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. Moreover, a prompt diagnosis is frequently delayed by the negative selection of trisomic cells in blood, with mosaicism percentage varying among tissues, which often entails the need for further testing. Purpose/topic: The aim of our work is to provide assistance in prenatal and postnatal genetic counseling by systematically delineating the current knowledge of the condition. This entails defining the prenatal and postnatal characteristics of the condition and presenting novel data from three cases, both prenatally and postnatally. Additionally, we report the developmental outcomes observed in two new patients.

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.

Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy.

The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.

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.

Changes in clinical, demographic, and outcome patterns of children hospitalized with non-SARS-CoV-2 viral low respiratory tract infections before and during the COVID pandemic in Rome, Italy.

INTRODUCTION: We performed this study aiming to evaluate changes in epidemiology, clinical presentation and outcomes of children hospitalized for viral lower respiratory tract infections (LRTI). METHODS: We performed a retrospective study of children younger than 18 years of age hospitalized for LRTIs with a positive respiratory viral testing from 2018 to 2022. We compared need of pediatric intensive care unit (PICU), invasive ventilation, and other respiratory support, viral etiologies, clinical presentations, imaging, and laboratory results in the precovid (2018-2019) and covid (2020-2022) period. RESULTS: A total of 523 were included in the analysis. In the pandemic period, the detection of influenza was 95% less likely to occur (odds ratio [OR]: 0.05; 95% confidence interval [95% CI]: 0.02-0.12; p < .001), likewise the detection of adenovirus was 77% less likely to occur (OR: 0.23; 95% CI: 0.10-0.51; p < .001). In the pandemic period, the number of codetections increased from 15.52% in 2018 to 57.25% in 2022, resulting in a significantly increasing trend (p < .001). The odds of transfer to PICU was more than five times greater during the pandemic period (OR: 5.31; 95% CI: 1.78-15.86; p = .003). CONCLUSIONS: We found that the pattern of LRTI in children during COVID-19 pandemic significantly changed in terms of etiologies and increased severity.

Artificial Intelligence Procedure for the Screening of Genetic Syndromes Based on Voice Characteristics.

Perceptual and statistical evidence has highlighted voice characteristics of individuals affected by genetic syndromes that differ from those of normophonic subjects. In this paper, we propose a procedure for systematically collecting such pathological voices and developing AI-based automated tools to support differential diagnosis. Guidelines on the most appropriate recording devices, vocal tasks, and acoustical parameters are provided to simplify, speed up, and make the whole procedure homogeneous and reproducible. The proposed procedure was applied to a group of 56 subjects affected by Costello syndrome (CS), Down syndrome (DS), Noonan syndrome (NS), and Smith-Magenis syndrome (SMS). The entire database was divided into three groups: pediatric subjects (PS; individuals < 12 years of age), female adults (FA), and male adults (MA). In line with the literature results, the Kruskal-Wallis test and post hoc analysis with Dunn-Bonferroni test revealed several significant differences in the acoustical features not only between healthy subjects and patients but also between syndromes within the PS, FA, and MA groups. Machine learning provided a k-nearest-neighbor classifier with 86% accuracy for the PS group, a support vector machine (SVM) model with 77% accuracy for the FA group, and an SVM model with 84% accuracy for the MA group. These preliminary results suggest that the proposed method based on acoustical analysis and AI could be useful for an effective, non-invasive automatic characterization of genetic syndromes. In addition, clinicians could benefit in the case of genetic syndromes that are extremely rare or present multiple variants and facial phenotypes.

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.

Validation and cross-cultural adaptation of the Italian version of the paediatric eating assessment tool (I-PEDI-EAT-10) in genetic syndromes.

BACKGROUND: The Pediatric Eating Assessment Tool (PEDI-EAT-10) is a reliable and valid tool for rapid identification of dysphagia in patients aged 18 months to 18 years. AIMS: To translate and adapt the PEDI-EAT-10 into the Italian language and evaluate its validity and reliability. METHODS & PROCEDURES: The translation and cross-cultural adaptation of the tool consisted of five stages: initial translation, synthesis of the translations, back translation, expert committee evaluation and test of the prefinal version. The internal consistency of the translated tool was analysed in a clinical group composed of 200 patients with special healthcare needs aged between 18 months and 18 years. They were consecutively enrolled at the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome. For test-retest reliability, 50 caregivers filled in the PEDI-EAT-10 questionnaire for a second time after a 2-week period. Construct validity was established by comparing data obtained from patients with data from healthy participants (n = 200). The study was approved by the local ethics committee. OUTCOMES & RESULTS: Psychometric data obtained from patients (104 M; mean age = 8.08 ± 4.85 years; median age = 7 years) showed satisfactory internal consistency (Cronbach's α = 0.89) and test-retest reliability (Pearson r = 0.99; Spearman r = 0.96). A total of 30% of children were classified as having a high risk of penetration/aspiration. The Italian PEDI-EAT-10 mean total score of the clinical group was significantly different from that resulting from healthy participants. CONCLUSIONS & IMPLICATIONS: The PEDI-EAT-10 was successfully translated into Italian, validated and found to be a reliable one-page rapid screening tool to identify dysphagia in children and adolescents with special needs. WHAT THIS PAPER ADDS: What is already known on the subject The PEDI-EAT-10 is a valid and reliable quick discriminative paediatric tool for identifying penetration/aspiration risks. What this paper adds to the existing knowledge In the present study we successfully translated and adapted the PEDI-EAT-10 into the Italian language. What are the potential or actual clinical implications of this work? This translation and adaptation increase access to valid feeding and swallowing assessment for children of Italian-speaking families. In addition, the I-PEDI-EAT-10 can suggest further assessment of patients' swallowing abilities.

From Feeding Challenges to Oral-Motor Dyspraxia: A Comprehensive Description of 10 New Cases with CTNNB1 Syndrome.

CTNNB1 syndrome is an autosomal-dominant neurodevelopmental disorder featuring developmental delay; intellectual disability; behavioral disturbances; movement disorders; visual defects; and subtle facial features caused by de novo loss-of-function variants in the CTNNB1 gene. Due to paucity of data, this study intends to describe feeding issues and oral-motor dyspraxia in an unselected cohort of 10 patients with a confirmed molecular diagnosis. Pathogenic variants along with key information regarding oral-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). Mild-to-severe coordination difficulties in single or in a sequence of movements involving the endo-oral and peri-oral muscles were noticed across the entire cohort. Mild-to-profuse drooling was a commonly complained-about issue by 30% of parents. The mean total I-MCH-FS t-score equivalent was 43.1 ± 7.5. These findings contribute to the understanding of the CTNNB1 syndrome highlighting the oral motor phenotype, and correlating specific gene variants with clinical characteristics.

Systematic ophthalmologic evaluation in cardio-facio-cutaneous syndrome: A genotype-endophenotype correlation.

Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder belonging to the RASopathies, a group of developmental syndromes caused by upregulated RAS/MAPK signaling. Pathogenic variants affecting four genes, KRAS, BRAF, MAP2K1 and MAP2K2, encoding core signal transducers of the pathway, underlie the condition. Major clinical features include a distinctive facies, ectodermal and cardiac anomalies, reduced postnatal growth, intellectual disability, and musculoskeletal abnormalities. Similar to other RASopathies, reports of visual impairment, high refractive error, optic nerve pallor, and other ocular abnormalities have been anecdotally reported in the literature. The aim of our study is to report the prevalence of ophthalmologic abnormalities in a large monocentric cohort of individuals affected by CFCS and explore the occurrence of genotype-endophenotype correlations in this series of patients. We observed that BRAF mutations are associated to a higher prevalence of anisometropia >3D (11.8% vs. 0%) and high astigmatism (29.4% vs. 0%; both p < 0.001) while patients with mutations in other genes had a significantly higher prevalence of myopia >6 D (60% vs. 5.9%; p = 0.012). Pale optic disc was associated with higher prevalence of inferior oblique muscle (IO) overaction (33.3% vs. 0%) and lower prevalence of ptosis (0% vs. 11.8%; both p < 0.001). Combined exotropia, IO overaction and nystagmus were frequent in patients with pale optic nerve. Our findings might suggest the need for earlier ophthalmologic referral for CFCS patients due to high risk of amblyopia, especially those expressing BRAF mutations.

Acute and post-acute multidisciplinary outcomes of newborns born from mothers with SARS-CoV-2 infection during pregnancy or the perinatal period.

INTRODUCTION: We performed a single-center, prospective, observational study of newborns born from mothers with microbiologically confirmed SARS-CoV-2 infection in pregnancy or at time of delivery to evaluate acute and mid-term multidisciplinary outcomes. METHODS: Infants were offered a multidisciplinary follow-up consisting of nasopharyngeal Polymerase Chain Reaction test at birth and at 48-72 h of life, auxological and ophthalmological assessments, and serologic testing. RESULTS: 791 women and their 791 children (52.3% males) were included. Most placentas (94.9%) had abnormal inflammatory findings. 171 (27.3%) and 36 (13.7%) children respectively had pathological TEOAEs in at least one ear and bilaterally, while only four of the 85 children that underwent ABR had pathological findings (4.7%). 64 children underwent fluorescein angiography, which resulted pathological only in 1 case (1.6%). Anti-SARS-CoV-2 IgGs were found in up to 60% of children tested at six months of age. Our findings showed no association between the maternal vaccination status or the presence of maternal symptoms during pregnancy and neonatal outcomes. CONCLUSIONS: Our study shows that the large majority of newborns exposed to SARS-CoV-2 infection in utero or during the first hours of life have optimal outcomes. Our previous report of abnormal ophthalmologic findings was not confirmed on a larger cohort, while further studies are needed to better characterize audiological outcomes. Further prospective, case-controlled studies are still needed.

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.

Metabolic Profile of Patients with Smith-Magenis Syndrome: An Observational Study with Literature Review.

Background: Smith-Magenis syndrome (SMS) is caused by either interstitial deletions in the 17p11.2 region or pathogenic variants in the RAI1 gene and is marked by a distinct set of physical, developmental, neurological, and behavioral features. Hypercholesterolemia has been described in SMS, and obesity is also commonly found. Aim: To describe and characterize the metabolic phenotype of a cohort of SMS patients with an age range of 2.9-32.4 years and to evaluate any correlations between their body mass index and serum lipids, glycated hemoglobin (HbA1c), and basal insulin levels. Results: Seven/thirty-five patients had high values of both total cholesterol and low-density lipoprotein cholesterol; 3/35 had high values of triglycerides; none of the patients with RAI1 variants presented dyslipidemia. No patients had abnormal fasting glucose levels. Three/thirty-five patients had HbA1c in the prediabetes range. Ten/twenty-two patients with 17p11.2 deletion and 2/3 with RAI1 variants had increased insulin basal levels. Three/twenty-three patients with the 17p11.2 deletion had prediabetes. Conclusion: Our investigation suggests that SMS 'deleted' patients may show a dyslipidemic pattern, while SMS 'mutated' patients are more likely to develop early-onset obesity along with hyperinsulinism.

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.

Congenital heart defects in CTNNB1 syndrome: Raising clinical awareness.

CTNNB1 [OMIM *116806] encodes ß-catenin, an integral part of the cadherin/catenin complex, which functions as effector of Wnt signaling. CTNNB1 is highly expressed in brain as well as in other tissues, including heart. Heterozygous CTNNB1 pathogenic variations are associated with a neurodevelopmental disorder characterized by spastic diplegia and visual defects (NEDSDV) [OMIM #615075], featuring psychomotor delay, intellectual disability, behavioral disturbances, movement disorders, visual defects and subtle facial and somatic features. We report on a new series of 19 NEDSDV patients (mean age 10.3 years), nine of whom bearing novel CTNNB1 variants. Notably, five patients showed congenital heart anomalies including absent pulmonary valve with intact ventricular septum, atrioventricular canal with hypoplastic aortic arch, tetralogy of Fallot, and mitral valve prolapse. We focused on the cardiac phenotype characterizing such cases and reviewed the congenital heart defects in previously reported NEDSDV patients. While congenital heart defects had occasionally been reported so far, the present findings configure a higher rate of cardiac anomalies, suggesting dedicated heart examination to NEDSDV clinical management.

The "FEEDS (FEeding Eating Deglutition Skills)" over Time Study in Cardiofaciocutaneous Syndrome.

Feeding, eating and deglutition difficulties are key concerns in patients with cardiofaciocutaneous syndrome (CFCS). This study intends to quantify the development of feeding skills from birth to adulthood in patients with CFCS. Twenty-seven patients (eight males; mean age: 16.7 ± 8.3 years; median age: 15 years, age range: 1.5-38 years) with molecularly confirmed clinical diagnosis of CFCS were prospectively recruited from the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome, Italy, over a one-year period. Pathogenic variants along with key information regarding oro-motor features were collected. Sialorrhea was quantified using the Drooling Quotient 5. Feeding abilities were screened using the Italian version of the Montreal Children's Hospital Feeding Scale (I-MCH-FS). The oral sensory processing section of the Sensory Profile completed the assessment. Mild-to-profuse drooling was experienced by 25% of patients, and food taste selectivity was a constant during infancy (65%), with persistence even beyond adolescence. Nineteen percent of participants with long-term enteral feeding dependency had BRAF, KRAS and MAP2K1 mutations. These findings document that mealtime challenges in CFCS do not remain restricted only to the paediatric age, and that supportive care until adulthood plays a key role.

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.

Acrodermatitis enteropathica during parenteral nutrition: a pediatric case report.

Background and aim Acrodermatitis enteropathica is a rare disorder characterized by the triad composed by dermatitis, alopecia and diarrhoea. Its acquired form can be caused by inadequate zinc intake, malabsorptive processes, excessive renal or intestinal loss. A rare cause of acquired zinc deficiency is iatrogenic nutritional deficiency due to parenteral nutrition. The diagnosis can be really difficult because the early clinical signs are non-specific and patient's eventual comorbidities can often mask symptoms. Methods: A 5-years-old child affected by several comorbidities, consequent to C. Koseri meningo-encephalitis occurred in the neonatal period, was admitted to Pediatric ward for acute pancreatitis and  had been fed via total parenteral nutrition for one month. Symptoms started approximately 15 days after the start of a  standardized parenteral nutrition mixture. The child presented with diarrhoea, alopecia and erythematous bullous skin lesions, distributed predominantly in acral and periorificial sites and not responsive to topical treatments. Zinc serum dosage were very low (10 µg/dL, with normal values 68-107 µg/dL). Clinical improvement was very fast after oral zinc supplementation (5mg/daily), with a rapid regularisation in the intestinal habits and re-epithelialization of the skin lesions. Results and Conclusions: Trace elements are an essential component of parenteral nutrition. The supplementation of trace elements is an important part of the parenteral nutrition prescription. Even few days of zinc shortage, especially in frail patients, may cause a severe dermatitis that can be easily prevented. Despite its rarity, acrodermatitis enteropathica should be strongly considered in the differential diagnosis of skin lesions for these patients.

Case report: Post-COVID new-onset neurocognitive decline with bilateral mesial-temporal hypometabolism in two previously healthy sisters.

Background: Long coronavirus disease (COVID) is increasingly recognized in adults and children; however, it is still poorly characterized from a clinical and diagnostic perspective, particularly in the younger populations. Case presentation: We described the story of two sisters-with high social and academic performance before their severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-who reported severe neurocognitive problems, initially classified as psychologic pandemic distress and eventually found to have significant brain hypometabolism. Conclusions: We provided a detailed clinical presentation of neurocognitive symptoms in two sisters with long COVID associated with brain hypometabolism documented in both sisters. We believe that the evidence of objective findings in these children further supports the hypothesis that organic events cause persisting symptoms in a cohort of children after SARS-CoV-2 infection. Such findings highlight the importance of discovering diagnostics and therapeutics.