RESUMO
The purpose of this study was to assess the frequency, severity, and clinical associations of dural ectasia (DE) in Loeys-Dietz syndrome (LDS). Database analysis of three German metropolitan regions identified 30 patients with LDS and TGFBR1 mutation in 6 and a TGFBR2 mutation in 24 individuals (17 men; mean age: 31 ± 19 years), as well as 60 age and sex-matched control patients with Marfan syndrome carrying a FBN1 mutation. DE was present in 22 patients with LDS (73%), and it related to skeletal score points (p = 0.008), non-skeletal score points (p < 0.001), and to the presence of ≥7 systemic score points (p = 0.010). Similarly, the severity of DE was related to body height (p = 0.010) and non-skeletal score points (p = 0.004). Frequency (p = 0.131) and severity of DE (p = 0.567) was similar in LDS and Marfan syndrome. DE is a manifestation of LDS that occurs with similar frequency and severity as in Marfan syndrome. Severity of DE may serve as a marker of the overall connective tissue disease severity. LDS may be considered in patients with DE.
Assuntos
Dilatação Patológica/genética , Síndrome de Loeys-Dietz/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Adolescente , Adulto , Idoso , Estatura , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Síndrome de Loeys-Dietz/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Síndrome de Marfan/genética , Síndrome de Marfan/fisiopatologia , Pessoa de Meia-Idade , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Adulto JovemRESUMO
Marfan syndrome is considered a clinical diagnosis. Three diagnostic classifications comprising first, Marfan genotype with a causative FBN1 gene mutation; second, Marfan phenotype with clinical criteria of the original Ghent nosology (Ghent-1); and third, phenotype with clinical criteria of its current revision (Ghent-2) in 300 consecutive persons referred for confirmation or exclusion of Marfan syndrome (150 men, 150 women aged 35 ± 13 years) were used. Sequencing of TGBR1/2 genes was performed in 128 persons without FBN1 mutation. Marfan genotype was present in 140, Ghent-1 phenotype in 139, and Ghent-2 phenotype in 124 of 300 study patients. Marfan syndrome was confirmed in 94 and excluded in 129 persons consistently by all classifications, but classifications were discordant in 77 persons. With combined genotype and phenotype information confirmation of Marfan syndrome was finally achieved in 126 persons by Ghent-1 and in 125 persons by Ghent-2 among 140 persons with Marfan genotype, and exclusion was accomplished in 139 persons by Ghent-1 and in 141 persons by Ghent-2 among 160 persons without Marfan genotype. In total, genotype information changed final diagnoses in 22 persons with Ghent-1, and in 32 persons with Ghent-2. It is concluded that genotype information is essential for diagnosis or exclusion of Marfan syndrome.
Assuntos
Genótipo , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Fenótipo , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The diagnosis of Marfan syndrome (MFS) is challenging and international criteria have been proposed. The 1996 Ghent criteria were adopted worldwide, but new diagnostic criteria for MFS were released in 2010, giving more weight to aortic root aneurysm and ectopia lentis. We aimed to compare the diagnosis reached by applying this new nosology vs the Ghent nosology in a well-known series of 1009 probands defined by the presence of an FBN1 mutation. A total of 842 patients could be classified as MFS according to the new nosology (83%) as compared to 894 (89%) according to the 1996 Ghent criteria. The remaining 17% would be classified as ectopia lentis syndrome (ELS), mitral valve prolapse syndrome or mitral valve, aorta, skeleton and skin (MASS) syndrome, or potential MFS in patients aged less than 20 years. Taking into account the median age at last follow-up (29 years), the possibility has to be considered that these patients would go on to develop classic MFS with time. Although the number of patients for a given diagnosis differed only slightly, the new nosology led to a different diagnosis in 15% of cases. Indeed, 10% of MFS patients were reclassified as ELS or MASS in the absence of aortic dilatation; conversely, 5% were reclassified as MFS in the presence of aortic dilatation. The nosology is easier to apply because the systemic score is helpful to reach the diagnosis of MFS only in a minority of patients. Diagnostic criteria should be a flexible and dynamic tool so that reclassification of patients with alternative diagnosis is possible, requiring regular clinical and aortic follow-up.
Assuntos
Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , Adolescente , Adulto , Criança , Fibrilina-1 , Fibrilinas , Seguimentos , Humanos , Masculino , Adulto JovemRESUMO
Tetrasomy 18p is a rare chromosomal disease (1:140,000 live births), which affects females and males equally, and might be hereditary or caused by spontaneous changes (de novo formation) within the chromosome. The phenotype results from the presence of a small extra metacentric marker chromosome, an isochromosome 18p. The syndrome is characterized by mild-to-moderate mental retardation, poor language acquisition, seizures, microcephaly, short statue, minor facial dysmorphic features, congenital heart diseases, uro/renal malformations, abnormal muscle tone, spasticity of the lower limbs, and delayed ability to stand and walk. To our knowledge sensorineural hearing loss is described in the literature but has not been described as a typical phenotypic symptom of tetrasomy 18p.In the following report, a boy with tetrasomy 18p is described. In addition to psychomotor retardation with muscular hypotonia and orofacial dismorphysms, bilateral severe hearing loss was diagnosed. Thus, in all infants with known chromosomal aberration, early diagnostic procedures must be performed to unveil sensorineural hearing loss that might be overseen because of mental retardation. In particular, a brainstem-evoked response audiometry (BERA) should be considered for early diagnosis and treatment of possible hearing loss. Furthermore, in all children with developmental delay and dysmorphic features a chromosomal analysis should be initiated.
Assuntos
Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Perda Auditiva Bilateral/congênito , Perda Auditiva Bilateral/diagnóstico , Aneuploidia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 18/genética , Humanos , MasculinoRESUMO
Mutations in the genes FBN1, TGFBR1, and TGFBR2 can result in heritable connective tissue disorders comprising the Marfan syndrome and the Loeys-Dietz syndrome. Dural ectasia is a characteristic manifestation of both syndromes. However, dural ectasia has not yet been investigated in connective tissue disorders that are unrelated to mutations in the FBN1, TGFBR1 or TGFBR2 genes. Here, we assessed dural ectasia in 33 individuals both with typical manifestations of heritable connective tissue disease and in whom mutations in all three genes had been excluded. We identified 19 individuals with dural ectasia (58%), who exhibited major skeletal manifestations of the Marfan syndrome more frequently than the remaining 14 persons without dural ectasia (p = 0.06). Moreover, only persons with dural ectasia fulfilled clinical criteria of the Marfan syndrome (p = 0.01). Conversely, aortic aneurysm (12 patients; p = 0.8), aortic dissection (five patients; p = 0.1), spontaneous dissection of the carotid arteries (five patients; p = 1), and mitral valve prolapse (13 patients; p = 0.4) were similarly frequent irrespective of dural ectasia. We conclude that dural ectasia is a marker for connective tissue disease which coincides with skeletal rather than with cardiovascular manifestations, and which may involve currently uncharacterized pathogenetic mechanisms and syndromes.
Assuntos
Dura-Máter/anormalidades , Síndrome de Marfan/diagnóstico , Proteínas dos Microfilamentos/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Seio Aórtico/anormalidades , Adolescente , Adulto , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Dilatação Patológica/diagnóstico , Dilatação Patológica/genética , Feminino , Fibrilina-1 , Fibrilinas , Testes Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Adulto JovemRESUMO
Marfan syndrome is an autosomal dominant disorder involving different organ systems. Marfan syndrome type 1 (MFS1) is caused by mutations in the FBN1 gene. Heterozygosity for mutations in the TGFBR1 or TGFBR2 genes cause Loeys-Dietz syndrome (LDS) types 2A and 2B that overlap with MFS1 in their clinical features. The phenotype of MFS1 is defined by the Ghent nosology, which classifies the clinical manifestations in major and minor criteria. Dural ectasia is one of the major criteria for Marfan syndrome but it is rarely tested for. We here report 22 novel and 9 recurrent mutations in the FBN1 gene in 36 patients with clinical features of Marfan syndrome. Sixty patients with identified mutations in the FBN1 gene and three patients with mutations in the TGFBR1 or TGFBR2 genes were examined for dural ectasia. Forty-seven of the 60 patients (78%) with MFS1 showed the dural ectasia criterion and 13 (22%) did not. Thirty-three (55%) patients were suspected of having Marfan syndrome and 24 (73%) of them had dural ectasia. Two of the three patients with LDS had dural ectasia.
Assuntos
Dura-Máter/anormalidades , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , Adolescente , Adulto , Aneurisma da Aorta Torácica/genética , Dilatação Patológica/epidemiologia , Dilatação Patológica/genética , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Masculino , Síndrome de Marfan/classificação , Síndrome de Marfan/diagnóstico , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Prevalência , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , SíndromeRESUMO
Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.
Assuntos
Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Adulto , Estudos de Coortes , Ectopia do Cristalino/diagnóstico , Ectopia do Cristalino/genética , Ectopia do Cristalino/patologia , Fibrilina-1 , Fibrilinas , Humanos , Masculino , Síndrome de Marfan/classificação , Síndrome de Marfan/patologia , Mutação , FenótipoRESUMO
To investigate the sudden death of a 31-year-old man, a medicolegal autopsy was performed. Major findings were a dilated aortic root with a longitudinal rupture of the intima and dissection of aorta and right coronary artery and consequent tamponade of the pericardial sac. Moreover, arachnodactyly and other skeletal deformities in combination with the histological finding of a pseudocystic medionecrosis of the aortic wall were noted. By sequencing of the FBN1 gene, a mutation (1622G>A) leading to the diagnosis of Marfan syndrome was found. Genetic counseling was recommended to the relatives who reported that the father of the deceased had died at the same age from aortic rupture. While fortunately the child of the deceased lacked this mutation, it was found in his younger sister. The results of the autopsy thus enabled early diagnosis and beginning of treatment in the sister and thus a considerable statistical increase in lifespan. With this report, we want to show that medicolegal autopsies can also have medical consequences for relatives. We argue that in all sudden and unexpected deaths in young persons up to 35 years an autopsy should be performed, not only to detect unnatural causes of death but also to identify heritable diseases and thus aid the relatives.
Assuntos
Ruptura Aórtica/patologia , Morte Súbita/etiologia , Síndrome de Marfan/diagnóstico , Adulto , Aorta/patologia , Tamponamento Cardíaco/patologia , Vasos Coronários/lesões , Vasos Coronários/patologia , Dilatação Patológica , Fibrilina-1 , Fibrilinas , Patologia Legal , Testes Genéticos , Humanos , Masculino , Proteínas dos Microfilamentos/genética , Mutação Puntual , IrmãosRESUMO
BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p<0.001), but the lifelong risk for ascending aortic dissection or surgery was not significantly different in both groups. CONCLUSIONS: Because of its implications for aortic follow-up, FBN1 molecular analysis is recommended in newly suspected MFS when two systems are involved with at least one major system affected. This is of utmost importance in patients without aortic dilatation and in children.
Assuntos
Cooperação Internacional , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Adolescente , Adulto , Idoso , Aorta/patologia , Criança , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Masculino , Mutação/genéticaRESUMO
We report 9 new mutations in German patients presenting with classical Marfan syndrome. All mutations occur in exons with calcium-binding (cb) epidermal growth factor-like (EGF) domains. Five mutations are missense involving exons 12, 27, 30, 44, and 52 with the resultant substitution of cysteine by phenylalanine (C504F), cysteine by tyrosine (C1129Y), tyrosine by cysteine (Y1261C), cysteine by serine (C1833S), and cysteine by tyrosine (C2142Y), respectively. The other four mutations are single base deletions in exons 39, 43, 48, and 58, at nucleotide A4826, C5311, T6018, and A7291, respectively, each resulting in frameshift with premature termination. Four mutations were detected in sporadic cases and are likely to be de novo.
Assuntos
Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Adulto , Proteínas de Ligação ao Cálcio/genética , Fator de Crescimento Epidérmico/genética , Éxons , Feminino , Fibrilina-1 , Fibrilinas , Mutação da Fase de Leitura , Alemanha , Humanos , Masculino , Mutação de Sentido IncorretoRESUMO
The structural rearrangement in the short arm of a chromosome 8 in a clinically affected patient has been reinvestigated by FISH using whole chromosome painting and region specific YAC probes. An inverted duplication of the segment p22-->p11.2 and a deletion of the subtelomeric region were demonstrated. By this approach, a more detailed resolution of the duplication/deletion 8p was possible. With the application of molecular cytogenetic methods the existence of different duplication segments within the clinical entity of duplication/deficiency 8p can be shown.
Assuntos
Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 8 , Sondas de DNA , Hibridização in Situ Fluorescente , Criança , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Inversão Cromossômica , Coloração Cromossômica , Cromossomos Artificiais de Levedura , Cromossomos Humanos Par 8/ultraestrutura , Feminino , Humanos , Cariotipagem , Metáfase , SíndromeRESUMO
Trisomy 6 and trisomy 6 mosaicism were found in chorionic villi cell culture and short term incubation in a prenatal diagnosis at 12 weeks of gestation in a pregnancy with a growth retarded fetus showing nuchal translucency. The child was born in the 25th gestational week with a number of malformations including heart defects, deep-set ears, cleft right hand, cutaneous syndactylies, and overlapping toes of irregular shape and length. Trisomy 6 was not found in peripheral blood lymphocytes but was confirmed in umbilical cord fibroblasts. Currently, at the age of 2-3/4 years, the development of the child is relatively normal despite considerable growth delay. At the age of two years, she developed a papular erythema clinically suggestive of epidermal nevi. Cytogenetic analysis of fibroblast cultures derived from skin from a right hand finger and the inguinal area confirmed the presence of a trisomy 6 mosaicism. This is the first observation of a liveborn with trisomy 6 mosaicism.
Assuntos
Cromossomos Humanos Par 6 , Mosaicismo/genética , Trissomia/genética , Pré-Escolar , Feminino , HumanosRESUMO
A new approach for the detection of chromosome deletion 22q11.2 in interphase nuclei from buccal mucosa cells obtained by a non-invasive procedure is described. FISH analysis has been performed on samples from a group of 101 patients that presented consecutively for speech therapy and/or surgical correction of cleft palate. A normal result has been obtained in 98 patients; a deletion 22q11.2 was present in three patients (2.8%) with cleft palate.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Fissura Palatina/genética , Adolescente , Adulto , Núcleo Celular/ultraestrutura , Criança , Pré-Escolar , Células Epiteliais/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Interfase , Masculino , Mucosa Bucal/patologiaRESUMO
Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.
Assuntos
Éxons/genética , Proteínas dos Microfilamentos/genética , Mutação , Códon sem Sentido , Análise Mutacional de DNA , Ectopia do Cristalino/genética , Fibrilina-1 , Fibrilinas , Humanos , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/metabolismo , FenótipoRESUMO
Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.
Assuntos
Síndrome de Marfan/diagnóstico , Proteínas dos Microfilamentos/genética , Adolescente , Adulto , Fator de Crescimento Epidérmico/genética , Éxons/genética , Feminino , Fibrilina-1 , Fibrilinas , Humanos , Masculino , Mutação , Fenótipo , Prognóstico , Estrutura Terciária de Proteína/genética , Índice de Gravidade de Doença , Fator de Crescimento Transformador beta/genéticaRESUMO
A new case of de novo isochromosome-formation in chromosome 9 associated with the translocation of long arm material of chromosome 9 onto chromosome 1 is described. The female patient is mentally retarded and shows only minor dysmorphisms. The cytogenetic investigation revealed a two-cell-line mosaicism with different isochromosomes of chromosome 9. In both cell lines, a translocation of 9qter-9q13 onto the short arm of chromosome 1 is observed.
Assuntos
Anormalidades Múltiplas/genética , Aberrações Cromossômicas/genética , Cromossomos Humanos Par 1/ultraestrutura , Cromossomos Humanos Par 9/ultraestrutura , Dedos/anormalidades , Deficiência Intelectual/genética , Mosaicismo , Translocação Genética , Transtornos Cromossômicos , Nanismo/genética , Face/anormalidades , Feminino , Humanos , Recém-Nascido , Cariotipagem , Microcefalia/genética , Família Multigênica , Estrabismo/genéticaRESUMO
Recurring upper respiratory tract infections in a previously healthy 4 years old boy led to an acute nephritic syndrome requiring haemodialysis. Renal biopsy showed poststreptococcal like immune complex glomerulonephritis with subepithelial humps, C3 deposition and crescent formation. Renal function improved after methyl-prednisolone pulse therapy. Two relapses occurred in the following six months which responded to immunosuppressive therapy. 21 months following the first presentation the boy has normal glomerular filtration rate but persistent glomerular proteinuria and haematuria. Detailed complement analyses revealed a persistent activation of the alternate pathway.
Assuntos
Ativação do Complemento/imunologia , Complemento C3/análise , Via Alternativa do Complemento/imunologia , Glomerulonefrite/imunologia , Doenças do Complexo Imune/imunologia , Infecções Estreptocócicas/imunologia , Pré-Escolar , Fator Nefrítico do Complemento 3/análise , Complemento C3d/análise , Complemento C4/análise , Humanos , Testes de Função Renal , MasculinoRESUMO
Microdeletions in chromosome 22q11.2 are associated with DiGeorge syndrome (DGS), velo-cardio-facial syndrome (VCFS), and several other syndromes, collectively referred to as DG/VCF. Non-dysmorphic patients with cardiac defects have also been attributed to deletions in this chromosomal region. In this study 157 consecutively catheterized patients with isolated, non-syndromic cardiac defects, and 25 patients with cardiac defects and additional stigmata (10 of whom were clinically diagnosed as DG/VCF cases prior to chromosome analysis) were analysed by fluorescence in situ hybridization with the DGS-specific probe D0832. Chromosome 22q11.2 deletions were observed only in the ten patients with the clinical diagnosis of DG/VCF. Conclusion In a large unselected cohort of patients with congenital heart disease no association between isolated or non-syndromic heart defects and the 22q11.2 microdeletion was observed. One can conclude that testing for the 22q11.2 microdeletion is clearly indicated in cases when even mild extracardiac abnormalities are present, particularly in very young infants.
Assuntos
Aberrações Cromossômicas/diagnóstico , Deleção Cromossômica , Cromossomos Humanos Par 22 , Cardiopatias Congênitas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Transtornos Cromossômicos , Estudos de Coortes , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/genética , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , SíndromeRESUMO
BACKGROUND: Keutel-Gabriel syndrome (chondrodysplasia) is a rare autosomal recessive disease. The patients have characteristic malformations such as midfacial hypoplasia, brachytelephalangia, and hearing loss as leading symptoms. PATIENTS: We report about two brothers with clinical and radiological features of Keutel-Gabriel syndrome. Congenital subglottic laryngeal stenosis was also present in both. In the younger brother an emergency tracheotomy had to be performed. In a staged procedure the stenosis was successfully treated with laryngotracheoplasty according to Cotton. CONCLUSIONS: This is the first description of a congenital subglottic laryngeal stenosis with Keutel-Gabriel syndrome. To avoid long-term tracheotomy, a tracheoplasty with autologous cartilage should be performed.
Assuntos
Laringoestenose/genética , Osteocondrodisplasias/genética , Estenose Traqueal/genética , Adolescente , Adulto , Cartilagem/transplante , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Genes Recessivos/genética , Humanos , Laringoestenose/diagnóstico , Laringoestenose/cirurgia , Masculino , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/cirurgia , Síndrome , Estenose Traqueal/diagnóstico , Estenose Traqueal/cirurgia , Traqueotomia , Transplante AutólogoRESUMO
We here describe the first example of the replacement of an autosome by two ring chromosomes originating from the missing chromosome, presented in a patient with a single chromosome 18 and two additional ring chromosomes. Detailed fluorescence in situ hybridization (FISH) analysis revealed the chromosome 18 origin of both ring chromosomes and characterized the small and the large ring chromosome as derivatives of the short and long arm of chromosome 18, respectively. The loss of subtelomeric regions of the short and the long arm of chromosome 18 in the ring chromosomes was confirmed by FISH studies. Molecular studies showed the exclusive presence of the paternal alleles for microsatellite markers located distal to the short and long arm loci D18S843 and D18S474, respectively. This indicates the maternal origin of both rings and provides evidence for substantial deletions of the distal parts of both arms of chromosome 18 in the ring chromosomes. The dysmorphic features of the patient can be explained by these deletions in both chromosome arms, as the clinical findings partly overlap with observations in 18p- and 18q-syndrome and are similar to some cases of ring chromosome 18. Centromere misdivision is suggested as one mechanism involved in the formation of the ring chromosomes.