Two cases of Legg-Perthes and intellectual disability in Tricho-Rhino-Phalangeal syndrome type 1 associated with novel TRPS1 mutations.

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.

Hypomorphic PCNA mutation underlies a human DNA repair disorder.

Numerous human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum, and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Together, our findings detail a mutation of PCNA in humans associated with a neurodegenerative phenotype, displaying clinical and molecular features common to other DNA repair disorders, which we showed to be attributable to a hypomorphic amino acid alteration.

Molecular characterization of an EWSR1-POU5F1 fusion associated with a t(6;22) in an undifferentiated soft tissue sarcoma.

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.

Newly described translocation (18;19)(q23;q13.2) in abdominal wall soft-tissue tumor resembling Ewing sarcoma/primitive neuroectodermal tumor.

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).

Acute leukemia associated with valproic acid treatment: a novel mechanism for leukemogenesis?

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.

Direct correlation between FRA3B expression and cigarette smoking.

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.