Phenotype assessment in neurologically impaired paediatric patients: Impact of a nutrition intervention protocol.

BACKGROUND: Deficits in nutritional status and functional feeding disorders are common in Neurologically Impaired Paediatric Patients (NIPP). Interventions addressing these problems could offer better overall health status and quality of life in this group of patients, but the extent of their effectiveness is yet to be determined. Recent guidelines concerning the nutritional care of NIPP have been published from ESPGHAN but compliance to them has not been assessed. AIM: The study aimed to assess the phenotypic profile of a group of NIPP attending the outpatient clinic of a pediatric department, and to implement, for the first time to our knowledge, an individualized nutritional intervention protocol following ESPGHAN guidelines 2017 as well as to assess the impact on phenotypic parameters and nutritional status. PATIENTS AND METHODS: 68NIPP and their caregivers aged 1m-17 years (83.8% suffering from cerebral palsy (CP) were invited to assess their phenotypic parameters and to implement in a nutrition intervention protocol in order to improve their dietary intake and nutritional status. Anthropometry (weight, height, triceps skinfold thickness, mid upper arm circumference) was expressed as z-scores for age and sex using WHO Anthro software and classified following the WHO criteria. Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), Dysphagia Disorder Survey (DDS), Saliva Severity Scale (SSS), gastrointestinal complications, energy and nutrient intake were assessed at the beginning (zero point), after 6 (point 1) and 12 (point 2) months period. Intake to Requirement ratio (I/R) was derived. At zero point, following the baseline evaluation, caregivers were advised and educated on nutrition protocol and customized nutrition plans were handed out. The impact of the nutritional intervention on the phenotypic parameters was recorded on follow up visits (points 1, 2).The primary outcomes analyzed were anthropometric parameters (Waz), as indicators of nutritional status. GMFCS, MACS, DDS, SSS, FA were evaluated as possible predictors of this outcome. Secondary outcomes included the impact of the intervention protocol on the phenotypic parameters during the study period. RESULTS: Based on weight for age z-score (Waz ≤ -2) (WHO) 17 patients (32.1%) were undernourished, 5/68 (10, 4%) were with triceps skinfold thickness z-score (TSTz) <-2 and 3/68 (7%) with mid upper arm circumference z-score (MUACz) <-2. Z-scores (WHO) for weight (p1 = 0, 036) (p2 = 0, 003), body mass index (BMI) (p2 = 0,000), MUAC (p1 = 0, 029) and TST (p1 = 0, 021) (p3 = 0, 044) were significantly improved in follow-up evaluations compared to the baseline. Less NIPP were found to be underweight according to Waz from point 1 to point 2 (p3 = 0, 006), as well as stunding according to height for age z-score (Haz) from point 1 to point 2 (p ≤ 0,001). Patients with higher levels of GMFCS (p1 = 0,040), MACS (p1 = 0,028) DDS (p1 = 0,001) and SSS (p1 = 0,005) had significantly lower Haz. Patients with higher levels of SSS (p1 = 0,002) had significantly lower TSTz scores. There were no significant changes in the classification of NIPP according to DDS or the patients' feeding ability. The energy (kcals) intake/kg of body weight (bw) was significantly higher at point 2 compared to point zero (p3 = 0,028), protein intake/kg of body weight was significantly higher at points 1 and 2 compared to point zero (p1 = 0,026, p3 = 0,003), and fat intake/kg of body weight (bw) was significantly higher at point 2 compared to point zero (p3 = 0,012). Intake of energy (kcals)/bw (p1 = 0,026), (p2 = 0,046), (p3 = 0,048) carbs/bw (p1 = 0,014) (p2 = 0,042), I/R of pro (p1 = 0,032), (p3 = 0,013), and fat/kg (p2 = 0, 033) (p3 = 0,037) were found to be significantly lower in higher GMFCS levels. DQI did not improve during the study period nor correlated to any of the anthropometric parameters. Gastrointestinal complications correlated with Waz (r = -, 285 p1 = 0, 011). Feeding Ability (FA) was found to be the only strong predictor for Waz at baseline evaluation (p = 0,012) when a multiple regression was run along with DDS. CONCLUSION: Underweight was detected in one third of the patients, some degree of dysphagia in 69% and gastrointestinal complications in 58.8% of the sample. Height for age z-score (Haz) was the anthropometric parameter most sensitive to the changes in ranking on motor and functional feeding scores. The implementation of a customized nutrition intervention protocol in line with ESPGHAN's guidelines had a beneficial effect on improving dietary intake and nutritional status of NIPP after a 12 months period. Better results could be expected if dysphagia and feeding ability were also addressed by appropriate intervention protocols. Patients' feeding ability is of importance for predicting Waz.

Hemolytic Uremic Syndrome Due to Methylmalonic Acidemia and Homocystinuria in an Infant: A Case Report and Literature Review.

Methylmalonic acidemia and homocystinuria cobalamin C (cblC) type is the most common inborn error of the intracellular cobalamin metabolism, associated with multisystem involvement and high mortality rates, especially in the early-onset form of the disease. Hemolytic uremic syndrome (HUS) is a rare manifestation and needs to be distinguished from other causes of renal thrombotic microangiopathy. We describe a case of a 3-month-old infant, with failure to thrive, hypotonia and pallor, who developed HUS in the setting of cblC deficit, along with dilated cardiomyopathy, and presented delayed response to optic stimulation in visual evoked potentials, as well as enlarged bilateral subarachnoid spaces and delayed myelination in brain magnetic resonance imaging. Renal damage was reversed, while neurodevelopmental profile and eye contact improved after supplementation with parenteral hydroxycobalamin, oral folic acid, betaine and levocarnitine. Homozygous mutation of c.271dupA in the MMACHC gene was ultimately detected. In this report, we highlight the diagnostic challenges as well as the significance of early recognition and multidisciplinary management of this unusual condition. A brief review of published case reports of early-onset cblC deficit and related HUS is depicted, pointing out the initial clinical presentation, signs of renal damage and outcome, MMACHC gene type of mutations and accompanying extra-renal manifestations.

Transient Severe Liver Injury: A Unique Presentation of COVID-19 Disease in a Pediatric Patient.

Liver dysfunction is highlighted by several studies as a relevant complication in the context of coronavirus disease 2019 (COVID-19). We present a pediatric patient with mild phenotype but transient severe liver injury. Hepatic damage should be considered even in mild cases of the disease to ensure prompt recognition and management.

Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder.

Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level. The patient exhibited early-onset neurometabolic abnormality culminating in severe brain atrophy and dystonia leading to death by the age of 3.5 years. Urine and plasma metabolite profiling was consistent with SUCL deficiency which was confirmed by enzyme analysis and lack of mitochondrial substrate-level phosphorylation (mSLP) in skin fibroblasts. Oxygen consumption- but not extracellular acidification rates were altered only when using glutamine as a substrate, and this was associated with mild mtDNA depletion and no changes in ETC activities. Immunoblot analysis revealed no detectable levels of SUCLG1, while SUCLA2 and SUCLG2 protein expressions were largely reduced. Confocal imaging of triple immunocytochemistry of skin fibroblasts showed that SUCLG2 co-localized only partially with the mitochondrial network which otherwise exhibited an increase in fragmentation compared to control cells. Our results outline the catastrophic consequences of the mutated SUCLG1 leading to strongly reduced SUCL activity, mSLP impairment, mislocalization of SUCLG2, morphological alterations in mitochondria and clinically to a severe neurometabolic disease, but in the absence of changes in mtDNA levels or respiratory complex activities.

Arterial Stiffness in a Toddler with Neurofibromatosis Type 1 and Refractory Hypertension.

Arterial hypertension is a common finding in patients with neurofibromatosis (NF) type 1. Renovascular hypertension due to renal artery stenosis or midaortic syndrome could be the underlying cause. We report the case of a 4-year-old girl with NF type 1 and midaortic syndrome whose changes in blood pressure and pulse wave velocity suggested the evolution of vasculopathy, diagnosis of renovascular hypertension, and provided insights of response to treatment. Hypertension persisted after percutaneous transluminal angioplasty in the abdominal aorta, requiring escalation of antihypertensive treatment, while arterial stiffness demonstrated a mild decrease. Regular assessment of blood pressure using ambulatory blood pressure monitoring and noninvasive assessment of arterial stiffness may enhance the medical care of patients with NF type 1.

Multiple Coronary Artery Microfistulas in a Girl with Kleefstra Syndrome.

Kleefstra syndrome is characterized by hypotonia, developmental delay, dysmorphic features, congenital heart defects, and so forth. It is caused by 9q34.3 microdeletions or EHMT1 mutations. Herein a 20-month-old girl with Kleefstra syndrome, due to a de novo subterminal deletion, is described. She exhibits a rare and complex cardiopathy, encompassing multiple coronary artery microfistulas, VSD/ASD, and PFO.

Nephrocalcinosis and Renal Failure in Lesch-Nyhan Syndrome: Report of Two Familial Cases and Review of the Literature.

Lesch-Nyhan syndrome is an X-linked recessive inborn error of purine metabolism, due to deficiency of the enzyme HPRT (hypoxanthine-guanine phosphoribosyl transferase) and underlying HPRT gene mutations (over 300 mutations identified up to date). It is characterized by a wide range of neurological symptoms and signs (mainly a combination of spastic diplegia with choreoathetosis and an overall psychomotor redardation). Herein, we report of two cousins with Lesch-Nyhan syndrome and a confirmed novel HPRT gene mutation: c.65T>C, who both developed nephrocalcinosis and renal failure, findings not been previously published in children with HPRT deficiency.

Brainstem Auditory Evoked Potentials in Boys with Autism: Still Searching for the Hidden Truth.

OBJECTIVE: Brainstem auditory evoked potentials (BAEPs) have long been utilized in the investigation of auditory modulation and, more specifically, auditory brainstem functions in individuals with autism. Although most investigators have reported significant abnormalities, no single BAEPs pattern has yet been identified. The present study further delineates the BAEPs deficits among subjects with autism. MATERIALS & METHODS: BAEPs were recorded in 43 male patients, aged 35-104 months, who underwent standard evaluations after receiving a diagnosis of autism. The control group consisted of 43 age-matched typically developing boys. The study took place in a tertiary neurodevelopmental center over a period of two years. RESULTS: The mean values of all absolute and/or interpeak latencies were longer in patients when compared to controls, albeit the differences were not significant for any of the parameters. Prolonged or shortened absolute/interpeak latencies (control group mean ± 2.5SD) were unilaterally or bilaterally identified in 33% of patients, compared to 9% of controls. The most frequent findings included prolongation of absolute latencies I, V and III, followed by shortening of interpeak latency I-V. In addition, abnormalities (either shortening or prolongation) of absolute latencies I and V, as well as interpeak latency I-V, were significantly more common among patients. Taken together, BAEPs in 23% of patients were indicative of a clinically abnormal response in 32% of patients. CONCLUSION: As can be easily concluded, BAEPs abnormalities characterize only a subset of subjects with autism, who may be important to identify clinically. The latter individuals may benefit from targeted intervention to utilize brainstem plasticity.

Association between iron deficiency and febrile seizures.

OBJECTIVE: The relationship between iron status and febrile seizures has been examined in various settings, mainly in the Developing World, with conflicting results. The aim of this study was to investigate any association between iron deficiency and febrile seizures (FS) in European children aged 6-60 months. DESIGN: Prospective, case-control study. SETTING: Greek population in Thessaloniki. PATIENTS: 50 patients with febrile seizures (cases) and 50 controls (children presenting with fever, without seizures). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Haematologic parameters (haemoglobin concentration, haematocrit, mean corpuscular volume, red cell distribution width), plasma iron, total iron-binding capacity, plasma ferritin, transferrin saturation and soluble transferrin receptors were compared in cases and controls. RESULTS: Plasma ferritin was lower (median [range]: 42.8 (3-285.7) vs 58.3 (21.4-195.3 ng/ml; p = 0.02) and Total Iron Binding Capacity (TIBC) higher (mean [Standard Deviation] 267 [58.9] vs 243 [58.45] µg/dl, p = 0.04) in cases than in controls. Results were similar for 12 complex FS cases (ferritin 30 (3-121 vs 89 (41.8-141.5ng/lL; TIBC 292.92 [68.0] vs 232.08 [36.27] µg/dL). Iron deficiency, defined as ferritin <30 ng/ml, was more frequent in cases (24%) than controls (4%; p = 0.004). Ferritin was lower and TIBC higher in 18 with previous seizures than in 32 with a first seizure although haemoglobin and mean cell haemoglobin concentration were higher. CONCLUSIONS: European children with febrile seizures have lower Ferritin than those with fever alone, and iron deficiency, but not anaemia, is associated with recurrence. Iron status screening should be considered as routine for children presenting with or at high risk for febrile seizures.

Growth hormone replacement therapy in Costello syndrome.

Costello syndrome (CS) is considered an overgrowth disorder given the macrosomia that is present at birth .However, shortly after birth the weight drops dramatically and the patients are usually referred for failure to thrive. Subsequently, affected patients develop the distinctive coarse facial appearance and are at risk for cardiac anomalies and solid tumor malignancies. Various endocrine disorders, although not very often, have been reported in patients with CS, including growth hormone deficiency, hypoglycemia, ACTH deficiency, cryptorchidism and hypothyroidism. We report a case of Costello syndrome with hypothyroidism, cryptorchidism and growth hormone deficiency and we evaluate the long-term safety and efficacy of growth hormone replacement therapy. The index patient is a paradigm of successful and safe treatment with growth hormone for almost 7 years. Since patients with CS are at increased risk for cardiac myopathy and tumor development they deserve close monitoring during treatment.

Moyamoya syndrome and neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is the most prevalent autosomal dominant genetic disorder among humans. NF1 vasculopathy is a significant but underrecognized complication of the disease, affecting both arterial and venous blood vessels of all sizes. Moyamoya syndrome is a cerebral vasculopathy that is only rarely observed in association with NF1, particularly in the pediatric age range. Herein, we report of a 5-year-old female with NF1 and moyamoya syndrome and we briefly review the existing literature.

Early-onset diabetes mellitus and neurodevelopmental retardation: the first Greek case of Wolcott-Rallison syndrome.

Wolcott-Rallison syndrome (WRS) is a very rare genetic disorder, which is transmitted by autosomal recessive inheritance and results from mutations in the gene encoding the eukaryotic initiation factor 2-α kinase-3 (EIF2AK3). The cardinal features of the syndrome include early-onset insulin-dependent diabetes mellitus, multiple epiphyseal dysplasia, and growth retardation. We present the case of a 13-year-old Greek boy with a known history of infancy-onset diabetes mellitus and was found to have WRS at the age of 4 years. He presented with acute liver and renal insufficiency in addition to skeletal dysplasia and neurodevelopmental retardation. The clinical suspicion of WRS was confirmed by molecular analysis of the EIF2AK3 gene. The patient was found to be a compound heterozygote with two different novel mutations (c.2776C>T, p.R902X and c.3038A>G, p.Y989C). The current patient is one of the longer survivors.

Severe clinical presentation in monozygotic twins with 10p15.3 microdeletion syndrome.

Submicroscopic deletion of 10p15.3 is a rare genetic disorder, currently reported in 21 unrelated patients. It is mainly associated with cognitive deficits, speech disorders, motor delay and hypotonia. The size of the deleted region ranges between 0.15 and 4 Mb and does not generally correlate with phenotype. A monozygotic female twin pair with a de novo 2.7 Mb deletion of 10p15.3 is herein reported. The girls presented at the age of 8 months with severe developmental delay and failure to thrive since the first month of life. Their perinatal and family history was unremarkable. On admission they both exhibited generalized dystonia, microcephaly, complete absence of voluntary movements and visual/auditory unresponsiveness. Their brain MRIs demonstrated dilatation of ventricles, subarachnoid spaces and anterior interhemispheric fissure and sylvian fissures bilaterally. Cranial radiography revealed partial fusion of both coronal sutures. Visual and brainstem auditory evoked potentials were markedly abnormal, indicating severe visual and sensorineural hearing impairment. The electroencephalogram, as well as a screening for inborn errors of metabolism, were unremarkable. Both patients required gastrostomy and tracheostomy before the age of 1 year. They were, additionally, managed with physical therapy, as well as baclofen and low-dose haloperidol. Their current state at the age of 2 years is relatively stable. The index patients' phenotype includes features, such as dystonic cerebral palsy, visual and sensorineural hearing impairment or craniosynostosis, which have not been previously reported in individuals with 10p15.3 deletion. It is necessary to consider these novel clinical features and investigate their possible relationship with the recently recognized syndrome.

Autism spectrum disorders: the quest for genetic syndromes.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disabilities with various etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of ASD remains unclear. A number of genetic syndromes manifest ASD at higher than expected frequencies compared to the general population. These syndromes account for more than 10% of all ASD cases and include tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Williams, Duchenne, etc. Clinicians are increasingly required to recognize genetic disorders in individuals with ASD, in terms of providing proper care and prognosis to the patient, as well as genetic counseling to the family. Vice versa, it is equally essential to identify ASD in patients with genetic syndromes, in order to ensure correct management and appropriate educational placement. During investigation of genetic syndromes, a number of issues emerge: impact of intellectual disability in ASD diagnoses, identification of autistic subphenotypes and differences from idiopathic autism, validity of assessment tools designed for idiopathic autism, possible mechanisms for the association with ASD, etc. Findings from the study of genetic syndromes are incorporated into the ongoing research on autism etiology and pathogenesis; different syndromes converge upon common biological backgrounds (such as disrupted molecular pathways and brain circuitries), which probably account for their comorbidity with autism. This review paper critically examines the prevalence and characteristics of the main genetic syndromes, as well as the possible mechanisms for their association with ASD.

Pontocerebellar hypoplasia in extreme prematurity: clinical and neuroimaging findings.

The involvement of the cerebellum in unfavorable outcomes of extreme prematurity is increasingly recognized. Evidence implicates both cerebellar injury and cerebellar growth failure, which, along with supratentorial lesions, aggravate motor and developmental outcomes. We describe clinical and neuroradiologic findings of 12 extremely premature patients with acquired pontocerebellar hypoplasia (mean follow-up, 4 years). Patients' neuromotor outcomes involved combined motor abnormalities (spasticity, dystonia, and ataxia), whereas 25% were ambulatory by age 4 years. All patients exhibited developmental delays of variable degrees. One patient died at age 7.5 years. The possible etiopathogenesis, presentations, sequelae, and differential diagnoses of acquired pontocerebellar hypoplasia are discussed.

Recurrent episodes of rhabdomyolysis in pontocerebellar hypoplasia type 2.

Pontocerebellar hypoplasia type 2 is an autosomal recessive disorder characterized by hypoplasia and atrophy of the cerebellum and pons, leading to microcephaly, dystonia/dyskinesia, seizures, and severe cognitive impairment. Until lately it was considered a CNS-refined disease, but recent reports have associated it with muscular defects, as well. A 5-year-old boy with genetically confirmed pontocerebellar hypoplasia type 2 is described. The patient had all the clinical and radiological features of the disease, but he, additionally, exhibited two episodes of rhabdomyolysis precipitated by respiratory infections. The possible mechanisms associating encephalopathy and myopathy in pontocerebellar hypoplasia type 2 are discussed.