Patients with Chromosome 11q Deletions Are Characterized by Inborn Errors of Immunity Involving both B and T Lymphocytes.

Disorders of the long arm of chromosome 11 (11q) are rare and involve various chromosomal regions. Patients with 11q disorders, including Jacobsen syndrome, often present with a susceptibility for bacterial and prolonged viral and fungal infections partially explained by hypogammaglobulinemia. Additional T lymphocyte or granular neutrophil dysfunction may also be present. In order to evaluate infectious burden and immunological function in patients with 11q disorders, we studied a cohort of 14 patients with 11q deletions and duplications. Clinically, 12 patients exhibited prolonged and repetitive respiratory tract infections, frequently requiring (prophylactic) antibiotic treatment (n = 7), ear-tube placement (n = 9), or use of inhalers (n = 5). Complicated varicella infections (n = 5), chronic eczema (n = 6), warts (n = 2), and chronic fungal infections (n = 4) were reported. Six patients were on immunoglobulin replacement therapy. We observed a high prevalence of low B lymphocyte counts (n = 8), decreased T lymphocyte counts (n = 5) and abnormal T lymphocyte function (n = 12). Granulocyte function was abnormal in 29% without a clinical phenotype. Immunodeficiency was found in patients with terminal and interstitial 11q deletions and in one patient with terminal 11q duplication. Genetically, FLI1 and ETS1 are seen as causative for the immunodeficiency, but these genes were deleted nor duplicated in 4 of our 14 patients. Alternative candidate genes on 11q may have a role in immune dysregulation. In conclusion, we present evidence that inborn errors of immunity are present in patients with 11q disorders leading to clinically relevant infections. Therefore, broad immunological screening and necessary treatment is of importance in this patient group.

[Prenatal diagnosis of Jacobsen syndrome in a fetus carried by a pregnant woman with intellectual disability].

OBJECTIVE: To assess the value of combined cytogenetic and molecular techniques for the prenatal diagnosis of a pregnant woman with intellectual disability (ID). METHODS: The fetus and its parents were subjected to G-banding karyotyping analysis, single nucleotide polymorphism array (SNP-array) and fluorescence in situ hybridization (FISH) analysis. RESULTS: G-banding karyotype analysis revealed that the woman has carried a chromosomal microdeletion 46,XX,del(11)(q24), and the fetus was a carrier of 46,XN,del(11)(q24)mat. Subsequent SNP-array and FISH analysis of the pregnant woman indicated that the microdeletion has mapped to 11q24.1-q25. Both the pregnant woman and her fetus were diagnosed with Jacobsen syndrome. CONCLUSION: Combined use of cytogenetic and molecular genetic techniques can facilitate diagnosis of patients with intellectual disability.

Partial Jacobsen syndrome phenotype in a patient with a de novo frameshift mutation in the ETS1 transcription factor.

Jacobsen syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen syndrome phenotype. One gene, ETS1, has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in ETS1, resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of Ets1 causes a "partial Jacobsen syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder.

11q24.2q24.3 microdeletion in two families presenting features of Jacobsen syndrome, without intellectual disability: Role of FLI1, ETS1, and SENCR long noncoding RNA.

This report presents two families with interstitial 11q24.2q24.3 deletion, associated with malformations, hematologic features, and typical facial dysmorphism, observed in Jacobsen syndrome (JS), except for intellectual disability (ID). The smallest 700 Kb deletion contains only two genes: FLI1 and ETS1, and a long noncoding RNA, SENCR, narrowing the minimal critical region for some features of JS. Consistent with recent literature, it adds supplemental data to confirm the crucial role of FLI1 and ETS1 in JS, namely FLI1 in thrombocytopenia and ETS1 in cardiopathy and immune deficiency. It also supports that combined ETS1 and FLI1 haploinsufficiency explains dysmorphic features, notably ears, and nose anomalies. Moreover, it raises the possibility that SENCR, a long noncoding RNA, could be responsible for limb defects, because of its early role in endothelial cell commitment and function. Considering ID and autism spectrum disorder, which are some of the main features of JS, a participation of ETS1, FLI1, or SENCR cannot be excluded. But, considering the normal neurodevelopment of our patients, their role would be either minor or with an important variability in penetrance. Furthermore, according to literature, ARHGAP32 and KIRREL3 seem to be the strongest candidate genes in the 11q24 region for other Jacobsen patients.

11q23 deletion syndrome (Jacobsen syndrome) with severe bleeding: a case report.

BACKGROUND: 11q23 deletion syndrome, also known as Jacobsen syndrome, is characterized by growth retardation, psychomotor retardation, facial dysmorphism, multiple congenital abnormalities, and thrombocytopenia. In 11q23 deletion syndrome, it is often difficult to anticipate the severity of bleeding. We report a neonatal case of 11q23 deletion syndrome with bleeding that was more severe than predicted by the platelet count. CASE PRESENTATION: We report a case of 11q23 deletion syndrome in an Asian male newborn with severe bleeding just after birth. The diagnosis of 11q23 deletion syndrome was made prenatally by amniocentesis. An array comparative genomic hybridization analysis revealed a deletion of the 13.0 Mb regions ranging from 11q24.1 to the q terminus encoding FLI1. Our patient was delivered by cesarean section and exhibited skull deformities, facial asymmetry, low-set ears, inguinal hernia, flat feet, and crowded toes. He had a low platelet count (45,000/µL) and a coagulation abnormality with a prothrombin time-international normalized ratio of 1.92 and an activated partial thromboplastin time of 158.6 seconds. Bleeding at the site of a peripheral vessel puncture was more severe than expected with thrombocytopenia. The peripheral blood featured two different sizes of platelets containing large α-granules. As a result, he required eight platelet transfusions and two fresh frozen plasma transfusions within 13 days of birth. Massive bleeding was avoided, and cerebral magnetic resonance imaging indicated the occurrence of only petechial hemorrhage. CONCLUSIONS: Our patient with 11q deletion including FLI1 avoided massive bleeding and serious sequelae because of careful management after prenatal diagnosis. We suggest that prenatal diagnosis and vigilant perinatal care including a cesarean section are warranted for patients with 11q23 deletion syndrome.

FEVR-like Presentation in an 11q Deletion Syndrome and 16p13.11 Microdeletion.

A 7-year-old boy was diagnosed and treated for familial exudative vitreoretinopathy. Genetic testing revealed a 16p13.11 microdeletion and unbalanced translocation causing 11q deletion syndrome. This is the first report describing retinal findings associated with this combination of genetic alterations. Patients with 11q deletion syndrome or 16p13 microdeletions should undergo ophthalmologic examination. [J Pediatr Ophthalmol Strabismus. 2017;54:e71-e74.].

Brain hemorrhages in Jacobsen syndrome: A retrospective review of six cases and clinical recommendations.

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.

11q terminal deletion and combined immunodeficiency (Jacobsen syndrome): Case report and literature review on immunodeficiency in Jacobsen syndrome.

Antibody deficiency is common finding in patients with Jacobsen syndrome (JS). In addition, there have been few reports of T-cell defects in this condition, possibly because most of the reported patients have not been specifically evaluated for T-cell function. In this article, we present a child with an 11q deletion and combined immunodeficiency and we perform a literature overview on immunodeficiency in JS. Our patient presented with recurrent bacterial and prolonged viral infections involving the respiratory system, as well as other classic features of the syndrome. In addition to low IgM, IgG4, and B-cells, also low recent thymic emigrants, helper and naïve T-cells were found. We propose that patients with Jacobsen syndrome need thorough immunological evaluations as T-cell dysfunction might be more prevalent than previously reported. Patients with infections consistent with T-cell defects should be classified as having combined immunodeficiency. © 2016 Wiley Periodicals, Inc.

De novo interstitial deletion in the long arm of chromosome 11: a case report.

The 11q terminal deletion disorder is a rare genetic disorder associated with numerous clinical features. A few case reports have been made about de novo interstitial deletion of chromosome 11q. However, due to the heterogeneity in size and position of the deletions, a clear genotype-phenotype correlation is not easily made. Here we report a case interstitial 20.5-Mb deletion at chromosome 11q13.4q21, as confirmed by array comparative genomic hybridization. Dysmorphic features such as coarse facial features, congenital laryngomalacia, oblique inguinal hernia, high-arched palate, and camptodactyly were observed in the subject. The present case broadens the spectrum of clinical findings observed in individuals with 11q interstitial deletion.

Interstitial 11q24 deletion: a new case and review of the literature.

We describe a 19-month-old male presenting with right stenotic megaureter, anemia and thrombocytopenia, cardiac and ophthalmologic abnormalities. Analysis with array-based comparative genomic hybridization (aCGH) revealed an interstitial deletion of about 2.4 Mb of chromosome 11q24.2q24.3. We compared the phenotype of our patient with that of recently reported patients studied by aCGH, who showed an overlapping deletion. We also analysed the gene content of the deleted region in order to investigate the possible involvement of specific genes in the clinical phenotype.

Jacobsen syndrome: Advances in our knowledge of phenotype and genotype.

In 1973, the Danish geneticist Petrea Jacobsen described a three-generation family in which the proband carried a presumed terminal deletion at the end of the long arm of chromosome 11 (11q). This patient had dysmorphic features, congenital heart disease, and intellectual disability. Since Dr. Jacobsen's initial report, over 200 patients with Jacobsen syndrome have been reported, suggesting that Jacobsen syndrome is a contiguous gene disorder. With the advent of high resolution deletion mapping and the completion of the human genome sequencing project, a comprehensive genotype/phenotype analysis for Jacobsen syndrome became possible. In this article, we review research describing individual causal genes in distal 11q that contribute to the overall Jacobsen syndrome clinical phenotype. Through a combination of human genetics and the use of genetically engineered animal models, causal genes have been identified for the clinical problems in JS that historically have caused the greatest morbidity and mortality: congenital heart disease, the Paris-Trousseau bleeding disorder, intellectual disability, autism, and immunodeficiency. Insights gained from these studies are being applied for future drug development and clinical trials, as well as for a potential strategy for the prevention of certain forms of congenital heart disease. The results of these studies will likely not only improve the prognostic and therapeutic approaches for patients with Jacobsen syndrome, but also for the general population afflicted with these problems.

Síndrome de Jacobsen (deleción parcial 11q) asociado a trombocitosis: presentación de un caso y revisión de la literatura científica / Jacobsen syndrome (partial 11q deletion) associated to thrombocytosis: report of a case and literature review

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)

Jacobsen syndrome detected by noninvasive prenatal testing.

BACKGROUND: Noninvasive prenatal testing has a high detection rate of common fetal chromosomal aneuploidies. However, detection of additional chromosome abnormalities has not been well described or validated. CASE: We report a case of Jacobsen syndrome, a congenital disorder involving deletion of chromosome 11q, detected by noninvasive prenatal testing at 14 weeks of gestation and confirmed on neonatal testing with array chromosomal genomic hybridization. CONCLUSION: Noninvasive prenatal testing should be considered when multiple fetal anomalies are present and invasive testing is declined. As the clinical application of noninvasive prenatal testing continues to evolve, additional submicroscopic chromosomal information may be clinically helpful and should be confirmed with diagnostic testing until larger studies help further define the screening characteristics of noninvasive prenatal testing.

A case with 46,XX,del(11)(q23.2) karyotype and poor vision with literature review.

Here we describe clinical and cytogenetic data on a female child whom had been referred to our laboratory suspected to have Turner syndrome since she had webbed neck. Cytogenetic analysis revealed that she had deletion at 11q23.2 to 11q terminal so her karyotype was ascertained as 46,XX,del(11)(q23.2). Her parents had normal karyotypes. In addition to many clinical features of del(11q ) syndrome the case had poor vision which is not common for this syndrome. Clinical features of this case and a few published cases will be reviewed briefly.

Terminal deletion of 11q with significant late-onset combined immune deficiency.

PURPOSE: We report a 45-year old female adult patient with terminal deletion of chromosome 11q resulting in clinical phenotype of late-onset combined immunodeficiency. METHODS: We describe the clinical phenotype and discuss the similarities between our patient and those with chromosome 22q11.2 deletion syndrome. Immunological evaluation included immunoglobulin levels, vaccine responses, number and function of T, NK and B cell subsets and comparative genomic hybridization test of blood and fibroblasts. RESULTS: The patient suffered from recurrent pneumococcal pneumonia and genital and cutaneous condylomas. She had a history of learning difficulties, dysmorphic features, autoimmune thyroiditis, chronic thrombocytopenia and severe asthma. We found Paris-Trousseau type thrombocytopenia, B-, T- and NK-lymphopenia, T cell oligoclonality and IgG hypogammaglobulinemia with inability to respond to pneumococcal polysaccharide, tetanus and diphtheria vaccines. A terminal deletion of chromosome 11q compatible with partial Jacobsen syndrome was found. CONCLUSIONS: This confirms Jacobsen syndrome as a chromosome deletion syndrome able to cause combined immunodeficiency.

Periventricular nodular heterotopia and transverse limb reduction defect in a woman with interstitial 11q24 deletion in the Jacobsen syndrome region.

Jacobsen syndrome (JS) is a disorder of developmental delay, growth retardation, thrombocytopenia, dysmorphic features, and cardiac abnormalities, among other congenital anomalies. JS is caused by contiguous gene deletion in distal chromosome 11q, generally varying in size from 7 to 20 Mb. Periventricular nodular heterotopia (PVNH) is a neuronal migration disorder in which neurons are abnormally located in nodules along the edges of the lateral ventricles. PVNH can also be seen with other congenital anomalies, including a recurrent association with distal limb defects. Transverse limb defects have previously been reported in two patients with JS. We report on a patient with a 3.162 Mb interstitial deletion at chromosome region 11q24 overlapping the region commonly affected in JS. The patient had PVNH and a transverse limb reduction defect, with minimal typical findings of JS. This is the first report of PVNH associated with a microdeletion at chromosome 11q and may represent an expansion of the phenotypic spectrum associated with JS. This is the third report of transverse limb reduction defects in association with JS, supporting a widening of the skeletal phenotypic spectrum in JS to include more severe limb anomalies. ETS1 is proposed as a candidate gene for involvement in limb anomalies in JS.

Hypoimmunoglobulinemia and protein C deficiency in a girl with Jacobsen syndrome: a case report.

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.

Jacobsen syndrome without thrombocytopenia: a case report and review of the literature.

Jacobsen syndrome (JS), a rare disorder with multiple dysmorphic features, is caused by the terminal deletion of chromosome 11q. Typical features include mild to moderate psychomotor retardation, trigonocephaly, facial dysmorphism, cardiac defects, and thrombocytopenia, though none of these features are invariably present. The estimated occurrence of JS is about 1/100,000 births. The female/male ratio is 2:1. The patient admitted to our clinic at 3.5 years of age with a cardiac murmur and facial anomalies. Facial anomalies included trigonocephaly with bulging forehead, hypertelorism, telecanthus, downward slanting palpebral fissures, and a carp-shaped mouth. The patient also had strabismus. An echocardiogram demonstrated perimembranous aneurysmatic ventricular septal defect and a secundum atrial defect. The patient was <3rd percentile for height and weight and showed some developmental delay. Magnetic resonance imaging (MRI) showed hyperintensive gliotic signal changes in periventricular cerebral white matter, and leukodystrophy was suspected. Chromosomal analysis of the patient showed terminal deletion of chromosome 11. The karyotype was designated 46, XX, del(11) (q24.1). A review of published reports shows that the severity of the observed clinical abnormalities in patients with JS is not clearly correlated with the extent of the deletion. Most of the patients with JS had short stature, and some of them had documented growth hormone deficiency, or central or primary hypothyroidism. In patients with the classical phenotype, the diagnosis is suspected on the basis of clinical findings: intellectual disability, facial dysmorphic features and thrombocytopenia. The diagnosis must be confirmed by cytogenetic analysis. For patients who survive the neonatal period and infancy, the life expectancy remains unknown. In this report, we describe a patient with the clinical features of JS without thrombocytopenia. To our knowledge, this is the first case reported from Turkey.