RESUMO
Objective: To highlight a novel, treatable syndrome, we report 4 patients with CNS-isolated inflammation associated with familial hemophagocytic lymphohistiocytosis (FHL) gene mutations (CNS-FHL). Methods: Retrospective chart review. Results: Patients with CNS-FHL are characterized by chronic inflammation restricted to the CNS that is not attributable to any previously described neuroinflammatory etiology and have germline mutations in known FHL-associated genes with no signs of systemic inflammation. Hematopoietic stem cell transplantation (HCT) can be well tolerated and effective in achieving or maintaining disease remission in patients with CNS-FHL. Conclusions: Early and accurate diagnosis followed by treatment with HCT can reduce morbidity and mortality in CNS-FHL, a novel, treatable syndrome. Classification of evidence: This study provides Class IV evidence that HCT is well tolerated and effective in treating CNS-FHL.
Assuntos
Doenças do Sistema Nervoso Central/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Doenças do Sistema Nervoso Central/genética , Criança , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Humanos , Linfo-Histiocitose Hemofagocítica/genéticaRESUMO
OBJECTIVE: To assess the utility of whole-exome sequencing (WES) in a sibling pair with undetermined liver disease and describe the phenotype associated with mutations discovered therein. STUDY DESIGN: Next-generation WES was performed on 2 siblings (S1 and S2) who were born to nonconsanguineous parents of European extraction. Both siblings developed cirrhosis of indeterminate etiology and required liver transplantation; S1 at 7 months and S2 at 22 months. RESULTS: Sequencing of germline DNA identified compound heterozygous mutations in PPP1R15B resulting in increased levels of phosphorylated eukaryotic translation initiation factor 2α. CONCLUSIONS: The first demonstration of PPP1R15B associated with liver disease expands the phenotypic spectrum of PPP1R15B related diseases. Our findings validate the application of WES in the diagnosis of children with undetermined liver disease. Understanding the genetic basis of liver disease may allow the development of targeted therapies for treatment and adequate counseling of families.
Assuntos
Transtornos do Crescimento/genética , Cirrose Hepática/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Proteína Fosfatase 1/genética , Feminino , Humanos , Lactente , Fenótipo , Proteína Fosfatase 1/deficiência , Análise de Sequência de DNARESUMO
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease that displays genetic heterogeneity; there are 9 known subtypes. HPS is characterized by oculocutaneous albinism, a platelet storage pool deficiency and resultant bleeding diathesis, and lysosomal accumulation of ceroid lipofuscin. Patients with HPS, specifically those with the genotypes HPS-1, HPS-2, or HPS-4, are predisposed to interstitial lung disease. In addition, some patients with HPS develop granulomatous colitis. Optimal health care requires a thorough knowledge of the unique health risks and functional limitations associated with this syndrome.
Assuntos
Síndrome de Hermanski-Pudlak/terapia , Assistência de Longa Duração/métodos , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/epidemiologia , Albinismo Oculocutâneo/genética , Albinismo Oculocutâneo/terapia , Criança , Aberrações Cromossômicas , Comportamento Cooperativo , Comparação Transcultural , Estudos Transversais , Análise Mutacional de DNA , Avaliação da Deficiência , Diagnóstico Precoce , Genes Recessivos , Genótipo , Síndrome de Hermanski-Pudlak/diagnóstico , Síndrome de Hermanski-Pudlak/epidemiologia , Síndrome de Hermanski-Pudlak/genética , Humanos , Comunicação Interdisciplinar , Fenótipo , Deficiência do Pool Plaquetário/diagnóstico , Deficiência do Pool Plaquetário/epidemiologia , Deficiência do Pool Plaquetário/genética , Deficiência do Pool Plaquetário/terapia , Porto RicoRESUMO
OBJECTIVE: To report new adverse effects of cysteamine. STUDY DESIGN: Detailed clinical information was obtained from the patients' physicians. RESULTS: New adverse events were reported in 8 of 550 patients with cystinosis treated with cysteamine in Europe during the last 5 years. Detailed clinical information was not available for 2 of these patients, 1 of whom died from cerebral ischemia. The 6 evaluable patients developed vascular elbow lesions (6/6), neurologic symptoms (1/6), bone and muscle pain (2/6), and/or skin striae (2/6). Analysis of biopsy specimens from the elbow lesions demonstrated angioendotheliomatosis with irregular collagen fibers. In 3 of the 6 patients, the daily cysteamine dose exceeded the recommended maximum of 1.95 g/m(2)/day. Dose reduction led to improvement of signs and symptoms in all 6 patients, suggesting a causal relationship with cysteamine administration. CONCLUSION: Cysteamine administration can be complicated by the development of skin, vascular, neurologic, muscular, and bone lesions. These lesions improve after cysteamine dose reduction. Doses >1.95 g/m(2)/day should be prescribed with great caution, but underdosing is not advocated.
Assuntos
Cisteamina/toxicidade , Cistinose/tratamento farmacológico , Toxidermias/etiologia , Pré-Escolar , Humanos , Lactente , MasculinoRESUMO
OBJECTIVES: To describe 3 children with mutations in a Meckel syndrome gene (MKS3), with features of autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis, and Joubert syndrome (JS). STUDY DESIGN: Biochemical evaluations, magnetic resonance and ultrasound imaging, electroretinograms, IQ testing, and sequence analysis of the PKHD1 and MKS3 genes were performed. Functional consequences of the MKS3 mutations were evaluated by cDNA sequencing and transfection studies with constructs of meckelin, the protein product of MKS3. RESULTS: These 3 children with MKS3 mutations had features typical of ARPKD, that is, enlarged, diffusely microcystic kidneys and early-onset severe hypertension. They also exhibited early-onset chronic anemia, a feature of nephronophthisis, and speech and oculomotor apraxia, suggestive of JS. Magnetic resonance imaging of the brain, originally interpreted as normal, revealed midbrain and cerebellar abnormalities in the spectrum of the "molar tooth sign" that characterizes JS. CONCLUSIONS: These findings expand the phenotypes associated with MKS3 mutations. MKS3-related ciliopathies should be considered in patients with an ARPKD-like phenotype, especially in the presence of speech and oculomotor apraxia. In such patients, careful expert evaluation of the brain images can be beneficial because the brain malformations can be subtle.
Assuntos
Anormalidades Múltiplas/genética , Transtornos da Motilidade Ciliar/genética , Proteínas de Membrana/genética , Mutação , Rim Policístico Autossômico Recessivo/genética , Anormalidades Múltiplas/diagnóstico , Encéfalo/anormalidades , Encéfalo/patologia , Criança , Transtornos da Motilidade Ciliar/diagnóstico , Feminino , Humanos , Rim/anormalidades , Rim/diagnóstico por imagem , Rim/patologia , Fígado/anormalidades , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Rim Policístico Autossômico Recessivo/diagnóstico , Irmãos , Síndrome , UltrassonografiaAssuntos
Cirrose Hepática/congênito , Cirrose Hepática/terapia , Rim Policístico Autossômico Recessivo/genética , Rim Policístico Autossômico Recessivo/terapia , Inibidores da Enzima Conversora de Angiotensina , Anticolesterolemiantes/uso terapêutico , Ductos Biliares/metabolismo , Canais de Cálcio/metabolismo , Criança , Progressão da Doença , Expressão Gênica , Humanos , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/epidemiologia , Túbulos Renais Distais/metabolismo , Túbulos Renais Proximais/metabolismo , Cirrose Hepática/epidemiologia , Fenótipo , Diester Fosfórico Hidrolases/metabolismo , Mutação Puntual/genética , Rim Policístico Autossômico Recessivo/epidemiologia , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismoRESUMO
OBJECTIVES: To report a high frequency of idiopathic intracranial hypertension (IIH) in patients with cystinosis and to speculate on the relationship between these two disorders. STUDY DESIGN: Retrospective case series and review of the literature regarding risk factors for the development of IIH in cystinosis. RESULTS: Eight patients with cystinosis had documented papilledema, normal neuroimaging of the brain, cerebrospinal fluid (CSF) opening pressure greater than 200 mm of H2O, and normal CSF composition. No common medication, condition, or disease except cystinosis was found in these persons. Six of the patients had received prednisone, growth hormone, cyclosporine, oral contraceptives, vitamin D, or levothyroxine at the time of onset of IIH. Five patients had previous renal transplants. CONCLUSION: No single risk factor for the development of IIH linked IIH to cystinosis in our patients. However, thrombosis susceptibility as a result of renal disease or impaired CSF reabsorption in the arachnoid villi as a result of cystine deposition might lead to the development of IIH in cystinosis.
Assuntos
Cistinose/complicações , Pseudotumor Cerebral/etiologia , Adolescente , Pré-Escolar , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/complicações , Fatores de RiscoRESUMO
We report the excellent clinical outcomes of siblings with nephropathic cystinosis treated diligently with cysteamine starting at 20 months and 2 months of age. Now 15 and 8 years old, they have glomerular filtration rates of 78 and 105 mL/min/1.73m 2 , respectively. These cases illustrate the critical importance of early diagnosis and treatment.