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THE JOURNAL OF THE JAPAN PEDIATRIC SOCIETY
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Vol.121, No.7, July 2017
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Review
Title
Risk-Grouping and Approach of Precision Medicine in Peripheral Neuroblastic Tumors
Author
Ryosuke Matsuno and Hiroyuki Shimada
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles
Abstract
In the previous chapter, we presented the details of International Pathology Classification (INPC) of peripheral neuroblastic tumors (pNTs). In the current chapter, we discuss prognostic factors other than INPC: those include clinical stage, age at diagnosis, and various molecular markers. Then the Children's Oncology Group Risk Grouping Scheme and the International Neuroblastoma Risk Group (INRG) Scheme, both of which are established based on the combination of prognostic factors, are outlined. Later in this chapter, we move on to the topic of "Precision Medicine" where we should look for "Actionable/Druggable" targets and build-up more efficient and less toxic treatment protocol especially for the high-risk pNTs patients. In this context, we briefly mention abnormalities of ALK oncogene, and then report recent progress of our research leading us to a new concept of "MYC family-driven Neuroblastoma". The concept is based on the data which shows that protein overexpression rather than DNA copy number increase is directly related to aggressive clinical behavior of pNTs. "MYC family-driven Neuroblastoma" is defined by augmented expression of MYCN or MYC protein, and the tumor cells often show nucleolar hypertrophy, i.e., prominent nucleolar formation for excess amount of protein synthesis. We are hoping that those proteins as well as prominent nucleoli could make potential targets critical for developing clinical protocol in future Neuroblastoma study.
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Original Article
Title
Necessity of Urinalysis after Group A Streptococcal Infection
Author
Shinsuke Matsumoto Ryugo Hiramoto and Hironobu Eguchi
Department of Pediatrics, Matsudo City Hospital Children's Medical Center
Abstract
Although routine urinalysis after group A streptococcal (GAS) infection is often performed in the field of pediatrics, there are various opinions regarding the necessity of this examination. In this study, we summarized the chances for discovering 35 cases of acute poststreptococcal glomerulonephritis (APSGN) and retrospectively examined all the cases, focusing on the necessity of urinalysis after GAS infection.
At first, we examined the relation between APSGN and the use of antibiotics. Five out of seven cases of GAS infection were treated with an adequate quantity of antibiotics, nevertheless, they developed APSGN. In other words, there remained some possibility of developing APSGN even if GAS infection is treated with a sufficient quantity of antibiotics.
Next, we evaluated the necessity of urinalysis after GAS infection. Three cases were discovered on routine urinalysis after GAS infection, all of which had eyelid edema when discovered. The other four cases treated with antibiotics for GAS infection were discovered due to eyelid edema or gross hematuria. Almost all the other cases also were detected due to eyelid edema or gross hematuria. Therefore, if we pay attention to the presence of eyelid edema and gross hematuria, we can discover almost all cases of APSGN.
In conclusion, it is not necessary to perform routine urinalysis for all cases after GAS infection. Instead, it is important to explain and make patients and their parents understand that there is some possibility of developing APSGN even if GAS infection is treated with a sufficient quantity of antibiotics, and also that APSGN exhibits some particular symptoms such as eyelid edema and gross hematuria.
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Original Article
Title
Change of Antibiotic Resistance of Streptococcus Pneumoniae Obtained from the Nasopharynx of Infants and Young Children before and after Transition to 13-valent Pneumococcal Conjugate Vaccine
Author
Akiyoshi Nariai Takanori Yanai and Taichi Kanetaka
Department of Pediatrics, Yokohama Minami Kyosai Hospital
Abstract
After the 7-valent pneumococcal conjugate vaccine (PCV7) introduction in 2010, we measured trends of penicillin (PCG), macrolide (EM), and high macrolide resistance (also resistance to clindamycin) in Streptococcus pneumoniae obtained from the nasopharynx of infants and young children with lower respiratory tract infections.
This report presents the results for each year between 2011 and October 2013 (before the transition to the 13-valent pneumococcal conjugate vaccine [PCV13]) and between November 2013 and October 2014 (after the transition to PCV13), in comparison to the findings in 2010.
The rates of PCG, EM, and high macrolide resistance in 2010 were 71%, 97%, and 64%, respectively. The rate of PCG resistance declined each year from 2011: 53%, 55%, 49%, and 43%. In 2010, 61% of the pneumococcal strains were PCV7 serotypes and PCG resistance was as high as 82%, but by 2014, the PCV7 serotypes had been largely eliminated, then the rate of PCG resistance had improved.
In contrast, the rate of EM resistance exceeded 96% and remained unchanged. The rate of high macrolide resistance increased each year: 50%, 61%, 69%, and 75%.
The introduction of PCV7 and switch to PCV13 were associated with significant reductions in the rate of PCG resistance, but did not influence the rate of macrolide resistance.
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Original Article
Title
Clinical Case Series Study of Pediatric Patients with Cystic Fibrosis in Japan
Author
Daisuke Sato and Hiroshi Koga
Department of Pediatrics, National Hospital Organization Beppu Medical Center
Abstract
Cystic fibrosis (CF) is an autosomal recessive genetic disorder caused by mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, major symptoms of which are repeated respiratory tract infections, exocrine pancreatic insufficiency, and meconium ileus. We investigated the clinical characteristics of 53 cases reported in Japan between 1994 and 2015, comprising 52 patients described in 44 case reports, in addition to one patient of our own. The most common major symptoms at the time of diagnosis were meconium ileus during the neonatal period (100%), poor weight gain during infancy (63%), and chronic respiratory symptoms from 1 year old (97%). The airway was colonized by Pseudomonas aeruginosa in 85% of cases. Although the phenotypes were similar between Japan and overseas, the genotypes varied, with 28% of CFTR mutations found in Japan never having been reported overseas. This suggests that clinical diagnosis based on characteristic symptoms may be more important than genetic screening in Japan. We also found that many of the patients diagnosed in Japan already suffered from growth failure or respiratory disorder at the time of diagnosis. Cystic fibrosis, even a rare disease in Japan, is needed to be kept in mind as a differential diagnosis for infants with meconium ileus and/or poor weight gain in terms of early diagnosis and treatment.
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Case Report
Title
Only Characteristic Vascular Lesions of Williams-Beuren Syndrome in a Girl with a Novel Nonsense ELN Mutation
Author
Shintaro Terashita1) Hideyuki Nakaoka1) Keijiro Ibuki1) Sayaka Ozawa1) Keiichi Hirono1) Yuichi Adachi1) Shuhei Fujita2) Toshio Nakanishi3) and Fukiko Ichida1)
1)Department of Pediatrics, University Toyama
2)Department of Pediatrics, Toyama Prefectural Central Hospital
3)Department of Pediatric Cardiology, Tokyo Women's Medical University
Abstract
Williams-Beuren syndrome (WBS) is caused by microdeletions of 7q11.23, including the ELN gene, and the characteristic vascular lesions include supravalvular aortic stenosis (SVAS) and peripheral pulmonary artery stenosis (PPS). We identified a patient who had the characteristic cardiovascular lesions of WBS but did not have the 7q11.23 deletion: analysis of ELN identified a nonsense mutation. This was a baby girl, whose cardiovascular abnormalities were not identified during fetal life. We admitted her with systemic cyanosis after birth, and we diagnosed SVAS and supravalvular pulmonary stenosis (SVPS). At age 10 months she underwent cardiac catheterization and confirmed SVAS, which was accompanied by a thin ascending aorta, PPS narrowing from hilar, and SVPS. Due to high blood pressure and hyperreninemia, she was diagnosed with renal vascular hypertension caused by bilateral renal artery stenosis identified on MDCT and began an oral carvedilol regimen. Mental retardation and malformations associated with WBS were not observed and a FISH analysis excluded a microdeletion encompassing ELN. Since mutations in ELN have been identified in cases of isolated SVAS it was screened and a novel nonsense mutation in Exon 24 was identified. Thus, the vascular lesions were considered to be caused by elastin deficiency due to the ELN mutation. We suggest that if a patient has the characteristic cardiovascular lesions of WBS, but is FISH-negative, then ELN should be screened for mutations.
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Case Report
Title
A Case of Refractory Kawasaki Disease Complicated by Fungal Infection after Various Anti-inflammatory Treatments Including Immunoglobulin, Steroids, Plasma Exchange, and Infliximab Therapy
Author
Tadashi Inoue Shintaro Kishimoto Yoshiyuki Kagiyama Hironaga Yoshimoto Yoshiyuki Kudo Yushiro Yamashita and Kenji Suda
Department of Pediatrics, Kurume University School of Medicine
Abstract
A 5-year-old boy presented with 6 typical diagnostic criteria of Kawasaki disease (KD) and was persistently febrile for 18 days. He was refractory to various anti-inflammatory treatments including multiple doses of intravenous immunoglobulins infusion, 2 doses of intravenous methylprednisolone, a 3-day-course of plasma exchange, and infliximab infusion. After this treatment, somehow he became afebrile, though retained with bilateral giant coronary aneurysms. His condition had gradually improved and he showed desquamation of peripheral skin. However, on the 29th day of illness, he became febrile again without any sign of KD but with increased inflammatory reaction. In the process of ruling out infection, we found increased serum levels of β -D glucan and Aspergillus antigen that indicated deep-seated Aspergillus infection. Though we could not identify the focus, anti-fungal treatment including voriconazole successfully controlled this infection.
This case illustrates that patients with KD treated with multiple anti-inflammatory treatments may suffer from fungal infection that may be difficult to differentiate from relapse of KD and physicians must keep this possibility in mind.
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Case Report
Title
Spontaneous Superficial Parenchymal and Leptomeningeal Hemorrhage in the Late Neonatal Period: A Case Report
Author
Takaya Iida1) Koji Tanoue1) Kiyoshi Matsui1) Jun Shibasaki2) Akira Tanaka3) Eriko Ando3) Haruko Horiguchi3) and Nobuyuki Kikuchi3)
1)Division of General Medicine, Kanagawa Children's Medical Center
2)Division of Neonatal Medicine, Kanagawa Children's Medical Center
3)Department of Pediatric Medicine, Yokohama City Minato Red Cross Hospital
Abstract
Spontaneous superficial parenchymal and leptomeningeal hemorrhage (SSPLH) is a rare form of intracranial hemorrhage in the early neonatal period, first reported by Hung et al. We herein describe an infant with SSPLH manifesting with poor feeding and vomiting in the late neonatal period. This female infant had been born at full term. An echo study on day 16 suggested a high echoic lesion in the right temporal lobe. CT showed a right temporal lobe hemorrhage. The lesion was a subcortical hemorrhage extending to several gyri, and there was a 1.5 cm in thickness leptomeningeal hemorrhage which had induced a midline shift to the left. Phenobarbital and glycerin were effective, respectively, for seizures and brain edema. MRI showed acute phase hemorrhage. She was discharged on day 33 without surgical intervention. We diagnosed SSPLH because laboratory tests and images ruled out thrombocytopenia, coagulopathy due to vitamin K deficiency, vascular malformation, sinus thrombosis, and abusive head trauma. Her development was within the normal range at one year of age and MRI indicated that the lesion had been replaced by ulegyria, with cyst formation and hemosiderosis. MRV showed a right Labbé vein defect, possibly indicating superficial vein thrombosis. This case was atypical because those reported by Huang et al, 4 other patients treated at our hospital, and an additional 7 cases reported in Japan all manifested symptoms before 6 days of age. The latent period of neonatal sinus thrombosis in our patient may explain late-onset SSPLH. Cranial ultrasound examination is useful for SSPLH screening.
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Case Report
Title
A Case of DEAP-HUS Successfully Treated with Eculizumab
Author
Hiromi Sakaguchi1) Hideaki Imamura1) Etsuko Tanaka1) Mayuko Orita1) Takao Konomoto1) Yasufumi Ohtsuka2) and Hiroyuki Nunoi1)
1)Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine, Faculty of Medicine, University of Miyazaki
2)Department of Pediatrics, Faculty of Medicine, Saga University
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disorder caused by abnormal activation of the alternative complement pathway. Eculizumab, a monoclonal anti-C5 antibody, is available as treatment for aHUS. A 7-year-old boy with no past medical history was referred to our hospital with vomiting and headache. Thrombotic microangiopathy was suspected from the findings of acute kidney injury, hemolytic anemia and thrombocytopenia, and plasma therapy was started immediately. Laboratory findings showed no evidence of infection with Shiga toxin and a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity was normal. Therefore, the patient was diagnosed with aHUS. After administration of eculizumab, his general condition and clinical parameters, including platelet count and serum creatinine, were dramatically improved. Detailed examination of complement factors revealed markedly elevated levels of autoantibodies to complement factor H (CFH). Subsequently, multiplex ligation-dependent probe amplification analysis revealed homozygous deletion of CFHR3 and CFHR1. These results met the criteria for deficiency of complement factor H-related proteins and CFH autoantibody-positive hemolytic uremic syndrome (DEAP-HUS). The patient continued maintenance eculizumab therapy for 18 months without recurrence, although CFH autoantibody titers were low after the acute phase. DEAP-HUS represents a unique subgroup of aHUS resulting from production of autoantibodies to CFH after triggering events such as infections. Recent studies recommend immunosuppressive agents such as maintenance therapy for DEAP-HUS; however, the etiology of DEAP-HUS and optimal treatment have not yet been fully elucidated. Therefore, eculizumab treatment should be taken into consideration not only in the acute phase, but also as maintenance therapy for DEAP-HUS.
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Case Report
Title
Neonatal Seizures due to Maternal Vitamin D Deficiency
Author
Yoko Hirano Akiko Kinumaki and Yoshiyuki Namai
Department of Pediatrics, Ohta-Nishinouchi Hospital, Ohta General Hospital Foundation
Abstract
Recently, cases of rickets or hypocalcemic seizures in infants attributable to vitamin D deficiency have been steadily increasing in Japan. In contrast to other countries where vitamin D supplementation is recommended and prescribed for infants and mothers, use of vitamin D supplements is uncommon in Japan. Furthermore, measures for preventing maternal vitamin D deficiency are inadequate.
We report the case of a 14-day-old, full-term, male infant who presented with myoclonic seizures. On admission, laboratory tests indicated severe hypocalcemia due to vitamin D deficiency. Additionally, asymptomatic maternal vitamin D deficiency was detected. This deficiency was due to an unbalanced diet, limited sun exposure, and lack of vitamin D intake by the mother. Insufficient vitamin D throughout the fetal period resulted in early-onset symptoms of this deficiency.
It is clear that vitamin D deficiency in early infancy is attributable to maternal vitamin D deficiency. Therefore, vitamin D supplements should be administered to infants as soon after birth as possible, in addition to promoting vitamin D intake and increased sun exposure for pregnant women.
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Case Report
Title
Two Cases of Congenital Syphilis
Author
Mizue Kanai and Satoshi Toishi
Department of Neonatal Medicine, Japanese Red Cross Narita Hospital
Abstract
Reported cases of congenital syphilis and syphilis among women aged 15-29 years have been increasing in Japan. Here, we report two cases of congenital syphilis born to mothers who did not receive regular perinatal care.
In Case A, a male newborn of a 20-year-old unmarried woman, an untreated maternal syphilis infection was detected at delivery. His birth weight was 1,536 g and estimated gestational age was 38 weeks. He presented with syphilitic pemphigus, syphilitic osteochondritis observed via bone X-ray, and abnormal cerebrospinal fluid. Intravenous ampicillin was administered for 7 days and oral amoxicillin for 7 additional days (total treatment, 14 days); he recovered without sequelae. In Case B, a male newborn of a 21-year-old unmarried woman, maternal syphilis infection was detected during perinatal care; however, appropriate treatment was not given because of irregular follow-up visits. Emergency cesarean section was performed because of fetal distress and hydrops. His birth weight was 2,196 g and estimated gestational age was 34 weeks. He presented with syphilitic pemphigus, splenohepatomegaly, and abnormal cerebrospinal fluid. His serum fluorescent treponemal antibody-absorption test (FTA-ABS) IgM test and rapid plasma reaction (RPR) titer were positive. Intravenous ampicillin was administered for 12 days and oral amoxicillin for 2 days (total treatment, 14 days); he recovered without sequelae.
Neonates born to mothers who fail to undergo perinatal syphilis testing or fail to attend regular perinatal visits pose an increased risk of congenital syphilis. Pediatricians should consider congenital syphilis and perform comprehensive examinations for these newborn. Additionally, encouraging regular perinatal visits and informing mothers on the prevention of infectious diseases during pregnancy is important.
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Case Report
Title
Autoimmune Neutropenia in a Two-year-old Infant with Associated Severe Parapneumonic Pleural Effusion
Author
Hanae Sugiura1) Yasuhiro Ikawa1) Eri Koshino1) Yusuke Yachi1) Natsumi Inoue1) Akiko Kato1) Taizo Wada1) Tomoko Toma1) Hiroyuki Okamoto2) Eiji Kato3) and Akihiro Yachie1)
1)The Department of Pediatrics, Kanazawa University Hospital
2)The Department of Pediatrics, Japan Community Health Care Organization Kanazawa Hospital
3)The Department of Pediatrics, Fukui-ken Saiseikai Hospital
Abstract
Autoimmune neutropenia (AIN) induced by neutrophil-specific antiantibodies is usually associated with mild infection. Since, AIN spontaneously resolves by 3 years of age and neutrophil counts transiently increase during infection, AIN is considered benign although it can be severe in children. However, AIN rarely progresses to an extreme infectious state. Here, we describe a 2-year-old girl with parapneumonic pleural effusion followed by pneumonia in whom fluid accumulation was resolved by video assisted thoracoscopic surgery (VATS). We also discuss why the severity increased in this patient with reference to published reports of other patients. We also analyzed neutrophil counts and CRP levels in 5,343 children who presented with fever at our pediatric clinic. We found neutrophil counts < 500/μL and high CRP values significantly more often in children 1 year or below, than 2 years or more. Our findings suggested that children aged below one year might include some with AIN. Early diagnosis and careful observation is warranted to avoid an increase in the severity of AIN.
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