Clinical and molecular-cytogenetic evaluation of a family with partial Jacobsen syndrome without thrombocytopenia caused by an approximately 5 Mb deletion del(11)(q24.3)

Clinical manifestations of Jacobsen syndrome (JBS) depend on the size of the 11qter deletion, which usually varies between approximately 7 and 20 Mb. Typical JBS features include developmental delay/mental retardation, short stature, congenital heart defects, thrombocytopenia, and characteristic dysmorphic facial features. We report on a family in which a 4-year-old girl as well as her mother and maternal uncle present with subtle features of JBS. Notably, neither thrombocytopenia nor congenital anomalies were detected in this family. Cytogenetic analyses revealed normal karyotypes. Using fluorescence in situ hybridization (FISH) and whole-genome oligonucleotide array CGH analyses, we identified an approximately 5 Mb deletion of the terminal part of chromosome 11q in all the three affected family members. The deletion breakpoint was mapped between 129,511,419 and 129,519,794 bp. This is the smallest deletion reported in a JBS patient. Interestingly, the FLI1 (friend leukemia virus integration 1) hematopoiesis factor gene located approximately 6.5 Mb from 11qter and usually deleted in patients with JBS, is intact. Our data support previous hypotheses that FLI1 haploinsufficiency is responsible for thrombocytopenia in patients with JBS.     

Jacobsen distal 11q deletion syndrome with a myelodysplastic change of hemopoietic cells

We describe a male infant with unusual facial appearance, relative pancytopenia, bilateral simian creases, and an accessory nipple. Cytogenetic analysis showed deletion of the long arm of chromosome 11 [46,XY,del(11)(pter→q23.2:)]. Bone-marrow study showed a myelodysplastic change of hemopoietic cells compatible with peripheral blood findings. Pachygyria of the temporal and frontal lobes was demonstrated by magnetic resonance image (MRI) of the brain. We present our findings in order to contribute to the information on 11q23 deletion. Am. J. Med. Genet. 75:341-344, 1998. © 1998 Wiley-Liss, Inc.     

An unusual chromosome 22q11 deletion associated with an apparent complementary ring chromosome in a phenotypically normal woman

We report an unusual chromosome 22q11 deletion associated with an apparent complementary ring chromosome in a phenotypically normal woman with a family medical history of 22q11 deletion. Using peripheral blood samples, conventional karyotyping, Fluorescence In Situ Hybridization (FISH) analysis on metaphase spreads and oligo array-based comparative genomic hybridization (oligo array-CGH) were performed. After conventional cytogenetic examination, the chromosome formula was as follows: 47,XX,+r(?)[16]/46,XX[6]. The FISH analysis revealed that this patient had a rearranged chromosome 22 with decreased centromeric fluorescence intensity and deletion of the 22q11.2 locus. She also had a supernumerary ring chromosome composed of an alpha-satellite centromere of 22 origin and 22q11.2 locus. The oligo array-CGH profile showed a deletion of approximately 4.18?Mb on chromosome 22 with a log 2 intensity ratio mean deviation of the deleted region of about -0.29. The 22q11 deletion associated with a complementary ring chromosome described in our patient could be consistent with a centromere misdivision mechanism, with one chromosomal break occurring in the alpha-satellite array and a second one in the 22q11 locus, a mechanism which has recently been referred to as the McClintock mechanism.     

Dandy-Walker malformation associated with heterozygous ZIC1 and ZIC4 deletion: Report of a new patient

We report on a female patient with Dandy-Walker malformation possibly caused by heterozygous loss of ZIC1 and ZIC4. The patient presented with mental retardation, epilepsy, and multiple congenital malformations including spina bifida, mild dysmorphic facial features including, thick eyebrows, broad nose, full lips, macroglossia, and hypoplasia of the cerebellar vermis with enlargement of the fourth ventricle on brain magnetic resonance imaging, which is consistent with Dandy-Walker malformation. A chromosome analysis showed interstitial deletion of chromosome 3q23-q25.1. Fluorescence in situ hybridization (FISH) and microarray-based genomic analysis revealed the heterozygous deletion of ZIC1 and ZIC4 loci on 3q24. Her facial features were not consistent with those observed in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) involving FOXL2 abnormality. Other deleted genes at 3q23-25.1 might contribute to the dysmorphic facial appearance. A milder phenotype as the Dandy-Walker malformation in our patient supports the idea that modifying loci/genes can influence the development of cerebellar malformation.     

Jacobsen and Beckwith–Wiedemann syndromes in a child with mosaicism for partial 11pter trisomy and partial 11qter monosomy

We report on a child with Jacobsen syndrome (JBS, OMIM 147791) and abnormalities consistent with Beckwith–Wiedemann syndrome (BWS, OMIM 130650). The constitutional karyotype was apparently normal, but FISH analysis with probes specific for the short and long arms of chromosome 11 found 11qter deletion with 11pter trisomy in 80% of the cells studied. Array‐CGH identified breakpoints in the 11p15.3 and 11q24.1 regions consistent with Jacobsen and Beckwith–Wiedemann syndromes. We suggest that this chromosome imbalance results from a pericentric inversion of chromosome 11 inherited from the father, with mosaicism resulting from meiotic recombination of a paternal inversion followed by mitotic recombination during the first embryonic divisions. This hypothesis is supported by the results of microsatellite marker analysis. Three previous cases of pericentric inversion and recombination of chromosome 11 have been reported. Our case is unusual in that it combines the Jacobsen and Beckwith–Wiedemann syndromes with mosaicism. © 2013 Wiley Periodicals, Inc.     

11q24-q25缺失2例临床表型及文献复习

目的应用全基因组微阵列芯片平台,对临床发现的多发性畸形患儿进行全基因组拷贝数变异（CNVs）的检测,并寻找基因型与临床表型的关系。方法采用cytogenetic whole genome芯片筛查全基因组CNVs,针对发现的CNVs进行分析,参照国际基因组CNVs多态性数据库除外正常人群多态性CNVs。结合本研究2例与已报道的Jacobsen综合征（JBS）患儿的临床表型进行比较。结果 2例患儿SNP芯片分析为11q24-q25缺失（7.5和5.6Mb）,均为末端的非单纯性缺失,例1存在12号染色体短臂的较大片段重复（11.5Mb）,例2存在11号染色体短臂的大片段重复（32.5Mb）。2例共同缺失的部分均为JBS的关键区段,但临床表型与已报道的JBS患儿有所区别。2例均表现为头面部畸形、心血管系统异常和头颅影像学异常,均未发现血液系统异常。例1还表现为隐睾,例2表现为脾肿大。结论对临床上难以诊断的多发性畸形可采用全基因组CNVs检测,以帮助明确诊断,对于丰富这一区段临床表型信息具有重要意义,尤其针对罕见疾病,更多的相似报道的后续出现,才能使建立表型-基因型关联性成为可能。     

Interstitial deletion of chromosome 11q in a pineoblastoma

A case of pineoblastoma with an interesting cytogenetic abnormality is reported. Chromosomal analysis of cultured cells from the tumor of a 10-week-old white male revealed an interstitial deletion of the long arm of chromosome 11, del(11)(q13.1q13.5). Tumors of the pineal region are relatively rare, and this is the first report of a pineoblastoma with del(11q).     

Familial deletion 11q14.3-q22.1 without apparent phenotypic consequences: a haplosufficient 8.5 Mb region

We present the prenatal diagnosis of a chromosome 11q14.3-q22.1 deletion identified in three generations without apparent phenotypic consequences. A 25-year-old G2, P1 woman underwent amniocentesis at 15 weeks' gestation because of a positive result for Down syndrome maternal serum-screening test (1/70). The fetal karyotype revealed an interstitial deletion of the long arm of chromosome 11 confirmed by CGH and FISH: 46,XX,del(11)(q14.3q22.1). The mother and grandfather of the fetus presented the same interstitial deletion with a little if any phenotype effect. The pregnancy was carried to term and resulted in the birth of a normal girl. To our knowledge, only one case of a chromosome 11q14.3-q21 deletion without phenotypic anomalies has been reported. Our study allows the initially described haplosufficient region to be extended from 3.6 Mb to at least 8.5 Mb. This large deletion was compatible with fertility and apparently normal phenotype. Identification of such chromosomal regions is important for prenatal diagnosis and genetic counseling.     

A subterminal deletion of the long arm of chromosome 10: a clinical report and review

We report on a girl with mental retardation, dysmorphic features, and behavioral problems. A small terminal deletion of the long arm of chromosome 10 was detected by subtelomeric fluorescence in situ hybridization (FISH) studies in all analyzed metaphases. The deletion was shown to be a de novo terminal deletion of approximately 6.1 Mb, with the deletion breakpoint localized at band 10q26.2, between BAC probes RP11-498K22 and RP11-42K2. A subterminal 10q deletion as found in the present patient has, to our knowledge, only been reported in 15 patients (including 8 familial cases). We review the clinical and behavioral phenotype of these patients with "pure" subterminal 10q deletion.     

Deletion of chromosome 15 represents a rare but recurrent chromosomal abnormality in myelocytic malignancies

We report on three cases with myelocytic malignancies cytogenetically characterized by a deletion of chromosome 15 occurring as the sole cytogenetic aberration. The deletions were defined as del(15) (q12q21) (two cases) and del(15)(q11q21) (one case). Cytogenetic analysis was supplemented by fluorescence in situ hybridization (FISH) using a chromosome 15 specific whole chromosome painting probe and probes hybridizing to the UBE3A gene on 15q11~q13, the PML gene on 15q22, and the telomeric region of 15q. Hereby, an interstitial deletion of 15q including UBE3A, but not PML and the telomeric region of 15q could be demonstrated. Two of our patients were diagnosed as acute myelocytic leukemia (AML) with bone marrow dysplasia classified as AML-M6 and AML-M4, respectively, according to the French-American-British classification; the third patient suffered from a chronic myelomonocytic leukemia (CMMoL). In two cases, the aberration was found at the time of primary diagnosis, whereas the third case showed the del(15) only during relapse of leukemia. Both cases with acute leukemia did not adequately respond to intensive chemotherapeutic treatment and died 13 and 11 months, respectively, after primary diagnosis. Our findings and the data of five previously published cases with an isolated del(15) indicate that: 1) del(15) represents a rare but recurrent abnormality in myelocytic hemopathies; 2) in our cases, del(15) was interstitial and included the region 15q11~q13/UBE3A, but not 15q22/PML and the telomeric region of 15q as shown by FISH; 3) del(15) occurs frequently in disorders with myelodysplastic or myeloproliferative features and may therefore affect early hematopoietic progenitor cells; and 4) del(15) may occur during disease progression and is often associated with an unfavorable prognosis.     

Ring chromosome 4 and Wolf-Hirschhorn syndrome (WHS) in a child with multiple anomalies

We report on a 16-month-old male patient with ring chromosome 4 and deletion of Wolf-Hirschhorn syndrome (WHS) region with multiple congenital anomalies including unilateral cleft lip and palate, iris coloboma, microcephaly, midgut malrotation, hypospadias, and double urethral orifices. Peripheral chromosome analysis of the patient showed 46,XY,r(4)(p16.3q35) de novo. Multicolor fluorescence in situ hybridization (FISH) study was also performed and according to multicolor banding (MCB) a r(4)(::p16.3 --> q34.3 approximately 35.1::) was found in all metaphases. Subtelomeric 4p region, subtelomeric 4q region, as well as, Wolf-Hirschhorn critical region were deleted in ring chromosome 4. Genomic microarray analysis was also performed to delineate the size of deletion. Cranial magnetic resonance imaging (MRI) showed hypoplastic corpus callosum, delayed myelinization, and frontal and occipital lobe atrophies. Both maternal and paternal chromosomal analyses were normal. We compare the phenotypic appearance of our patient with the previously reported 16 cases of ring chromosome 4 in the medical literature.     

Co‐existence of 9p deletion and Silver‐Russell syndromes in a patient with maternally inherited cryptic complex chromosome rearrangement involving chromosomes 4, 9, and 11

We report a patient with a maternally inherited unbalanced complex chromosomal rearrangement (CCR) involving chromosomes 4, 9, and 11 detected by microarray comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). This patient presents with clinical features of 9p deletion syndrome and Silver‐Russell syndrome (SRS). Chromosome analysis performed in 2000 showed what appeared to be a simple terminal deletion of chromosome 9p22.1. aCGH performed in 2010 revealed a 1.63 Mb duplication at 4q28.3, a 15.48 Mb deletion at 9p24.3p22.3, and a 1.95 Mb duplication at 11p15.5. FISH analysis revealed a derivative chromosome 9 resulting from an unbalanced translocation between chromosomes 9 and 11, a chromosome 4 fragment inserted near the breakpoint of the translocation. The 4q28.3 duplication does not contain any currently known genes. The 9p24.3p22.3 deletion region contains 36 OMIM genes including a 3.5 Mb critical region for the 9p‐phenotype. The 11p15.5 duplication contains 49 OMIM genes including H19 and IGF2. Maternal aCGH was normal. However, maternal chromosomal and FISH analyses revealed an apparently balanced CCR involving chromosomes 4, 9, and 11. To the best of our knowledge, this is the first report of a patient with maternally inherited trans‐duplication of the entire imprinting control region 1 (ICR1) among the 11p15.5 duplications reported in SRS patients. This report supports the hypothesis that the trans‐duplication of the maternal copy of ICR1 alone is sufficient for the clinical manifestation of SRS and demonstrates the usefulness of combining aCGH with karyotyping and FISH for detecting cryptic genomic imbalances. © 2012 Wiley Periodicals, Inc.     

Elucidation of a cryptic interstitial 7q31.3 deletion in a patient with a language disorder and mild mental retardation by array-CGH

We report on a 14-year-old boy who presented with bilateral cleft lip and palate, hearing loss, a language processing disorder, and mild mental retardation (MR). G-banded chromosome analysis of the patient and his family revealed he carried an apparently balanced de novo complex translocation involving chromosomes 5, 6, and 7. Chromosomal comparative genomic hybridization (CGH) was performed to investigate the possibility of any genomic imbalance as a result of the complex rearrangement. No abnormality was detected at any of the translocation breakpoint regions (5p13.2, 6p24, 7q21.1, and 7q21.3), nor was there any other imbalance which fell inside our significance level of 0.8-1.2. Array-CGH analysis was initiated to perform a higher resolution search for gains and losses, and revealed a deletion of two adjacent clones, CTB-133K23 and RP11-112P4, mapping to 7q31.3, which are 4.4 Mb apart. Fluorescence in situ hybridization (FISH) using these two clones confirmed the deletion. 7q31 has frequently been implicated in the search for genes involved in speech and language disorders. The specific 7q31.3 region deleted in our patient has significant overlap with some such areas of the genome. These findings are, therefore, of value in identifying genes involved in the speech and language phenotypes. This study has shown the importance of array-CGH in investigating patients who have clinical features suggestive of a chromosome abnormality, but with apparently balanced chromosome rearrangements. It has demonstrated that the array-CGH technique provides a much greater insight into submicroscopic chromosome imbalances than conventional cytogenetic techniques.     

Lung hypoplasia in a patient with del(2)(q33-q35) demonstrated by chromosome microdissection

We report on a 17-month-old girl with multiple malformations, including lung hypoplasia, multiple ventricular septal defects, craniofacial anomalies, and malrotation of the intestine. Moreover, the patient showed Robin sequence, developmental delay, as well as pre- and postnatal growth retardation. Postnatal cytogenetic analysis revealed an interstitial deletion on the long arm of chromosome 2. Microdissection and reverse chromosome painting of the aberrant chromosome 2 as well as FISH with a panel of chromosome 2q band-specific YACs mapped the deletion to 2q33-q35. Lung hypoplasia has not been described so far in patients with del(2)(q33-q35). A review of previously reported patients showed variable phenotypes apparently due to different deleted chromosomal segments.     

Different mechanisms lead to a karyotypically identical t(20;21) in myelodysplastic syndrome and in acute myelocytic leukemia

A new t(20;21)(q11;q11), associated with a deletion on the long arm of chromosome 20, was found in one patient with an acute myelocytic leukemia (AML) and in one with myelodysplastic syndrome (MDS). In both cases deletion was interstitial, extending from band q11 to band q13, as shown by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). FISH analysis with whole arm paints, subtelomeric probes, and locus-specific probes for the long arms of chromosomes 20 and 21 revealed in patient 1 a reciprocal translocation between the deleted 20q and the long arm of chromosome 21, that is, del(20)(q11q13)t(20;21)(q11;q11), and in patient 2, material from 21q was inserted into the deleted 20q, that is, del(20)(q11q13)ins(20;21)(q11;q11q22). This is the first identification of a complex 20;21 rearrangement in MDS/AML. Deletion at 20q and juxtaposition between 20q11 and 21q11 appear to be the critical genomic events.     

Giant platelets in a case of deletion 11q24-qter confirmed by fluorescence in situ hybridization

Here we report the association of giant platelets and an increase in platelet volume in a 19-month-old black female with de novo del 11q24-qter. The deletion, which was visible on karyotype, was further confirmed and more precisely localized by fluorescence in situ hybridization studies (FISH) that showed the deletion to lie distal to the MLL gene region (11q23). Clinically, the case presented less severe symptoms than Jacobsen syndrome-the well known partial deletion of the distal end of chromosome 11. Platelet glycoproteins CD 41, CD 42a, C 42b, CD 61, and PAC-1 were also assayed and found to be normally expressed. To our knowledge, giant platelets are described for the first time in the relevant deleted region.     

17q21.31 microdeletion in a patient with pituitary stalk interruption syndrome

We report the case of a 26-month-old boy with mental retardation, facial dysmorphism, childhood feeding difficulties, short stature, bilateral cryptorchidism, micropenis, and heart defect. Endocrinal evaluation revealed complete growth hormone deficiency (GHD) and gonadotropic deficiency, and pituitary magnetic resonance imaging showed partial pituitary stalk interruption syndrome (PSIS). A de novo 493 kb microdeletion on chromosome 17q21.31 was identified using array comparative genomic hybridization (array-CGH) analysis. This is the first report of PSIS in the phenotypical spectrum of 17q21.31 microdeletion syndrome, although other midline abnormalities have previously been described. Our report suggests that GHD should be investigated in patients with 17q21.31 microdeletion syndrome and short stature, defined by a body height below - 2 standard deviation scores (SDS) for age and sex. This finding also opens new avenues of research on the etiopathogenesis of PSIS, for which the genetic mechanisms remain unknown.     

Cryptic duplication of 12q24.33 --> qter in a child with Angelman syndrome-simultaneous occurrence of two unrelated cytogenetic events

Simultaneous occurrence of two unrelated cytogenetic events is rare. We present a case of Angelman Syndrome (AS) deletion and 12q duplication in a child with a history of developmental delay, microcephaly, cerebral palsy, and seizures. Traditional cytogenetic studies showed a normal 46,XY karyotype. Fluorescence in situ hybridization (FISH) using probe D15S10 (AS region/15q11.2) revealed a deletion. In addition, we serendipitously detected 12q24.3 duplication by FISH with 12q subtelomere probe. He inherited this duplication from the mother who presented with a balanced translocation karyotype 46,XX,add(12)(q24.3).ish t(12;13)(q24.3;p11.2)(12qtel-;12qtel+,D13Z1/D21Z1+,RB1+). Array comparative genomic hybridization (array-CGH) revealed a duplication of three bacterial artificial chromosome (BAC) clones (RP11-46H11, RP11-386I8, and RP11-309H3) covering about 423 Kb of DNA sequence. The published 12q terminal duplication cases had a detectable segment by classical banded cytogenetics techniques. To our knowledge, this is the smallest 12q cryptic rearrangement characterized by array-CGH and confirmed by BAC-clone FISH analysis. Based on these findings, we attempted to separate the clinical features associated with AS deletion and those features that are probably due to partial 12q duplication. We then reviewed the genes mapped in the duplicated region using the human genome database to understand the clinical significance. A subsequent pregnancy in the mother revealed an apparently balanced t(12;13) karyotype. We compare our case with the published cases, and discuss the implications of our findings and its relevance in addressing genetic counseling issues.     

Holoprosencephaly in an infant with a minute deletion of chromosome 21(q22.3)

We evaluated an infant because holoprosencephaly had been detected by prenatal ultrasound examination and magnetic resonance imaging (MRI). Postnatally, high-resolution cytogenetic studies showed a minute deletion of chromosome 21(q22.3). This patient lacks many of the characteristics associated with monosomy 21, partial monosomy 21, and ring 21 chromosome patients. She also lacks the midline facial abnormalities often seen with holoprosencephaly. The similarity in facial appearance between this case and one previously reported patient with holoprosencephaly and a ring chromosome 21 suggests a causal relationship between holoprosencephaly and deletion of chromosome 21(q22.3). These findings also suggest that infants and children with developmental delay and apparently normal facial appearance should be examined for holoprosencephaly and that all identified patients with holoprosencephaly need high-resolution cytogenetic studies with careful attention to the terminal portion of 21q.     

Mosaicism del(22)(q11.2q11.2)/dup(22)(q11.2q11.2) in a patient with features of 22q11.2 deletion syndrome

The chromosome 22q11 region is prone to rearrangements, including deletions and duplications, due to the presence of multiple low copy repeats (LCRs). DiGeorge/velo-cardio-facial syndrome is the most common microdeletion syndrome with more than 90% of patients having a common 3-Mb deletion of 22q11.2 secondary to non-homologous recombination of flanking LCRs. Meiotic reciprocal events caused by LCR-mediated rearrangement should theoretically lead to an equal number of deletions and duplications. Duplications of this region, however, have been infrequently reported and vary in size from 3 to 6 Mb. This discrepancy may be explained by the difficulty in detecting the duplication and the variable, sometimes quite mild phenotype. This newly described 22q duplication syndrome is characterized by palatal defects, cognitive deficits, minor ear anomalies, and characteristic facial features. We report on a male with truncus arteriosus and an interrupted aortic arch, immunodeficiency, and hypocalcemia. The patient is mosaic for two abnormal cell lines: a deletion [del(22)(q11.2q11.2)] found in 11 cells and a duplication [dup(22)(q11.2q11.2)] found in 9 cells. Molecular cytogenetic analysis in our patient revealed a 1.5 Mb deletion/duplication, the first duplication reported of this size. Deletion/duplication mosaicism, which is rare, has been reported in a number of cases involving many different chromosome segments. We present the clinical phenotype of our patient in comparison to the phenotypes seen in patients with the 22q11.2 deletion or duplication alone. We propose that this rearrangement arose by a mitotic event involving unequal crossover in an early mitotic division facilitated by LCRs.