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1.
Hum Mutat ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131168

RESUMO

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.

2.
Clin Exp Nephrol ; 24(11): 1069-1076, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32720203

RESUMO

BACKGROUND: Immunization with various vaccines is considered desirable for children with idiopathic nephrotic syndrome (NS) because of their high risk of severe infections. Vaccinations may precipitate relapses of NS, but there is no available data regarding inactivated influenza (flu) virus vaccines. METHODS: We retrospectively reviewed the medical records of children with NS who had received flu vaccines between 2002 and 2015. The day of flu vaccination was defined as day 0, and the period between the pre-vaccination and the post-vaccination days was defined as - X to + Y. The risk ratios and their 95% confidence intervals for NS relapse rate were estimated by generalized estimating equation (GEE) Poisson regression. RESULTS: A total of 104 pediatric patients received 208 flu vaccines. The mean age at onset of NS was at 4.85 ± 3.87 years old. There were 261 NS relapses between days - 180 and + 180. Compared with the relapse rate in the - 180 to 0 interval (1.19 times/person-year), those in 0 to + 30 (1.23), + 31 to + 60 (1.58), + 61 to + 90 (1.41), + 91 to + 120 (1.41), and + 121 to + 180 (1.32) days groups were slightly increased, but without significance. Multivariate analysis using GEE Poisson regression also showed no significant increase in relapse rate in each day group compared with days - 180 to 0. Risk ratios for NS relapse were significantly higher in children who were treated with steroids at the first vaccination. CONCLUSIONS: Our results suggest that flu vaccines should not be avoided in children with NS based on the potential for NS relapses.

3.
J Hum Genet ; 65(10): 847-853, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32451492

RESUMO

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by obesity, mental impairment, rod-cone dystrophy, polydactyly, male hypogonadism, and renal abnormalities. This disorder is caused by mutations in BBS1-21. Alström syndrome (AS), caused solely by mutations in ALMS1, is another genetic obesity syndrome clinically similar to BBS. We previously conducted the first nationwide survey of BBS in Japan and found four patients with genetically definite BBS. In this study, exome analyses were performed on new patients whose symptoms fulfilled the diagnostic criteria for BBS. We identified one reported heterozygous mutation in BBS1 (p.R429*) in one patient, two novel mutations (p.L493R and p.H719Y) in BBS20 in a second patient, and one novel mutation (p.Q920*) and one reported mutation (p.R2928*) in ALMS1 in a third patient, who was subsequently diagnosed with AS. The first patient with BBS was previously considered to have digenic heterozygous mutations in BBS1 and BBS4. RT-PCR and long-range genomic PCR analyses identified a new heterozygous mutation in BBS1, the deletion of exons 10 and 11. Thus, this patient was compound heterozygous for mutations in BBS1. Many studies have described digenic heterozygous mutations in BBS. However, undetected mutations might have existed in either one of the mutated genes.

4.
Pediatr Int ; 62(8): 937-943, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32153091

RESUMO

BACKGROUND: Despite advances in non-invasive vascular imaging, detection of renal artery stenosis via catheter angiography is the criterion standard for the diagnosis of renovascular hypertension (RVH). However, because of lack of evidence, the utility of various blood tests and imaging modalities remains unclear. METHODS: We retrospectively analyzed the utility of blood tests (plasma renin activity [PRA], aldosterone, and renal vein renin [RVR] values) and imaging studies (computed tomography angiography [CTA], kidney ultrasonography [US]) by comparing them with catheter angiography. Ten pediatric patients with RVH at two institutions from January 2008 to December 2017 were recruited. The sensitivities for diagnosing RVH via imaging and blood tests (kidney [US], PRA, and aldosterone) were derived by examining patient records. Furthermore, the sensitivity and specificity of CT angiography were calculated by considering both the affected and non-affected renal arteries of the patients. RESULTS: A high sensitivity for diagnosing RVH via kidney US (89%) and PRA (80%) was observed. The sensitivity and specificity of CTA were 100%, each. RVR sampling did not aid in the diagnosis of RVH; only two of six patients with unilateral RVH showed significant laterality of RVR boundary ratios. Renal scintigraphy facilitated detection of a non-functional kidney (split renal function <5%). CONCLUSIONS: RVH in children could be diagnosed utilizing non-invasive blood and imaging tests, without catheter angiography. We recommend kidney length measurement along with measurement of PRA level, as a simple and highly useful screening test, followed by CTA as a diagnostic test.

5.
Hum Mutat ; 41(3): 591-599, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31821646

RESUMO

RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher-facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Using whole-exome and ultra-deep amplicon sequencing and comparing genomic data of affected and unaffected areas of the skin, we discovered that all four individuals carried the identical RHOA missense variant, c.139G>A; p.Glu47Lys, in a postzygotic state. Molecular modeling and in silico analysis of the affected p.Glu47Lys residue in RHOA indicated that this exchange is predicted to specifically alter the interaction of RHOA with its downstream effectors containing a PKN-type binding domain and thereby disrupts its ability to activate signaling. Our findings indicate that the recurrent postzygotic RHOA missense variant p.Glu47Lys causes a specific mosaic disorder in humans.

6.
CEN Case Rep ; 9(1): 19-23, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31538321

RESUMO

Renal coloboma syndrome (RCS, MIM#120330), also known as papillorenal syndrome, is an inherited autosomal dominant disease characterized by ocular and/or renal involvement due to PAX2 mutation. The renal involvement typically consists of a hypo/dysplatic kidney and/or vesicoureteral reflux. Recent studies reported that missense PAX2 mutations cause familial focal segmental glomerular sclerosis (FSGS) without renal morphological malformations. To date, the reports of genotype-phenotype correlation including pathological findings regarding PAX2 mutations are scarce. We report a case of RCS with a novel PAX2 mutation that was pathologically diagnosed as FSGS and rapidly progressed to end-stage kidney failure (ESKD) with a review of past literature. A 6-year-old boy, who had bilateral coloboma and loss of vision in the left eye, was noted non-nephrotic proteinuria and renal dysfunction via school urine screening. Abdominal ultrasound showed no renal and urinary tract malformations and kidney biopsy showed FSGS. Genetic analysis revealed a novel insertion-deletion mutation in PAX2 (NM003987.4: c.70_72delinsA; p.Gly24Argfs*29). His kidney function deteriorated gradually during the following 2 years and kidney transplantation was performed at 9 years of age. In previous reports describing PAX2 mutations with FSGS, affected individuals with missense PAX2 mutations developed ESKD in adulthood, whereas one case with truncating PAX2 mutations developed ESKD in childhood similar to the current case. Our case highlighted the association of truncating PAX2 mutations with the risk of rapid progression to ESKD. Thus, PAX2 mutations should be included in genetic screening for such cases even in the absence of renal and urinary tract malformations.

7.
CEN Case Rep ; 9(1): 59-64, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31677115

RESUMO

Alport syndrome (AS) is a rare hereditary disease that presents with chronic kidney disease and sensorineural hearing loss, and is diagnosed by its clinical features, pathological features on renal tissue, and mode of inheritance. We report a woman in her 20 s who exhibited persistent haematuria with normal renal function and sensorineural hearing loss. Her family members exhibited the same clinical findings among three generations and were suspected of having autosomal dominant AS (ADAS). Renal biopsy showed minor glomerular abnormalities on light microscopy and extensive thinning of the glomerular basement membrane on electron microscopy. Whole-exome analysis revealed a known COL4A4 (type IV collagen α4) mutation (c. 2510 G > C: p. Gly837Ala). Two pedigrees with the same variant have been reported previously, one as ADAS and the other as autosomal recessive AS. However, these two cases exhibited no sensorineural hearing loss. The analysis in the present case revealed another missense variant in ESPN (Espin), an actin-bundling protein, which is a causative gene for sensorineural hearing loss. Although the pathophysiological significance of this novel missense variant needs to be clarified, computational analysis predicted that the variant creates a new phosphorylation site for protein kinase C. Our case suggests a possible association of hereditary sensorineural hearing loss with ADAS. Whole-exome analysis should be considered to diagnose hereditary and multiple-organ disorders.

8.
J Hum Genet ; 64(9): 885-890, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270375

RESUMO

Pediatric hypertension can cause hypertensive emergencies, including hemorrhagic stroke, contributing to rare but serious childhood morbidity and mortality. Renovascular hypertension (RVH) is one of the major causes of secondary hypertension in children. Grange syndrome (MIM#602531) is a rare disease characterized by multiple stenosis or occlusion of the renal, abdominal, coronary, and cerebral arteries, which can cause phenotypes of RVH and fibromuscular dysplasia (MIM#135580). We report the case of a 7-year-old girl with Grange syndrome who showed RVH and multiple seizure episodes. At 1 year of age, she experienced seizures and sequential hemiparesis caused by a left thalamic hemorrhage without cerebral vascular anomalies. Chronic hypertension was observed, and abdominal computed tomography angiography showed characteristic bilateral renal artery stenosis. Whole-exome sequencing revealed a novel homozygous pathogenic variant in the YY1AP1 gene (NM_001198903.1: c.1169del: p.Lys390Argfs*12). Biallelic YY1AP1 mutations are known to cause Grange syndrome. Unlike previously reported patients, our patient presented with intracerebral hemorrhagic stroke without anomalous brain artery or bone fragility. The phenotype in our patient may help better understand this ultra-rare syndrome. Grange syndrome should be considered in patients presenting with childhood-onset hypertension and/or hemorrhagic stroke for early clinical intervention.


Assuntos
Sequência de Aminoácidos , Arteriopatias Oclusivas/genética , Osso e Ossos/anormalidades , Braquidactilia/genética , Proteínas de Ciclo Celular/genética , Cardiopatias Congênitas/genética , Hipertensão Renovascular/genética , Hipertensão/genética , Hemorragias Intracranianas/genética , Deleção de Sequência , Acidente Vascular Cerebral/genética , Sindactilia/genética , Fatores de Transcrição/genética , Arteriopatias Oclusivas/patologia , Arteriopatias Oclusivas/fisiopatologia , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Braquidactilia/patologia , Braquidactilia/fisiopatologia , Criança , Feminino , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Homozigoto , Humanos , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertensão Renovascular/patologia , Hipertensão Renovascular/fisiopatologia , Hemorragias Intracranianas/patologia , Hemorragias Intracranianas/fisiopatologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Sindactilia/patologia , Sindactilia/fisiopatologia
9.
Nat Commun ; 10(1): 2506, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175295

RESUMO

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.


Assuntos
Variação Genética , Espasmos Infantis/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Epilepsias Mioclônicas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Japão , Síndrome de Lennox Gastaut/genética , Modelos Logísticos , Mutação , Neurofibromina 1/genética , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Canais de Cátion TRPM/genética , Sequenciamento Completo do Exoma
10.
Am J Med Genet A ; 179(3): 338-340, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30569574

RESUMO

SOFT syndrome (MIM614813) is an extremely rare primordial dwarfism caused by biallelic mutations in the POC1A gene. It is characterized by prenatal short stature, onychodysplasia, facial dysmorphism, hypotrichosis, and variable skeletal abnormalities including hypoplastic pelvis and sacrum, small hands, and cone-shaped epiphyses, as well as delayed bone age. To the best of our knowledge, only eight POC1A mutations have been reported in humans to date. We report a 7-year-old Chilean girl with SOFT syndrome arising from a novel POC1A mutation c. 649C>T, p.Arg217Trp. Although her clinical features were largely compatible with SOFT syndrome, hand X-ray examinations at 3.5 and 6 years unexpectedly showed normal bone age. Automated bone age determination was performed using image analysis software, BoneXpert. This case highlights the importance of the accumulation of patients with POC1A mutations to further elucidate the detailed clinical features of SOFT syndrome.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Nanismo/diagnóstico , Nanismo/genética , Mutação , Criança , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Fenótipo , Síndrome , Sequenciamento Completo do Genoma
11.
BMC Nephrol ; 19(1): 365, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30558570

RESUMO

BACKGROUND: Bordetella pertussis infection is a known trigger of atypical hemolytic uremic syndrome (HUS). For patients suspected of having atypical HUS, prompt plasma exchange/infusion (PE/PI) or eculizumab (ECZ) treatment is recommended. CASE PRESENTATION: We report a 1-month-old female infant who was admitted with a severe cough and a B. pertussis-positive sputum culture. She was born at 38 weeks gestation and did not have a family history of renal diseases. Hemophagocytic syndrome was suspected and she was transferred to our hospital 17 days after her initial admission. One day later, she developed acute kidney injury and was diagnosed with HUS triggered by B. pertussis infection. Her plasma complement levels were low and her kidney function continued to worsen over the next few days. However, prior to starting ECZ treatment, her kidney function improved spontaneously; she did not receive PE/PI or ECZ. She was discharged 46 days after her initial hospitalization, without complications. A genetic workup revealed no mutations in CFH, CFI, CFB, C3, MCP, THBD, or DGKE. CONCLUSIONS: This case demonstrates that B. pertussis infection-related HUS may resolve spontaneously. The decision to treat during the acute phase is challenging because B. pertussis often affects infants suspected of having atypical HUS. However, ECZ may not be the first treatment option for patients with B. pertussis infection-related HUS unless they show an indicated genetic abnormality; if ECZ is used, early discontinuation should be considered.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Síndrome Hemolítico-Urêmica/microbiologia , Síndrome Hemolítico-Urêmica/terapia , Troca Plasmática , Coqueluche/complicações , Bordetella pertussis , Feminino , Humanos , Lactente , Remissão Espontânea
12.
Am J Hum Genet ; 103(2): 305-316, 2018 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-30057029

RESUMO

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.


Assuntos
Proteínas F-Box/genética , Variação Genética/genética , Transtornos do Neurodesenvolvimento/genética , Proteína-Arginina N-Metiltransferases/genética , Criança , Exoma/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Complexo de Endopeptidases do Proteassoma/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação/genética , Sequenciamento Completo do Exoma/métodos
13.
Brain Dev ; 40(7): 566-569, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29678278

RESUMO

BACKGROUND: Coffin-Lowry syndrome is a rare X-linked disease, caused by loss-of-function mutations in the RPS6KA3 gene. Patients exhibit severe intellectual disability with characteristic dysmorphism. As there are no specific laboratory findings to support the diagnosis of Coffin-Lowry syndrome, it may be difficult to diagnose-especially in young children, where the characteristic craniofacial features are less discernible. CASE: Here we report on a 2-year-old boy with Coffin-Lowry syndrome with a novel missense mutation in the RPS6KA3 gene. On magnetic resonance imaging, his brain exhibited periventricular signal abnormalities with multiple small cystic lesions. These findings may aid in diagnosis of Coffin-Lowry syndrome.


Assuntos
Encéfalo/diagnóstico por imagem , Síndrome de Coffin-Lowry/diagnóstico , Síndrome de Coffin-Lowry/genética , Mutação de Sentido Incorreto , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Pré-Escolar , Síndrome de Coffin-Lowry/patologia , Diagnóstico Diferencial , Face/anormalidades , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo
14.
Nephrology (Carlton) ; 23(6): 592-596, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28976051

RESUMO

Children with systemic lupus erythematosus (SLE) generally undergo a pretreatment kidney biopsy. However, some of these patients, especially those with antiphospholipid syndrome (APS), may experience serious coagulopathic complications. We report herein two cases of paediatric SLE with APS in which, despite normal blood test results, the disparate coagulopathic complications of haemorrhage and embolism developed following a kidney biopsy. Case 1 was, an 8-year-old male in whom, primary APS was initially diagnosed. Fourteen months later SLE was diagnosed. Based on a percutaneous kidney biopsy, International Society of Nephrology and the Renal Pathology Society (ISN/RPS) class III-A lupus nephritis was histologically diagnosed. On post-biopsy Day 9, a giant haematoma in the fascia of the left kidney developed and was accompanied by changes in the vital signs. Case 2, a 13-year-old male, initially received the diagnosis of SLE with APS and underwent two courses of pulse methylprednisolone therapy. His coagulation abnormalities improved, and a percutaneous needle kidney biopsy was performed, leading to the histological diagnosis of ISN/RPS class III-A lupus nephritis. Furthermore, thrombotic microangiopathy was also detected in the renal histopathology. On post biopsy Day 6, the patient experienced right leg pain. A contrast CT and lower extremity ultrasonography detected a massive deep vein thrombosis and partial left pulmonary artery thrombosis. A kidney biopsy in children with SLE and APS can cause lethal coagulopathic complications, and the risks to such patients should be weighed carefully before the procedure is performed.


Assuntos
Síndrome Antifosfolipídica/complicações , Arteriopatias Oclusivas/etiologia , Biópsia/efeitos adversos , Hematoma/etiologia , Rim/patologia , Lúpus Eritematoso Sistêmico/complicações , Nefrite Lúpica/etiologia , Trombose Venosa/etiologia , Adolescente , Idade de Início , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/tratamento farmacológico , Arteriopatias Oclusivas/sangue , Arteriopatias Oclusivas/diagnóstico , Arteriopatias Oclusivas/tratamento farmacológico , Coagulação Sanguínea , Criança , Glucocorticoides/uso terapêutico , Hematoma/sangue , Hematoma/diagnóstico , Hematoma/tratamento farmacológico , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nefrite Lúpica/patologia , Masculino , Fatores de Risco , Tomografia Computadorizada por Raios X , Ultrassonografia Doppler em Cores , Trombose Venosa/sangue , Trombose Venosa/diagnóstico , Trombose Venosa/tratamento farmacológico
16.
Nephrology (Carlton) ; 22(7): 566-571, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28621010

RESUMO

WDR19 has been reported as a causative gene of nephronophthisis-related ciliopathies. Patients with WDR19 mutations can show various extrarenal manifestations such as skeletal disorders, Caroli disease, and retinal dystrophy, and typically display nephronophthisis as a renal phenotype. However, there is limited information on the renal phenotypes of patients with WDR19 mutations. We report two Japanese infants with Sensenbrenner syndrome caused by WDR19 mutations who demonstrated different features in renal ultrasound and histopathological results, despite several common extrarenal manifestations. Patient 1 had normal sized and hyperechogenic kidneys with several small cysts and histopathological findings compatible with infantile nephronophthisis. Renal ultrasound of Patient 2 showed enlarged kidneys with diffuse microcysts resembling those of autosomal recessive polycystic kidney disease. Her renal histopathology revealed dysplastic kidney with diffuse glomerular cysts. Genetic testing identified compound heterozygous mutations in WDR19 in both patients (Patient 1: c.953delA, c.3533G > A, Patient 2: c.2645 + 1G > T, c.3533G > A). Our patients suggest that WDR19 mutations can cause dysplastic kidney in addition to nephronophthisis pathologically. In addition, differences in pathology of the kidneys from WDR19 mutations may result in heterogeneous features in renal ultrasound findings. Renal phenotypes from WDR19 mutations may thus be more diverse than previously reported. Extrarenal manifestations and genetic testing can therefore help to diagnosis this disease more precisely.


Assuntos
Osso e Ossos/anormalidades , Craniossinostoses/genética , Displasia Ectodérmica/genética , Doenças Renais Císticas/genética , Rim/anormalidades , Mutação , Rim Policístico Autossômico Recessivo/genética , Proteínas/genética , Biópsia , Pré-Escolar , Craniossinostoses/diagnóstico , Craniossinostoses/terapia , Análise Mutacional de DNA , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/terapia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Lactente , Rim/diagnóstico por imagem , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/terapia , Imagem por Ressonância Magnética , Fenótipo , Rim Policístico Autossômico Recessivo/diagnóstico , Rim Policístico Autossômico Recessivo/terapia , Ultrassonografia
17.
Pediatr Int ; 58(6): 537-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27322865

RESUMO

The incidence of ampicillin (ABPC)-resistant Escherichia coli (E. coli) infection in very low-birthweight infants has been increasing. The rate of ABPC/sulbactam (ABPC/SBT)-resistant E. coli in this population, however, is currently unknown. We encountered two cases of severe infection due to resistant E. coli and retrospectively studied the prevalence of ABPC- and ABPC/SBT-resistant E. coli in regular surveillance cultures obtained from all neonatal intensive care unit (NICU) patients between 2000 and 2013. The overall prevalence of ABPC-resistant E. coli was 39% (47/120), accounting for 63% of cases (32/51) between 2007 and 2013, compared with 22% (15/69) between 2000 and 2006. The prevalence of ABPC/SBT resistance was 17% (20/120), which was similar in both periods (16%, 8/51 vs 17%, 12/69). According to these results, not only ABPC, but also ABPC/SBT-resistant E. coli must be considered in the NICU.


Assuntos
Ampicilina/uso terapêutico , Farmacorresistência Bacteriana , Infecções por Escherichia coli/epidemiologia , Escherichia coli/isolamento & purificação , Unidades de Terapia Intensiva Neonatal/estatística & dados numéricos , Sulbactam/uso terapêutico , Fatores Etários , Antibacterianos/uso terapêutico , Quimioterapia Combinada , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Feminino , Humanos , Incidência , Recém-Nascido , Japão/epidemiologia , Masculino
18.
Clin Exp Nephrol ; 20(2): 265-72, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26156042

RESUMO

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a severe life-threatening disease with frequent progression to end-stage renal disease (ESRD). Eculizumab, a humanized anti-C5 monoclonal antibody targeting the activated complement pathway, has recently been introduced as a novel therapy against aHUS. We, therefore, investigated the efficacy and safety of eculizumab in Japanese pediatric patients. METHODS: We retrospectively analyzed clinical course and laboratory data of the first ten children with aHUS treated with eculizumab nationwide. RESULTS: Seven patients were resistant to plasma therapy and three were dependent on it. Causative gene mutations were found in five patients. Two patients had anti-complement factor H autoantibody. Three patients had a family history of thrombotic microangiopathy (TMA). After initiation of eculizumab, all patients immediately achieved hematological remission and could successfully discontinue plasma therapy. The median periods to normalization of platelet count, lactate dehydrogenase levels and disappearance of schistocytes were 5.5, 17 and 12 days, respectively. Nine patients recovered their renal function and the median period to terminate renal replacement therapy (RRT) was 3 days. However, two patients progressed to ESRD and required chronic RRT at the last observation. No patients had a relapse of TMA under regular eculizumab therapy. No serious adverse events occurred during the follow-up period. CONCLUSIONS: Eculizumab is efficacious and well-tolerated therapy for children with aHUS. Although pathogenic mutations could not be detected in five patients, all patients showed immediate normalization of hematological abnormalities, strongly suggesting complement-related aHUS. This prompt hematological amelioration can become an indicator for therapeutic efficacy of eculizumab. However, appropriate indications and optimal duration of the treatment remain unclear.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos
19.
PLoS One ; 10(9): e0136317, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26325687

RESUMO

Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder characterized by central obesity, mental impairment, rod-cone dystrophy, polydactyly, hypogonadism in males, and renal abnormalities. The causative genes have been identified as BBS1-19. In Western countries, this disease is often reported, but remains undiagnosed in many patients until later in life, while only a few patients with no mutations identified have been reported in Japan. We thus conducted the first nationwide survey of BBS in Japan by sending questionnaires to 2,166 clinical departments with board-certified specialists and found 7 patients with clinically definite BBS. We performed exome analyses combined with analyses of mRNA and protein in these patients. We identified 2 novel mutations in the BBS5 gene (p.R89X and IVS7-27 T>G) in 2 sibling patients. The latter mutation that resided far from the authentic splicing site was associated with skipping of exon 8. We also found 3 previously reported mutations in the BBS2 (p.R413X and p.R480X) and BBS7 (p.C243Y) genes in 2 patients. To our knowledge, a nationwide survey of BBS has not been reported in any other country. In addition, this is the first study to identify genetic alterations in Japanese patients with BBS. Our results indicate that BBS in Japan is genetically heterogeneous and at least partly shares genetic features with BBS in other countries.


Assuntos
Síndrome de Bardet-Biedl/epidemiologia , Adolescente , Síndrome de Bardet-Biedl/genética , Criança , Pré-Escolar , Proteínas do Citoesqueleto , Exoma/genética , Feminino , Humanos , Japão/epidemiologia , Masculino , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Ligação a Fosfato , Proteínas/genética , Inquéritos e Questionários , Adulto Jovem
20.
Eur J Pediatr ; 174(4): 551-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25194957

RESUMO

UNLABELLED: Staphylococcal scalded skin syndrome (SSSS) demonstrates dermal symptoms due to exfoliative toxin (ET) A or ETB produced by Staphylococcus aureus. We examined the association between anti-ETA antibodies and SSSS onset in neonates. Three preterm infants carried an ETA-producing strain of S. aureus, manifesting as either SSSS or bullous impetigo; a full-term infant carrying the same strain was asymptomatic. The infants (n=106) were categorized into three groups according to their gestational age (GA) as follows: <30 weeks, 30-37 weeks, and >37 weeks. The measured levels of anti-ETA antibody in the three infants displaying SSSS were low before the onset of dermal symptoms; only the asymptomatic full-term infant displayed a high antibody level. Anti-ETA antibody levels in the preterm group with a GA of <30 weeks were statistically lower than those in the term infant group; the prevalences of anti-ETA antibodies above a cutoff value in the three groups of neonates were 55 % (18/33) among preterm infants with a GA <30 weeks, 73 % (25/34) among those with a GA of 30-37 weeks, and 90 % (35/39) among infants with a GA >37 weeks. CONCLUSION: The presence of anti-ETA antibodies below a particular cutoff level might be associated with SSSS onset in preterm infants.


Assuntos
Exfoliatinas/imunologia , Infecções Estafilocócicas/diagnóstico , Síndrome da Pele Escaldada Estafilocócica/diagnóstico , Staphylococcus aureus/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Infecções Estafilocócicas/imunologia , Síndrome da Pele Escaldada Estafilocócica/imunologia
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