Mosaic tetrasomy 13q and phylloid hypomelanosis: a case report and review of the literature.

A 6-year-old girl presented for evaluation of skin discoloration. Examination revealed oval and oblong hypopigmented macules on her trunk and extremities. Cytogenetic studies and immunohistochemistry of biopsies from normally pigmented and hypopigmented skin revealed mosaicism for partial tetrasomy for 13q with low melanocyte levels in lesional skin. The patient was diagnosed with phylloid hypomelanosis (PH), a distinct clinical entity linked to abnormalities in chromosome 13. This article reviews the literature regarding PH and supports the notion that mosaicism of the melanocyte region of chromosome 13q is responsible for PH.

Genotoxicity associated with hydroxyurea exposure in infants with sickle cell anemia: results from the BABY-HUG Phase III Clinical Trial.

BACKGROUND: The laboratory and clinical benefits of hydroxyurea therapy for children with sickle cell anemia (SCA) are well recognized, but treatment in young patients is limited in part by concerns about long-term genotoxicity, and specifically possible carcinogenicity. PROCEDURE: The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) was a multicenter double-blinded placebo-controlled randomized clinical trial (NCT00006400) testing whether hydroxyurea could prevent chronic organ damage in very young patients with SCA. An important secondary objective was the measurement of acquired genotoxicity using three laboratory assays: chromosomal karyotype, illegitimate VDJ recombination events, and micronucleated reticulocyte formation. RESULTS: Our data indicate that hydroxyurea treatment was not associated with any significant increases in genotoxicity compared to placebo treatment. CONCLUSIONS: These data provide additional support to the safety profile of hydroxyurea for young patients with SCA, and suggest that genotoxicity in this patient population is low.

Fine mapping of breakpoints in two unrelated patients with rare overlapping interstitial deletions of 9q with mild dysmorphic features.

Approximately, 20 cases of interstitial deletions of 9q have been reported in the literature spanning the breakpoints from 9q21 to 9q34. Unlike the 9q subtelomeric deletions, the interstitial deletions do not demonstrate a specific recognizable phenotype, although the majority of patients had microcephaly. Lack of precise molecular delineation of the extent of deletions in the published cases makes it difficult to develop an accurate genotype-phenotype correlation. We report on fine mapping of breakpoints using the Affymetrix Human Mapping 500K Array Set in two unrelated female patients with overlapping de novo deletion in 9q. SNP oligonucleotide microarray analysis (SOMA) indicated these to be relatively large deletions with Patient 1 having a 6.47 Mb deletion (>60 genes) spanning 9q32-q33.2 and Patient 2 having a 9.68 Mb deletion (>20 genes) localized to 9q31.1-q33.1. FISH analysis with BAC clones localized to the breakpoints showed discrepant results in Patient 1. Based on the review of previously reported interstitial 9q deletion patients and our patients, the minimal region of overlap (MRO) appears to encompass the 9q32 region and a phenotype characterized by microcephaly, neurological dysfunction and facial dysmorphism can be deduced. Our study shows the investigative nature of the latest array technology and the limitations of this technology in the accurate delineation of breakpoints.

Unusual mosaic karyotype resulting from adjacent 1 segregation of t(11;22): importance of performing skin fibroblast karyotype in patients with unexplained multiple congenital anomalies.

We report a patient with a mosaic karyotype resulting from an adjacent 1 segregation of the familial autosomal translocation (11;22). The karyotype seen in fibroblast is 46,XY,der(22)t(11;22)(q23.3;q11.2)/46,XY. No evidence of the abnormal cell line was seen in the cultures obtained from the lymphocytes. The clinical phenotype of the patient does not fit a particular pattern of partial monosomy 22 or partial trisomy 11. There are some features that have been previously reported in patients with trisomy 11q23 --> qter. The mosaic karyotype in our patient could be a result of a series of postzygotic mitotic events of a zygote carrying the der(22) chromosome. These mechanisms involve events that are well documented for several chromosomes. This case underscores the necessity of performing exhaustive cytogenetic analysis in patients with an abnormal phenotype with a family history of a chromosome rearrangement in fibroblast cells if lymphocyte analysis is normal.

Acute leukemia with PICALM-MLLT10 fusion gene: diagnostic and treatment struggle.

Patients with various hematologic malignancies, including acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), diffuse histiocytic lymphoma, and granulocytic sarcoma, have sometimes been shown to carry the PICALM-MLLT10 fusion gene (alias CALM-AF10) by various cytogenetic methodologies. Cases with the PICALM-MLLT10 fusion gene can involve a diagnostic dilemma for the following reasons: (1) the fusion gene occurs very rarely, (2) the cases do not have a distinct myeloid or lymphoid morphology and cells often appear immature, (3) cases usually have a mixed T-cell and myeloid phenotype, and (4) cases often have a mixed clinical presentation (e.g., mediastinal mass in a patient with AML). A 27-year-old woman was diagnosed with AML with the PICALM-MLLT10 fusion gene. The patient was treated on an AML regimen and achieved a complete remission. Although the reported treatment of these patients varies greatly, outcome remains very poor in the vast majority. Furthermore, central nervous system involvement at diagnosis and relapse are reported in pediatric populations. Routine acute leukemia fluorescence in situ hybridization panels do not include a probe for the PICALM-MLLT10 fusion gene, and therefore diagnosis can be made only when karyotyping is available; that delay can result in initial misdiagnosis and mistreatment. The case report and literature review here (including discussion of the poor prognosis and of management, including CNS prophylaxis) are intended to raise awareness and to inform about PICALM-MLLT10 in acute leukemia.

Long-term follow-up and analysis of monozygotic twins concordant for 45,X/46,XY peripheral blood karyotype but discordant for phenotypic sex.

We report on the follow-up of a set of monozygotic (MZ) twins who were concordant for peripheral blood karyotype 45,X/46,XY but discordant for phenotypic sex. One twin is a phenotypically normal male and the other twin has asymetrical gonadal dysgenesis. The female twin has the mos45,X/46,XY karyotype in all four tissues: left testis, right streak, vas deferens, and clitoral skin. The normal male twin has the normal 46,XY karyotype in all three tissues tested: foreskin, scrotal skin, and testis. Follow-up of the twins at age 21, revealed persistence of mos45,X/46,XY karyotype in peripheral blood into adult life. However, the male grew up with normal male stature, reaching an adult height of 182 cm. The female twin received low dose estrogen replacement with complete breast development at age 14 years. She reached an adult height of 156 cm. At 21 years of age the male twin had normal testicular endocrine function, but severe oligospermia. The long-term follow-up of this set of MZ twins indicate that the male twin has the mosaicism confined to peripheral blood and has the normal 46,XY male constitution. This was further confirmed by his normal male stature and normal testicular endocrine function. The 45X cell line is likely due to his receiving these cells passively from his twin sister via placental anastomoses in utero. The exposure to these 45,X cells during development may have had an impact on his spermatogenesis.

Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients.

Chromosome 22, particularly band 22q11.2, is predisposed to rearrangements due to misalignments of low-copy repeats (LCRs). DiGeorge/velocardiofacial syndrome (DG/VCFS) is a common disorder resulting from microdeletion within the same band. Although both deletion and duplication are expected to occur in equal proportions as reciprocal events caused by LCR-mediated rearrangements, very few microduplications have been identified. We have identified 13 cases of microduplication 22q11.2, primarily by interphase fluorescence in situ hybridization (FISH). The size of the duplications, determined by FISH probes from bacterial artificial chromosomes and P(1) artificial chromosomes, range from 3-4 Mb to 6 Mb, and the exchange points seem to involve an LCR. Molecular analysis based on 15 short tandem repeats confirmed the size of the duplications and indicated that at least 1 of 15 loci has three alleles present. The patients' phenotypes ranged from mild to severe, sharing a tendency for velopharyngeal insufficiency with DG/VCFS but having other distinctive characteristics, as well. Although the present series of patients was ascertained because of some overlapping features with DG/VCF syndromes, the microduplication of 22q11.2 appears to be a new syndrome.