A 2 8/12-year-old boy with severe growth failure and mental retardation was found to have a maternally derived tandem duplication of the long arm of X chromosome, dup(X) (q13.3----q21.2). Karyotypic interpretation was further confirmed in this patient by a double gene dose for red blood cell phosphoglycerate kinase. DNA replication study showed that the duplicated X chromosome was always late replicating in peripheral blood lymphocytes as well as in skin fibroblasts from the mother. Endocrine studies in the patient demonstrated growth hormone deficiency. Magnetic resonance imaging of the head then disclosed the empty sella syndrome. This appears to be the first report of a dup(Xq) patient associated with a growth hormone deficiency and the empty sella syndrome. We emphasize that duplication of the proximal Xq in males represents another microduplication syndrome (Thode-Leonard syndrome).

Campomelic dysplasia (CMPD), a rare congenital disorder, is characterized by a variety of skeletal anomalies, low-set ears and, in nearly half of genotypical-male patients, sex reversal. Observations of chromosomal translocations involving chromosome 17q24-q25 in several CMPD patients have implied that disruption of one or more genes in the breakpoint region is responsible for this disease. Using fluorescence in situ hybridization, we mapped the chromosome-17 breakpoint in a patient with acampomelic CMPD and sex reversal, who carries a de novo constitutional t(12;17) translocation, between two known cosmid markers in the 17q24-q25 region. Through positional cloning, we isolated a 3.5 kb cDNA that is located at a close but distinct position from the SOX9 gene, from the region surrounding this breakpoint. Its mRNA, approximately 3.7 kb long, was expressed specifically in testis among 16 adult tissues examined by Northern blot analysis. As we were unable to find any long open reading frame in the 3.5 kb cDNA sequence or to detect any peptide following an in vitro translation experiment using RNA transcribed from this cDNA, we speculate that this gene may play a critical role in differentiation or sex determination as a functional RNA.

Copy number losses in chromosome arm 9p are well-known aberrations in malignancies, including leukemias. The CDKN2A gene is suggested to play a key role in these aberrations. In this study overviewing 9p losses in hematologic neoplasias, we introduce the term focal 9p instability to indicate multiple areas of copy number loss or homozygous loss within a larger heterozygous one in 9p. We have used microarray comparative genomic hybridization to study patients with acute lymphoblastic leukemia (ALL, n = 140), acute myeloid leukemia (n = 50), chronic lymphocytic leukemia (n = 20), and myelodysplastic syndromes (n = 37). Our results show that 9p instability is restricted to ALL. In total, 58/140 (41%) patients with ALL had a loss in 9p. The 9p instability was detected in 19% of the patients with ALL and always included homozygous loss of CDKN2A along with loss of CDKN2B. Other possibly important genes included MTAP, IFN, MLLT3, JAK2, PTPLAD2, and PAX5. 13/27 (48%) patients with the instability had the BCR/ABL1 fusion gene or other oncogene-activating translocation or structural aberrations. Two patients had homozygous loss of hsa-mir -31, a microRNA known to regulate IKZF1. IKZF1 deletion at 7p12.1 was seen in 10 (37%) patients with the 9p instability. These findings suggest that, in ALL leukemogenesis, loss of CDKN2A and other target genes in the instability region is frequently associated with BCR/ABL1 and IKZF1 dysfunction. The multiple mechanisms leading to 9p instability including physical or epigenetic loss of the target genes, loss of the microRNA cluster, and the role of FRA9G fragile site are discussed.

A 7 month old girl with psychomotor retardation, hypotonia, and minor malformations was found to have a terminal deletion of the long arm of chromosome 22, del(22)(ql3.31). The partial deficiency of arylsulphatase A (ARSA) and the normal level of NADH diaphorase 1 (DIAl) suggests that the ARSA locus can be regionally assigned to 22q13.31-+qter and the DIAl locus can be excluded from the same segment. This report is the third published case with a terminal 22q deletion.Partial monosomy 22 has been reported in relatively few cases. Most of them have an r(22), and there have been only two instances of a terminal deletion of the long arm.' 2 We describe here another patient with a terminal 22q deletion. Gene dosage studies of arylsulphatase A (ARSA) and diaphorase 1 (DIAl) supported their localisations on the distal long arm of chromosome 22.

We describe a family in which autosomal dominant congenital cataract and microphthalmia were segregating together with a reciprocal translocation t(2;16) (p22.3;p13.3) through three generations. This family included four individuals with balanced translocations, three with partial trisomy 2p derived from this translocation, and two with a normal karyotype. All of the subjects with balanced and unbalanced translocations had congenital cataract and microphthalmia, whereas the two individuals with normal karyotypes did not show any ocular anomalies. These observations suggest that the altered function of a gene that lies on the 16p13.3 band and that has an important role in the development of the eye is responsible for this disorder.