A new family with a case of severe early-onset muscle fatigue and a peculiar maternally inherited painful swelling in chewing muscles associated with homoplasmic m.15992A>T mutation in mitochondrial tRNAPro.

A 16-year-old boy was evaluated for a history of exercise-induced fatigability associated with nausea even after minimal effort, lower limbs muscle hypotrophy, and swelling of the masseter muscles after chewing. Laboratory tests were remarkable for hyperlactatemia and metabolic acidosis after short physical activity. The muscle biopsy showed non-specific mitochondrial alterations and an increase in intrafibral lipids. Biochemical analysis showed reduced activity of the respiratory chain complexes. Mitochondrial DNA sequencing revealed the presence of a homoplasmic variant m.15992A>T in the MT-TP gene, coding for the mt-tRNAPro in the patient, in his mother and in his brother. Pathogenic or likely pathogenic variants in MT-TP gene are rare. They are responsible for different clinical presentation, almost ever involving the muscle tissue. We report the first family with exercise-induced muscle weakness and swelling of the chewing muscles due to m.15992A>T variant in absence of J1c10 haplogroup, confirming its pathogenicity.

Case report: Revascularization failure in NF1-related moyamoya syndrome after selumetinib: A possible pathophysiological correlation?

Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome caused by pathogenic variants in the NF1 gene, encoding a multidomain inhibitor of Ras activity. Thus, NF1 is considered a RASopathy and drugs targeting the RAS/mitogen-activated protein kinase (MAPK) pathway, such as the MAP kinase (MEK) 1/2 inhibitor Selumetinib, are promising therapeutic options to treat NF1-associated tumors, especially plexiform neurofibromas and optic way gliomas. However, surgical treatment is often required for NF1-related cerebrovascular manifestations, such as moyamoya syndrome (MMS). We report a case of an 8-year-old patient receiving Selumetinib at the dose of 25 mg/m2 orally 2 times a day as a treatment for many plexiform neurofibromas. He suffered from two close strokes and brain MRI revealed a severe cerebral vasculopathy consistent with MMS, with marked stenosis of both the internal carotid arteries. A two-step surgical revascularization procedure was performed, consisting of a direct by-pass with an encephalo-mio-synangiosis (EMS) followed by encephalo-duro-arterio-synangiosis (EDAS). Surprisingly, despite the surgical technical success, follow-up MRI revealed lack of the expected revascularization. Selumetinib is a powerful therapeutic option in the treatment of severe NF1-related tumors. However, our findings suggest that this drug may interfere with cerebral neovascularization in patients with MMS requiring surgical revascularization. This is supported by the crucial role of the Vascular-Endothelial Growth Factor (VEGF), whose signaling pathway involve MAPK, as promoter of the neovascularization. Our observations suggest to adopt an imaging surveillance strategy to prevent unfavorable surgical outcome in patients with NF1-associated MMS receiving Selumetinib, and that priority should be given to surgical revascularization.

Characterization of Cardiac Function by Echocardiographic Global Longitudinal Strain in a Cohort of Children with Neurofibromatosis Type 1 Treated with Selumetinib.

BACKGROUND: Plexiform neurofibromas are benign neoplasms that develop in 20-50% children with neurofibromatosis type 1 (NF1). Selumetinib was approved as treatment for symptomatic and inoperable plexiform neurofibromas. Subclinical left ventricular ejection fraction reduction is a less common effect of selumetinib. OBJECTIVE: We aimed to investigate the contractile function of the heart in a cohort of children with NF1 treated with selumetinib. METHODS: We designed a cross-sectional study including 17 patients with NF1 who received selumetinib. Echocardiographic parameters were compared with a cohort of 17 healthy children matched by sex and age and another group of 17 children with untreated NF1. RESULTS: Compared with healthy controls, patients with NF1 treated with selumetinib had lower mean values of global longitudinal strain (- 22.9 ± 2% vs -25.5 ± 2%; p = 0.001), fractional shortening (36 ± 4% vs 43 ± 8%; p = 0.02) and tricuspid annular plane systolic excursion (19 ± 3 mm vs 23 ± 2 mm; p = 0.001); no difference was found in left ventricular ejection fraction (63 ± 4% vs 65 ± 3%; p = 0.2 respectively). Median treatment time with selumetinib at the time of the echocardiographic evaluation was 22 ± 16 months. CONCLUSIONS: Patients with NF1 treated with selumetinib may experience subtle changes in systolic function identified by global longitudinal strain and not revealed by left ventricular ejection fraction. Global longitudinal strain might be useful to monitor cardiac function in this cohort of patients for the duration of therapy.

Natural history of KBG syndrome in a large European cohort.

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Heterozygous variants in ZBTB7A cause a neurodevelopmental disorder associated with symptomatic overgrowth of pharyngeal lymphoid tissue, macrocephaly, and elevated fetal hemoglobin.

By clinical whole exome sequencing, we identified 12 individuals with ages 3 to 37 years, including three individuals from the same family, with a consistent phenotype of intellectual disability (ID), macrocephaly, and overgrowth of adenoid tissue. All 12 individuals harbored a rare heterozygous variant in ZBTB7A which encodes the transcription factor Zinc finger and BTB-domain containing protein 7A, known to play a role in lympho- and hematopoiesis. ID was generally mild. Fetal hemoglobin (HbF) fraction was elevated 2.2%-11.2% (reference value <2% in individuals > 6 months) in four of the five individuals for whom results were available. Ten of twelve individuals had undergone surgery at least once for lymphoid hypertrophy limited to the pharynx. In the most severely affected individual (individual 1), airway obstruction resulted in 17 surgical procedures before the age of 13 years. Sleep apnea was present in 8 of 10 individuals. In the nine unrelated individuals, ZBTB7A variants were novel and de novo. The six frameshift/nonsense and four missense variants were spread throughout the gene. This is the first report of a cohort of individuals with this novel syndromic neurodevelopmental disorder.

Selumetinib side effects in children treated for plexiform neurofibromas: first case reports of peripheral edema and hair color change.

BACKGROUND: Plexiform neurofibromas (PNs) are congenital tumors that affect around 50 % of the subjects with neurofibromatosis type 1. Despite being histologically benign, PNs can grow rapidly, especially in the pediatric age, and cause severe morbidities. In the past, various therapeutic approaches have been proposed to treat these masses, none of which obtained valuable results. Selumetinib, an inhibitor of mitogen-activated protein kinase (MEK) 1 and 2, has been the first molecule to demonstrate the ability of tackling the growth of PNs. The drug's most common side effects, which usually are mild or moderate, include gastrointestinal symptoms (diarrhea, abdominal pain), dermatologic manifestations (maculo-papular and acneiform rash, paronychia, mucositis), and various laboratory test abnormalities (elevation of creatine kinase and aminotransferase). CASES PRESENTATION: We report two previously undescribed adverse events in pediatric patients: peripheral edema and hair color change. The first case of peripheral edema occurred in a 7-year-old boy affected by a severe form of NF1, after two years of treatment with selumetinib at the standard dose (25 mg/m2twice a day). The edema involved the right leg, and the patient did not complain of pain. The second case of peripheral edema occurred in a 12-year-old girl after six months of therapy with selumetinib at the standard dose, involving her lower left leg. The patient initially complained of pain in that area, but it gradually and spontaneously resolved. In both patients, all the radiological exams, including lymphoscintigraphy, pelvic and abdominal ultrasound, and doppler ultrasound of the affected limb, as well as blood tests, revealed no abnormalities. Hair color change appeared in a 4-year-old boy after six months of therapy at the standard dose. The boy's hair, whose natural color was dark blonde, became lighter in some areas. Despite the appearance of these side effects, all the patients and their families decided to continue the treatment with selumetinib, in considerations of its clinical benefits. CONCLUSIONS: Since the use of selumetinib to treat plexiform neurofibromas is increasing in the pediatric population, clinicians should be aware of its side effects, so to decide whether continuing the treatment, reducing the dose or even interrupting it, when appropriate.

Remnant cholesterol as a risk factor for cardiovascular, cancer or other causes mortality: A competing risks analysis.

BACKGROUND AND AIMS: Cardiovascular diseases (CVDis) are leading causes of morbidity and mortality. Even after the introduction of pharmacological therapy to lower Cholesterol, there is still a residual risk that may be ascribed to remnant cholesterol (RC). We aimed, by analyzing two prospective cohort studies, to estimate the effect of RC on risk and hazard of cardiovascular deaths (CVDs), while accounting for competing risks such as cancer (CDs) and other-causes deaths (OCDs). METHODS AND RESULTS: Cohorts were enrolled in 1992 and 2005. Personal data history was recorded. A fasting venous blood sample was obtained, and RC was calculated at baseline. Cause of Death was coded by using ICD-10th version. Follow-up ended on December 31, 2017. Flexible parametric competing-risks models were applied, with age at death as time-axis. In total, 5729 subjects were enrolled. There were 861 (15.1%) deaths: 234 CVDs (27.2%), 245 CDs (28.5%), 271 OCDs (31.5%) and 111 unknown causes of death (12.8%). RC exposure was a strong risk factor only for CVDs (Risk 2.54, 95% Confidence Interval 1.21; 5.34; Trend 1.26 (1.00; 1.58) for ≥1.29 mmol/L). CONCLUSIONS: RC is a strong independent risk factor for cardiovascular mortality. Competing risk analysis is demonstrably a useful tool to disentangle associations among different competing events with a common risk factor.

Selumetinib in the Treatment of Symptomatic Intractable Plexiform Neurofibromas in Neurofibromatosis Type 1: A Prospective Case Series with Emphasis on Side Effects.

BACKGROUND: Plexiform neurofibromas (PN) are congenital tumors that affect up to 50% of individuals with neurofibromatosis type 1. Despite their benign nature, they can grow rapidly and cause severe morbidities. Selumetinib, an inhibitor of mitogen-activated protein kinase (MEK) 1 and 2, was reported to induce a clinical response in pediatric subjects with inoperable PN. OBJECTIVE: The aim of this paper is to describe a prospective case series of patients treated with selumetinib with emphasis on drug adverse events. PATIENTS AND METHODS: All the subjects who received selumetinib at the Pediatric Department of Scientific Research Institute and Hospital "Burlo Garofolo", from November 2017 to January 2020, were progressively included. We monitored the patients with a follow-up visit every 3 months. MRI or CT scans to monitor the growth of the tumor were performed after 3 months of treatment, and then every 6-9 months. RESULTS: Selumetinib was prescribed to nine children, with a total of 17 inoperable PN. The mean follow-up period was 12 months. During the follow-up, one patient experienced an ischemic stroke, unrelated to the treatment. Only minor adverse events were observed: six individuals developed gastrointestinal side effects, seven patients presented a mild form of acne, six had paronychia, four developed irritability, and two showed a mild increase in creatine kinase. None of the patients stopped the treatment. Tumor reduction > 20% was recorded in 16 out of 17 PN (94%). One PN remained stable. No tumor growth was recorded during the treatment. CONCLUSIONS: In this case series, selumetinib appears to be effective and safe for the pediatric population.

Hallazgo incidental en tomografía computada de haz cónico / Incidenal finding in cone beam computed tomography

El creciente número de técnicas radiográficas realizadas por paciente para diagnóstico y planificación provoca un aumento en el número de hallazgos incidentales. La descripción de un hallazgo incidental puede desencadenar atención médica adicional, que incluye otros procedimientos y tratamientos de diagnóstico, con lo cual, en muchas ocasiones es necesario derivar al paciente para tratar la patología descubierta en forma incidental. La CBCT puede ayudar a detectar la presencia de lesión periapical no diagnosticada previamente, donde la evaluación clínica previa y las radiografías convencionales no han revelado la patología. La patología asintomática u oculta puede conducir a un diagnóstico tardío, lo que puede afectar negativamente las posibles estrategias de tratamiento y los resultados. La detección temprana y la precisión diagnóstica son esenciales. La CBCT es una técnica que proporciona vistas de zonas anatómicas con las cuales la mayoría de los odontólogos no están familiarizados y que pueden revelar patología oculta, permitiendo diagnósticos más precisos y confiables, y reduciendo así la posibilidad de perder la patología clínicamente relevante. Este articulo trata de sintetizar las ventajas del uso de la tomografía para diagnosticar el hallazgo incidental (AU)

The increasing number of radiographic techniques performed by the patient for diagnosis and planning causes an increase the number of incidental findings. The description of an unexpected finding can trigger additional medical care including, other diagnostic procedures and treatments, therefore, in many occasions it is necessary to refer the patient to treat the pathology discovered incidentally. CBCT may aid in detecting the presence of previously undiagnosed periapical disease, where prior clinical evaluation and conventional radiographs have failed to reveal pathology. Asymptomatic or occult pathology may lead to delayed diagnosis, which may adversely affect eventual treatment strategies and outcomes. Early detection and improved diagnostic accuracy are essential, also, provide views of anatomy that most dentists have never before seen; in addition, they may reveal occult pathology, enabling more accurate and reliable diagnoses thereby reducing the possibility of missing clinically relevant disease (AU)

Nuevas modalidades de imagen en el diagnóstico odontológico / New image modalities in dental diagnosis

La radiología odontológica ha jugado un rol fundamental en el diagnóstico odontológico. El avance en la adquisición y procesado de la imagen digital produjo el desarrollo de nuevas tecnologías que han revolucionado el manejo del intercambio de la información en odontología. Las radiografías intraorales y extraorales se han adaptado a esa revolución digital. La búsqueda automatizada, el acceso a la literatura en formato electrónico y el intercambio de texto, imágenes y sonido en tiempo real son algunas de las características que lo hacen un elemento imprescindible dentro de la práctica en salud y los actuales estándares de la atención odontológica. El reciente desarrollo de la tomografía computada de haz cónico ha reemplazado el uso de la tomografía computada médica en odontología. En este artículo se hace una introducción en los métodos actuales y en cómo han cambiado el diagnóstico radiológico en odontología.

Dental radiology has played a fundamental role in the dental diagnosis. The advance of the acquisition and processing of the digital image produced the development of new technologies that have revolutionized the management of the information exchange in dentistry. Intraoral and extraoral radiographies have adapted to this digital revolution. The automated search, access to literature in electronic format and the interchange of text, images and sound in real time, are some of the features that make an essential element within the practice in health and the standard of dental care. The recent development of cone beam computerized tomography has replaced the use of computed tomography in dentistry. This article is an introduction to the current methods employed and how they have changed the radiological diagnosis in dentistry.

Legius syndrome: case report and review of literature.

A 8-month-old child was referred to our Dermatologic Unit for suspected Neurofibromatosis type 1 (NF 1), because of the appearance, since few days after birth, of numerous café-au-lait spots (seven larger than 5 mm); no other sign evocative of NF 1 was found. Her family history was remarkable for the presence of multiple café-au-lait spots in the mother, the grandfather and two aunts. The family had been already examined for NF 1, but no sign evocative of the disease was found. We then suspected Legius syndrome, a dominant disease characterized by a mild neurofibromatosis 1 phenotype. The diagnosis was confirmed by the finding of a mutation in SPRED1 gene, a feedback regulator of RAS/MAPK signaling. Here, we discuss the differential diagnosis of cafè-au-lait spots and we briefly review the existing literature about Legius syndrome.

Variations in the vestibular cortical bone of permanent canine teeth in orthodontic patients. A comparative study: linear tomography vs. CBCT 3D Accuitomo

La finalidad del presente trabajo fue comparar los resultados de la medición de la altura de la cortical vestibular de caninos, por tomografía lineal (TL) y tomografía computada de haz cónico,3D Accuitomo (CBCT, cone beam computed tomography) antes y después de alinear ortodóncicamente las arcadas dentarias. Se realizaron TL y CBCT pre y post alineación ortodóncica de 12 caninos, correspondientes a tres pacientesen tratamiento ortodóncico y se midió en mm la altura de las corticales óseas vestibulares de los caninos. Las medidasfueron tomadas por dos operadores a doble ciego. La variación de la altura promedio de la cortical vestibular con el tratamiento ortodóncico utilizando CBCT fue de -0,33 mm ± 0.233 de error standard y con TL de -0,08mm ± 0.55 de error standard. Se realizó Análisis de varianza (ANOVA) comparando las técnicas, los pacientes y los caninos superiores e inferiores, sin encontrarse diferencia estadísticamente significativa en ninguno de los casos. La evaluación de la cortical de la cresta vestibular de caninos utilizando TL es un método comparable en eficiencia a la CBCT. La medida de la altura en milímetroses menor en la TL debido a que la resolución de las imágenes es menor y no es apreciable por este método cuando ésta es extremadamente delgada...

Autosomal recessive Stickler syndrome due to a loss of function mutation in the COL9A3 gene.

Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis.

Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: clinical and functional characterization of two novel ABCC8 mutations.

Congenital hyperinsulinism (CHI) occurs as a consequence of unregulated insulin secretion from the pancreatic beta-cells. Severe recessive mutations and milder dominant mutations have been described in the ABCC8 and KCNJ11 genes encoding SUR1 and Kir6.2 subunits of the beta-cell ATP-sensitive K(+) channel. Here we report two patients with CHI unresponsive to medical therapy with diazoxide. Sequencing analysis identified a compound heterozygous mutation in ABCC8 in both patients. The first one is a carrier for the known mild dominant mutation p.Glu1506Lys jointly with the novel mutation p.Glu1323Lys. The second carries the p.Glu1323Lys mutation and a second novel mutation, p.Met1394Arg. Functional studies of both novel alleles showed reduced or null cell surface expression, typical of recessive mutations. Compound heterozygous mutations in congenital hyperinsulinism result in complex interactions. Studying these mechanisms can improve the knowledge of this disease and modify its therapy.

A novel CRYBB2 missense mutation causing congenital autosomal dominant cataract in an Italian family.

Congenital cataract is a leading cause of visual impairment in children and brings approximately 10% of childhood blindness worldwide. Molecular analysis revealed ~60 loci to be associated with several phenotypes of childhood cataracts. Until now, more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract (ADCC). Here, we present a three-generation Italian family with a non syndromic ADCC. A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease. All the genes located in these regions were scored for possible relationship with ADCC and, according to a strict clinical and genetic selection, 4 genes have been analyzed. A novel sequence variant was found in the CRYBB2 gene (p.Ser143Phe). This variant affects a conserved aminoacid in the third Greek key motif of the protein, cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects. Finally, we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC.