Somatic and germline analysis of a familial Rothmund-Thomson syndrome in two siblings with osteosarcoma

Rothmund–Thomson syndrome (RTS) is characterized by a rash that begins in the first few months of life and eventually develops into poikiloderma. Associated symptoms are alterations in the teeth, sparse hair, thin eyebrows, lack of eyelashes, low stature, bone abnormalities, hematological illnesses, gastrointestinal disease, malnutrition, cataracts, and predisposition to cancer, principally to bone tumors and skin cancer. Diagnostic certitude is provided by a genetic study involving detection of pathogenic variants of the RECQL4 gene. We hereby present a familiar case of RTS in two siblings from a Portuguese family, both diagnosed with osteosarcoma. Genomic analysis (203 genes) of both tumors as well as germline analysis of the RECQL4 gene, thus confirming the syndrome in the family, have been performed. The relevance of clinical recognition of the hallmarks of the disease and thus early diagnosis with early intervention is highlighted

Severe cardiac and abdominal manifestations without lung involvement in a child With COVID-19

Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic, affecting humans of all ages. Clinical features of the pediatric population have been published, but there is not yet enough information to make a definitive description. Fever is typical, as it is respiratory symptom. Rarely are the infection and complications severe, and, when they are, it is almost always in a patient with another underlying disease. However, some otherwise healthy children with COVID-19 do suffer critical organ injury, such as acute myocarditis, heart failure and gastrointestinal inflammation. The mechanism of these organ damages remains unclear. An otherwise normally healthy 13-year-old male was admitted to the pediatric intensive care unit with acute abdomen pain, possible myocarditis and a suspected diagnosis of COVID-19. Noteworthy basal findings were ventricular extrasystoles in the electrocardiogram (EKG) and moderate left ventricular systolic dysfunction. Chest X-ray was normal. Blood tests revealed altered levels of inflammation factors (C-reactive protein (CRP), D-dimer, fibrinogen, interleukin 6 (IL-6)), lymphopenia and elevated cardiac enzymes. The first test for polymerase chain reaction (PCR) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was negative. The patient’s condition worsened, and he entered cardiogenic shock (hypotension, tachycardia and oliguria). He was vomiting continuously, which made pain control difficult; imaging of his abdomen was undertaken. There was no response to fluid resuscitation, and so milrinone and epinephrine were administered. Empiric treatment began with azithromycin, foscarnet, carnitine and immunoglobulins. Hydroxychloroquine was given before the results of repeated SARSCoV-2 and serology tests were available. Tocilizumab was administered once COVID-19 had been confirmed and massive inflammation had been observed. Progressively the clinical situation and the levels of the parameters studied improved. The patient was discharged 8 days after admission. Most children with SARS-CoV-2 infection are asymptomatic or present only mild symptoms. However, physicians should be aware of atypical and severe manifestations that may occur in the hyperinflammatory phase of the illness

Identification of germline cancer predisposition variants in pediatric sarcoma patients from somatic tumor testing

Genetic predisposition is an important risk factor for cancer in children and adolescents but detailed associations of individual genetic mutations to childhood cancer are still under intense investigation. Among pediatric cancers, sarcomas can arise in the setting of cancer predisposition syndromes. The association of sarcomas with these syndromes is often missed, due to the rarity and heterogeneity of sarcomas and the limited search of cancer genetic syndromes. This study included 43 pediatric and young adult patients with different sarcoma subtypes. Tumor profiling was undertaken using the Oncomine Childhood Cancer Research Assay (Thermo Fisher Scientific). Sequencing results were reviewed for potential germline alterations in clinically relevant genes associated with cancer predisposition syndromes. Jongmans¿ criteria were taken into consideration for the patient selection. Fifteen patients were selected as having potential pathogenic germline variants due to tumor sequencing that identified variants in the following genes: CDKN2A, NF1, NF2, RB1, SMARCA4, SMARCB1 and TP53. The variants found in NF1 and CDKN2A in two different patients were detected in the germline, confirming the diagnosis of a cancer predisposition syndrome. We have shown that the results of somatic testing can be used to identify those at risk of an underlying cancer predisposition syndrome

Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain

Background Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admitted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia. Methods A multicentric prospective national registry including 47 PICUs was carried out. Data from children admitted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared. Results Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5–11.8) vs 3.4 years (IQR 0.4–9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more frequently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lymphocyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5–8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group. Conclusions MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infection. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients

Utilidad de los estudios genómicos basados en paneles de NGS (Next Generation Sequencing) para el manejo clínico de los sarcomas en pacientes pediátricos

Las técnicas genómicas permiten el diagnóstico y manejo de niños y adultos jóvenes con sarcomas mediante la identificación de pacientes de alto riesgo y de aquellos que pueden beneficiarse de una terapia dirigida o de la participación en ensayos clínicos. Objetivo: analizar el rendimiento de un panel de genes NGS para el manejo clínico de pacientes con sarcoma pediátrico. Se estudiaron 53 pacientes pediátricos y adultos jóvenes diagnosticados de sarcoma, procedentes de dos centros españoles. Los datos genómicos se obtuvieron utilizando el Oncomine Childhood Cancer Research Assay, y se categorizaron según su valor diagnóstico, predictivo o pronóstico. En 44 (83%) de los 53 pacientes se identificó al menos una alteración genética. En el 80% de estos pacientes se obtuvo (n = 11) o cambió (n = 9) el diagnóstico, por lo que los datos genómicos afectaron al tratamiento. El diagnóstico inicial erróneo más frecuente fue el de sarcoma de Ewing, en lugar de liposarcoma mixoide (FUS-DDDIT3), tumor rabdoide de tejidos blandos (SMARCB1) o histiocitoma fibroso angiomatoide (EWSR1-CREB1). En nuestra serie, dos pacientes tenían una alteración genética con una terapia dirigida aprobada por la FDA, y el 30% tenía al menos una alteración potencialmente procesable. Los estudios genómicos basados en NGS son útiles y factibles en el diagnóstico y manejo clínico de los sarcomas pediátricos. La caracterización genómica de estos tumores raros y heterogéneos también ayuda en la búsqueda de biomarcadores pronósticos y oportunidades terapéuticas

Methotrexate-induced epidermal necrosis in a child with osteosarcoma

Methotrexate is a folic acid antagonist used to treat psoria-sis, rheumatoid arthritis and neoplasms. It is renally excreted unchanged, at levels of about 90% within 24 hours. Several risk factors for intoxication have been described, including folate deficiency, liver cirrhosis, renal failure or the use of me-dications such as sulfonamides, salicylate and nonsteroidal anti-inflammatory drugs. Adverse cutaneous reactions such as photosensitivity, alopecia, urticaria, mucositis, erythe-ma, desquamation, Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) are well known. Methotrexate epidermal necrosis (MEN) should also be considered because of its severity, its similarity to TEN and the importance of rapidly administering appropriate treatment. Some cases of MEN have been reported in psoriasis patients, in whom the occurrence with an underlying skin disease has been found to be more common

Somatic and germline analysis of a familial Rothmund-Thomson syndrome in two siblings with osteosarcoma

Rothmund–Thomson syndrome (RTS) is characterized by a rash that begins in the first few months of life and eventually develops into poikiloderma. Associated symptoms are alterations in the teeth, sparse hair, thin eyebrows, lack of eyelashes, low stature, bone abnormalities, hematological illnesses, gastrointestinal disease, malnutrition, cataracts, and predisposition to cancer, principally to bone tumors and skin cancer. Diagnostic certitude is provided by a genetic study involving detection of pathogenic variants of the RECQL4 gene. We hereby present a familiar case of RTS in two siblings from a Portuguese family, both diagnosed with osteosarcoma. Genomic analysis (203 genes) of both tumors as well as germline analysis of the RECQL4 gene, thus confirming the syndrome in the family, have been performed. The relevance of clinical recognition of the hallmarks of the disease and thus early diagnosis with early intervention is highlighted

Severe cardiac and abdominal manifestations without lung involvement in a child With COVID-19

Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic, affecting humans of all ages. Clinical features of the pediatric population have been published, but there is not yet enough information to make a definitive description. Fever is typical, as it is respiratory symptom. Rarely are the infection and complications severe, and, when they are, it is almost always in a patient with another underlying disease. However, some otherwise healthy children with COVID-19 do suffer critical organ injury, such as acute myocarditis, heart failure and gastrointestinal inflammation. The mechanism of these organ damages remains unclear. An otherwise normally healthy 13-year-old male was admitted to the pediatric intensive care unit with acute abdomen pain, possible myocarditis and a suspected diagnosis of COVID-19. Noteworthy basal findings were ventricular extrasystoles in the electrocardiogram (EKG) and moderate left ventricular systolic dysfunction. Chest X-ray was normal. Blood tests revealed altered levels of inflammation factors (C-reactive protein (CRP), D-dimer, fibrinogen, interleukin 6 (IL-6)), lymphopenia and elevated cardiac enzymes. The first test for polymerase chain reaction (PCR) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was negative. The patient’s condition worsened, and he entered cardiogenic shock (hypotension, tachycardia and oliguria). He was vomiting continuously, which made pain control difficult; imaging of his abdomen was undertaken. There was no response to fluid resuscitation, and so milrinone and epinephrine were administered. Empiric treatment began with azithromycin, foscarnet, carnitine and immunoglobulins. Hydroxychloroquine was given before the results of repeated SARSCoV-2 and serology tests were available. Tocilizumab was administered once COVID-19 had been confirmed and massive inflammation had been observed. Progressively the clinical situation and the levels of the parameters studied improved. The patient was discharged 8 days after admission. Most children with SARS-CoV-2 infection are asymptomatic or present only mild symptoms. However, physicians should be aware of atypical and severe manifestations that may occur in the hyperinflammatory phase of the illness

Severe manifestations of SARS-CoV-2 in children and adolescents: from COVID-19 pneumonia to multisystem inflammatory syndrome: a multicentre study in pediatric intensive care units in Spain

Background Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) has been described as a novel and often severe presentation of SARS-CoV-2 infection in children. We aimed to describe the characteristics of children admitted to Pediatric Intensive Care Units (PICUs) presenting with MIS-C in comparison with those admitted with SARS-CoV-2 infection with other features such as COVID-19 pneumonia. Methods A multicentric prospective national registry including 47 PICUs was carried out. Data from children admitted with confirmed SARS-CoV-2 infection or fulfilling MIS-C criteria (with or without SARS-CoV-2 PCR confirmation) were collected. Clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients were compared. Results Seventy-four children were recruited. Sixty-one percent met MIS-C definition. MIS-C patients were older than non-MIS-C patients (p = 0.002): 9.4 years (IQR 5.5–11.8) vs 3.4 years (IQR 0.4–9.4). A higher proportion of them had no previous medical history of interest (88.2% vs 51.7%, p = 0.005). Non-MIS-C patients presented more frequently with respiratory distress (60.7% vs 13.3%, p < 0.001). MIS-C patients showed higher prevalence of fever (95.6% vs 64.3%, p < 0.001), diarrhea (66.7% vs 11.5%, p < 0.001), vomits (71.1% vs 23.1%, p = 0.001), fatigue (65.9% vs 36%, p = 0.016), shock (84.4% vs 13.8%, p < 0.001) and cardiac dysfunction (53.3% vs 10.3%, p = 0.001). MIS-C group had a lower lymphocyte count (p < 0.001) and LDH (p = 0.001) but higher neutrophil count (p = 0.045), neutrophil/lymphocyte ratio (p < 0.001), C-reactive protein (p < 0.001) and procalcitonin (p < 0.001). Patients in the MIS-C group were less likely to receive invasive ventilation (13.3% vs 41.4%, p = 0.005) but were more often treated with vasoactive drugs (66.7% vs 24.1%, p < 0.001), corticosteroids (80% vs 44.8%, p = 0.003) and immunoglobulins (51.1% vs 6.9%, p < 0.001). Most patients were discharged from PICU by the end of data collection with a median length of stay of 5 days (IQR 2.5–8 days) in the MIS-C group. Three patients died, none of them belonged to the MIS-C group. Conclusions MIS-C seems to be the most frequent presentation among critically ill children with SARS-CoV-2 infection. MIS-C patients are older and usually healthy. They show a higher prevalence of gastrointestinal symptoms and shock and are more likely to receive vasoactive drugs and immunomodulators and less likely to need mechanical ventilation than non-MIS-C patients