Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems.

Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4(-/-) mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome.

Review of disrupted sleep patterns in Smith-Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion.

Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body's signal for nighttime darkness. Published reports of 24-hr melatonin secretion patterns in two independent SMS cohorts (US and France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion ( approximately 6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.2p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern.

Cytogenetic analysis of a hemosiderotic fibrolipomatous tumor.

Hemosiderotic fibrolipomatous tumor is an extremely rare, nonencapsulated, fatty lesion with a consistent histologic appearance that was originally considered reactive in nature. To our knowledge, there are no previous reports on the cytogenetics of this lesion. Reported here is a case of hemosiderotic fibrolipomatous tumor arising within the subcutaneous tissue of the right foot, dorsal aspect, of an otherwise healthy 35-year-old woman. Subsequent cytogenetic analysis revealed a clonal reciprocal translocation between chromosomes 1 and 10, with a further rearrangement involving this derivative chromosome 1 and chromosome 3. This, in addition to its characteristic morphology and immunophenotype, supports the neoplastic nature of this tumor and may aid in its diagnosis.

Chondromyxoid fibroma of the nasal cavity with an interstitial insertion between chromosomes 6 and 19.

Chondromyxoid fibroma is an uncommon benign cartilaginous tumor that rarely presents in the sino-nasal region as a locally destructive, erosive lesion. Both clinically and histologically, it is a difficult diagnosis and can be confused with malignant processes such as myxoid chondrosarcoma. Histology of the tumor, especially with a small sample, can be challenging because of its heterogeneous nature showing an admixture of fibrous, myxoid, and chondroid areas. We are reporting unique cytogenetic findings in a case of chondromyxoid fibroma involving the floor of the nasal cavity with a clonal rearrangement between chromosomes 6 and 19. To our knowledge, karyotypes of 14 cases are reported in literature, with 11 cases reporting nonrandom, clonal abnormalities of chromosome 6. These results illustrate the distinctive nature of this tumor and may help identify genes involved in the pathogenesis of this tumor.

Myxoinflammatory fibroblastic sarcoma with complex supernumerary ring chromosomes composed of chromosome 3 segments.

Myxoinflammatory fibroblastic sarcoma is a rare, recently described, and distinctive low-grade tumor of soft tissue. To our knowledge, there is only one previous report on the cytogenetics of this tumor. That case showed complex structural abnormalities, including a reciprocal translocation between chromosomes 1 and 10 [t(1;10)(p22;q24)] with loss of chromosomes 3 and 13. We describe here a second case showing supernumerary ring chromosomes, and a derivative chromosome 13, with additional material on the short arm. We conclude that the presence of chromosomal abnormalities supports the neoplastic nature of this tumor and aids in its diagnosis. Furthermore, we also postulate that the finding of ring chromosomes, which have been identified in other low-grade soft-tissue tumors, may have important prognostic implications regarding the aggressiveness of this neoplasm.

Cytogenetic analysis of a primary bone angiosarcoma.

Primary bone angiosarcomas are rare and aggressive vascular malignancies with a high mortality rate. To our knowledge, there are no reported cytogenetic abnormalities in primary bone angiosarcomas, although several have been reported in soft tissue angiosarcomas. We report a case of primary bone angiosarcoma, arising in the tibia of a 79-year-old woman, with a unique clonal chromosomal rearrangement: t(1;14)(p21;q24), that has not been reported in either soft tissue or primary bone angiosarcoma. The biologic significance of this translocation is not clear; however, the 1p21 locus is in the region of colony stimulating factor (CSF-1), which may play a role in tumorigenesis, as has been described in pigmented villonodular synovitis and tenosynovial giant cell tumor.

Specific extra chromosomes occur in a modal number dependent pattern in pediatric acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (>50 chromosomes) are considered to have a relatively good prognosis. The specific extra chromosomes are not random; extra copies of some chromosomes occur more frequently than those of others. We examined the extra chromosomes present in high hyperdiploid ALL to determine if there were a relation of the specific extra chromosomes and modal number (MN) and if the extra chromosomes present could differentiate high hyperdiploid from near-triploid and near-tetraploid cases. Karyotypes of 2,339 children with ALL and high hyperdiploidy at diagnosis showed a distinct nonrandom sequential pattern of gain for each chromosome as MN increased, with four groups of gain: chromosomes 21, X, 14, 6, 18, 4, 17, and 10 at MN 51-54; chromosomes 8, 5, 11, and 12 at MN 57-60; chromosomes 2, 3, 9,16, and 22 at MN 63-67; chromosomes 1, 7 13, 15, 19, and 20 at MN 68-79, and Y only at MN >or=80. Chromosomes gained at lower MN were retained as the MN increased. High hyperdiploid pediatric ALL results from a single abnormal mitotic division. Our results suggest that the abnormal mitosis involves specific chromosomes dependent on the number of chromosomes aberrantly distributed, raising provocative questions regarding the mitotic mechanism. The patterns of frequencies of tetrasomy of specific chromosomes differs from that of trisomies with the exception of chromosome 21, which is tetrasomic in a high frequency of cases at all MN. These results are consistent with different origins of high hyperdiploidy, near-trisomy, and near-tetrasomy.

Sexual maldevelopment and sex reversal, chromosomal causes.

The SRY gene on the Y chromosome is the testis determining factor (TDF). It is therefore the initial male determining factor. However, phenotypic sex determination includes a cascade of genes located on autosomes as well as sex chromosomes. Aberrations of these genes may cause sexual maldevelopment or sex reversal. Abnormalities may include single gene mutations and gene loss or gain-changes may involve only sex organs or may be part of syndromes. These changes may also arise as chromosome abnormalities involving contiguous genes. Eight cases with chromosomal abnormalities involving different causative mechanisms are described herein. The most common cause is nondisjunction, including loss or gain of sex chromosomes. Less common causes are mispairing and crossing over in meiosis, chromosome breaks with repair, nonhomologous pairing due to low copy repeats and crossing over, and translocation (familial or de novo) with segregation. Cases include: [see: text].

RAI1 point mutations, CAG repeat variation, and SNP analysis in non-deletion Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation disorder characterized by distinct craniofacial features and neurobehavioral abnormalities usually associated with an interstitial deletion in 17p11.2. Heterozygous point mutations in the retinoic acid induced 1 gene (RAI1) have been reported in nine SMS patients without a deletion detectable by fluorescent in situ hybridization (FISH), implicating RAI1 haploinsufficiency as the cause of the major clinical features in SMS. All of the reported point mutations are unique and de novo. RAI1 contains a polymorphic CAG repeat and encodes a plant homeo domain (PHD) zinc finger-containing transcriptional regulator. We report a novel RAI1 frameshift mutation, c.3103delC, in a non-deletion patient with many SMS features. The deletion of a single cytosine occurs in a heptameric C-tract (CCCCCCC), the longest mononucleotide repeat in the RAI1 coding region. Interestingly, we had previously reported a frameshift mutation, c.3103insC, in the same mononucleotide repeat. Furthermore, all five single base frameshift mutations preferentially occurred in polyC but not polyG tracts. We also investigated the distribution of the polymorphic CAG repeats in both the normal population and the SMS patients as one potential molecular mechanism for variability of clinical expression. In this limited data set, there was no significant association between the length of CAG repeats and the SMS phenotype. However, we identified a 5-year-old girl with an apparent SMS phenotype who was a compound heterozygote for an RAI1 missense mutation inherited from her father and a polyglutamine repeat of 18 copies, representing the largest known CAG repeat in this gene, inherited from her mother.

Angelman syndrome 2005: updated consensus for diagnostic criteria.

In 1995, a consensus statement was published for the purpose of summarizing the salient clinical features of Angelman syndrome (AS) to assist the clinician in making a timely and accurate diagnosis. Considering the scientific advances made in the last 10 years, it is necessary now to review the validity of the original consensus criteria. As in the original consensus project, the methodology used for this review was to convene a group of scientists and clinicians, with experience in AS, to develop a concise consensus statement, supported by scientific publications where appropriate. It is hoped that this revised consensus document will facilitate further clinical study of individuals with proven AS, and assist in the evaluation of those who appear to have clinical features of AS but have normal laboratory diagnostic testing.

Overview of Smith-Magenis syndrome.

Increased awareness of the phenotype associated with SMS permits early diagnosis and optimal management and intervention. From a management standpoint, the unique constellation of behavioral dysfunction and sleep disturbances has a significant impact on the parents, siblings and relatives of individuals with SMS as well as the professionals involved in their care. Support groups for families of persons with SMS like PRISMS in the US [http://www.prisms.org], provide families with up-to-date information, as well as emotional and peer support, enabling them to better care for their child.

Y chromosome heterochromatin of differing lengths in two cell populations of the same individual.

OBJECTIVE: To present a prenatal diagnosis report on a case where G-banding analysis of fetal metaphase chromosomes showed populations of cells with two different Y chromosomes; one with a short block of heterochromatin (Yqh-) and one with a longer block of heterochromatin (Yqh+). METHODS: These two populations of the Y chromosome were studied using fluorescent quinacrine banding and fluorescent in situ hybridization (FISH). A chromosome paint corresponding to the euchromatic region of the Y chromosome, and probes corresponding to the SRY, DYZ1, and DYZ3 regions were used for this study. RESULTS: Both Y chromosomes appeared to be structurally normal by these analyses. Subsequent ultrasound examination at 20 weeks' gestation revealed normal male genitalia. Follow-up with a neonatal blood sample analysis confirmed the above findings. CONCLUSIONS: This study reports a direct prenatal diagnosis case of two populations of the Y chromosome in the same individual. This apparent mosaicism may be explained by a postzygotic simple deletion or unequal crossover event between sister chromatids in the DYZ region.

Meiotic exchange event within the stalk region of an inverted chromosome 22 results in a recombinant chromosome with duplication of the distal long arm.

Meiotic recombination occurs between homologous euchromatic regions of human chromosomes in early meiosis. However, such exchanges have been thought not to occur in the stalk regions of acrocentric chromosomes. We describe a child whose chromosome analysis suggests that crossovers do occur in homologous stalk regions. The proband, initially seen as a term female infant, was born to a 28-year-old mother. Dysmorphic features included wide metopic sutures, low anterior hairline, hypertelorism, external ear malformations, and cleft lip and palate. Blood chromosomes of the proband and parents were studied by G-banding, Q-banding, R-banding, and silver staining. The infant karyotype showed a sub-metacentric chromosome 22; that of the mother showed a pericentric inversion of chromosome 22. Chromosomes of the father were normal. In the infant, the abnormal chromosome 22 long arm appeared normal, but with additional long arm material attached to the distal short arm. In the mother, the distal long arm of the abnormal chromosome 22 was translocated to the distal short arm. The abnormal chromosome stalk in the child was intermediate in size to the stalk size of the abnormal and normal chromosomes 22 in the mother. Fluorescent in situ hybridization (FISH) analysis using chromosome 22 paint and ARSA gene probe confirmed that the duplicated material in the proband was of chromosome 22 origin; the karyotype interpretation is: 46,XX,rec(22)dup(22q)inv(22)(p13q13.1)mat. This abnormal karyotype is most likely due to a crossover event within the inversion loop during meiosis. The stalk length discrepancy suggests that the crossover site occurred in the stalk region.

Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months' experience.

Imatinib mesylate, an Abl kinase inhibitor, produces sustained complete hematologic responses (CHRs) in chronic myelogenous leukemia (CML) patients, but the sequence and timing of morphologic and cytogenetic changes in CML patients during prolonged imatinib mesylate treatment has not been described. In this report, we document sequential hematologic and bone marrow findings in 19 interferon-refractory/interferon-intolerant chronic phase CML patients on imatinib mesylate for at least 14 months. Patients treated at an effective oral dose (300 to 600 mg per day) were followed with peripheral blood (PB) counts, marrow examination, and cytogenetic studies at 0, 2, 5, 8, 11, and 14 months. By 2 months, 17 of 19 patients achieved CHR; 1 reached CHR by 5 months, and 1 at 11 months. Five of 19 patients developed cytopenias requiring treatment interruption and/or dose reduction, but all were able to continue in CHR on study. In contrast to interferon-alfa treatment, imatinib mesylate-treated CML patients achieved not only CHR but complete morphologic marrow response. Normalization of marrow lagged behind PB response; however, by 8 months, all marrows showed normal or reduced cellularity without morphologic evidence of CML. Eighteen of 19 patients continued in CHR and morphologic marrow remission at 14 months; 1 patient relapsed with chronic phase CML. Although hematologic and marrow responses were uniform, cytogenetic responses were variable. Complete cytogenetic responses occurred in 6 patients, with 4 also in remission by fluorescent in situ hybridization and/or reverse-transcription-polymerase chain reaction. Six of 19 had partial and 7 of 19 no cytogenetic response. Several patients acquired additional clonal cytogenetic abnormalities during therapy, a finding with significant implications for prognosis and laboratory monitoring in imatinib mesylate-treated CML patients.