: restricted diffusion in 2/7, focal area of pcASL perfusion change in 2/7, focal cortical T2/FLAIR hyperintensity in 2/7. Follow-up images were available for 4/7 SE. No acute changes were detected in 2/7 (MRI performed 4 days after SE termination). SIGNIFICANCE: Acute focal neuroimaging changes concomitant with ictal EEG focus were present in 5/7 episodes, though with different findings. The heterogeneous patterns suggest different contributing factors, possibly including the presence of focal cortical malformations and autoinflammation. When cytotoxic edema is revealed by MRI, it can be followed by permanent structural damage, as already observed in other genetic conditions. A better understanding of the physiopathology will provide access to targeted treatments allowing to prevent long-term adverse neurological outcome. PLAIN LANGUAGE SUMMARY: Cardio-facio-cutaneous syndrome is a genetic disorder that often causes prolonged seizures known as status epilepticus. This study has a focus on electroclinical and neuroimaging patterns in patients with cardio-facio-cutaneous syndrome. During these status epilepticus episodes, we found different abnormal brain imaging patterns in patients, indicating various causes like brain malformations and inflammation. Understanding these patterns could help doctors find specific treatments, protecting cardio-facio-cutaneous syndrome patients from long-term brain damage.

How pain affect real life of children and adults with achondroplasia: A systematic review.

The clinical features of achondroplasia can cause acute self-limited pain that can evolve into chronic pain. Pain causes a low quality of life, in terms of physical, emotional, social, and school functioning in both adult and children with achondroplasia. We conducted a systematic review according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement to describe prevalence, assessment tools, causes and management strategies of pain in this rare disease. We found that shoulder and knee pain is typically referred during infancy, while knee pain is generally referred around 5-6 years of age. The prevalence of general pain in adolescence can be as high as 90%. Chronic pain in the achondroplasia population increases with age, with up to 70% of adults reporting general pain and back pain. Recognizing the multiple determinants of acute and chronic pain in patients with achondroplasia may enable physicians to better understand and manage this burden, particularly with the advent of new drugs that may modify some of the striking features of achondroplasia.

Bladder and bowel dysfunction in Down syndrome with neural tube defect: case report and review of the literature.

BACKGROUND: Down syndrome is a genetic disorder caused by trisomy of chromosome 21 and characterized by an increased risk of multiorgan involvement. In Down syndrome children, functional constipation and lower urinary tract infections have been described, together with higher risk for incontinence and delayed sphincter control. At present, to our knowledge, no clear association between Down syndrome, Bladder Bowel Dysfunction and neural tube defects has been previously described. CASE PRESENTATION: We describe two female patients with Down syndrome presenting Bladder Bowel Dysfunction in association with neural tube defects, who both underwent personalized multidisciplinary intervention and pelvic floor rehabilitation, with good clinical outcomes. CONCLUSION: At present, no screening program has been established in order to rule out neural tube defects or neurogenic urinary anomalies in Down syndrome patients presenting bowel and/or bladder dysfunction. In our opinion, presence of spinal abnormalities, despite rare, may be contribute to urinary symptoms and should be ruled out in patients presenting progressive or persistent Bladder Bowel Dysfunction. Early diagnosis and management of spinal cord defects associated with neurogenic urinary dysfunction may allow to prevent possible complications.

Nasal polyposis in pediatric patients with Cornelia de Lange syndrome: endoscopic diagnosis, treatment and follow up in two case reports.

BACKGROUND: Cornelia de Lange syndrome is a rare genetic disease with otolaryngological involvement. The classic phenotype is characterized by distinctive facial features, intellectual disability, growth delay, hirsutism, and upper-limb reduction. Nasal polyposis was previously reported in association with chronic rhinosinusitis, however data about prevalence, diagnosis, treatment and prognosis are lacking for this cohort of patients, affected by rare disease. CASE PRESENTATION: We describe the whole diagnostic and therapeutic workflow of nasal polyps in two pediatric patients with Cornelia de Lange, successfully diagnosed and treated by nasal endoscopy. CONCLUSION: Our report confirm that nasal endoscopy is a safe and useful tool in the diagnosis, treatment and follow-up of nasal polyps, even in Cornelia de Lange syndrome pediatric patients. We want to increase the alert for the detection of nasal polyps in patients with Cornelia de Lange syndrome since pediatric age. We recommend endoscopy in all patients with Cornelia de Lange syndrome and symptoms of chronic nasal obstruction and/or OSAS. Multidisciplinary team and sedation service could be useful in the management of Cornelia de Lange syndrome patients with airway obstruction symptoms and sleep disturbance when severe intellectual disability, autism or psychiatric findings are present.

Lifetime impact of achondroplasia study in Europe (LIAISE): findings from a multinational observational study.

BACKGROUND: Achondroplasia, caused by a pathogenic variant in the fibroblast growth factor receptor 3 gene, is the most common skeletal dysplasia. The Lifetime Impact of Achondroplasia Study in Europe (LIAISE; NCT03449368) aimed to quantify the burden of achondroplasia among individuals across a broad range of ages, including adults. METHODS: Demographic, clinical and healthcare resource use data were collected from medical records of achondroplasia patients enrolled in 13 sites across six European countries in this retrospective, observational study. Descriptive statistics or event rates per 100 person-years were calculated and compared across age groups as well as by history of limb lengthening. Patient-reported outcomes (quality of life [QoL], pain, functional independence, work productivity and activity impairments) were evaluated using questionnaires at the time of enrolment. An exploratory analysis investigated correlations between height (z-score or centimetres) and patient-reported outcomes. RESULTS: Overall, 186 study patients were included, with a mean age of 21.7 ± 17.3 years (range 5.0-84.4). At least one complication or surgery was reported for 94.6% and 72.0% of patients, respectively, at a rate of 66.6 and 21.5 events per 100 person-years. Diverse medical and surgical complications were reported for all ages in a bimodal distribution, occurring more frequently in the youngest and oldest age groups. A total of 40 patients had previously undergone limb lengthening (capped at 20% per the study protocol). The most frequent surgery types varied by age, in line with complication profiles. Healthcare resource use was high across all age groups, especially among the youngest and oldest individuals, and did not differ substantially according to history of limb lengthening. Compared to general population values, patients reported impaired QoL particularly for physical functioning domains. In addition, patients reported difficulty carrying out daily activities independently and pain starting in childhood. Patient height correlated with multiple patient-reported outcomes. CONCLUSIONS: The findings of this study suggest that, across an individual's lifetime, achondroplasia is associated with multisystem complications, reduced QoL and functionality, and increased pain. These results highlight the large amount of healthcare resources that individuals with achondroplasia require throughout their lifespans and provide novel insights into current achondroplasia management practices across Europe. Trial registration ClinicalTrials.gov, NCT03449368, Submitted 14 December 2017 - prospectively registered, https://clinicaltrials.gov/ct2/show/record/NCT03449368.

Further case of enlarged spinal nerve roots in KRAS-related Noonan syndrome.

Noonan syndrome (NS) belongs to RASopathies, a family of disorders caused by unregulated signaling through the RAS-MAPK pathway. Herein, we report on an individual with molecularly confirmed diagnosis of NS showing asymptomatic enlarged spinal nerve roots, which are distinctive features of neurofibromatosis type 1. To date, a total of 16 patients with neurogenic tumors resembling neurofibromas/schwannomas and a molecularly confirmed diagnosis of a non-NF1 RASopathy have been reported, adding this further feature shared among RASopathies.

What to Expect of Feeding Abilities and Nutritional Aspects in Achondroplasia Patients: A Narrative Review.

Achondroplasia is an autosomal dominant genetic disease representing the most common form of human skeletal dysplasia: almost all individuals with achondroplasia have identifiable mutations in the fibroblast growth factor receptor type 3 (FGFR3) gene. The cardinal features of this condition and its inheritance have been well-established, but the occurrence of feeding and nutritional complications has received little prominence. In infancy, the presence of floppiness and neurological injury due to foramen magnum stenosis may impair the feeding function of a newborn with achondroplasia. Along with growth, the optimal development of feeding skills may be affected by variable interactions between midface hypoplasia, sleep apnea disturbance, and structural anomalies. Anterior open bite, prognathic mandible, retrognathic maxilla, and relative macroglossia may adversely impact masticatory and respiratory functions. Independence during mealtimes in achondroplasia is usually achieved later than peers. Early supervision of nutritional intake should proceed into adolescence and adulthood because of the increased risk of obesity and respiratory problems and their resulting sequelae. Due to the multisystem involvement, oral motor dysfunction, nutrition, and gastrointestinal issues require special attention and personalized management to facilitate optimal outcomes, especially because of the novel therapeutic options in achondroplasia, which could alter the progression of this rare disease.

Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants.

BACKGROUND: Postzygotic activating PIK3CA variants cause several phenotypes within the PIK3CA-related overgrowth spectrum (PROS). Variant strength, mosaicism level, specific tissue involvement and overlapping disorders are responsible for disease heterogeneity. We explored these factors in 150 novel patients and in an expanded cohort of 1007 PIK3CA-mutated patients, analysing our new data with previous literature to give a comprehensive picture. METHODS: We performed ultradeep targeted next-generation sequencing (NGS) on DNA from skin biopsy, buccal swab or blood using a panel including phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway genes and GNAQ, GNA11, RASA1 and TEK. Additionally, 914 patients previously reported were systematically reviewed. RESULTS: 93 of our 150 patients had PIK3CA pathogenetic variants. The merged PROS cohort showed that PIK3CA variants span thorough all gene domains, some were exclusively associated with specific PROS phenotypes: weakly activating variants were associated with central nervous system (CNS) involvement, and strongly activating variants with extra-CNS phenotypes. Among the 57 with a wild-type PIK3CA allele, 11 patients with overgrowth and vascular malformations overlapping PROS had variants in GNAQ, GNA11, RASA1 or TEK. CONCLUSION: We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping 'vascular' phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.

Multimodal ocular imaging in Proteus syndrome.

In this report we illustrate the ophthalmologic assessment of two patients affected by Proteus Syndrome (PS), an extremely rare genetic disorder. Case #1 describes a 26 year old male patient followed for multiple ophthalmic anomalies: a limbal dermoid cyst, a unilateral cataract, bilateral nystagmus, severe myopia and unilateral optic nerve head drusen. Case #2 describes a 20 year old female patient referred to our Ophthalmology Department for a routine ophthalmologic evaluation after being treated for 3 years with Miransertib (an experimental AKT-pathway inhibitor). Both patients underwent a complete ophthalmologic examination and a multimodal imaging evaluation. The multimodal imaging approach has revealed useful to evaluate both cases in detail and to keep track of disease evolution over time, moreover providing helpful features to further characterize this rare syndrome.

Management of nutritional and gastrointestinal issues in RASopathies: A narrative review.

Noonan, Costello, and cardio-facio-cutaneous syndrome are neurodevelopmental disorders belonging to the RASopathies, a group of syndromes caused by alterations in the RAS/MAPK pathway. They are characterized by similar clinical features, among which feeding difficulties, growth delay, and gastro-intestinal disorders are frequent, causing pain and discomfort in patients. Hereby, we describe the main nutritional and gastrointestinal issues reported in individuals with RASopathies, specifically in Noonan syndrome, Noonan syndrome-related disorders, Costello, and cardio-facio-cutaneous syndromes. Fifty percent of children with Noonan syndrome may experience feeding difficulties that usually have a spontaneous resolution by the second year of life, especially associated to genes different than PTPN11 and SOS1. More severe manifestations often require artificial enteral nutrition in infancy are observed in Costello syndrome, mostly associated to c.34G>A substitution in the HRAS gene. In cardio-facio-cutaneous syndrome feeding issues are usually present (90-100% of cases), especially in individuals carrying variants in BRAF, MAP2K1, and MAP2K2 genes, and artificial enteral intervention, even after scholar age, may be required. Moreover, disorders associated with gastrointestinal dysmotility as gastro-esophageal reflux and constipation are commonly reported in all the above-mentioned syndromes. Given the impact on growth and on the quality of life of these patients, early evaluation and prompt personalized management plans are fundamental.

Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype.

Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.

Thoracolumbar stenosis and neurologic symptoms: Quantitative MRI in achondroplasia.

BACKGROUND AND PURPOSE: Whole-spine magnetic resonance imaging (MRI) studies, to identify structural abnormalities associated with the development of symptomatic spinal stenosis in achondroplasia. METHODS: Forty-two subjects with achondroplasia were grouped into four age-related categories. Congenital spinal deformities (vertebral body and disc height, interpedicular distance), acquired spinal degenerative changes, thoracic kyphotic (TK) angle, thoracolumbar kyphotic (TLK) angle, spinal canal widths were evaluated by MRI. RESULTS: Patients in the first three groups were asymptomatic and younger (group 1: 4.4 ± 0.78 years; group 2: 8.18 ± 0.60 years; group 3: 10.95 ± 0.93 years) than the symptomatic group (group 4: 23 ± 1.30 years). Patients showed height of vertebral bodies, whole canal width, and average lumbar interpedicular distance reduced. Discs degeneration was more pronounced in the lumbar region and in symptomatic adult patients. TK and TLK angles showed a positive correlation with age (p < .05, r = .42; p < .05, r = .41), whereas thoracic and thoracolumbar canal width had a negative correlation (p < .05, r = -.69; p < .05, r = -.58). A negative correlation between lumbar discs degeneration and canal width was found only at L1-L3 level (p < .05, r = -.35). At L1-L3, the canal width cutoff value of .59 allowed the differentiation between asymptomatic and symptomatic patients (area under the curve of .966, p < .0001). CONCLUSION: In achondroplasia, the spinal canal narrowing, due to accelerated degenerative changes, is a predisposing factor of symptomatic lumbar spinal stenosis. Lumbar canal MRI is a helpful tool to detect the risk of the development of neurological symptoms; in adult patients, a stenosis higher than 60% of upper lumbar canal could be a critical value for the onset of neurological symptoms.

Airways and craniofacial assessment in children affected by achondroplasia with and without sleep-disordered breathing: quantitative magnetic resonance study.

PURPOSE: To identify MRI-based quantitative craniofacial variables linked to airways narrowing and obstructive sleep apnea (OSA) development in children with achondroplasia. METHODS: We evaluated skull base and midface MRI in two cohorts of children affected by achondroplasia, with (group 1) or without OSA (group 2). 3DFSPGR-T1weighted images were used to assess airways volume (nasopharynx, oropharynx, and laryngopharynx), jugular foramina (JF) and hypoglossal foramina (HF) areas, foramen magnum area, cervical cord area, and maxillary retrusion (SNA angle). RESULTS: Nineteen out of 27 children with achondroplasia exhibited different degrees of obstructive respiratory impairment (n.4 mild, n.8 moderate, n.7 severe), while 8 children did not show OSA. Each group was compared with age-matched controls without neuroimaging abnormalities. Both groups showed reduced nasopharynx volume, JF areas, and SNA angle, while group 1 showed also reduced oropharynx volume, ratio of FM/cervical cord areas, and HF areas (p < 0.05). A positive correlation between nasopharynx volume and SNA angle was found in both groups, while a positive correlation among upper airways volume, JF and HF areas was found only in group 1. No correlation between upper airways volume and OSA severity was found. CONCLUSION: In children with achondroplasia, multifaced craniofacial abnormalities contribute to airways volume reduction predisposing to sleep disordered breathing. MRI-based quantitative assessment allows the appraisal of craniofacial variables linked to the development of sleep-disordered breathing such as FM stenosis, jugular and hypoglossal foramina stenosis, and retruded maxillary position and may be a valuable tool for clinical surveillance.

Metabolic profiling of Costello syndrome: Insights from a single-center cohort.

Costello syndrome (CS) is a rare disorder caused by activating dominantly acting germline variants in the HRAS gene. CS is defined by a clinical phenotype characterized by a distinctive gestalt, multiple congenital anomalies, and increased risk to develop tumors. Hypoglycemia and hypercholesterolemia have been reported to occur in affected individuals, but the underlying molecular events remain to be characterized. Here, we provided data on glucose/lipid metabolism and amino acid profile of a large single-center cohort of individuals affected by CS to systematically assess the extent of metabolic dysregulation characterizing this disorder and optimize patient management.

Prevalence of bladder cancer in Costello syndrome: New insights to drive clinical decision-making.

Costello syndrome (CS) is a rare disorder affecting development and growth characterized by cancer predisposition and caused by mutations in HRAS proto-oncogene. Somatic HRAS mutations drive bladder carcinogenesis. The aim of this study was to analyze prevalence and histological characterization of bladder cancer (BC) in a cohort of patients with CS to help clinicians plan effective management strategies. This study included 13 patients above 10 years of age with molecular diagnosis of CS. Screening cystoscopies (31 total procedures) were performed to exclude BC. Any lesion was analyzed through cold-cup biopsy or trans-urethral resection of the bladder. According to histology, patients were followed-up with urinalysis and abdominal ultrasound yearly, and cystoscopies every 12-24 months. During study enrollment, bladder lesions (often multifocal) were detected in 11/13 patients. Histological analysis documented premalignant lesions in 90% of cystoscopies performed, epithelial dysplasia in 71%, and papillary urothelial neoplasm of low-malignant potential in 19%. BC G1/low grade (Ta) were removed in 10%. Overall, 76% of patients showed a bladder lesion at first cystoscopy. The present findings document that individuals with CS aged 10 years and older have high prevalence of bladder lesions (premalignant/malignant), highlighting the importance of personalized screening protocols.

Characterization of bone homeostasis in individuals affected by cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous syndrome (CFCS) is a rare disorder characterized by distinctive craniofacial appearance, cardiac, neurologic, cutaneous, and musculoskeletal abnormalities. It is due to heterozygous mutations in BRAF, MAP2K1, MAP2K2, and KRAS genes, belonging to the RAS/MAPK pathway. The role of RAS signaling in bone homeostasis is highly recognized, but data on bone mineral density (BMD) in CFCS are lacking. In the present study we evaluated bone parameters, serum and urinary bone metabolites in 14 individuals with a molecularly confirmed diagnosis of CFCS. Bone assessment was performed through dual X-ray absorptiometry (DXA); height-adjusted results were compared to age- and sex-matched controls. Blood and urinary bone metabolites were also analyzed and compared to the reference range. Despite vitamin D supplementation and almost normal bone metabolism biomarkers, CFCS patients showed significantly decreased absolute values of DXA-assessed subtotal and lumbar BMD (p ≤ 0.05), compared to controls. BMD z-scores and t-scores (respectively collected for children and adults) were below the reference range in CFCS, while normal in healthy controls. These findings confirmed a reduction in BMD in CFCS and highlighted the importance of monitoring bone health in these affected individuals.

Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by RASopathies: Clinical implications and literature review.

Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype- phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single-center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid-shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.

Hyperactive HRAS dysregulates energetic metabolism in fibroblasts from patients with Costello syndrome via enhanced production of reactive oxidizing species.

Germline-activating mutations in HRAS cause Costello syndrome (CS), a cancer prone multisystem disorder characterized by reduced postnatal growth. In CS, poor weight gain and growth are not caused by low caloric intake. Here, we show that constitutive plasma membrane translocation and activation of the GLUT4 glucose transporter, via reactive oxygen species-dependent AMP-activated protein kinase α and p38 hyperactivation, occurs in primary fibroblasts of CS patients, resulting in accelerated glycolysis and increased fatty acid synthesis and storage as lipid droplets. An accelerated autophagic flux was also identified as contributing to the increased energetic expenditure in CS. Concomitant inhibition of p38 and PI3K signaling by wortmannin was able to rescue both the dysregulated glucose intake and accelerated autophagic flux. Our findings provide a mechanistic link between upregulated HRAS function, defective growth and increased resting energetic expenditure in CS, and document that targeting p38 and PI3K signaling is able to revert this metabolic dysfunction.

Impairment of motor skills in children with achondroplasia-usefulness of brain and cranio-cervical junction evaluation by quantitative magnetic resonance imaging: a case-control study.

BACKGROUND: Most infants and children with achondroplasia show delayed motor skill development; however, some patients may have clinical consequences related to cranio-cervical junction stenosis and compression. PURPOSE: To assess, using brain magnetic resonance imaging (MRI), quantitative variables linked to neuromotor impairment in achondroplasic children. MATERIAL AND METHODS: In total, 24 achondroplasic children underwent pediatric neurological assessment and were grouped in two cohorts according to relevant motor skill impairment. Achondroplasic children with (n=12) and without (n=12) motor symptoms were identified, and brain MRI scans were quantitatively evaluated. 3D fast spoiled gradient echo T1-weighted images were used to assess: supratentorial intracranial volumes (SICV); supratentorial intracranial brain volume (SICBV); SICV/SICBV ratio; posterior cranial fossa volume (PCFV); posterior cranial fossa brain volume (PCBFV); PCFV/PCFBV ratio; ventricular and extra-ventricular cerebrospinal fluid (CSF) volumes; foramen magnum (FM) area; and jugular foramina (JF) areas. RESULTS: In both groups, SICV/SICBV ratio, supratentorial ventricular and extra-ventricular space volumes were increased while SICBV was increased only in the asymptomatic group (P < 0.05). PCFV/PCFBV ratio, IV ventricle, infratentorial extra-ventricular spaces volumes were reduced (P < 0.05) in the symptomatic group while PCFBV was increased only in the asymptomatic group (P < 0.05). Foramen magnum (FM) area was more reduced in the symptomatic group than the asymptomatic group (P < 0.05) but no correlation between FM area and ventriculomegaly was found (P > 0.05). CONCLUSION: Evaluation of the FM area together with infratentorial ventricular and extra-ventricular space volume reduction may be helpful in differentiating patients at risk of developing motor skill impairment. Further investigation is needed to better understand the temporal profile between imaging and motor function in order to propose possible personalized surgical treatment.