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Tricho-Rhino-Phalangeal syndrome is a rare autosomal dominant genetic disorder caused by mutations in the TRPS1 gene. This malformation syndrome is characterized by distinctive craniofacial features including sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. In this report, we describe two patients with the physical manifestations and genotype of TRPS type I but with learning/intellectual disability not typically described as part of the syndrome. The first patient has a novel heterozygous two-base-pair deletion of nucleotides at 3198-3199 (c.3198-3199delAT) in the TRPS1 gene causing a translational frameshift and subsequent alternate stop codon. The second patient has a 3.08 million base-pair interstitial deletion at 8q23.3 (113,735,487-116,818,578), which includes the TRPS1 gene and CSMD3. Our patients have characteristic craniofacial features, Legg-Perthes syndrome, various skeletal abnormalities including cone shaped epiphyses, anxiety (first patient), and intellectual disability, presenting unusual phenotypes that add to the clinical spectrum of the disease.

We report a soft tissue sarcoma from the thigh with morphologic features resembling Ewing sarcoma, clear cell sarcoma, and myoepithelial tumor of soft tissue. In addition, the genetic and immunohistochemical findings do not correspond to any established pattern, so the tumor does not clearly fit into any one classification. The karyotype analysis revealed a rare chromosomal rearrangement, t(6;22)(p22;q12), that previously has been reported in bone and epithelial tumors. Molecular studies confirmed the presence of an EWSR1–POU5F1 fusion creating a chimeric gene with the N-terminal transcriptional activation domain of EWSR1 and the C-terminal POU DNA binding domain of POU5F1 . This report is novel in that to our knowledge, it is the first complete molecular characterization of an EWSR1–POU5F1 fusion in a soft tissue sarcoma. Evaluation of existing data on the known EWSR1–POU5F1 tumors suggests that the fusion gene functions in a wide variety of cell types and may modify the differentiation state of cells, resulting in susceptibility to tumorigenesis.

Valproic acid has been previously associated with hematologic toxicity, including a reversible myelodysplasia-like syndrome without chromosomal abnormalities. We now report three cases of acute leukemia with features of secondary leukemia associated with valproic acid therapy: two cases of acute myelogenous leukemia with multilineage dysplasia, one with trisomy 8 and one with monosomy 7, and one case of secondary acute lymphoblastic leukemia with del (7) (q22q34), del (9) (q21.11q22), del (11) (q12q23). One patient had a previous myelodysplastic syndrome while on valproic acid. Valproic acid has been previously shown to be a histone deacetylase inhibitor. Inhibition of histone deacetylase causes a relaxation of chromatin structure and thus increases susceptibility to DNA damage and sensitizes cells to radiation. We propose that valproic acid therapy may lead to secondary leukemia by increasing DNA damage through chronic inhibition of histone deacetylase.

A minority of the reported cases of terminal 2q37 deletion clinically resemble Albright hereditary osteodystrophy (AHO)/pseudopseudohypoparathyroidism and have only mild-to-moderate mental retardation. Our molecular and cytogenetic fluorescence in situ hybridization (FISH) findings on an additional three patients further reduce the size of the minimal critical region deleted in this syndrome to about 3 Mb. This region includes the G-protein-coupled receptor 35 (GPR35), glypican 1 (GPC1), and serine/threonine protein kinase 25 (STK25) genes on 2q37.3. We have further defined several polymorphic variants within the coding region and flanking regions of GPR35 gene, which could potentially be useful for rapid detection of GPR35 gene deletion. We postulate that the absence of GPR35 may, at least partly, account for the phenotypic resemblance to the AHO. We also believe that the deletion of GPR35 could be responsible for the entity brachydactyly mental retardation syndrome (OMIM #600430), which was coined based on the above minority of patients with terminal 2q37 deletion. We recommend that every patient with AHO phenotype should undergo 2q subtelomeric FISH screen and subsequently a molecular study on the GPR35 gene. GPC1 and/or STK25 haploinsufficiency may also contribute to the AHO-like phenotype.

Giemsa-11 or G-11 is a specialized staining technique utilized to (1) differentiate heterochromatic regions of human chromosomes, (2) identify the presence of human chromosomes in human-rodent hybrid cells, and (3) identify human-rodent translocation products in hybrid cells. Earlier procedures, though useful, are problematic and may fail to yield results due to inadequate differentiation between light and dark staining regions. The improved protocol presented here is easy, reliable, and applicable in both clinical and research situations. A discussion of the biology of the staining process is also given.

From a morphologic standpoint, Ewing sarcoma (EWS) is one of a number of pediatric malignancies that are characterized by sheets of small, round, blue cells. Ewing sarcoma can usually be differentiated from other small round blue cell tumors by the presence of a gene rearrangement having a consistent breakpoint within the Ewing sarcoma gene (EWSR1) at 22q12. Although the most common translocation partner is FLI1, located at 11q24, there is a growing list of alternate rearrangements involving different loci. We describe the first example of a soft-tissue sarcoma morphologically and immunohistochemically similar to Ewing sarcoma, but with a novel t(18;19)(q23;q13.2).

Cytogenetic deletions and/or loss of heterozygosity (LOH) of the short arm of chromosome 3, often with a break at 3p14, are well documented in lung tumors. The coincidence of a chromosomal fragile site, FRA3B, at a common chromosomal breakpoint in lung cancer has suggested that fragility at this site may predispose to breakage that could contribute to multistep carcinogenesis. This idea is supported by the more recent finding that FRA3B maps within the FHIT (fragile histadine triad) gene, and that aberrant transcripts and genomic deletions of FHIT/FRA3B occur in a variety of tumors including lung tumors. To determine whether some individuals have increased fragility of FRA3B that might increase the risk for breakage or deletion in 3p14.2, fragile site expression was examined in smokers, nonsmokers, and small cell lung cancer (SCLC) patients. The data clearly show that active smokers exhibit a significantly higher frequency of fragile site expression, including FRA3B, compared to that of nonsmokers and patients diagnosed with SCLC who have stopped smoking. These results suggest that active tobacco exposure increases chromosome fragile site expression, and that this fragility is transient and reversible. The data support the hypothesis that exposure to tobacco carcinogens increases the potential for chromosome breakage at fragile sites. © 2002 Wiley-Liss, Inc.

A patient with a 14q32.3 terminal band deletion and cat cry is reported. Review of four other 14q32.3 deletion cases suggests the possible presence of a recognisable 14q32.3 terminal deletion syndrome, which is characterised by (1) apparently postnatal onset of small head size in comparison to body size, (2) high forehead with lateral hypertrichosis, (3) epicanthic folds, (4) broad nasal bridge, (5) high arched palate, (6) single palmar crease, and (7) mild to moderate developmental delay. Although none of the above seven features in unique to this syndrome, and indeed are quite common in other chromosomal disorders or genetic syndromes, patients with a terminal 14q32.3 deletion do show a recognisable facial gestalt. Interestingly, unlike ring chromosome 14, the 14q32.3 terminal deletion has rarely been reported, possibly because it is harder to detect, and an optimal chromosome preparation is required for its identification.

A third case of an interstitial deletion of the long arm of chromosome 6 with clinical features mimicking Prader-Willi syndrome (PWS) is presented. Although preliminary clinical evaluation in each case suggested PWS, further review revealed that the features in all three cases are not completely compatible with the characteristic findings in Prader-Willi syndrome. Furthermore, the deletions in the three cases do not show a consistent region of overlap. Consequently, no particular band or region in 6q can be defined as associated with obesity. However, our findings confirm the suggestion of Villa et al. in 1995, that individuals with a PWS phenotype who are cytogenetically and molecularly negative for a deletion of 15q11-q13 should be examined for a deletion of 6q.

Von Recklinghausen neurofibromatosis (NF1) is a common autosomal dominant disorder mapped to 17q11.2 and typically characterized by the occurrence of neural crest-derived tumors. The gene has recently been cloned using reverse genetics or "positional cloning" approaches. Its function, however, remains unknown. We have performed cytogenetic and molecular analyses on 9 malignant tumors from NF1 patients to look for loss of alleles or chromosome rearrangements involving chromosome 17 to test the hypothesis that the NF1 gene acts as a recessive "tumor suppressor" gene. Loss of alleles on this chromosome was detected for 3 of 9 malignant tumors. Two peripheral nerve sheath tumors showed allele loss at informative loci on both the long and short arms of chromosome 17. In contrast, a glioblastoma with focal gliosarcoma showed loss of heterozygosity on the short arm of chromosome 17 only, and not at loci on the long arm. One nerve sheath tumor was previously shown by direct sequence analysis to have a point mutation at the TP53 locus at 17p13. These data support a role for the TP53 gene or other genes on the short arm of chromosome 17 in at least some malignancies in NF1. Six other neurofibrosarcomas showed no allele loss at informative loci on chromosome 17. Cytogenetic analysis was performed on 7 tumors, including 2 with allele loss. The two tumors with allele loss showed abnormal karyotypes while all others were normal. Southern blot and pulsed-field gel analysis using probes within or closely linked to the NF1 locus detected no gross deletions or rearrangements in the tumors studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Valproic acid (VA) is the most commonly used antiepileptic drug. It has a wide spectrum of hematologic toxicity including thrombocytopenia, anemia, leukopenia, macrocytosis and the presence of the Pelger-Huet abnormality. Serious but reversible hematologic toxicity resembling a myelodysplastic syndrome (MDS) has also been reported. In these cases, cytogenetics, when tested, was normal and progression to acute leukemia was not reported. We now report three cases of acute leukemia associated with VA therapy, accompanied by cytogenetic abnormalities and features suggestive of secondary leukemia. Three patients were recognized as having acute leukemia associated with VA at a single institution over an eight-year period. All three cases had characteristics of secondary acute leukemia. Two had Acute Myelogenous Leukemia (AML) with multilineage dysplasia (one patient with monosomy 7 and one with trisomy 8) and one had Acute Lymphocytic Leukemia (ALL)(partial deletions of chromosome 7, 9, and 11, with a breakpoint at 11q23). One patient with AML had a recognized preceeding myelodysplastic syndrome with normal cytogenetics that acquired trisomy 8 at progression. All three patients had no other risk factors for secondary leukemia. Two patients had been treated with VA for Lenox-Gaustat syndrome for > 20 years and 2 years, and one was treated for idiopathic epilepsy for > 15 years. The leukemogenic mechanism for secondary leukemia is thought to be DNA damage from radiation, chemotherapy drugs, organic solvents or inability to repair such damage from genetic defects in DNA repair enzymes. Chromatin is a dynamic structure and changes in it regulate multiple processes. It is modified through post-translational modifications of the DNA binding histone proteins, including acetylation of lysinses on the tails of histone proteins. Histone acetylation is associated with gene expression and deacetylation is associated with inhibition of gene expression. DNA in chromatin that has a relaxed conformation due to increased histone acetylation is more susceptible to DNA damage by radiation. VA was recently shown to be an inhibitor of histone deacetylase (HDAC). It causes hypereacetylation of histones in cultured cells and relieves HDAC induced transcriptional repression. These findings suggest a novel mechanism of leukemogenesis by VA. We hypothesize that chronic HDAC inhibition by VA results in hyperacetylation of chromatin and relaxation in chromatin structure. This, in turn, may cause increased sensitivity to double-stranded DNA breaks caused by low-level exposure to radiation, exogneous chemicals, or perhaps by cellular oxidant stress. Alternatively, chronic inhibition of HDAC may decrease the ability to repair DNA damage. The resultant DNA damage may subsequently lead to leukemogenesis through several genetic pathways. Interestingly, VA is being studied as a potential treatment for leukemia and MDS and it has been shown to induce expression of silenced tumor suppressor genes, and cause differentiation and/or apoptosis of leukemia cell lines in vitro. The fact that VA may have therapeutic effects in some cases of leukemia is, however, not incompatible with it also being potentially leukemogenic. Further study is needed to better define the incidence and mechanism of VA associated acute leukemia.

Somatic cell hybrids that retain derivative X chromosomes from women with sporadic incontinentia pigmenti (IP1) and de novo X/autosomal translocations with consistent breakpoints at Xp11.21 were constructed. An assembled hybrid panel was used to physically map DNA sequences in relationship to the 1P breakpoint. DSX14 was found to map to region Xp11.21→p11.1. Regional assignments of 19 X-chromosomal loci were reviewed.

Incontinentia pigmenti is a familial disorder affecting tissues derived from neuroectoderm. Statistical analysis of reported pedigrees is consistent with transmission of incontinentia pigmenti by an X-linked dominant gene with male hemizygote lethality. This report describes a male infant with the classic clinical features of this condition and a 47,XXY chromosomal constitution. These findings support the concept that incontinentia pigmenti is an X-linked dominant disorder. This case illustrates the importance of a full genetic investigation in all males with physical findings suggestive of an X-linked dominant disorder lethal in males.