RESUMEN
Jacobsen syndrome or JBS (OMIM #147791) is a contiguous gene syndrome caused by a deletion affecting the terminal q region of chromosome 11. The phenotype of patients with JBS is a specific syndromic phenotype predominately associated with hematological alterations. Complete and partial JBS are differentiated depending on which functional and causal genes are haploinsufficient in the patient. We describe the case of a 6-year-old Bulgarian boy in which it was possible to identify all of the major signs and symptoms listed by the Online Mendelian Inheritance in Man (OMIM) catalog using the Human Phenotype Ontology (HPO). Extensive blood and marrow tests revealed the existence of thrombocytopenia and leucopenia, specifically due to low levels of T and B cells and low levels of IgM. Genetic analysis using whole-genome single nucleotide polymorphisms (SNPs)/copy number variations (CNVs) microarray hybridization confirmed that the patient had the deletion arr[hg19]11q24.3q25(128,137,532-134,938,470)x1 in heterozygosis. This alteration was considered causal of partial JBS because the essential BSX and NRGN genes were not included, though 30 of the 96 HPO identifiers associated with this OMIM were identified in the patient. The deletion of the FLI-1, ETS1, JAM3 and THYN1 genes was considered to be directly associated with the immunodeficiency exhibited by the patient. Although immunodeficiency is widely accepted as a major sign of JBS, only constipation, bone marrow hypocellularity and recurrent respiratory infections have been included in the HPO as terms used to refer to the immunological defects in JBS. Exhaustive functional analysis and individual monitoring are required and should be mandatory for these patients.
Asunto(s)
Síndromes de Inmunodeficiencia/complicaciones , Síndrome de Deleción Distal 11q de Jacobsen/inmunología , Fenotipo , Niño , Deleción Cromosómica , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 3 , Variaciones en el Número de Copia de ADN , Humanos , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Síndrome de Deleción Distal 11q de Jacobsen/genética , MasculinoRESUMEN
INTRODUCTION: In 1973, Petrea Jacobsen described the first patient showing dysmorphic features, developmental delay and congenital heart disease (atrial and ventricular septal defect) associated to a 11q deletion, inherited from the father. Since then, more than 200 patients have been reported, and the chromosomal critical region responsible for this contiguous gene disorder has been identified. PATIENTS' PRESENTATION: We report on two unrelated newborns observed in Italy affected by Jacobsen syndrome (JBS, also known as 11q23 deletion). Both patients presented prenatal and postnatal bleeding, growth and developmental delay, craniofacial dysmorphisms, multiple congenital anomalies, and pancytopenia of variable degree. Array comparative genomic hybridization (aCGH) identified a terminal deletion at 11q24.1-q25 of 12.5 Mb and 11 Mb, in Patient 1 and 2, respectively. Fluorescent in situ hybridization (FISH) analysis of the parents documented a de novo origin of the deletion for Patient 1; parents of Patient 2 refused further genetic investigations. CONCLUSIONS: Present newborns show the full phenotype of JBS including thrombocytopenia, according to their wide 11q deletion size. Bleeding was particularly severe in one of them, leading to a cerebral hemorrhage. Our report highlights the relevance of early diagnosis, genetic counselling and careful management and follow-up of JBS patients, which may avoid severe clinical consequences and lower the mortality risk. It may provide further insights and a better characterization of JBS, suggesting new elements of the genotype-phenotype correlations.
Asunto(s)
Hemorragia Cerebral/etiología , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Femenino , Estudios de Asociación Genética , Humanos , Recién Nacido , ItaliaAsunto(s)
Discapacidades del Desarrollo/patología , Síndrome de Deleción Distal 11q de Jacobsen/patología , Sustancia Blanca/patología , Niño , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/etiología , Imagen de Difusión Tensora , Humanos , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Síndrome de Deleción Distal 11q de Jacobsen/diagnóstico por imagen , Lenguaje , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/patología , Sustancia Blanca/diagnóstico por imagenRESUMEN
CASE: We describe the first reported case of scurvy developing secondary to behavioral traits of Jacobsen syndrome. The diagnosis of scurvy was significantly delayed because bleeding symptoms were initially attributed to baseline thrombocytopenia and platelet dysfunction associated with Jacobsen syndrome and patient's medication. Following vitamin C supplementation, signs and symptoms of the patient's disease quickly resolved. CONCLUSIONS: We aim to reinforce the need to consider nutritional deficiencies in patients with complex medical histories and behavioral issues, especially when presenting with new complaints.
Asunto(s)
Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Escorbuto/etiología , Niño , Femenino , Humanos , Escorbuto/diagnóstico por imagenRESUMEN
Jacobsen syndrome is a rare chromosomal disorder caused by distal deletions in the long arm of chromosome 11. All patients with Jacobsen syndrome have Paris-Trousseau syndrome, a bleeding disorder that causes neonatal thrombocytopenia, and persistent platelet dysfunction. Despite that, to date there are no reported cases of hemorrhagic strokes occurring in patients with Jacobsen syndrome. In the last 6 years at least six cases of brain hemorrhages in patients with Jacobsen syndrome have occurred. In this report, we perform a retrospective review of these six cases. The analysis indicates that the etiology of brain hemorrhages in Jacobsen syndrome is likely multifactorial. A likely cause (or causes) was identified in three of the cases, and additional potential risk factors were identified. Based on these findings, clinical recommendations are provided that should aid in the identification of those individuals with Jacobsen syndrome that are at increased risk for brain hemorrhages, and will hopefully decrease the occurrence of this devastating complication in people with Jacobsen syndrome.© 2017 Wiley Periodicals, Inc.
Asunto(s)
Hemorragias Intracraneales/diagnóstico , Hemorragias Intracraneales/etiología , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Adolescente , Niño , Diagnóstico por Imagen , Manejo de la Enfermedad , Resultado Fatal , Femenino , Pruebas Hematológicas , Humanos , Lactante , Síndrome de Deleción Distal 11q de Jacobsen/diagnóstico , Síndrome de Deleción Distal 11q de Jacobsen/genética , Masculino , Factores de Riesgo , Adulto JovenRESUMEN
Jacobsen syndrome is a rare disorder caused by partial deletions of the long arm of chromosome 11. The phenotype is variable with involvement of multiple organ systems, resulting in congenital heart defects, blood dyscrasias, and impaired growth. We describe a case of a 30-year-old man with multiple ophthalmic manifestations and brain magnetic resonance imaging (MRI) that was remarkable for multiple T2-hyperintense subcortical white matter lesions. It is important to be aware that patients with Jacobsen syndrome may have nonspecific white changes seen on MRI.
Asunto(s)
Encefalopatías/complicaciones , Encefalopatías/patología , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Imagen por Resonancia Magnética , Sustancia Blanca/patología , Adulto , Medios de Contraste , Gadolinio , Humanos , Aumento de la Imagen , MasculinoRESUMEN
Introducción: El síndrome de Jacobsen se debe a una deleción parcial del brazo largo del cromosoma 11. En un 85% de los casos, la deleción ocurre de novo. Los signos más comunes incluyen retraso en el crecimiento pre/posnatal, retraso psicomotor y malformaciones, así como una dismorfia facial característica. Con frecuencia, desde el nacimiento existe una función plaquetaria anormal, una trombocitopenia o una pancitopenia. Aproximadamente un 20% de los pacientes fallece durante los 2 primeros años de vida. Caso clínico: Recién nacida a término, sin antecedentes familiares de interés, que presenta un fenotipo peculiar (pabellones auriculares pequeños, de implantación baja, puente nasal ancho, hipertelorismo, fisuras palpebrales inclinadas hacia abajo, boca «en carpa», microrretrognatia), fisura palatina, lesiones de aspecto petequial en tórax y muslo derecho, asociado a himen imperforado. Cariotipo 46,XX,del(11)(q14.1q23.3)dn, el estudio de ambos progenitores fue normal. Desde las 2 semanas de vida, la niña presentó una importante trombocitosis, con nula adquisición de los ítems madurativos. La paciente falleció a los 3 meses de vida, tras un accidente cerebrovascular hemorrágico espontáneo. Conclusiones: Las manifestaciones clínicas se relacionan con el tamaño de la deleción. Generalmente, el punto de rotura se localiza en 11q23.3. Entre las alteraciones hematológicas, la más frecuente es la trombopenia, aunque no fue así en esta paciente, que presentaba una trombocitosis. Esto parece deberse a que cuando la deleción afecta a la banda 11q24 se produce la pérdida del gen FLI-1, entre otros genes, que desempeñan un papel fundamental en la megacariopoyesis (AU)
Introduction: Jacobsen syndrome is due to partial deletion of the long arm of chromosome11. A de novo deletion occurs in 85% of cases. Most common signs include pre- and postnatal growth retardation, psychomotor delay, malformations and characteristic facial dysmorphism. Abnormal platelet function thrombocytopenia or pancytopenia are frequent from birth. Approximately, 20% of patients die during the first 2 years of life. Case report: Newborn female born at term, without any family history of congenital anomalies, presenting with peculiar phenotype (small and low-set ears, broad nasal bridge, hypertelorism, downslanting palpebral fissures, micro-retrognathia), carp-like mouth, cleft palate, petechial-like lesion in thorax and right thigh, associated to imperforate hymen. Karyotype 46,XX,del(11)(q14.1q23.3)dn, being normal for both her parents. Since the age of 2 weeks she had a marked thrombocytosis, with no acquisition of developmental milestones. The patient died at 3 months after a spontaneous hemorrhagic cerebral-vascular accident. Conclusions: Clinical manifestations of the syndrome are related to the size of the deletion. Generally, the breakpoint is located at 11q23.3. Among the hematological alterations the most frequent one is thrombopenia, unlike our patient, who had thrombocytosis. This seems to be due to the loss of FLI-1, among other genes with a key role in megakaryopoiesis, when the deletion affects the band 11q24 (AU)
Asunto(s)
Femenino , Humanos , Recién Nacido , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Trombocitosis/etiología , Síndrome de Deleción Distal 11q de Jacobsen/diagnóstico , Trombocitosis/diagnóstico , Anomalías Congénitas/diagnóstico , Trastornos Psicomotores/diagnósticoRESUMEN
A preterm infant presenting with a congenital cardiac malformation and thrombocytopenia was found to have a karyotype showing a terminal deletion of the long arm of chromosome 11 of the segment 11q24.1-11qter consistent with Jacobsen syndrome. The infant was later diagnosed with Paris-Trousseau syndrome, commonly associated with Jacobsen syndrome. Because children with cardiac malformations often require high-risk surgical procedures in the early neonatal period, those with platelet dysfunction require prompt identification at birth.
Asunto(s)
Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Anomalías Múltiples , Femenino , Humanos , Recién Nacido , CariotipoRESUMEN
PURPOSE: Jacobsen syndrome, also called the 11q terminal deletion disorder, is a contiguous gene disorder caused by the deletion of the end of the long arm of chromosome 11. Intellectual skills range from low average to severe/profound intellectual disability and usually correlate with deletion size. Comprehensive genotype/phenotype evaluations are limited, and little is known about specific behavioral characteristics associated with 11q terminal deletion disorder. METHODS: In this prospective study, 17 patients with 11q terminal deletion disorder underwent cognitive and behavioral assessments. Deletion sizes were determined by array comparative genomic hybridization. RESULTS: Deletion sizes ranged from 8.7 to 14.5 Mb across the patients. We found that 8 of 17 patients (47%) exhibited behavioral characteristics consistent with an autism spectrum disorder diagnosis. There was no correlation between deletion size and the presence of autism spectrum disorder, implicating at least one predisposing gene in the distal 8.7 Mb of 11q. The findings from three additional patients with autistic features and "atypical" distal 11q deletions led to the identification of an autism "critical region" in distal 11q containing four annotated genes including ARHGAP32 (also known as RICS), a gene encoding rho GTPase activating protein. CONCLUSION: Results from this study support early autism spectrum disorder screening for patients with 11q terminal deletion disorder and provide further molecular insights into the pathogenesis of autism spectrum disorder.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/diagnóstico , Trastornos Generalizados del Desarrollo Infantil/etiología , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Síndrome de Deleción Distal 11q de Jacobsen/genética , Adolescente , Niño , Preescolar , Puntos de Rotura del Cromosoma , Cromosomas Humanos Par 11 , Hibridación Genómica Comparativa , Femenino , Humanos , Masculino , Estudios Prospectivos , Pruebas PsicológicasRESUMEN
Jacobsen syndrome is a rare contiguous gene syndrome caused by partial deletion of the long arm of chromosome 11. The typical clinical manifestations include physical growth retardation, mental retardation,facial dysmorphisms, congenital heart disease, thrombocytopenia, or pancytopenia. A Thai-Australian girl was born with multiple abnormalities. Typical features and her karyotype, 46, XX, del(ll) (q23-qter), confirmed Jacobson syndrome. She had many uncommon findings including upslanting palpebral fissures, tortuousity of retinal vessels and hypogammaglobulinemia. In addition, this case also presented with protein C deficiency, which has not been reported previously in Jacobsen syndrome. The patient was treated with phototherapy, intravenous antibiotic injection, and platelet transfusion in neonatal period. Cranioplasty was performed for prevention of the increased intracranial pressure at three months of age. Surgical correction for strabismus was in the treatment plan.
Asunto(s)
Disgammaglobulinemia/complicaciones , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Síndrome de Deleción Distal 11q de Jacobsen/diagnóstico , Deficiencia de Proteína C/complicaciones , Disgammaglobulinemia/diagnóstico , Disgammaglobulinemia/terapia , Femenino , Humanos , Inmunoglobulina M/sangre , Lactante , Síndrome de Deleción Distal 11q de Jacobsen/terapia , Deficiencia de Proteína C/diagnóstico , Deficiencia de Proteína C/terapiaRESUMEN
Ipercaloric diet and reduced physical activity have driven the rise in the prevalence of childhood obesity over a relatively short time interval. Family and twin studies have led to the conclusion that the strong predictive value of parental body mass index (BMI) mainly stems from genetic rather than environmental factors. Whereas the common polygenic obesity arises when an individual genetic make-up is susceptible to an environment that promotes energy consumption over energy expenditure, monogenic obesity, on the contrary, is the obesity associated with a single gene mutation, which is sufficient by itself to cause weight gain in a food abundant context. Genes involved in the leptin-melanocortin pathway are often mutated in these cases. The cumulative prevalence of monogenic obesity among children with severe obesity is about 5%. Recently, deletions in the region p11.2 of the chromosome 16 encompassing the gene SH2B1, which is involved in the leptin and insulin signaling, have been reported in about 0.5% of children with severe early-onset obesity. These patients show extreme hyperphagia, severe insulin resistance and, in some cases, mild developmental delay.
Asunto(s)
Predisposición Genética a la Enfermedad , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Obesidad/genética , Niño , Humanos , Síndrome de Deleción Distal 11q de Jacobsen/genéticaAsunto(s)
Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Deformidades Congénitas de las Extremidades/complicaciones , Deleción Cromosómica , Hibridación Genómica Comparativa , Femenino , Humanos , Lactante , Recién Nacido , Síndrome de Deleción Distal 11q de Jacobsen/genética , Deformidades Congénitas de las Extremidades/genética , Embarazo , Trombocitopenia/complicaciones , Trombocitopenia/genéticaRESUMEN
The 11q terminal deletion disorder (11q-) is a rare chromosomal disorder caused by a deletion in distal 11q. Fifty-six percent of patients have clinically significant congenital heart defects. A cardiac "critical region" has been identified in distal 11q that contains over 40 annotated genes. In this study, we identify the distal breakpoint of a patient with a paracentric inversion in distal 11q who had hypoplastic left heart and congenital thrombocytopenia. The distal breakpoint mapped to JAM-3, a gene previously identified as a candidate gene for causing HLHS in 11q-. To determine the role of JAM-3 in cardiac development, we performed a comprehensive cardiac phenotypic assessment in which the mouse homolog for JAM-3, JAM-C, has been deleted. These mice have normal cardiac structure and function, indicating that haplo-insufficiency of JAM-3 is unlikely to cause the congenital heart defects that occur in 11q- patients. Notably, we identified a previously undescribed phenotype, jitteriness, in most of the sick or dying adult JAM-C knockout mice. These data provide further insights into the identification of the putative disease-causing cardiac gene(s) in distal 11q, as well as the functions of JAM-C in normal organ development.
Asunto(s)
Moléculas de Adhesión Celular/genética , Cardiopatías Congénitas/genética , Corazón/fisiología , Síndrome de Deleción Distal 11q de Jacobsen/genética , Adulto , Animales , Moléculas de Adhesión Celular/fisiología , Cromosomas Humanos Par 11 , Modelos Animales de Enfermedad , Femenino , Eliminación de Gen , Corazón/embriología , Cardiopatías Congénitas/complicaciones , Humanos , Recién Nacido , Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Masculino , Ratones , Ratones Noqueados , Fenotipo , Embarazo , Trombocitopenia Neonatal Aloinmune/genética , Adulto JovenRESUMEN
Characteristics of sleep and sleep problems were investigated in 43 individuals with 11q terminal deletion disorder (Jacobsen syndrome). Data were collected using a sleep questionnaire. Ten individuals (23%) had a sleep problem. Settling problems, frequent night waking and early waking occurred in 2 (4%), 7 (16%) and 2 (6%) individuals, respectively. Twenty-two individuals (54%) had a history of sleep problems. Twenty-five individuals (60%) showed restless sleep and 23 individuals (54%) slept in an unusual position. Apart from frequent coughs, no significant relationships were found between the presence of a sleep problem and other variables, such as age, level of ID, breathing problems, heart defects, constipation, daytime activity and behavioral diagnosis, restless sleep and sleeping in an unusual positions.
Asunto(s)
Síndrome de Deleción Distal 11q de Jacobsen/complicaciones , Trastornos del Sueño-Vigilia/etiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Responsabilidad Parental , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/terapia , Encuestas y CuestionariosRESUMEN
As chromosomal instability may contribute to leukemogenesis in patients with congenital bone marrow failure (CBMF) disorders, it was the aim of this study to characterize chromosomally aberrant clones that arise during the clinical course of disease by means of R-banding and fluorescence in situ hybridization (FISH) analyses. In addition, multicolor-FISH and array-comparative genomic hybridization (CGH) were applied to characterize clonal chromosome aberrations in more detail. Between January 2004 and December 2005, we prospectively analyzed 90 samples of 73 patients with proven or suspected CBMF disorders enrolled in a German Study Network of CBMF diseases. Clonal aberrations could be identified in four of 73 patients examined. In one child with congenital thrombocytopenia, Jacobsen syndrome [del(11)(q24)c] was diagnosed, and thus a CBMF could be excluded. In a girl with Shwachman-Diamond syndrome, two independent clones, one with an isochromosome i(7)(q10), another with a complex aberrant karyotype, were identified. Simultaneously, transition into a myelodysplastic syndrome (MDS) occurred. The brother, who was also afflicted with Shwachman-Diamond syndrome, showed an isochromosome i(7q) as a single aberration. In the fourth patient with severe congenital neutropenia, an add(21)(q22) marker containing a low-level amplification of the AML1 gene was identified at the time point of transition into acute myelogenous leukemia (AML). In summary, we suggest that follow-up of patients with CBMF using chromosome and FISH analyses will be helpful for the early detection of transition into MDS or AML and thus should be an integral part of the clinical management of these patients.