RESUMO
Chromosome 4q deletion syndrome (4q- syndrome) is a rare condition, with an estimated incidence of 1 in 100,000. Although variable, the clinical spectrum commonly includes craniofacial, developmental, digital, skeletal, and cardiac involvement. Data on the genotype-phenotype correlation within the 4q arm are limited. We present detailed clinical and genetic information by array CGH on 20 patients with 4q deletions. We identified a patient who has a â¼465 kb deletion (186,770,069-187,234,800, hg18 coordinates) in 4q35.1 with all clinical features for 4q deletion syndrome except for developmental delay, suggesting that this is a critical region for this condition and a specific gene responsible for orofacial clefts and congenital heart defects resides in this region. Since the patients with terminal deletions all had cleft palate, our results provide further evidence that a gene associated with clefts is located on the terminal segment of 4q. By comparing and contrasting our patients' genetic information and clinical features, we found significant genotype-phenotype correlations at a single gene level linking specific phenotypes to individual genes. Based on these data, we constructed a hypothetical partial phenotype-genotype map for chromosome 4q which includes BMP3, SEC31A, MAPK10, SPARCL1, DMP1, IBSP, PKD2, GRID2, PITX2, NEUROG2, ANK2, FGF2, HAND2, and DUX4 genes.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 4 , Hibridização Genômica Comparativa , Feminino , Genótipo , Humanos , Hibridização in Situ Fluorescente , Lactente , Fenótipo , SíndromeRESUMO
Mitochondrial diseases (MD) are a group of diseases that can be caused by either mutations in the mitochondrial genome or nuclear DNA. MD may be difficult to diagnose since very often they are highly heterogeneous and with overlapping phenotypes. Molecular genomics approaches, especially NGS have helped in this sense. In this study we have sequenced the mitochondrial genome of a girl with an unspecific neurological disorder and her mother. The later, while neurologically unaffected, suffers from a myopathy without clear cause. We were able to detect two non-synonymous mutations in the MT-ATP6 gene, which we propose are strong candidates for causative agents. 9017C as the main candidate present at high heteroplasmy frequency in the patient (83,2%) and moderate in the mother (45,4%) while it has a low frequency in the general population. It might act alone or in conjunction with 9010A as an accessory mutation. Evolutionary analysis showed that both mutations were located in a critical position in the F0 a subunit, from F0-F1 ATPase. Functional studies showed that carriers of those mutations in comparison to an unaffected individual (father) presented a decrease in the basal and ATP-dependent oxygen consumption rate and a decrease in the maximum respiration rate.
Assuntos
Predisposição Genética para Doença , Doenças Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Mutação de Sentido Incorreto , Doenças Neurodegenerativas/genética , Pré-Escolar , DNA Mitocondrial/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Doenças Mitocondriais/patologia , Doenças Neurodegenerativas/patologiaRESUMO
We present clinical and developmental data on a patient with a de novo recombinant pseudodicentric bisatellited chromosome 22 associated with a partial trisomy 22pter-22q12.1. The patient was evaluated at birth and followed-up until 21 years of age. Clinical findings include facial and digital dysmorphism, hydrocephalus and postnatal-onset growth deficiency. The patient showed bilateral microphthalmia with severe palpebral ptosis and coloboma of the iris and left optic nerve. She also has skeletal and neurological abnormalities, cholesteatoma and seizures. She had absence of speech, poor mobility, poor vision and required help with all daily living skills. Conventional chromosome GTG banded analysis showed that the proband had an abnormal karyotype:46,XX,add(22)(q13). Fluorescence in situ hybridization (FISH) analyses and microsatellite markers for DNA polymorphism study ascertained the karyotype as 46,XX,add(22)(q13.3).ish psu dic(22;22)(q13.3;q12.1)(D14Z1/D22Z1++, N25++, ARSA+, PCP22q+). The recombinant chromosome was stable and present in all cells examined. The paternal origin of the psu dic(22;22) chromosome was determined by using five highly polymorphic microsatellite markers located to the region of chromosome 22q11.2-22q13.33. A 22q13.3 monosomy was ruled out with 22q13.3 cosmid probes covering the terminal 22q-140Kb. The proband carried a recombinant pseudodicentric bisatellited chromosome psu dic(22;22)(q13.3;q12.1). To our knowledge, this is the first report of such rearrangement resulting in partial trisomy 22pter-22q12.1.
Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 22/genética , Citogenética , Trissomia , Anormalidades Múltiplas/patologia , Adulto , Criança , Pré-Escolar , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Feminino , Seguimentos , Humanos , Hidrocefalia/genética , Hidrocefalia/patologia , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , CariotipagemRESUMO
INTRODUCTION The consequences of de novo balanced structural chromosome aberrations diagnosed antenatally are unpredictable, and, as a result, they introduce uncertainty into genetic counseling decisions. OBJECTIVE Describe de novo balanced structural aberrations present at antenatal diagnosis in samples from pregnant women in five Latin American countries and determine their effect on carrier individuals. METHODS This was a retrospective observational study based on analysis of 109,011 antenatal tests conducted from January 1981 to December 2016 in Cuba, Uruguay, Costa Rica, Mexico, and Colombia. Thirteen cytogenetic laboratories provided information that included the cases analyzed during the study period; number of de novo balanced structural aberrations diagnosed antenatally; number of diagnoses with de novo balanced structural aberrations that resulted in termination of pregnancy; detailed descriptions of the karyotypes of de novo balanced structural aberration carriers, and descriptions of the form of diagnosis, including types of samples used (amniotic fluid, chorionic villus or fetal blood). Each laboratory also provided pathology reports and genetic counseling at time of diagnosis. Postnatal followup for pregnancies carried to term continued for at least two years. RESULTS Of the 109,011 antenatal tests studied, 72 (0.07%) showed de novo balanced structural aberrations. These events primarily involved chromosomes 1, 2, 7, 14, 18, and 20. Of the 79 breakpoints identified, the most common were 5p15.3, 7q11.2, 7q22, and 14q24. We identified three breakpoints corresponding to 3.8% (3q13.1, 3q13.2, and 9p12) that were not reported in other studies of de novo balanced structural aberrations diagnosed antenatally in patients from other geographic regions or in studies of chromosomal fragile sites. Two of these breakpoints (3q13.1 and 3q13.2) were associated with high risk of phenotypic abnormalities. Information on antenatal or postnatal followup was available for 62 (86%) of de novo balanced structural aberration carriers; of the 44 carriers with postnatal followup, 10 had phenotypic abnormalities. CONCLUSIONS Three new de novo breakpoints were identified, presumably related to genetic admixture characteristics in Latin America. Since some diseases associated with de novo balanced structural aberrations detected antenatally have a late onset, followup for at least two years is recommended for carriers of these aberrations. The information in this study is useful in genetic counseling for pregnant women in Latin America.
Assuntos
Aberrações Cromossômicas , Diagnóstico Pré-Natal , Pontos de Quebra do Cromossomo , Colômbia , Costa Rica , Cuba , Feminino , Aconselhamento Genético , Humanos , Cariotipagem/métodos , México , Gravidez , Diagnóstico Pré-Natal/métodos , UruguaiRESUMO
Partial trisomy 12q and monosomy 12p lead to multiple malformation syndromes. Only four cases were previously reported with the association of these two aneusomies resulting from a familial pericentric inversion of chromosome 12. We report on the clinical, cytogenetic and molecular findings in a boy with an unbalanced karyotype which resulted from a familial pericentric inversion of chromosome 12. The patient was evaluated at birth and followed up until 14 years of age. He showed severe mental retardation, seizures, and dysmorphic features related both to a trisomy 12q and a monosomy 12p. Chromosome breakpoint BAC-FISH mapping revealed that the rec(12) chromosome had a terminal deletion of a 6.7Mb region extending from 12pter to 12p13.31 and a duplicated region of 19.8Mb extending from 12qter to 12q24.13. The findings from the case reported here emphasize the occurrence of some consistent clinical features and illustrate the deficiencies associated with the recombinants from the inversion inv(12)(p13.31q24.13)mat.
Assuntos
Aneuploidia , Deleção Cromossômica , Inversão Cromossômica , Cromossomos Humanos Par 12/genética , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Citogenética , Seguimentos , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Cariotipagem , Masculino , Fenótipo , Recombinação Genética , Convulsões/genéticaRESUMO
We present clinical and developmental data on a girl with a de novo terminal deletion of the long arm of chromosome 4, del(4)(q33). The patient was evaluated at birth and followed up until 5 years of age. She showed facial and digital dysmorphism, a complex congenital heart defect, a large occipital encephalocele, and postnatal growth deficiency. Her neuropsychomotor milestones were delayed, and she developed learning difficulties. Apart from standard Giemsa banding, a molecular genetic analysis was performed using a comparative genomic hybridization (CGH) array. This revealed a terminal deletion at the band 4q32.3, which is directly adjacent to 4q33. The clinical findings in our patient differ from those described previously in patients with del(4)(q33) and del(4)(q32), respectively. In particular, the prominent occipital encephalocele has not been observed before in a terminal 4q deletion.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 4 , Encefalocele/genética , Bandeamento Cromossômico , Feminino , Humanos , Recém-Nascido , CariotipagemRESUMO
OBJECTIVE: To describe a de novo complex chromosome rearrangement(CCR) detected prenatally and studied afterbirth. METHODS: Conventional cytogenetics and fluorescent in situ hybridization (FISH) were performed on amniotic fluid and peripheral blood. High-resolution comparative genomic hybridization (HR-CGH) analysis was made postnatally. RESULTS: Prenatal/postnatal cytogenetic, FISH and HR-CGH analyses revealed an apparently balanced de novo CCR ascertained as 46,XY,t(2; 3;9)(q21;p24;q22),der(5)inv(5)(?p11q13)t(5; 11)(?p13;q25),ins(5; 3)(?p13;?p23p24). At 9 months,the child has neither congenital anomalies nor evidence of delayed psychomotor development. CONCLUSIONS: Our report describes a rare CCR detected prenatally and shows the usefulness of FISH and CGH in complementing conventional cytogenetics.
Assuntos
Aberrações Cromossômicas/embriologia , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 2 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 5 , Cromossomos Humanos Par 9 , Análise Citogenética/métodos , Diagnóstico Pré-Natal/métodos , Adulto , Bandeamento Cromossômico , Feminino , Aconselhamento Genético , Testes Genéticos , Humanos , Hibridização in Situ Fluorescente , Lactente , Nascido Vivo , Hibridização de Ácido Nucleico , GravidezRESUMO
We present a case of a de novo Xq22.1 chromosomal terminal deletion discovered prenatally by conventional cytogenetics. The pregnancy resulted in the birth of a normal girl. Preferential inactivation of the abnormal X was demonstrated postnatally. Fluorescence in situ hybridization (FISH) demonstrated a terminal Xq deletion spanning Xq22.1 -->qter. An X painting probe ruled out a translocation. The deleted X chromosome was determined to be of paternal origin. The girl is now 4 years old with normal physical and psychomotor development. X chromosomal deletions are infrequent findings in prenatal diagnosis and present a difficult counseling challenge when they occur. Prenatal X-inactivation studies provide an opportunity for more informative genetic counseling when a de novo X chromosome deletion is detected.
Assuntos
Cromossomos Humanos X , Diagnóstico Pré-Natal/métodos , Aberrações dos Cromossomos Sexuais , Adulto , Pré-Escolar , Deleção Cromossômica , Feminino , Humanos , Recém-Nascido , Gravidez , Inativação do Cromossomo XRESUMO
BACKGROUND: Previously, we reported a rare X-linked disorder, Uruguay syndrome in a single family. The main features are pugilistic facies, skeletal deformities, and muscular hypertrophy despite a lack of exercise and cardiac ventricular hypertrophy leading to premature death. METHODS AND RESULTS: An ≈19 Mb critical region on X chromosome was identified through identity-by-descent analysis of 3 affected males. Exome sequencing was conducted on one affected male to identify the disease-causing gene and variant. A splice site variant (c.502-2A>G) in the FHL1 gene was highly suspicious among other candidate genes and variants. FHL1A is the predominant isoform of FHL1 in cardiac and skeletal muscle. Sequencing cDNA showed the splice site variant led to skipping of exons 6 of the FHL1A isoform, equivalent to the FHL1C isoform. Targeted analysis showed that this splice site variant cosegregated with disease in the family. Western blot and immunohistochemical analysis of muscle from the proband showed a significant decrease in protein expression of FHL1A. Real-time polymerase chain reaction analysis of different isoforms of FHL1 demonstrated that the FHL1C is markedly increased. CONCLUSIONS: Mutations in the FHL1 gene have been reported in disorders with skeletal and cardiac myopathy but none has the skeletal or facial phenotype seen in patients with Uruguay syndrome. Our data suggest that a novel FHL1 splice site variant results in the absence of FHL1A and the abundance of FHL1C, which may contribute to the complex and severe phenotype. Mutation screening of the FHL1 gene should be considered for patients with uncharacterized myopathies and cardiomyopathies.
Assuntos
Anormalidades Múltiplas/genética , Cardiomiopatias/genética , Morte Súbita Cardíaca/patologia , Exoma/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas com Domínio LIM/genética , Proteínas Musculares/genética , Músculo Esquelético/patologia , Doenças Musculares/genética , Mutação/genética , Sítios de Splice de RNA/genética , Análise de Sequência de DNA , Adolescente , Adulto , Western Blotting , Pré-Escolar , Fácies , Feminino , Regulação da Expressão Gênica , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Hipertrofia , Lactente , Masculino , Mioblastos/metabolismo , Linhagem , Fenótipo , Isoformas de Proteínas/genética , Adulto JovemRESUMO
La atrofia muscular espinal y bulbar es una enfermedad neurológica caracterizada por degeneración gradual de la motoneurona inferior, que resulta en debilidad muscular, atrofia y fasciculaciones. Es una entidad de etiología genética con mecanismo de herencia ligado al cromosoma X recesivo, por lo que afecta a varones, en la que se produce una expansión del triplete CAGn en el gen del receptor de andrógenos. Se manifiesta por signos de insensibilidad a los andrógenos (ginecomastia e infertilidad). A partir de los 20-30 años, aproximadamente, comienzan los signos de afectación de la motoneurona inferior a nivel espinal con calambres y temblor de acción y posteriormente debilidad muscular. En la evolución se evidencia compromiso bulbar. Se presenta el caso clínico-genealógico de un varón de 32 años con temblores en quien se confirma molecularmente la enfermedad de Kennedy. Este es el primer caso, hasta nuestro conocimiento, reportado en Uruguay. Se destaca la importancia de plantear dicha afección en un paciente joven con "temblores" cuando aún no es ostensible la debilidad muscular. La historia familiar es de capital importancia. La presencia de fasciculaciones en el estudio eléctrico a nivel perioral es muy sugestiva de esta patología. La confirmación molecular es importante para el asesoramiento genético.
Spinal and bulbar muscular atrophy (SBMA) is a neurological disease characterized by the progressive degeneration of the inferior motor neurones, what results in muscle weakness, atrophy and fasciculations. It possesses a genetic etiology with X-linked recessive inheritance mode, and thus affects men. There is an abnormal expansion of the CAG polyglutamine encoding repeat within the androgen receptor gene. It is noticed by signs of androgen insentistivity (gynecomastia and infertility). At 20-30 years old approximately signs of compromise of the lower motor neurones in the spine are seen in cramps and action tremor followed by muscle weakness, evidencing bulbar involvement in the evolution. The study presents the ciínical-genealogical case of a 32 year-old male with tremor, whose Kennedy disease was confirmed with molecules. This is the first case reported in Uruguay as far as we know. The importance of considering this condition is pointed out in a young patient with "tremor" when muscle weakness is not evident yet. Family history is key. The presence of fasciculation in the electrical study strongly suggests this condition. Molecular confirmation is important for genetic advice purposes.
A atrofia muscular bulbo-espinal (BSMA) é uma doença neurológica caracterizada pela degeneração gradual do neurônio motor inferior causando fraqueza muscular, atrofia e fasciculações. É uma entidade de etiologia genética com mecanismo de herança ligada ao cromossoma X recessivo, afetando por isso a indivíduos do sexo masculino, nos quais se observa a expansão do triplete CAGn no gene do Receptor de Andrógenos (RA). Manifesta-se pela ausência de sensibilidade aos andrógenos (ginecomastia e infertilidade); a partir dos 20-30 anos aproximadamente começam a manifestar-se os sinais de afetação do neurônio motor inferior na região espinal com câimbras e tremor de ação e posteriormente debilidade muscular. Em sua evolução observa-se compromisso bulbar. Apresenta-se o caso clínico - genealógico de um indivíduo de sexo masculino de 32 anos com tremores, no qual foi realizado diagnóstico molecular de doença de Kennedy. Este é o primeiro caso informado no Uruguai, que seja de nosso conhecimento. Destaca-se a importância da suspeita desta afecção em um paciente jovem com "tremores" mesmo quando a debilidade muscular ainda não é ostensível. A história familiar é fundamental. A presença de fasciculações no estudo elétrico na região perioral é muito sugestiva desta patologia. A confirmação molecular é importante para o assessoramento genético.
Assuntos
Atrofia Bulboespinal Ligada ao X , Atrofia Bulboespinal Ligada ao X/genéticaRESUMO
We report a girl with a de novo pure partial trisomy 21 with some clinical features of Down syndrome. The girl patient presented a flat broad face, brachycephaly, and a flat nasal bridge. She also had upwardly slanted palpebral fissures, epicanthal folds, blepharitis, brushfield spots, and strabismus. Her mouth was wide with downturned corners, prominent lower lip, narrow and furrowed tongue, and short palate. G-banded chromosomal analysis of metaphases in cells from both skin and blood showed a 46,XX karyotype with additional chromosomal material on the distal short arm of one chromosome 21. Parental chromosomes were normal. Molecular analyses with the short-tandem-repeat (STR) marker D21S2039 (interferon-alpha/beta receptor [IFNAR]) (21q22.1) showed a triallelic pattern. Subtelomeric fluorescent in situ hybridization (FISH) analyses, LSI 13 (retinoblastoma 1 [RB1])/LSI 21(21q22.13-q22.2), and whole chromosome painting probes specific for chromosome 21 showed trisomy for the segment 21q22.13-21q22.2 due to a de novo intrachromosomal duplication. A 500K SNP microarray analysis was then performed and revealed a 13-Mb duplication of 21q22.11-qter. This duplicated material had been translocated onto the end of the "p" arm of one of the chromosome 21s. The karyotype was provisionally defined as 46,XX,add(21)(p12).ish der (21)t(21;21)(p12;q22.11)(WCP21q+,PCP21q++,D215259/D21S341/D21S342++)dn. At the age of 4 years and 10 months, a comprehensive psychological examination was performed and the diagnostic criteria for mental retardation were not fulfilled. In comparison with previously published cases of pure partial trisomy 21, this is a rare finding. Additional studies of such rare patients should aid in the study of the pathogenesis of Down syndrome.
Assuntos
Cromossomos Humanos Par 21/genética , Síndrome de Down/genética , Pré-Escolar , Síndrome de Down/patologia , Síndrome de Down/psicologia , Feminino , Marcadores Genéticos , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Repetições de Microssatélites , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A balanced complex chromosome rearrangement (CCR) involving three chromosomes is rare and may lead to different types of aneuploid germ cells. We report here a 14-year follow-up of a boy with a karyotype defined as 46,XY,der(18)t(6;13;18)(q21;q21.32;q22.3).ish der(18)(13qter+,18qter-) characterized by multiple congenital abnormalities, including distinctive minor facial anomalies, short neck, abnormalities of the extremities, anogenital abnormalities, flexion contractures, especially at extremities, and severe mental and growth retardation. Chromosome analysis in the mother showed a CCR involving chromosomes 6, 13, and 18. This CCR was the result of a three-break rearrangement, and the derivative chromosome 13 consisted of parts of chromosomes 18 and 13. The karyotype of the child was not balanced, and resulted in partial trisomy for 13q and partial monosomy for 18q detected prenatally by conventional and molecular cytogenetics. Although such a karyotype and its phenotype have not previously been reported, we have compared the clinical and cytogenetic data from our patient with previously described cases of partial trisomy 13q and monosomy 18q despite different break points. We are presenting a new CCR in a woman with normal phenotype with a history of four early abortions and a long follow-up of her malformed newborn with partial 13q trisomy and 18q monosomy.
Assuntos
Cromossomos Humanos Par 13 , Cromossomos Humanos Par 18 , Cromossomos Humanos Par 6 , Monossomia/genética , Trissomia/genética , Anormalidades Múltiplas/genética , Adolescente , Bandeamento Cromossômico , Quebra Cromossômica , Seguimentos , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Cariotipagem , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de TempoRESUMO
The brachyolmias constitute a clinically and genetically heterogeneous group of skeletal dysplasias characterized by a short trunk, scoliosis and mild short stature. Here, we identify a locus for an autosomal dominant form of brachyolmia on chromosome 12q24.1-12q24.2. Among the genes in the genetic interval, we selected TRPV4, which encodes a calcium permeable cation channel of the transient receptor potential (TRP) vanilloid family, as a candidate gene because of its cartilage-selective gene expression pattern. In two families with the phenotype, we identified point mutations in TRPV4 that encoded R616Q and V620I substitutions, respectively. Patch clamp studies of transfected HEK cells showed that both mutations resulted in a dramatic gain of function characterized by increased constitutive activity and elevated channel activation by either mechano-stimulation or agonist stimulation by arachidonic acid or the TRPV4-specific agonist 4alpha-phorbol 12,13-didecanoate (4alphaPDD). This study thus defines a previously unknown mechanism, activation of a calcium-permeable TRP ion channel, in skeletal dysplasia pathogenesis.
Assuntos
Doenças do Desenvolvimento Ósseo/genética , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Linhagem Celular , Feminino , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , RadiografiaRESUMO
OBJECTIVE: To learn about parental decisions to abort or continue a pregnancy after prenatal diagnosis of chromosomal abnormalities among the population in Uruguay. METHODS: Between 1982 and 2003, 14 656 amniocentesis and 2740 chorionic villus samplings were performed in a referral Genetic Unit. Chromosomal anomalies were found in 376 cases (2.16%) and included Down syndrome, aneuploidies in which a severe prognosis was expected, sex chromosome aneuploidy and aneuploidies with a low risk of an abnormal clinical phenotype. The couples that received abnormal results were contacted by phone and asked if they had continued or interrupted the pregnancy after the diagnosis and genetic counseling. RESULTS: We contacted 207 couples (55%). When confronted with Down syndrome or an aneuploidy in which a severe prognosis was expected, 89% and 96% of patients, respectively, decided to terminate the pregnancy. When confronted with sex chromosome aneuploidy or aneuploidies with a low risk of an abnormal clinical phenotype, 79% and 90% of patients, respectively, decided to continue the pregnancy. CONCLUSIONS: The present study shows that when faced with an anomaly such as Down syndrome and aneuploidies in which a severe prognosis was expected, most of the couples decided to terminate the pregnancy, although TOP is not legally available in Uruguay.
Assuntos
Aborto Eugênico/psicologia , Aberrações Cromossômicas/embriologia , Transtornos Cromossômicos/diagnóstico , Tomada de Decisões , Aborto Criminoso/estatística & dados numéricos , Aborto Eugênico/legislação & jurisprudência , Amniocentese , Amostra da Vilosidade Coriônica , Síndrome de Down/diagnóstico , Feminino , Humanos , Gravidez , UruguaiRESUMO
Introducción: la fibrosis quística (FQ) es una enfermedad hereditaria autosómica recesiva causada por mutaciones en el gen que codifica una proteína con función de canal de cloruro (CFTR). Se manifiesta como una enfermedad multiorgánica y se caracteriza por una gran heterogeneidad clínica. Existen pacientes que no manifiestan las características clínicas de la forma clásica y se describen como FQ atípica o no clásica. El diagnóstico se basa en unfenotipo clínico consistente más evidencia de disfunción del canal CFTR y/o en la identificación de dos mutaciones causantes de FQ. Ninguna de estas definiciones es suficientepor sí misma para establecer el diagnóstico. Objetivos: mostrar algunas limitaciones de los estudios de genética molecular en el proceso diagnóstico de FQ. Material y método: se consideran cinco casos clínicos de niños referidos con dato clínico de probable FQ y solicitud de estudio genético para la confirmación diagnóstica. Resultados: los estudios realizados no permiten confirmar el diagnóstico de FQ ni descartar un posible diagnóstico de FQ atípica. Conclusiones: la mayoría de las veces el diagnóstico de FQ es claro y los estudios genéticos permiten la confirmación diagnóstica, el asesoramiento genético y eventual diagnóstico prenatal. Sin embargo, el uso y la interpretación de los análisis genéticos presentan diversasdificultades relacionadas con la condición clínico-paraclínica del paciente, las limitaciones técnicas y la elección del conjunto de mutaciones a ser analizadas, especialmente en los casos de FQ atípica. Este trabajo muestra el desafío que puede implicar para el clínico interpretar un resultado molecular e integrarlo en el proceso diagnóstico de FQ.
Introduction: cystic fibrosis is an autosomal recessive hereditary disease caused by mutations of the gene whichencodes a protein with a CFTR chloride channel function. It appears as a multi-organ disease and is characterized bya great clinical heterogeneity. There are patients who do not evidence the classic clinical characteristics and aredescribed as atypical or non-classic cystic fibrosis. Diagnosis is based on a consistent clinical phenotype andevidence of dysfunction in the CFTR channel and/or in the identification of two mutations causing cystic fibrosis.None of these definitions is enough in itself to confirm diagnosis. Objectives: to show a few limitations on the molecular genetic studies in the cystic fibrosis diagnostic process. Method: five clinical cases of children referred withclinical data of probable cystic fibrosis were considered, and they were requested a genetic study to confirm diagnosis. Results: studies conducted do not enable the confirmation of cystic fibrosis diagnosis and neither do theyallow discarding a possible diagnosis of atypical cystic fibrosis. Conclusions: in most cases the diagnosis of cysticfibrosis is clear and genetic studies enable the confirmation of diagnosis, genetic counseling and the final prenataldiagnosis. However, use and interpretation of genetic analysis result in several difficulties regarding the clinical and paraclinical characteristics of patients, technical limitations and choosing the mutations to be analysed, especially in the case of atypical cystic fibrosis. The present study shows the challenge faced by clinicians when interpreting a molecular result to incorporate it into the cystic fibrosis diagnostic process.
Introdução: a fibrose cística FC é uma doença hereditária autossômica recessiva causada por mutações no gene que codifica uma proteína com função nos canais de cloretos CFTR. É uma doença com manifestações múltiplas e se caracteriza por apresentar-se com grande variedade clínica. Alguns pacientes não apresentam as características clínicas clássicas e nesses casos a doença é chamada FC atípica ou não clássica. O diagnóstico é feito através do fenótipo clínico mais consistente associado a evidencia de disfunção do canal CFTR e/ou na identificação de duas mutações causadoras da FC. Nenhuma dessas definições é suficiente para estabelecer o diagnóstico. Objetivos: mostrar algumas limitações dos estudos de genética molecular no diagnóstico de FC.Material e método: são discutidos cinco casos clínicos de crianças referidas com historia clínica de FC provável e pedido de estudo genético para confirmaçãodo diagnóstico. Resultados: os estudos realizados não permitem confirmaro diagnóstico de FC nem descartar um possível diagnóstico de FC atípica.Conclusões: na maioria dos casos o diagnóstico de FC é claro e os estudos genéticos permitem confirmar odiagnóstico, o assessoramento genético e eventual diagnóstico pré-natal. No entanto, o emprego e a interpretaçãodas análises genéticas apresentam varias dificuldades relacionadas com a condição clínica do paciente, aslimitações técnicas e a escolha do conjunto de mutações a ser estudadas, especialmente nos casos de fibrose cística atípica. Este trabalho mostra o desafio que o médico clínico enfrenta para interpretar um resultado molecular e integrá-lo ao processo de diagnóstico de FC.
Assuntos
Fibrose Cística/diagnóstico , Fibrose Cística/genéticaRESUMO
Cole disease is an uncommon disorder characterized by distinctive cutaneous hypopigmentation and punctate keratosis of the palms and soles. It is a congenital skin disease with an autosomal dominant inheritance pattern. We report two patients from a family with 15 members, 5 of whom were affected. One of the patients had both types of lesions since birth, while in the other they arose in the first months of life. We studied the pedigree, histopathology, immunohistochemistry, and electron microscopy findings of the hypopigmented macules with the patients' normal skin used as a control. The pedigree showed involvement of both genders, with a Mendelian autosomal dominant inheritance pattern with phenotypic variability in the family. Immunohistochemistry showed a reduction in the melanin pigment in the keratinocytes and normal pigmentation in the melanocytes. Ultrastructural studies showed a strong contrast between the large number of melanosomes in the body and dendrites of the melanocytes, in contrast with the small number of these organelles in the neighboring keratinocytes. These findings suggest that this disease is a primary congenital disorder of the transfer mechanisms of the melanosomes from melanocytes to keratinocytes in hypopigmented lesions, associated with abnormal epidermopoiesis in the punctate hyperkeratosis.
Assuntos
Hipopigmentação/diagnóstico , Hipopigmentação/genética , Ceratodermia Palmar e Plantar/diagnóstico , Ceratodermia Palmar e Plantar/genética , Biópsia por Agulha , Criança , Pré-Escolar , Feminino , Humanos , Hipopigmentação/complicações , Imuno-Histoquímica , Ceratodermia Palmar e Plantar/complicações , Masculino , Microscopia Eletrônica , Linhagem , Prognóstico , Irmãos , Pele/patologia , Pele/ultraestrutura , Dermatopatias Genéticas/diagnósticoRESUMO
En el presente trabajo se describe un caso de síndrome de pterigium múltiple recurrente familiar de particulares características clínicas. Esta descripción se presenta a continuación del artículo Síndrome de Escobar: a propósito de un caso para mostrar la heterogeneidad fenotípica y genotípica de esta entidad. El diagnóstico presuntivo se realizó en el primer hijo a los 5 días de vida y el confirmatorio a los dos meses; sobrevivió hasta los 8 meses con desnutrición, ceguera, retraso global del desarrollo y patología renal crónica. Las manifestaciones clínicas incluían fijación generalizada de articulaciones, pterigium de axila, codo y región poplítea, cifosis dorsal, desviación cubital de las manos, pie bot talo-valgo, pabellones auriculares de implantación baja y micrognatia. El diagnóstico presuntivo del segundo hijo fue ecográfico- genealógico, a las 20 semanas de gestación por síndrome de hipoquinesia fetal y fijación articular. El feto obitó a las 21 semanas de edad gestacional. La anatomía- patológica confirmó los hallazgos ecográficos, constatándose un fenotipo muy similar al de su hermano.
A recurrent and familiar case of pterygium multiple syndrome with particular clinical features is presented. This description comes after the article Escobar syndrome: a case report in order to show the phenotypic and genotypic heterogeneity of these cases. A preliminary diagnosis was made at 5 days of age in the first child of the couple; the definitive diagnosis was made at 2 months of age. The patient lived 8 months with malnutrition, blindness, developmental delay and chronic renal pathology. Clinical manifestations included joint contractures; elbow, armpit and popliteal region pterygium; dorsal kyphosis; cubital deviation of hands; club foot deformity; low outer ear and micrognathia. The preliminary diagnosis of the second child was ecographic, at 20 weeks of gestation by Hypokinesia fetal and joint contracture. The pregnancy was ended at 21 weeks. The anatomy pathology confirmed the ecographic findings with a phenotype very similar to the first case.
Assuntos
Humanos , Masculino , Criança , Herança Multifatorial , Pterígio/complicações , Pterígio/genética , Anormalidades Congênitas , Prognóstico , Pterígio/diagnósticoRESUMO
La neoplasia endocrina múltiple tipo 1 (MEN1) incluye una combinación variable de más de 20 tumores endocrinos y no endocrinos, con herencia mendeliana autosómica dominante. El paciente, con antecedentes familiares de neoplasias, consultó a los 39 años con historia detumor mediastinal y neoplasma de cabeza de páncreas. Se realizó diagnóstico clínico de MEN1 y aceptó ser incluido en un estudio cooperativo conducido por el grupo francés para elestudio de MEN. Se realizó la secuenciación del gene MEN1 detectándose una mutación puntual en el exon 10: 1596delA. Se le informó de la relevancia de realizar el mismo estudioen otros integrantes de la familia en riesgo de presentar igual patología. Dos años después, consultó la hermana de 39 años con historia de hiperparatiroidismo, calciuria, hormonaparatiroidea (PTH) elevada, litiasis renal y operada de adenoma paratiroideo. Refiere que el propósito falleció. Dado el antecedente familiar, se estudió específicamente la mutaciónpreviamente encontrada en el hermano, confirmando el diagnóstico de MEN1. La consultante decidió conocer el estatus molecular de sus dos hijas asintomáticas, no detectándose lamutación en ninguna de ellas. Este trabajo ilustra el beneficio de un diagnóstico que requiere tecnología de alto costo (secuenciación) a través de un estudio colaborativo y que permiteque otros integrantes de la familia puedan conocer su definición molecular. Destacamos la importancia del asesoramiento genético en la toma de decisión de realización del diagnósticomolecular en individuos asintomáticos y la jerarquía del diagnóstico precoz para definir el protocolo de seguimiento en este grupo de pacientes.
Multiple endocrine neoplasia type 1(MEN1) comprises a variable combination of over 20 endocrine and non-endocrine tumors, with Mendelian autosomal dominant inheritance. The patient, who had a family history of tumors, was seen, at age 39, due to a mediastinal tumor and neoplasmat the head of the pancreas. We performed clinical diagnosis of MEN1, and we had the collaboration of aFrench team involved in MEN1 research. We conducted sequenciation of the MEN 1 gene and identified a single mutation in exon 10: 1596delA. The patient was informed about the relevance of performing the same study in othermembers of the family who were likely to carry the same pathology. Two years later, his 39-year-old sister visitedthe clinic, with a history of hyperparathyroidism, calciuria, high parathyroid hormone (PTH), renal lithiasis, and who had undergone parathyroid adenoma surgery. She informed her brother had died. Given the family history, we especially studied the mutation previously found in herbrother, and confirmed the MEN1 diagnosis. Thus, the patient decided to learn about the molecular status in hertwo asymptomatic daughters, whereby no mutations were identified. The present study illustrates the benefit of diagnosis, requiring high cost technology (sequenciation) through a collaborative study, which enables other membersof a family to learn about their molecular definition. We stress the importance of genetic counseling to make a decision regarding the conduction of molecular diagnosisin asymptomatic individuals and the relevance of early diagnosis to define the follow-up protocol for these patients.
A neoplasia endócrina múltipla tipo 1 (MEN1) inclui uma combinação variável de mais de 20 tumores endócrinos enão endócrinos com herança mendeliana autossômica dominante. O paciente, com antecedentes familiares de neoplasmas, consultou aos 39 anos com história de tumor mediastinal e neoplasma de cabeça de pâncreas. Foi realizadoo diagnóstico clínico de MEN1 e o paciente concordou em ser incluído em um estudo cooperativo conduzido por um grupo francês de estudo das MEN. Nasecuenciaçao do gen MEN1 detectou-se uma mutação pontual no éxon 10: 1596delA. O paciente foi informadoda importância de realizar o mesmo estudo em outros integrantes da família com risco de apresentar uma patologia similar. Dois anos depois, sua irmã com 39 anos, consultou apresentando hiperparatiroidismo, calciúria, hormônioparatireóideo (PTH) elevado, litiase renal e operada de um adenoma paratiroideo. A paciente relata o falecimento de seu irmão. Considerando o antecedente familiar, a mutaçãoapresentada pelo irmão foi estudada, o que confirmou o diagnóstico de MEN1. A paciente decidiu estudar o estadomolecular de suas duas filhas assintomáticas, nas quais não se detectou mutação. Este trabalho mostra o beneficio de um diagnóstico que requer tecnologia de alto custo(sequenciação) através de um estudo colaborativo que permite a outros integrantes da família conhecer suadefinição molecular. Destacamos a importância do assessoramentogenético para a tomada de decisão na realização de diagnóstico molecular em indivíduos assintomáticos e a importância do diagnóstico precoce para definir o protocolo de seguimento neste grupo de pacientes.
Assuntos
/genética , Neoplasia Endócrina Múltipla Tipo 1/genéticaRESUMO
Introducción: el síndrome CADASIL (Cerebral Dominant Arteriopathy with Subcortical Infarcts and Leukoencephlopathy) es una microangiopatía no amiloidea, no ateromatosa que se transmite en forma autosómica dominante y cuyas principales manifestaciones clínicasocurren a nivel cerebral. Su diagnóstico requiere criterios clínicos, imagenológicos y genéticos moleculares.Material y método: se estudiaron anatomopatológicamente mediante biopsia de piel y músculo y estudio genético molecular a tres integrantes de una familia con diagnóstico de CADASIL.Resultados: los exámenes clínicos, paraclínicos, neurológicos y ultraestructural de biopsia de piel mostraron resultados consistentes con CADASIL. La secuenciación de exones 2,3,4,5,8,11,20,23 del gene NOTCH3 detectó una mutación en forma heterocigota en el exón 5 no descripta en la literatura.Conclusiones: destacamos la importancia del diagnóstico precoz de esta enfermedad y la definición molecular que permite el asesoramiento genético a todos los integrantes de lafamilia y, eventualmente, el diagnóstico prenatal.
Introduction: CADASIL syndrome (Cerebral Dominant Arteriopathy with Subcortical Infarcts and Leukoencephlopathy),the most common form of hereditary stroke disorder is a nonamyloid, non-atheromatous microangiopathy. Main clinical features are found in the brain. The disease may be diagnosed by clinical findings, images and geneticmolecular criteria.Methods: an anatomopathological analysis through a skin and muscle biopsy and molecular study was performed on three members of the same family diagnosed with CADASIL.Results: clinical, paraclinical, neurological and ultrastructuralskin biopsy study's findings were consistent with CADASIL. NOTCH3 sequence exonal analysis(2,3,4,5,8,11,20,23) suggested heterocigotic mutations in exon 5, not previously described in literature.Conclusions: we stress the importance of early diagnosis of this disease and the molecular definition that enablesgenetic counselling to all members of the family and, potentially, prenatal diagnosis of the disease.
Introdução: a síndrome CADASIL (Cerebral Dominant Arteriopathy with Subcortical Infarcts and Leukoencephlopathy)é uma microangiopatia não amiloidea, não ateromatosa que se transmite de maneira autossômica dominantecujas principais manifestações clinicas são observadas no cérebro. Para seu diagnóstico é necessário realizarprovas clínicas, imagenológicas e de genética molecular.Material e método: foram realizados exames de anatomia patológica e de genética molecular em biopsias depele e músculo a três integrantes de uma família com diagnóstico de CADASIL.Resultados: os exames clínicos, paraclínicos, neurológicos e ultra-estrutural da biopsia de pele mostraram resultados consistentes com CADASIL. A seqüenciação dos exons 2,3,4,5,8,11,20,23 do gene NOTCH3 detectou uma mutação em forma heterozigótica no exon 5 não descritana literatura.Conclusões: destacamos a importância do diagnóstico precoce desta doença e a definição molecular que permite o assessoramento genético a todos os integrantes da família e, eventualmente, o diagnóstico pré-natal.
Assuntos
CADASIL , Mutação/genética , Receptores Notch/genéticaRESUMO
La trisomía 9p es una anomalía cromosómica que se define por la duplicación parcial o completa del brazo corto de un integrante del par cromosómico 9. Clínicamente se caracteriza por retraso mental y psicomotor, malformaciones craneofaciales distintivas y anomalías de manos y pies. En el presente trabajo describimos el seguimiento clínico durante 12 años de una niña con diagnóstico de trisomía del brazo corto del cromosoma 9, con un cariotipo no balanceado definido por la siguiente fórmula: 46,XX,t(9;21)(q10;q10),+i(9)(p10). Los hallazgos fenotípicos observados en la niña ilustran las deficiencias asociadas con una duplicación completa del brazo corto del cromosoma 9 y ayudan en el asesoramiento genético para esta particular anomalía cromosómica.
Trisomy 9p is a chromosomal anomaly defined by partial or complete duplication of the short arm of one of the members of the 9 pair chromosome. Clinical findings include growth and mental retardation, characteristic craniofacial malformations and hand-foot anomalies. We report a 12 year follow-up of a female patient with trisomy 9p with an unbalanced karyotype defined as: 46,XX,t(9;21)(q10;q10),+i(9)(p10). The observed phenotypic findings illustrate the deficiencies associated with a complete duplication of the short arm of chromosome 9 and can aid in the genetic counseling of this particular chromosomal anomaly.