Ventricular noncompaction and distal chromosome 5q deletion

We describe a 7 1/2-year-old girl with mildly unusual phenotype and complex heart disease including ventricular myocardial noncompaction. She was found to have a distal 5q deletion, del(5)(q35.1q35.3). Fluorescent in situ hybridization showed that this deletion included the locus for the cardiac specific homeobox gene, CSX. This suggests that some instances of ventricular myocardial noncompaction may be caused by haploinsufficiency of CSX. Am. J. Med. Genet. 85:419–423, 1999. © 1999 Wiley-Liss, Inc.     

Inverted duplication with terminal deletion of 5p and no cat-like cry

We report on a 6-year-old boy referred for cytogenetics study. A few non-specific features were observed in the newborn: hypotonia, failure to thrive, seizures, pre-auricular skin tags. Cat-like cry was not identified. No remarkable facial dysmorphism, gastrointestinal, respiratory or cardiac abnormalities were identified. At age 4 years, speech and motor skill delays were apparent. Karyotyping and FISH analysis revealed a de novo rearranged chromosome 5p, with subtelomeric deletion of 5p and a duplication of the cri-du-chat critical region. Array CGH using sub-megabase resolution tiling-set (SMRT) array followed by FISH analysis with labeled BACs showed a deletion of 5pter to 5p15.31 (0-6.9 Mb) and an inverted duplication of the greater part of 5p15.31 to the distal end of 5p14.3 (6.9-19.9 Mb). Although very rare, inverted duplications with terminal deletion (inv dup del) have been reported at different chromosomal ends. Our finding adds a second patient of inv dup del 5p to this growing list, and the potential causative mechanisms for this rearrangement are discussed. Review of the mapping information of cri-du-chat patients and the comparison with a previously reported patient suggested that the critical region for cat-like cry is located within a 0.6 Mb region.     

De novo 1q32q44 duplication and distal 1q trisomy syndrome

We report on an infant with minor anomalies and a de novo 1q duplication. The chromosomal abnormality was diagnosed prenatally after sonographic detection of cerebral ventriculomegaly and bilateral choroid plexus cysts in the fetus. The amniocentesis showed an abnormal male karyotype, 46,XY,dup(1)(q32q44), subsequently confirmed by fluorescence in situ hybridization using whole chromosome paint 1 and comparative genomic hybridization. The baby, born at 37 weeks of gestation, had wide cranial sutures and large fontanelles, sloping forehead, hypertelorism, short and downward-slanting palpebral fissures, a high-arched and narrow palate, malformed ears, and long feet with overriding second and third toes. This is the sixth case of known duplication involving the 1q32q44 segment; the physical findings in the case reported herein are similar to those of other patients reported previously, providing further evidence of the existence of the "distal 1q trisomy" phenotype.     

Ventricular noncompaction and distal chromosome 5q deletion.

We describe a 7 1/2-year-old girl with mildly unusual phenotype and complex heart disease including ventricular myocardial noncompaction. She was found to have a distal 5q deletion, del(5)(q35.1q35.3). Fluorescent in situ hybridization showed that this deletion included the locus for the cardiac specific homeobox gene, CSX. This suggests that some instances of ventricular myocardial noncompaction may be caused by haploinsufficiency of CSX.     

Chromosome 5q subtelomeric deletion syndrome

The pure 3.5 Mb subtelomeric deletion syndrome is very rare but causes a recognizable phenotype characterized by prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia in infancy, borderline intelligence, postnatal short stature with delayed bone age due to growth hormone deficiency, and multiple minor anomalies including mildly bell-shaped chest, minor congenital heart defects, and a distinct facial gestalt. Terminal deletions including the adjacent approximately 2 Mb NSD1-locus show a compound phenotype with overlap to Sotos syndrome. Larger terminal deletions including also chromosomal bands 5q35.1 and 5q35.2 cause a more severe phenotype with normal body length, significant congenital heart defect, microcephaly, profound developmental retardation or early death due to respiratory failure. Heart defects in the latter are explained by haploinsufficiency of the NKX2.5 gene at 5q35.1. The deletion breakpoint of the 3.5 Mb subtelomeric microdeletion maps to a low copy repeat which is identical to the distal copy of two highly similar regions flanking the recurrent interstitial NSD1 microdeletion. As meiotic mispairing between these low copy repeats seem to be much more likely than a terminal aberration, these neighborhood may prevent occurrence of the subtelomeric deletion syndrome, which could explain the rareness of the latter.     

Distal 5q deletion syndrome: phenotypic correlations

We describe the phenotypes of two male sibs with partial monosomy of chromosome 5 [46,XY,der(5)inv ins(1;5)(p32;q35.4q34)]; maternally derived from a balanced insertion of 1 and 5 [inv ins (1;5)(p.32;q35.4q34)]. One sib had microcephaly, cleft lip and palate, facial anomalies, atrial (ASD) and ventricular (VSD) septal defects, camptodactyly 4th and 5th fingers, and developmental delay. The other sib showed microcephaly, facial anomalies, ASD, hypotonia, primary optic nerve hypoplasia, and developmental delay. Only seven other patients with 5q deletions distal to 5q33 have been reported and none showed the putative breakpoints identified in our two patients. All nine showed developmental delay or malformations of the CNS and facial anomalies; six of nine had defects of cardiac septation. Our two patients and one other were shown to have only one copy of the cardiac specific hCSX gene that defines in part the etiology of their ASD and VSD. The other components of their phenotypes cannot be related at present to genes identified in the deleted segments.     

Further delineation of the chromosome 14q terminal deletion syndrome

A patient with hypotonia, blepharophimosis, ptosis, a bulbous nose, a long philtrum, upturned corners of the mouth, and mild developmental delay was found to have a small subtelomeric deletion of the long arm of chromosome 14 (q32.31-qter). In comparing her phenotype with previously reported patients with similar 14q deletions, due to either a linear deletion or to a ring chromosome 14, a clinically recognizable terminal 14q microdeletion syndrome was evident. Due to the limited number of cases reported, it was not possible to assign specific features to specific regions of terminal 14q. The comparison of features in cases with a linear deletion of 14qter (n = 19) to those in cases with a deletion due to a ring chromosome 14 (n = 23), both with the same breakpoint in 14q, showed that seizures and retinitis pigmentosa have been found only in patients with ring chromosomes. Several hypotheses are put forward to explain this difference: mitotic instability of ring chromosomes; a telomere position effect in ring chromosomes in which the 14p telomere silences nearby gene(s) on the q-arm; and dose-dependent gene(s) involved in seizures and retinitis pigmentosa located on the short arm of chromosome 14. In our opinion, only seizures may be explained by the mitotic instability of ring chromosomes, while both seizures and retinitis pigmentosa may be explained by silencing of gene(s) on 14q by the 14p telomere; the third hypothesis seems unlikely to explain either symptom.     

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.     

Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32‐q27.2

Partial duplications of the long arm of chromosome 3, dup(3q), are a rare but well‐described condition, sharing features of Cornelia de Lange syndrome. Around two thirds of cases are derived from unbalanced translocations, whereas pure dup(3q) have rarely been reported. Here, we provide an extensive review of the literature on dup(3q). This search revealed several patients with caudal malformations and anomalies, suggesting that caudal malformations or anomalies represent an inherent phenotypic feature of dup(3q). In this context, we report a patient with a pure de novo duplication 3q26.32‐q27.2. The patient had the clinical diagnosis of Currarino syndrome (CS) (characterized by the triad of sacral anomalies, anorectal malformations and a presacral mass) and additional features, frequently detected in patients with a dup(3q). Mutations within the MNX1 gene were found to be causative in CS but no MNX1 mutation could be detected in our patient. Our comprehensive search for candidate genes located in the critical region of the duplication 3q syndrome, 3q26.3‐q27, revealed a so far neglected phenotypic overlap of dup(3q) and the Pierpont syndrome, associated with a mutation of the TBL1XR1 gene on 3q26.32.     

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.     

Familial insertion (3;5)(q25.3;q22.1q31.3) with deletion or duplication of chromosome region 5q22.1-5q31.3 in ten unbalanced carriers

We report on the clinical and cytogenetic data of a large family with an unbalanced insertion translocation (3;5)(q25.3;q22.1q31.3). Analysis of GTG-banded chromosomes demonstrated that unbalanced inheritance of a parental insertion translocation caused either a partial deletion or duplication 5q in this family. The derivative chromosomes were characterized further using microdissection and FISH with band-specific probes. The clinical picture of the proband with a partial deletion of chromosome 5 was characterized by moderate psychomotor retardation, mild facial dysmorphism, cleft palate, and single transverse crease. The family members with a partial duplication of chromosome 5 were borderline intelligent, had mild facial dysmorphism, a cardiac anomaly, and a high-pitched voice. The unbalanced carriers were compared with patients reported in the literature with a duplication or deletion of chromosome region 5q22.1 --> 5q31.3.     

Craniosynostosis associated with partial duplication of 15q and deletion of 2q

We report on an infant with multiple congenital anomalies including complex craniosynostosis associated with an unbalanced karyotype, 46,XY, ? 2, + der(2),t(2;15)(q37;q26)pat. The previous report of a child with cloverleaf skull and partial duplication of 15q25→qter and the Man-on-Mouse Homology map suggests that a critical segment for synostosis of sutures may be in this region. © 1992 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.     

5q35 duplication syndrome: Narrowing the critical region on the distal side and further evidence of intrafamilial variability and expression

The key features of patients with a microduplication 5q35.2q35.3 (including the NSD1 gene) are short stature, microcephaly, mild developmental delay, behavioral problems, digital anomalies and congenital anomalies of internal organs. This core phenotype can be viewed as the reversed phenotype of Sotos syndrome, which is caused by a microdeletion in the same chromosomal region or a pathogenic variant in the NSD1 gene, and includes tall stature and macrocephaly, developmental delay, and epilepsy. Here, we report on a patient and his mother, both with a 5q35.2q35.3 duplication, adding a fifth family to the recently published overview of 39 patients of Quintero-Rivera et al. Our patient had several congenital anomalies, intrauterine growth restriction with a persisting short stature, while his mother was only mildly affected with decreased growth parameters. In addition, he had hemophagogocytic lymphohistiocytosis (HLH) triggered by Haemophilus influenzae and was recently diagnosed with Ewing sarcoma. Our cases carry the smallest duplication published (ca 332 kb, arr[hg19] 5q35.2q35.3(176493106-176824785)x3) further narrowing the distal side of the critical region of the 5q35.2q35.3 duplication. Besides broadening the clinical phenotypic spectrum, our report indicates that the 5q35.2q35.3 microduplication also shows a large intra-familial variability and expression.     

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.