Postnatal overgrowth by 15q‐trisomy and intrauterine growth retardation by 15q‐monosomy due to familial translocation t(13;15): Dosage effect of IGF1R?

We report a 4‐year‐old boy, a 6‐month‐old girl, and a 17‐week‐old fetus all with a chromosomal imbalance derived from a balanced translocation t(13;15)(q34;q26.1) of their father. The boy had a partial trisomy for 15q26.1‐qter (46,XY,der(13)t(13;15)(q34;q26.1)) and postnatal overgrowth, as well as craniosynostosis, facial anomalies, and finger joint contractures, while the girl with the same chromosomal aberration did not show overgrowth, although she had similar craniofacial and skeletal abnormalities. The fetus had a partial monosomy for 15q26.1‐qter and intrauterine growth retardation (IUGR). Fluorescence in situ hybridization (FISH) analysis with a BAC clone covering the insulin‐like growth factor 1 receptor gene (IGF1R) that is located to 15q25‐q26 revealed three copies in the boy, one copy in the fetus, and two copies in their phenotypically normal father. Since deletion of IGF1Rhas repeatedly been reported to be associated with IUGR, it is tempting to speculate that the dosage of IGF1R may have determined growth in these children. © 2002 Wiley‐Liss, Inc.     

15q26.3 deletions distal to IGF1R cause growth retardation,congenital heart defect and skeletal anomalies: Case report and review of literature

15q26 deletion is a rare genomic disorder characterized by intrauterine and postnatal growth retardation, microcephaly, intellectual disability, and congenital malformations. Here, we report a 4-month-old female with intrauterine growth retardation, short stature, pulmonary hypertension, atrial septal defect and congenital bowing of long bones of the legs. Chromosomal microarray analysis showed a de novo deletion of approximately 2.1 Mb at 15q26.3 region that does not include IGF1R. Our analysis of patients documented in the literature and the DECIPHER database with 15q26 deletions distal to IGF1R, including 10 patients with de novo pure deletions, allowed us to define the smallest region of overlap to 686 kb. This region includes ALDH1A3, LRRK1, CHSY1, SELENOS, SNRPA1, and PCSK6. We propose haploinsufficiency of one or more genes, besides IGF1R, within this region may contribute to the clinical findings in patients with 15q26.3 deletion.     

Clinical and molecular cytogenetic characterization of two patients with partial trisomy 1q41‐qter: Further delineation of partial trisomy 1q syndrome

We report the clinical and molecular cytogenetic characterization of two patients with partial trisomy 1q. The first patient is a currently 11‐year‐old female proposita with a de novo unbalanced translocation 46,XX,der(8)(8qter‐8p23.3::1q41‐1qter), leading to a partial trisomy 1q41‐qter and a partial monosomy for 8p23.3‐pter. The most prominent clinical features of the girl are a triangular face, almond‐shaped eyes, low‐set ears, short stature with relatively long legs, and mild psychomotor retardation. To our knowledge, the cytogenetic aberration in this girl is the most proximal partial trisomy 1q leading to a mild phenotype. Recently, we identified a second patient with a similar partial trisomy 1q combined with a cri du chat syndrome caused by a de novo unbalanced translocation 46,XX,der(5)(5qter‐5p13.1::1q41‐1qter). Comparison of the phenotype of the two girls as well as with already published trisomy 1q cases was performed, and fluorescence in situ hybridization probes from selected YACs were used to delineate the extent of the partial trisomy in more detail. © 2001 Wiley‐Liss, Inc.     

Subtelomeric monosomy 11q and trisomy 16q in siblings and an unrelated child: molecular characterization of two der(11)t(11;16)

We report here three children with a der(11)t(11;16), two sibs (patients 1 and 2) having inherited a recombinant chromosome from a maternal t(11;16)(q24.3;q23.2) and a third unrelated child with a de novo der(11)t(11;16)(q25;q22.1), leading to partial monosomy 11q and trisomy 16q. Fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones and array‐CGH were performed to determine the breakpoints involved in the familial and the de novo rearrangements. The partial 11 monosomy extended from 11q24.3 to 11qter and measured 6.17–6.21 Mb in Patients 1 and 2 while the size of the partial 11q25‐>qter monosomy was estimated at 1.97–2.11 Mb for Patient 3. The partial 16 trisomy extended from 16q23.2 to 16qter and measured 8.93–8.95 Mb in Patients 1 and 2 while the size of the partial 16q22.1‐>qter trisomy was 20.82 Mb for Patient 3. Intraventricular hemorrhage and transitional thrombocytopenia were found in both sibs but not in the third patient. The FLI1 gene, which is the most relevant gene for thrombocytopenia in Jacobsen syndrome, was neither deleted in family A nor in Patient 3. We suggest that a positional effect could affect the FLI1 expression for these two sibs. Deafness of our three patients confirmed the association of this anomaly to 11q monosomy and tended to confirm the hypothetic role of DFNB20 in Jacobsen syndrome hearing loss. Both sibs shared most of the features commonly observed in Jacobsen syndrome, but not the third patient. This confirmed that terminal 11q trisomy spanning 1 to 1.97–2.11 Mb is not associated with a typical Jacobsen syndrome. © 2011 Wiley‐Liss, Inc.     

High risk for unbalanced segregation of some reciprocal translocations: A large pedigree containing distal 4q trisomy from t(4;7)(q28;p22)

We report on a familial t(4;7)(q28;p22) with 2:2 adjacent‐1 unbalanced segregation producing duplication of 4q28→qter in multiple offspring. Within the large four‐generation pedigree, a carrier had a reproductive outcome that was approximately equal for 1) the balanced translocation, 2) normal chromosomes, and 3) viable 4q trisomy or pregnancy loss. The three individuals with chromosomal confirmation of trisomy 4q28→qter (comprising approximately 1.8% of the haploid autosomal length) had similar mental and developmental retardation, hypotonia, restricted speech, seizures, and facial anomalies but no cardiac, renal, or skeletal anomalies. It is suggested that these latter severe malformations, associated with the classic 4q2 to 3 group of anomalies, were from an imbalance outside 4q28→qter and were not necessarily related to the relatively large size of the trisomic segment. Multiple different chromosomes are reported to be rearranged with 4q in the production of distal 4q trisomy. The incidence of 4q rearrangement remains unexplained, but once it is present in a family, viability of a large trisomy in 4q seems to explain the number of affected individuals reported. © 2001 Wiley‐Liss, Inc.     

Tetrasomy 15q25.3 → qter resulting from an analphoid supernumerary marker chromosome in a patient with multiple anomalies and bilateral Wilms tumors

We describe a girl who had been followed since birth for apparent Shprintzen‐Goldberg syndrome (SGS), with macrosomia, long fingers and toes, and craniosynostosis, and presented at 4 years of age with bilateral Wilms tumors (also called nephroblastoma). Cytogenetic analysis of her peripheral blood revealed a de novo supernumerary marker chromosome. This stable marker chromosome is present in 19 of 20 lymphocytes analyzed, as well as in all 40 tumor cells (20 from each tumor) studied. Classical and molecular cytogenetic studies indicate that the marker is derived from an inverted duplication of chromosome 15q25.3 → qter and contains a neocentromere. The presence of this marker chromosome in our patient results in tetrasomy 15q25.3 → qter. The relationship between her genotype and phenotype are discussed in light of genes, including IGF1R and FES, mapped to the aneusomic segment. © 2002 Wiley‐Liss, Inc.     

Girl with combined cellular immunodeficiency,pancytopenia, malformations,deletion 11q23.3 → qter,and trisomy 8q24.3 → qter

We describe here a 3‐year‐old girl demonstrating combined cellular immunodeficiency of B‐ and T‐cells, pancytopenia, multiple anomalies, and severe mental retardation. Cytogenetic analysis and fluorescent in situ hybridization (FISH) indicated an unbalanced translocation of chromosomes 8q and 11q, resulting in monosomy 11q23.3‐qter and trisomy 8q24.3‐qter. The association of cellular immunodeficiency and partial deletion 11q and/or partial trisomy 8q has not been described previously; however, the 11q deletion has been reported with humoral immunodeficiency or pancytopenia. Some one‐third to one‐half of patients with partial monosomy 11q were reported to have pancytopenia, which has been related to the absence of the 11q23‐q24 region. Our case narrows down the critical interval for thrombo‐ or pancytopenia to 11q23.3‐q24 and excludes both the ATM (which resides on 11q23.1) and the MLL genes as possible candidate genes. We are proposing that haploinsufficiency of the NFRKB gene on 11q24‐q25 and/or the ETS‐1 proto‐oncogene on 11q24 may have caused or contributed to the immunodeficiency (decreased levels of B‐ and T‐lymphocytes) in our patient. © 2002 Wiley‐Liss, Inc.     

Inv dup del (1)(pter→q44::q44→q42:) with the classical phenotype of trisomy 1q42–qter

We report on a girl with a trisomy 1q42–q44 due to an inverted duplication of this region, associated with a terminal deletion of the long arm of the rearranged chromosome 1. Both the large duplication (more than 30 cM) and the small deletion were detected by FISH. Complete karyotype was: (46,XX, inv dup(1)(q44q42).ish(dup del 1)(q44q42)(D1S446×2, D1S423×2, tel1q‐). The phenotype of the patient is characterized by macrocephaly with prominent forehead, downslanting palpebral fissures, micrognathia, and psychomotor retardation. All these clinical features are the same as observed for the typical trisomy 1q42–qter syndrome. The phenotypic effects of the inversion and the terminal deletion of 1q in addition to the trisomy are discussed here. © 2001 Wiley‐Liss, Inc.     

Interstitial deletion 4q32‐34 with ulnar deficiency: 4q33 may be the critical region in 4q terminal deletion syndrome

We report on an infant with Robin sequence; mild developmental delay; a left ulnar ray defect with absent ulna and associated metacarpals, carpals and phalanges; and a right ulnar nerve hypoplasia. He had a de novo interstitial deletion of 4q32→q34. The critical region involved in the 4q terminal deletion syndrome may be 4q33. This conclusion was suggested by showing that del(4)(q31qter), del(4)(q32qter), and del(4)(q33qter) result in a similarly severe phenotype. In addition, we propose that genes for distal arm development, in particular for development of the left ulnar ray, central nervous system development, and cleft lip and palate, may be located at 4q33. © 2001 Wiley‐Liss, Inc.     

Partial trisomy 13q identified by sequential fluorescence in situ hybridization

We report on a 19-month-old boy with partial trisomy 13q resulting from a probable balanced translocation involving chromosomes 1 and 13. The infant presented with omphalocele, malrotation, microcephaly with overriding skull bones, micrognathia, apparently low-set ears, rocker-bottom feet, and congenital heart disease, findings suggestive of trisomy 13. Karyotypic studies from peripheral blood lymphocytes documented an unbalanced karyotype 46,XY,−1, +der(1). The mother's chromosomes were normal, and the father was not available. Conventional cytogenetic techniques were unable to identify the extra material on the terminal 1q. Using fluorescence in situ hybridization (FISH) on the GTL-banded metaphases, the extra material on 1q was identified as the terminal long arm of 13, thus resulting in partial trisomy 13 (q32–qter). © 1995 Wiley-Liss, Inc.     

Monosomy 9p24→pter and trisomy 5q31→qter: Case report and review of two cases

Partial deletion of the short arm of chromosome 9 (p24→pter) and partial duplication of the long arm of chromosome 5 (q32→qter) were observed in an abnormal boy who died at age 8 weeks of a complex cyanotic cardiac defect. He also had minor anomalies, sagittal craniosynostosis, triphalangeal thumbs, hypospadias, and a bifid scrotum. Two other infants with similar cytogenetic abnormalities were described previously. These patients had severe congenital heart defect, genitourinary anomalies, broad nasal bridge, low hairline, apparently low-set ears, short neck, and triphalangeal thumbs, in common with our patient. We suggest that combined monosomy 9p23,24→pter and trisomy 5q31,32→qter may constitute a clinically recognizable syndrome. © 1995 Wiley-Liss, Inc.     

Prenatal diagnosis of a de novo trisomy 6q22.2→6qter and monosomy lpter→1p36.3. Case report with a 2-year follow-up and a brief review of other prenatal cases of partial trisomy 6q

We report a de novo trisomy 6q22.2→6qter and monosomy lpter→1p36.3 identified in amniocytes by GTG banding and FISH. While ultrasonography demonstrated malformations that did not suggest a specific chromosomal syndrome, a male infant with features consistent with trisomy 6q was born. He was followed up until 23 months, when he died after cardiac surgery. The only two other prenatal cases of trisomy 6q were compared with our patient. A literature review showed that trisomy 6q has not been reported in association with the anomalies seen by ultrasound in this case.     

Subtelomeric familial translocation t(2;7)(q37;q35) leading to partial trisomy 7q35→qter: Molecular cytogenetic analysis and clinical phenotype in two generations

Few patients with trisomy of the most distal region of chromosome 7q have been described. We report on a familial translocation t(2;7)(q37;q35) leading to trisomy 7q35→7qter in a child and her paternal uncle and a minimal deletion of distal 2q as demonstrated by FISH with probes located in the chromosome 2q subtelomeric region. The clinical phenotype included macrocephaly and low‐set ears, also found in other reported patients trisomic for the distal part of chromosome 7q. Phenotypic findings probably useful for the clinical diagnosis include normal size at birth, large head with frontal bossing, low‐set ears of normal shape, small nose and low nasal bridge, feeding difficulties in infancy, and severe neurodevelopmental delay. Am. J. Med. Genet. 93:349–354, 2000. © 2000 Wiley‐Liss, Inc.     

Small supernumerary marker chromosome 15 and a ring chromosome 15 associated with a 15q26.3 deletion excluding the IGF1R gene

Array comparative genomic hybridization is essential in the investigation of chromosomal rearrangements associated with epilepsy, intellectual disability, and dysmorphic features. In many cases deletions, duplications, additional marker chromosomes, and ring chromosomes originating from chromosome 15 lead to abnormal phenotypes. We present a child with epilepsy, cardiac symptoms, severely delayed mental and growth development, behavioral disturbances and characteristic dysmorphic features showing a ring chromosome 15 and a small supernumerary marker chromosome. Array CGH detected a 1 Mb deletion of 15q26.3 in a ring chromosome 15 and a 2.6 Mb copy number gain of 15q11.2 corresponding to a small supernumerary marker chromosome involving proximal 15q. Our findings add to previously published results of 15q11q13 duplications and 15q26 terminal deletions. Based on our study we can support the previous reported limited information about the role of SELS, SNRPA1, and PCSK6 genes in the development of the heart morphology. On the other hand, we found that the copy number loss of our patient did not involve the IGF1R gene which is often associated with growth retardation (short stature and decreased weight). We hypothesize that haploinsufficiency of the 15q26 genomic region distal to IGF1R gene might be related to growth disturbance; however, presence of the ring chromosome 15 itself could also be responsible for the growth delay.

     

Neuroblastoma in a boy with MCA/MR syndrome,deletion 11q,and duplication 12q

Deletion 11q23→qter and duplication 12q23→qter are described in a boy with neuroblastoma, multiple congenital anomalies, and mental retardation. The patient has clinical manifestations of 11q deletion and 12q duplication syndromes. The possible involvement of the segment 11q23→24 in the cause of the neuroblastoma is discussed. © 1995 Wiley-Liss, Inc.     

A complex chromosome rearrangement resulting in trisomy 15q22→qter

A black infant with malformations was found to have trisomy 15q22→qter. The mother had a complex chromosomal rearrangement involving three chromosomes (5, 13, and 15). A comparison with previously published cases of trisomy for distal 15q suggests a pattern of clinical findings including retardation in growth and development, microcephaly, asymmetrical facies, prominent occiput, antimongoloid slant of the palpebral fissures, micrognathia, prominent nose, and congenital heart disease.     

Acute leukemia in a patient with 15q overgrowth syndrome

Overgrowth syndromes are rare genetic conditions which present as global or segmental hyperplasia and are sometimes associated with increased risk of malignancy. Trisomy of the terminal portion of 15q which includes the IGFR1 gene, produces a rare overgrowth phenotype that has been termed 15q overgrowth syndrome (15q OGS). Upregulation of IGF1R has long been implicated in oncogenesis of multiple cancer types, including acute leukemias, and has been shown to render cells more susceptible to other transforming events. To date, too few cases of 15q OGS have been reported to identify any cancer predisposition. We present a case of a 34‐year‐old female with intellectual disability, macrocephaly, and subtle dysmorphic features who was diagnosed with mixed phenotype acute leukemia (lymphoid and myeloid). Prior to initiation of therapy she was referred to medical genetics for further evaluation and was identified as having a chromosomal translocation resulting in a partial trisomy of chromosome 15q, consistent with 15q OGS. A review of the literature for cases of malignancy in individuals with increased copy number of 15q revealed only one other reported patient. Given the small number of reported individuals, we cannot rule out an increased risk of cancer associated with this chromosomal overgrowth syndrome. Although concerns have been raised regarding treatment feasibility in the setting of chromosomal disorders, the reported patient underwent successful treatment with allogeneic hematopoietic stem‐cell transplant.     

Partial 18q trisomy and 18p monosomy resulting from a maternal pericentric inversion,inv(18)(p11.2q21.3)

A 7-year-old boy with dysmorphic features was found to have a recombinant chromosome 18, rec(18), resulting from meiotic recombination of a maternal pericentric inversion, inv(18) (p11.2q21.3), as defined by high-resolution banding. He was trisomic for the long arm (q21.3-qter) and monosomic for the short arm (p11.2-pter) of chromosome 18. His clinical features were compared with those in other rec(18) cases, and also those in monosomy 18p, trisomy 18qter and full trisomy 18 syndromes. The risk of recombinant formation for inv(18) carriers was also discussed.