Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1.

RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen-activated protein kinase pathway and share overlapping clinical and molecular features. This study is aimed to describe the clinical and molecular features of 38 patients with RASopathies. Sanger or targeted next-generation sequencing of related genes and multiplex ligation-dependent-probe amplification analysis for NF1 were performed. The pathogenic variant detection rate was 94.4%. While PTPN11 was responsible for 50% of 18 patients with Noonan syndrome (NS), SOS1, LZTR1, RIT1, and RAF1 were responsible for the remaining 27.8%, 11.1%, 5.5%, and 5.5%, respectively. Three variants in LZTR1 were novel, of which two were identified in the compound heterozygous state in a patient with intellectual disability and hypertrophic cardiomyopathy, whereas the third variant was found in the heterozygous state in a patient with pulmonary stenosis and normal intelligence. We described pyloric stenosis, knee dislocation, and cleft palate in patients with SOS1, RIT1, and RAF1 variants, respectively, that was not previously reported. We detected a PTPN11 variant in three patients from same family with NS with multiple lentigines. BRAF and MAP2K2 variants were found in eight patients with Cardiofaciocutaneous syndrome. Two variants in HRAS were detected in two Costello syndrome patients, one with a mild and the other with a severe phenotype. While large NF1 deletions were identified in four Neurofibromatosis-NS patients with intellectual disability, intelligence was normal in one patient with missense variant. In conclusion, this study provided three novel variants in LZTR1 and expanded the clinical phenotype of rare RASopathies.

Dietary management of infants and young children with feeding difficulties and unsatisfactory weight gain using a nutritionally complete hypercaloric infant formula. practical considerations from clinical cases.

INTRODUCTION: A decrease in weight velocity and feeding difficulties in infants may be caused by an inadequate caloric intake and underlying medical conditions. CASE DESCRIPTION: By focusing on four clinical cases, this article illustrates the temporary use of a special infant formula in orally-fed and enterally-fed infants with unsatisfactory weight gain and special medical conditions such as gastrointestinal and neurological disorders. The formula was a nutritionally complete hypercaloric infant formula containing partially hydrolyzed whey protein. It was used after full consideration of all feeding options including breastfeeding. CONCLUSION: Implementing appropriate feeding behaviors, adapted to age and potential comorbidities, is an essential prerequisite for therapeutic management. The use of a nutritionally complete hypercaloric infant formula can be helpful to manage unsatisfactory weight gain and feeding difficulties in infants.

Clinical characterization of individuals with the distal 1q21.1 microdeletion.

Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome-wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.

A Novel method for the identification and quantification of weight faltering.

OBJECTIVE: We describe a new method for identifying and quantifying the magnitude and rate of short-term weight faltering episodes, and assess how (a) these episodes relate to broader growth outcomes, and (b) different data collection intervals influence the quantification of weight faltering. MATERIALS AND METHODS: We apply this method to longitudinal growth data collected every other day across the first year of life in Gambian infants (n = 124, males = 65, females = 59). Weight faltering episodes are identified from velocity peaks and troughs. Rate of weight loss and regain, maximum weight loss, and duration of each episode were calculated. We systematically reduced our dataset to mimic various potential measurement intervals, to assess how these intervals affect the ability to derive information about short-term weight faltering episodes. We fit linear models to test whether metrics associated with growth faltering were associated with growth outcomes at 1 year, and generalized additive mixed models to determine whether different collection intervals influence episode identification and metrics. RESULTS: Three hundred weight faltering episodes from 119 individuals were identified. The number and magnitude of episodes negatively impacted growth outcomes at 1 year. As data collection interval increases, weight faltering episodes are missed and the duration of episodes is overestimated, resulting in the rate of weight loss and regain being underestimated. CONCLUSIONS: This method identifies and quantifies short-term weight faltering episodes, that are in turn negatively associated with growth outcomes. This approach offers a tool for investigators interested in understanding how short-term weight faltering relates to longer-term outcomes.

Metabolic reprogramming and epigenetic changes of vital organs in SARS-CoV-2-induced systemic toxicity.

Extrapulmonary manifestations of COVID-19 are associated with a much higher mortality rate than pulmonary manifestations. However, little is known about the pathogenesis of systemic complications of COVID-19. Here, we create a murine model of SARS-CoV-2-induced severe systemic toxicity and multiorgan involvement by expressing the human ACE2 transgene in multiple tissues via viral delivery, followed by systemic administration of SARS-CoV-2. The animals develop a profound phenotype within 7 days with severe weight loss, morbidity, and failure to thrive. We demonstrate that there is metabolic suppression of oxidative phosphorylation and the tricarboxylic acid (TCA) cycle in multiple organs with neutrophilia, lymphopenia, and splenic atrophy, mirroring human COVID-19 phenotypes. Animals had a significantly lower heart rate, and electron microscopy demonstrated myofibrillar disarray and myocardial edema, a common pathogenic cardiac phenotype in human COVID-19. We performed metabolomic profiling of peripheral blood and identified a panel of TCA cycle metabolites that served as biomarkers of depressed oxidative phosphorylation. Finally, we observed that SARS-CoV-2 induces epigenetic changes of DNA methylation, which affects expression of immune response genes and could, in part, contribute to COVID-19 pathogenesis. Our model suggests that SARS-CoV-2-induced metabolic reprogramming and epigenetic changes in internal organs could contribute to systemic toxicity and lethality in COVID-19.

DGAT1 mutations leading to delayed chronic diarrhoea: a case report.

BACKGROUND: Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol o-acyltransferase 1 (DGAT1) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period or within 2 months after birth. CASE PRESENTATION: Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea. The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status improved after nutritional therapy, including a fat restriction diet. CONCLUSIONS: This case expanded our knowledge of the clinical features of patients with DGAT1 mutations. Intractable diarrhoea with delayed onset could also be a congenital disorder.

Eficacia y seguridad de somatropina administrada con dispositivo electrónico, en comparación con somatropina administrada sin dispositivo electrónico, en el tratamiento de pacientes pediatricos con deficit de hormona de crecimiento / Efficacy and safety of somatropin administered with an electronic device, compared with somatropin administered without an electronic device, in the treatment of pediatric patients with growth hormone deficiency

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de somatropina administrada con dispositivo electrónico, en comparación con somatropina administrada sin dispositivo electrónico, en el tratamiento de pacientes pediátricos con déficit de hormona del crecimiento. Una falla específica en la glándula pituitaria genera una deficiencia de hormona del crecimiento (DHC), que es la causa endocrina más común de baja estatura. Se estima que la incidencia de baja estatura asociada a DHC se encuentra alrededor de 1:4000 a 1:10000 en niños. Así, el tratamiento estándar para la población pediátrica con falla en el crecimiento por DHC es la terapia hormonal de reemplazo con hormona de crecimiento (HC) sintética, llamada somatropina. En la actualidad EsSalud cuenta con somatropina en polvo liofilizado para solución inyectable para el tratamiento de pacientes pediátricos con baja estatura asociada a DHC. La concentración de somatropina disponible en la institución corresponde a un vial de 10 UI, en una presentación sin dispositivo electrónico para aplicación. El procedimiento actual para la aplicación de las dosis requeridas (i.e., 0.025-0.035 mg/kg/día), es que los padres o cuidadores del paciente preparen las ampollas e inyecten el medicamento utilizando una jeringa común. No obstante, algunos especialistas de la institución manifiestan dos preocupaciones con respecto a este procedimiento. Por un lado, mencionan que la dificultad en la preparación y aplicación asociadas a este proceso puede impactar sobre la precisión en las dosis inyectadas, lo que podría llevar a la aplicación de dosis sub-optimas; y, por otro lado, el uso de una jeringa común puede afectarla adherencia al tratamiento ya que el dolor luego de la inyección dificultaría sus siguientes aplicaciones. METODOLOGIA: Se llevó a cabo una búsqueda de la literatura con respecto a la eficacia y seguridad de somatropina administrada con dispositivo electrónico, en comparación con somatropina administrada sin dispositivo electrónico, en pacientes pediátricos con déficit de hormona del crecimiento en las bases de datos de PubMed, TRIPDATABASE y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Instituto de Evaluación de Efectividad Clínica y Sanitaria (IECS), Instituto de Evaluación de Tecnología en Salud (IETS); y en sitios especializados en endocrinología pediátrica como Pediatric Endocrine Society (PES), Endocrine Society of Australia (ESA), Japan Endocrine Society, European Society for Pediatric Endocrinology (ESPE). RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de somatropina administrada con dispositivo electrónico, en comparación con somatropina administrada sin dispositivo electrónico, en pacientes pediátricos con déficit de hormona del crecimiento. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: A la fecha no se han publicado estudios sobre la eficacia comparativa entre la aplicación de somatropina con un dispositivo electrónico y la aplicación con una ampolla común, en el tratamiento de pacientes pediátricos con falla de crecimiento por DHC. Se identificó uno que podría brindar información de relevancia pero no se encuentra disponible en texto completo, sino únicamente el resumen. La evidencia disponible en la actualidad en torno al uso de somatropina en dicha población corresponde a una guía de práctica clínica (GPC) del 2016 de La Sociedad de Endocrinología Pediátrica (PES, por sus siglas en inglés), y 4 evaluaciones de tecnología sanitaria (ETS) de National Institute for Health and Care Excellence (NICE) 2010, Scottish Medicines Consortium (SMC) 2006 y 2010, y Canadian Agency for Drugs and Technologies in Health (CADTH) 2013. En la GPC de PES, los elaboradores de la guía recomiendan el uso de somatropina en el tratamiento de pacientes pediátricos con DHC, pero no hacen mención a ningún aspecto relacionado a la administración del medicamento, ni a los factores involucrados en la adherencia al mismo. Con lo que se tiene que una GPC de buena calidad metodológica no plantea ninguna pregunta ni recomendación con respecto al uso de dispositivos para administración. De las ETS identificadas, dos (SMC 2010 y NICE 2010) mencionan aspectos relacionados a la administración de somatropina. En ambos contextos, (Reino Unido y Escocia) los respectivos sistemas de salud cuentan con diversas alternativas de presentaciones de somatropina que cuentan con dispositivo para aplicación, sobre los cuales se ha determinado que no hay diferencias en eficacia. Por lo que, por un lado, NICE recomienda que, para la elección de una presentación entre las disponibles, se considere la adherencia al tratamiento asociada a la administración del mismo, aunque la recomendación se basa únicamente en opinión de expertos. Por otro lado, SMC menciona que la elección del producto estaría sujeta a la preferencia del paciente en cuanto a la facilidad de uso del dispositivo. Sin embargo, si bien las ETS emiten recomendaciones en torno a los dispositivos de aplicación de somatropina, es posible que estas recomendaciones se refieran a elecciones entre los dispositivos disponibles y no entre el uso o no de un dispositivo, como lo requiere la pregunta PICO. Por lo que no queda claro si las recomendaciones responden a la pregunta PICO. Las dos ETS restantes consideradas en los resultados (SMC 2006 y CADTH 2010) no brindan información sobre el uso de dispositivos o la adherencia, sino que únicamente dan cuenta de las alternativas que están siendo evaluadas en los respectivos contextos, de las alternativas disponibles en dichos sistemas de salud y las opciones que se sopesan en las evaluaciones más recientes. Al considerar la evidencia disponible a la fecha, proveniente de una GPC y cuatro ETS, y la ausencia de estudios que comparen la eficacia y seguridad de somatropina con y sin dispositivo electrónico para su aplicación en el tratamiento de pacientes pediátricos con DHC, no es posible determinar el beneficio de la aplicación de somatropina con dispositivo electrónico por sobre la aplicación con jeringa común, ni en términos de eficacia ni de adherencia al tratamiento. El informe solicitado a la Dirección de Guías de práctica clínica, Farmacovilgilancia, y Tenocviglancia (DGPCFyT) del IETSI, menciona que durante el periodo de 2017 a 2019 no se ha recibido ninguna notificación de sospecha de reaccion adversa al medicamento ni de falta de efectividad. Así, no se cuenta con un registro que sustente las preocupaciones mencionadas por algunos de los especialistas. Por lo expuesto, el IETSI no aprueba el uso de somatropina con dispositivo electrónico en el tratamiento de pacientes pediátricos con falla en el crecimiento por DHC.

Cardiac manifestations and gene mutations of patients with RASopathies in Taiwan.

RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible.

Weight gain velocity in infants with achondroplasia.

There are virtually no data regarding appropriate oral intake in infants with dwarfing disorders such as achondroplasia, nor is there clear information regarding appropriate weight gain velocity in this population. Yet, these individuals are at increased risk for both early failure to thrive and, later in life, for obesity. Having appropriate expectations regarding weight gain and reasonable goals in management is imperative. We sought to clarify the rate of weight gain in infants with achondroplasia during the first year of life through analysis of data from 60 infants with achondroplasia seen at least twice during the first year of life in the Midwest Regional Bone Dysplasia Clinic, University of Wisconsin-Madison between 1998 and 2018. The mean weight gain velocity during the first 3 months was 23 g/day which contrasts with 30 g/day in average statured infants. Mean weight gain from 0 to 12 months of age was 13 g/day. The 3% of weight gain velocity during the first year of life was 8 g/day, and this rate did not differ between 0-3 months and 0-12 months of age. Infants with achondroplasia slightly more than doubled their birth weights by 1 year of age in contrast to averaged statured infants who typically triple birth weights by 1 year. Infants with achondroplasia can be thriving but erroneously assessed as failing to thrive if the incorrect reference values are used. This article describes infant weight gain velocity reference data for this population.

Endocrine abnormalities in cardiofaciocutaneous syndrome: a case of precocious puberty, hyperprolactinemia and diabetes insipidus.

A 7-year-8-month-old boy with cardiofaciocutaneous syndrome caused by the D638E mutation of the B-Raf proto-oncogene (BRAF) presented with new-onset seizures. He was incidentally found to have advanced Tanner staging on physical examination. Hormonal testing revealed pubertal levels of gonadotropins and sex steroid hormones. On brain imaging, a lack of visualisation of the posterior pituitary bright spot was observed, in addition to mild thinning of the corpus callosum and the lateral gyri of the cerebellar hemispheres. A diagnosis of idiopathic central precocious puberty was made and the patient was started on leuprolide depot treatment. Pituitary hormone testing revealed hyperprolactinemia for which the patient did not receive treatment as he was asymptomatic. During a subsequent hospital admission for seizures, the patient was diagnosed with transient central diabetes insipidus for which he required treatment with a desmopressin infusion.

Hyperferritinaemia following intrauterine transfusions for Rh isoimmunisation.

Intrauterine transfusion is one of the mainstays of treatment in isoimmunised pregnancies guided by the changes in middle cerebral artery Doppler of the fetus. The common postnatal complications associated with Rh isoimmunisation are high unconjugated bilirubin requiring blood exchange transfusions, cholestasis due to bile inspissation, thrombocytopenia and anaemia. Hyperferritinaemia is an uncommon adverse effect observed in Rh isoimmunised pregnancies. In this case report, we describe the clinical course of a Rh isoimmunised neonate with hyperferritinaemia and transfusion acquired cytomegalovirus disease which resolved. Iron chelation therapy was not necessary.

Effects of oral zinc supplementation on zinc status and catch-up growth during the first 2 years of life in children with non-organic failure to thrive born preterm and at term.

BACKGROUND: We aimed to analyze the effect of oral zinc supplementation on serum insulin-like growth factor-1 (IGF-1) levels and catch-up growth in infants with non-organic failure to thrive (NOFTT) who were born preterm as compared to those born at term. METHODS: Totally, 105 NOFTT infants aged 2 years or less were enrolled and divided into two groups according to gestational age at birth. Oral zinc sulfate was administered for 6 months to 49/66 children born at term, and 21/39 children born preterm. Serum zinc, IGF-1, weight, and height were measured at baseline and at 6 months. RESULTS: There were no differences in baseline serum zinc levels between the two groups. In preterm NOFTT infants, zinc supplementation significantly increased serum zinc levels compared to those in the non-supplementation group (Δ zinc 0-6 month 10.3 ± 26.4 µg/dL vs. -8.8 ± 23.7 µg/dL, p = 0.018), but it did not significantly change serum IGF-1 levels or weight- and height for age Z-scores. In NOFTT infants born at term who received zinc supplementation, serum zinc levels, IGF-1, weight for age Z-score, and height for age Z-score increased at 6 months (p = 0.001, p = 0.014, p = 0.049, and p = 0.029, respectively), but this increase was not significantly greater than in the non-supplementation group. Only the increase in serum zinc levels was significant after 6 months (Δ zinc 0-6 month 16.8 ± 32.0 µg/dL vs. -10.0 ± 22.6 µg/dL, p = 0.002). CONCLUSION: Zinc supplementation in NOFTT infants improves serum zinc status, regardless of gestational age at birth. Zinc supplementation in NOFTT infants born at term may improve serum IGF-1 levels and growth, but it does not in NOFTT infants born preterm. Overall nutritional support rather than supplementation of a single nutrient may be more effective for catch-up growth in NOFTT infants born preterm.

C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome.

Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.

An acute encephalopathy with reduced diffusion in BRAF-associated cardio-facio-cutaneous syndrome.

BACKGROUND: Cardio-facio-cutaneous syndrome (CFCS) is a rare genetic disorder characterized by cardiovascular anomalies, dysmorphic faces, ectodermal abnormalities and developmental delays. Mutations in BRAF and other RAS-MAPK pathway-associated genes are commonly identified in patients with CFCS. While this molecular pathway is known to be associated with neuro-inflammatory conditions, only one case with CFCS has been reported thus far to develop acute encephalopathy in childhood. CASE REPORT: A 3-year-old boy with dysmorphic features and mild psychomotor delay developed acute encephalopathy. After a 45-min long, generalized seizure, the magnetic resonance imaging revealed that the restricted diffusion signals spread to the bilateral subcortical white matters on day 1 of illness. Despite the 14 days of intensive care, the acute symptoms of encephalopathy left him intractable epilepsy and severe neurocognitive impairments. The whole-exome sequencing analysis identified a de novo heterozygous mutation of BRAF (NM_004333:p.Thr241Met) in this case. CONCLUSION: The present case suggests that the hyperactive condition of ERK signals might augment the development of acute encephalopathy and post-encephalopathic epilepsy in childhood.

MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy.

MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376-9T>G near-splice variant, which was shown to result in an in-frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy.

Complex congenital cardiac anomalies in the setting of right isomerism in a 31-month-old infant: a case report.

BACKGROUND: Congenital cardiac defects are not rare among neonates. Prompt assessment for life-threatening anomalies is essential for rapid management decisions and positive outcomes. Extracardiac anomalies can occur in congenital heart defects, and their presence increases morbidity and mortality in these neonates. CASE PRESENTATION: We report a case of a 31- month-old infant black girl in Tanzania who presented with an on-and-off history of difficulty in breathing, easy fatigability, facial and lower-limb swelling, recurrent respiratory tract infections, and failure to thrive. CONCLUSIONS: Management of patients with heterotaxy syndrome is complex and largely depends on specific anatomy of both cardiac and noncardiac lesions. Cardiac and noncardiac management must be tailored to individual anatomy, including prophylaxis against encapsulated organisms for asplenic patients.