RESUMO
BACKGROUND: The pretreatment International Neuroblastoma Risk Group Staging System (INRGSS) discriminates localized tumors L1/L2 depending on the absence/presence of image-defined risk factors (IDRFs) at diagnosis. Referring to this new staging system, we assessed initial imaging of localized thoracic neuroblastoma (NB) and ganglioneuroma (GN) and the extent of initial tumor resection. METHODS: Patients with localized thoracic NB/GN from the German clinical trials NB97 and NB2004 were included. Imaging at diagnosis and operative reports were reviewed retrospectively. IDRFs were assessed centrally and correlated to International Neuroblastoma Staging System (INSS) stage and extent of tumor resection. Additionally, we analyzed data on surgery-related complications. RESULTS: Imaging series of 88 patients were available for central review. In 18 children, no IDRF was present, 28 exhibited one IDRF, 42 two or more IDRFs, resulting in 70 patients with L2 disease. The most frequently observed IDRF was encasement of any vessel (n = 38). Initial surgical resection was aimed for in 45 patients (L1: n = 11; L2: n = 34). Complete and gross total resection rates were higher children with L2 NB (n = 8/25 L1, n = 17/25 L2 vs. n = 2/15 L1, n = 13/15 L2, respectively). The proportion of surgical complications was very similar between INRGSS L1 and L2 (n = 4/11 vs. n = 17/34). All complications were manageable, and no surgery-related deaths were observed. CONCLUSION: In this retrospective cohort, the extent of resection and the rate of surgical complications did not differ substantially between patients classified as L1/L2, indicating that INRGSS L2 does not equate unresectability. It appeared that individual IDRFs differ in value. Larger studies are needed to assess the significance and therapeutic/prognostic impact of such findings.
Assuntos
Ganglioneuroma , Neuroblastoma , Criança , Humanos , Lactente , Estudos Retrospectivos , Ganglioneuroma/diagnóstico por imagem , Ganglioneuroma/cirurgia , Ganglioneuroma/patologia , Estadiamento de Neoplasias , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/cirurgia , Fatores de RiscoRESUMO
CAPRIN1 is a ubiquitously expressed protein, abundant in the brain, where it regulates the transport and translation of mRNAs of genes involved in synaptic plasticity. Here we describe two unrelated children, who developed early-onset ataxia, dysarthria, cognitive decline and muscle weakness. Trio exome sequencing unraveled the identical de novo c.1535C > T (p.Pro512Leu) missense variant in CAPRIN1, affecting a highly conserved residue. In silico analyses predict an increased aggregation propensity of the mutated protein. Indeed, overexpressed CAPRIN1P512L forms insoluble ubiquitinated aggregates, sequestrating proteins associated with neurodegenerative disorders (ATXN2, GEMIN5, SNRNP200 and SNCA). Moreover, the CAPRIN1P512L mutation in isogenic iPSC-derived cortical neurons causes reduced neuronal activity and altered stress granule dynamics. Furthermore, nano-differential scanning fluorimetry reveals that CAPRIN1P512L aggregation is strongly enhanced by RNA in vitro. These findings associate the gain-of-function Pro512Leu mutation to early-onset ataxia and neurodegeneration, unveiling a critical residue of CAPRIN1 and a key role of RNA-protein interactions.
Assuntos
Proteínas de Ciclo Celular , Agregados Proteicos , Ataxia , Proteínas de Ciclo Celular/metabolismo , Criança , Humanos , Mutação , RNA Mensageiro/metabolismoAssuntos
Micção , Refluxo Vesicoureteral , Meios de Contraste , Humanos , Lactente , UltrassonografiaRESUMO
PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications. Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients. This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability.
Assuntos
Epilepsia , Microcefalia , Malformações do Sistema Nervoso , Protocaderinas/genética , Caderinas/genética , Criança , Epilepsia/genética , HumanosRESUMO
Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.
Assuntos
Rim/fisiopatologia , Rim Policístico Autossômico Recessivo/mortalidade , Rim Policístico Autossômico Recessivo/fisiopatologia , Adolescente , Biomarcadores , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Lactente , Cirrose Hepática/fisiopatologia , Estudos Longitudinais , Masculino , Tamanho do Órgão/genética , Tamanho do Órgão/fisiologia , Rim Policístico Autossômico Recessivo/metabolismo , Prognóstico , Receptores de Superfície Celular/genética , Insuficiência Renal Crônica/fisiopatologia , UltrassonografiaRESUMO
BACKGROUND: Neuroblastomas are tumors of the sympathetic nervous system that arise from the sympathetic trunk and adrenal glands. Tissue compositions, molecular genetics, and overall prognosis are heterogeneous. With an incidence of 1:6000, neuroblastomas account for 5.5% of childhood tumors. They usually occur in children up to preschool age with the mean age of 14 months. Adults are very rarely affected. Imaging, especially magnetic resonance imaging (MRI), plays an essential role in diagnosis, risk stratification, and therapy control. MATERIALS AND METHODS: Based on a selective literature search in the PubMed database, the national and international societies' guidelines and study protocols, the imaging standards and the latest developments are presented. CONCLUSION: Imaging plays a key role in neuroblastomas due to the heterogeneous prognosis and the resulting very different therapy. A high degree of standardization in implementation and interpretation is important in every phase of the disease process. Sonography, MRI with diffusion weighting, and 123ImIBG-SPECT are essential modalities. The extent of the diffusion restriction for assessing the degree of maturity and assessing the therapeutic response is becoming increasingly important in clinical routine. Up to now, PET imaging has mostly been complementary. Newly developed PET tracers promise comprehensive diagnostics and may also play a major role in theranostics.
Assuntos
3-Iodobenzilguanidina , Neuroblastoma , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Imageamento por Ressonância Magnética , Neuroblastoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , RadiografiaRESUMO
Various parameters can be used for the estimation of gestational age and maturity with arising challenges in the assessment of decomposed bodies. In order to assess gestational age and thus maturity, the study measured the femoral length, the diameter of the distal femoral epiphysis and the presence of the proximal tibial epiphysis compared to a known clavicle length. The resulting gestational ages were compared and statistically evaluated. As a result, discrepancies between the estimated gestational ages became apparent in some cases when comparing the individual structures to be measured. However, there was a clear tendency towards a lower gestational age calculated based on clavicle length and a higher gestational age calculated based on femoral length and distal femoral epiphysis. With regard to the assessment of maturity, it has been concluded that, if the proximal tibial epiphysis is present, maturity can also be assumed based on the diameter of the distal femoral epiphysis and the length of the femur.
Assuntos
Determinação da Idade pelo Esqueleto/métodos , Clavícula/diagnóstico por imagem , Epífises/diagnóstico por imagem , Fêmur/diagnóstico por imagem , Idade Gestacional , Cadáver , Clavícula/crescimento & desenvolvimento , Epífises/crescimento & desenvolvimento , Feminino , Fêmur/crescimento & desenvolvimento , Antropologia Forense , Humanos , Recém-Nascido , Masculino , Tomografia Computadorizada por Raios XRESUMO
Nephronophthisis-related ciliopathies (NPHP-RCs) are a group of inherited diseases that are associated with defects in primary cilium structure and function. To identify genes mutated in NPHP-RC, we performed homozygosity mapping and whole-exome sequencing for >100 individuals, some of whom were single affected individuals born to consanguineous parents and some of whom were siblings of indexes who were also affected by NPHP-RC. We then performed high-throughput exon sequencing in a worldwide cohort of 800 additional families affected by NPHP-RC. We identified two ADAMTS9 mutations (c.4575_4576del [p.Gln1525Hisfs∗60] and c.194C>G [p.Thr65Arg]) that appear to cause NPHP-RC. Although ADAMTS9 is known to be a secreted extracellular metalloproteinase, we found that ADAMTS9 localized near the basal bodies of primary cilia in the cytoplasm. Heterologously expressed wild-type ADAMTS9, in contrast to mutant proteins detected in individuals with NPHP-RC, localized to the vicinity of the basal body. Loss of ADAMTS9 resulted in shortened cilia and defective sonic hedgehog signaling. Knockout of Adamts9 in IMCD3 cells, followed by spheroid induction, resulted in defective lumen formation, which was rescued by an overexpression of wild-type, but not of mutant, ADAMTS9. Knockdown of adamts9 in zebrafish recapitulated NPHP-RC phenotypes, including renal cysts and hydrocephalus. These findings suggest that the identified mutations in ADAMTS9 cause NPHP-RC and that ADAMTS9 is required for the formation and function of primary cilia.
Assuntos
Proteína ADAMTS9/genética , Ciliopatias/genética , Mutação , Doenças Renais Policísticas/genética , Proteína ADAMTS9/metabolismo , Animais , Cílios/patologia , Ciliopatias/patologia , Feminino , Humanos , Masculino , Fenótipo , Doenças Renais Policísticas/patologia , Esferoides Celulares , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
For nasal application of neurotrophins and mesenchymal stem cells, successful delivery to the brain and therapeutic effects are known from experimental data in animals. Human breast milk contains neurotrophins and stem cells, but gavage tube feeding in preterm infants bypasses the naso-oropharynx. This is a first exploration on additional nasal breast milk and neuromorphological outcome after severe neonatal brain injury. We present a retrospective summary of 31 very low birth weight preterm infants with intraventricular hemorrhage °3/4 from one third-level neonatal center. All were breast milk fed. Sixteen infants additionally received nasal drops of fresh breast milk daily with informed parental consent for at least 28 days. Cerebral ultrasound courses were reviewed by a pediatric radiologist blinded to the intervention. The main outcome measure was severity of porencephalic defects before discharge. Clinical covariates were comparable in both groups. With nasal breast milk, a trend to a lower incidence for severe porencephalic defects (21% vs. 58%) was detected. Incidences were lower for progressive ventricular dilatation (71% vs. 91%) and surgery for posthemorrhagic hydrocephalus (50% vs. 67%).Conclusion: The hypothesis is generated that early intranasal application of breast milk could have a beneficial effect on neurodevelopment in preterm infants. Controlled investigation is needed. What is Known: ⢠Successful delivery to the brain and therapeutic effects are known for nasal application of neurotrophins and mesenchymal stem cells from experimental data in animal studies. ⢠Human breast milk contains neurotrophins and stem cells, but gavage tube feeding in preterm infants bypasses the naso-oropharynx. What is New: ⢠This is the first report on additional nasal breast milk application in very low birth weight preterm infants with severe brain injury observing a trend for less severe porencephalic defects. ⢠The hypothesis is generated that nasal breast milk might exert neuroprotective effects in preterm infants.
Assuntos
Hemorragia Cerebral/terapia , Leite Humano , Fatores de Crescimento Neural/administração & dosagem , Transplante de Células-Tronco/métodos , Administração Intranasal , Aleitamento Materno , Estudos de Casos e Controles , Hemorragia Cerebral/complicações , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Recém-Nascido de muito Baixo Peso , Masculino , Estudos Retrospectivos , Células-Tronco , Resultado do Tratamento , Ultrassonografia Doppler TranscranianaRESUMO
BACKGROUND: Exacerbation of hyperkinesia is a life-threatening complication of dyskinetic movement disorders, which can lead to multi-organ failure and even to death. GNAO1 has been recently identified to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders. Patients with GNAO1 mutations can present with a severe, progressive hyperkinetic movement disorder with prolonged life-threatening exacerbations, which are refractory to most anti-dystonic medication. OBJECTIVE: The objective was to investigate the evolution of symptoms and the response to deep brain stimulation of the globus pallidus internus (GPi-DBS) in patients with different GNAO1 mutations. METHODS: We report six patients presenting with global motor retardation, reduced muscle tone and recurrent episodes of severe, life-threatening hyperkinesia with dystonia, choreoathetosis, and ballism since early childhood. Five of them underwent GPi-DBS. RESULTS: The genetic workup revealed mutations in GNAO1 for all six patients. These encompass a new splice site mutation (c.723+1G>T) in patient 1, a new missense mutation (c.610G>C; p.Gly204Arg) in patient 2, a heterozygous mutation (c.625>T; p.Arg209Cys) in patients 3 and 4, and a heterozygous mutation (c.709G>A; p.Glu237Lys) in patients 5 and 6. By intervention with GPi-DBS the severe paroxysmal hyperkinetic exacerbations could be stopped in five patients. One patient is still under evaluation for neuromodulation. CONCLUSION: In complex movement disorders of unsolved etiology clinical WES can rapidly streamline pathogenic genes. We identified two novel GNAO1 mutations. GPi-DBS can be an effective and life-saving treatment option for patients with GNAO1 mutations and has to be considered early.
Assuntos
Estimulação Encefálica Profunda , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Hipercinese/genética , Hipercinese/terapia , Mutação , Criança , Pré-Escolar , Feminino , Globo Pálido/diagnóstico por imagem , Humanos , Hipercinese/diagnóstico por imagem , Lactente , Masculino , Resultado do TratamentoRESUMO
Mutations in SCN2A are associated with a heterogeneous clinical spectrum including epilepsy and autism. Here, we have identified a peculiar phenotype associated with vaccination related exacerbations of ataxia. We report the first family with three individuals affected by SCN2A-associated episodic ataxia (EA) with impaired speech development. The index patient manifested his first episode of subacute cerebellar ataxia at the age of 12 months, 3 weeks after vaccinations for measles, mumps, rubella, and varicella. Cranial magnetic resonance imaging showed a lesion of the left cerebellar hemisphere, which was first considered as a potential cause of the ataxia. The patient fully recovered within 3 weeks, but developed three very similar episodes of transient ataxia within the following 24 months. Whole exome sequencing of the index patient revealed a heterozygous autosomal-dominant mutation in SCN2A (NM_021007, c.4949T > C; p.L1650P), which was confirmed in the likewise affected mother, and was then also identified in the younger brother who developed the first episode of ataxia. We hereby extend the recently described spectrum of SCN2A-associated neurologic disorders, emphasizing that SCN2A mutations should also be considered in familial cases of EA. Coincidental imaging findings or other associated events such as immunizations should not protract genetic investigations.
Assuntos
Ataxia Cerebelar/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Distúrbios da Fala/genética , Adulto , Feminino , Humanos , Lactente , Masculino , LinhagemRESUMO
BACKGROUND: Protein-losing enteropathy (PLE) is characterised by gastrointestinal protein leakage due to loss of mucosal integrity or lymphatic abnormalities. PLE can manifest as congenital diarrhoea and should be differentiated from other congenital diarrhoeal disorders. Primary PLEs are genetically heterogeneous and the underlying genetic defects are currently emerging. OBJECTIVES: We report an infant with fatal PLE for whom we aimed to uncover the underlying pathogenic mutation. METHODS: We performed whole exome sequencing (WES) for the index patient. Variants were classified based on the American College of Medical Genetics and Genomics guidelines. WES results and our detailed clinical description of the patient were compared with the literature. RESULTS: We discovered a novel homozygous stop mutation (c.988C>T, p.Q330*) in the Plasmalemma Vesicle-Associated Protein (PLVAP) gene in a newborn with fatal PLE, facial dysmorphism, and renal, ocular and cardiac anomalies. The Q330* mutation is predicted to result in complete loss of PLVAP protein expression leading to deletion of the diaphragms of endothelial fenestrae, resulting in plasma protein extravasation and PLE. Recently, another single homozygous stop mutation in PLVAP causing lethal PLE in an infant was reported. CONCLUSIONS: Our findings validate PLVAP mutations as a cause of syndromic PLE. Prenatal anomalies, severe PLE and syndromic features may guide the diagnosis of this rare disease.
Assuntos
Proteínas de Transporte/genética , Homozigoto , Proteínas de Membrana/genética , Mutação , Enteropatias Perdedoras de Proteínas/genética , Evolução Fatal , Humanos , Recém-Nascido , Masculino , Enteropatias Perdedoras de Proteínas/metabolismo , Enteropatias Perdedoras de Proteínas/patologia , Sequenciamento do ExomaRESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of dialysis-requiring end-stage renal disease in adults and is characterized by the slowly progressing replacement of renal tissue by focal macrocysts. Alport syndrome (AS; hereditary nephritis) is a rare, inherited disorder of the basement membrane associated with hematuria, proteinuria, and loss of kidney function as well as sensorineural hearing loss and ocular abnormalities. Here, we report on a family in which both ADPKD and AS are present. In a male patient, both -ADPKD and AS coincided. This patient shows the very rare coexistence of two severe, inherited renal disorders and illustrates the importance of considering additional diagnoses in the setting of positive family history for a common hereditary disorder.â©.
Assuntos
Nefrite Hereditária/complicações , Rim Policístico Autossômico Dominante/complicações , Adulto , Humanos , MasculinoRESUMO
BACKGROUND: Growth restriction and retarded bone age are common findings in children with chronic kidney disease (CKD). We compared the automated BoneXpert™ method with the manual assessment of an X-ray of the non-dominant hand. METHODS: In this retrospective multicenter study, 359 patients with CKD stages 2-5, aged 2-14.5 (girls) or 2.5-17 years (boys) were included. Bone age was determined manually by three experts (according to Greulich and Pyle). Automated determination of bone age was performed using the image analysis software BoneXpert™. RESULTS: There was a strong correlation between the automatic and the manual method (r = 0.983, p < 0.001). The automatic method tended to generate higher bone age values (0.64 ± 0.73 years) in the younger patients (4-5 years) and to underestimate retardation or acceleration of bone age. The so-called "bone health index" (BHI) was reduced in comparison to the reference population. Bone health index standard deviation score (BHI-SDS) was not related to the stage of CKD, but weakly negatively correlated with plasma PTH concentrations (r = 0.12, p = 0.019). CONCLUSIONS: BoneXpert™ allows an objective, time-saving, and in general valid bone age assessment in children with CKD. Possible underestimation of retarded or accelerated bone age should be taken into account. Validation of the BHI needs further study.
Assuntos
Determinação da Idade pelo Esqueleto/métodos , Doenças Ósseas/diagnóstico , Doenças Ósseas/etiologia , Insuficiência Renal Crônica/complicações , Adolescente , Automação , Doenças Ósseas/diagnóstico por imagem , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/patologia , Mãos/diagnóstico por imagem , Nível de Saúde , Humanos , Processamento de Imagem Assistida por Computador , Testes de Função Renal , Masculino , Hormônio Paratireóideo/sangue , Insuficiência Renal Crônica/diagnóstico por imagem , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Determination of variant pathogenicity represents a major challenge in the era of high-throughput sequencing. Erroneous categorization may result if variants affect genes that are in fact dispensable. We demonstrate that this also applies to rare, apparently unambiguous truncating mutations of an established disease gene. By whole-exome sequencing (WES) in a consanguineous family with congenital non-syndromic deafness, we unexpectedly identified a homozygous nonsense variant, p.Arg1066*, in AHI1, a gene associated with Joubert syndrome (JBTS), a severe recessive ciliopathy. None of four homozygotes expressed any signs of JBTS, and one of them had normal hearing, which also ruled out p.Arg1066* as the cause of deafness. Homozygosity mapping and WES in the only other reported JBTS family with a homozygous C-terminal truncation (p.Trp1088Leufs*16) confirmed AHI1 as disease gene, but based on a more N-terminal missense mutation impairing WD40-repeat formation. Morpholinos against N-terminal zebrafish Ahi1, orthologous to where human mutations cluster, produced a ciliopathy, but targeting near human p.Arg1066 and p.Trp1088 did not. Most AHI1 mutations in JBTS patients result in truncated protein lacking WD40-repeats and the SH3 domain; disease was hitherto attributed to loss of these protein interaction modules. Our findings indicate that normal development does not require the C-terminal SH3 domain. This has far-reaching implications, considering that variants like p.Glu984* identified by preconception screening ('Kingsmore panel') do not necessarily indicate JBTS carriership. Genomes of individuals with consanguineous background are enriched for homozygous variants that may unmask dispensable regions of disease genes and unrecognized false positives in diagnostic large-scale sequencing and preconception carrier screening.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Estudos de Associação Genética , Mutação , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transporte Vesicular , Animais , Encéfalo/patologia , Cerebelo/anormalidades , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Modelos Animais de Doenças , Evolução Molecular , Exoma , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Feminino , Ordem dos Genes , Genes Recessivos , Loci Gênicos , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Imageamento por Ressonância Magnética , Masculino , Modelos Moleculares , Linhagem , Conformação Proteica , Retina/anormalidades , Peixe-Zebra/genéticaRESUMO
BACKGROUND: WWOX, encoding WW domain-containing oxidoreductase, spans FRA16D, the second most common chromosomal fragile site frequently altered in cancers. It is therefore considered a tumor suppressor gene, but its direct implication in cancerogenesis remains controversial. METHODS AND RESULTS: By whole-exome sequencing, we identified a homozygous WWOX nonsense mutation, p.Arg54*, in a girl from a consanguineous family with a severe syndrome of growth retardation, microcephaly, epileptic seizures, retinopathy and early death, a phenotype highly similar to the abormalities reported in lde/lde rats with a spontaneous functional null mutation of Wwox. As in rats, no tumors were observed in the patient or heterozygous mutation carriers. CONCLUSIONS: Our finding, a homozygous loss-of-function germline mutation in WWOX in a patient with a lethal autosomal recessive syndrome, supports an alternative role of WWOX and indicates its importance for human viability.
Assuntos
Epilepsia/genética , Microcefalia/genética , Humanos , Lactente , Mutação , Oxirredutases/genética , Degeneração Retiniana/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WWRESUMO
Fryns anophthalmia-plus syndrome is a very rare condition initially described by Fryns and colleagues in 1995 in a pair of siblings of nonconsanguineous parents. Since that time, only a few cases have been reported, most of them in newborns and young children. Clinical presentation is variable and includes anophthalmia/microphthalmia, cleft lip/palate, and other facial deformities. Furthermore, skeletal, central nervous system, and endocrine anomalies have been described. We report the case of a male fetus of 18 weeks of gestation with normal karyotype and findings matching Fryns anophthalmia-plus syndrome. Pregnancy was terminated because of sonographically proven facial midline defects and a marked cerebral ventriculomegaly. Macroscopic and histological findings obtained at autopsy showed extreme bilateral microphthalmia, unilateral cleft palate, unilateral nasal deformity, and low-set ears. Skeletal anomalies included 13 pairs of ribs, premature ossification of the calcaneus, and talipes.
Assuntos
Anormalidades Múltiplas/patologia , Anoftalmia/patologia , Doenças Fetais/patologia , Aborto Eugênico , Adulto , Anoftalmia/complicações , Feminino , Feto , Idade Gestacional , Humanos , Masculino , GravidezRESUMO
Cystic renal diseases are characterized by intrarenal cysts of different size and number. Further important diagnostic criteria include, e.g., liver fibrosis. The latter represents a significant cause of morbidity and mortality in autosomal-recessive polycystic kidney disease (ARPKD), whereas patients with autosomal-dominant polycystic kidney disease (ADPKD) can develop hepatic cysts without fibrosis. We report the use of transient elastography [FibroScan®, (FS)] for early and noninvasive detection of increased liver stiffness as marker of liver fibrosis. Compared with matched healthy controls, ADPKD patients (n = 7) showed no significant difference in liver stiffness (5.3 kPa vs. 4.5 kPa; ns). ARPKD patients (n = 7) had significantly increased median liver stiffness compared with controls (12.0 kPa vs. 4.5 kPa, p = 0.002) and ADPKD patients (12.0 kPa vs. 5.3 kPa, p = 0.002). Conventional ultrasound revealed evidence of liver fibrosis in only four of seven ARPKD patients (57%) compared with 100% detection by FS. Additional laboratory examinations showed no pathologic liver parameters. In conclusion, our data found FS to be a valuable, sensitive, and noninvasive new tool for early evaluation of liver fibrosis in cystic kidney diseases. This could facilitate diagnosis, monitoring, and management of liver involvement in ARPKD or any other cystic kidney disease.
Assuntos
Técnicas de Imagem por Elasticidade/métodos , Cirrose Hepática/diagnóstico por imagem , Doenças Renais Policísticas/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Humanos , Lactente , Masculino , Adulto JovemRESUMO
Warburg Micro syndrome and Martsolf syndrome are clinically overlapping autosomal recessive conditions characterized by congenital cataracts, microphthalmia, postnatal microcephaly, and developmental delay. The neurodevelopmental and ophthalmological phenotype is more severe in Warburg Micro syndrome in which cerebral malformations and severe motor and mental retardation are common. While biallelic loss-of-function mutations in RAB3GAP1 are present in the majority of patients with Warburg Micro syndrome; a hypomorphic homozygous splicing mutation of RAB3GAP2 has been reported in a single family with Martsolf syndrome. Here, we report a novel homozygous RAB3GAP2 small in-frame deletion, c.499_507delTTCTACACT (p.Phe167_Thr169del) that causes Warburg Micro syndrome in a girl from a consanguineous Turkish family presenting with congenital cataracts, microphthalmia, absent visually evoked potentials, microcephaly, polymicrogyria, hypoplasia of the corpus callosum, and severe developmental delay. No RAB3GAP2 mutations were detected in ten additional unrelated patients with RAB3GAP1-negative Warburg Micro syndrome, consistent with further genetic heterogeneity. In conclusion, we provide evidence that RAB3GAP2 mutations are not specific to Martsolf syndrome. Rather, our findings suggest that loss-of-function mutations of RAB3GAP1 as well as functionally severe RAB3GAP2 mutations cause Warburg Micro syndrome while hypomorphic RAB3GAP2 mutations can result in the milder Martsolf phenotype. Thus, a phenotypic severity gradient may exist in the RAB3GAP-associated disease continuum (the "Warburg-Martsolf syndrome") which is presumably determined by the mutant gene and the nature of the mutation.
Assuntos
Homozigoto , Deleção de Sequência , Proteínas rab3 de Ligação ao GTP/genética , Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso , Sequência de Bases , Catarata/congênito , Catarata/genética , Consanguinidade , Córnea/anormalidades , Éxons/genética , Feminino , Predisposição Genética para Doença , Humanos , Hipogonadismo/genética , Lactente , Deficiência Intelectual/genética , Microcefalia/genética , Dados de Sequência Molecular , Atrofia Óptica/genética , Splicing de RNA/genéticaRESUMO
OBJECTIVES: Focal nodular hyperplasia of the liver is a tumor-like lesion, uncommon in children, but it has recently been more frequently observed in children treated for malignant diseases, especially neuroblastoma. The aetiology is unclear, the pathogenesis remains controversial. Focal nodular hyperplasia of the liver is suspected to be a sequela of tumor therapy. METHODS: Besides the clinical data we evaluated the imaging modalities needed to diagnose focal nodular hyperplasia of the liver in children with neuroblastoma who have been followed in our institution for more than 5 years. RESULTS: Out of 60 children six developed focal nodular hyperplasia at a median time of 10.5 years after diagnosis of neuroblastoma and 9.4 years after the end of treatment. The diagnosis of focal nodular hyperplasia was based on imaging criteria which are variable in ultrasonography and specific in MRI. Only one child underwent surgical biopsies to rule out liver metastases. CONCLUSIONS: Longterm survivors of neuroblastoma are at risk of developing focal nodular hyperplasia, especially if they underwent toxic chemotherapy and/or radiotherapy to the liver during initial treatment. The recommended diagnostic imaging tools are ultrasonography for detecting liver lesions and MRI for confirming and characterizing these lesions as focal nodular hyperplasia.