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K Hirschhorn

Publications and source records attributed to K Hirschhorn.

At least 37 records · Page 2Linked to original sources
PubMed1992

Proposed guidelines for diagnosis of chromosome mosaicism in amniocytes based on data derived from chromosome mosaicism and pseudomosaicism studies.

Currently, accepted protocol which has been developed at the Prenatal Diagnosis Laboratory of New York City (PDL) requires that when a chromosome abnormality is found in one or more cells in one flask, another 20-40 cells must be examined from one or two additional flasks. Chromosome mosaicism is diagnosed only when an identical abnormality is detected in cells from two or more flasks. In a recent PDL series of 12,000 cases studied according to this protocol, we diagnosed 801 cases (6.68 per cent) of single-cell pseudomosaicism (SCPM), 126 cases (1.05 per cent) of multiple-cell pseudomosaicism (MCPM), and 24 cases (0.2 per cent) of true mosaicism. Pseudomosaicism (PM) involving a structural abnormality was a frequent finding (2/3 of SCPM and 3/5 of MCPM), with an unbalanced structural abnormality in 55 per cent of SCPM and 24 per cent of MCPM. We also reviewed all true mosaic cases (a total of 50) diagnosed in the first 22,000 PDL cases. Of these 50 cases, 23 were sex chromosome mosaics and 27 had autosomal mosaicism; 48 cases had numerical abnormalities and two had structural abnormalities. Twenty-five cases of mosaicism were diagnosed in the first 20 cells from two flasks, i.e., without additional work-up, whereas the other 25 cases required extensive work-up to establish a diagnosis (12 needed additional cell counts from the initial two culture flasks; 13 required harvesting a third flask for cell analysis). Our data plus review of other available data led us to conclude that rigorous efforts to diagnose true mosaicism have little impact in many instances, and therefore are not cost-effective. On the basis of all available data, a work-up for potential mosaicism involving a sex chromosome aneuploidy or structural abnormality should have less priority than a work-up for a common viable autosomal trisomy. We recommend revised guidelines for dealing with (1) a numerical versus a structural abnormality and (2) an autosomal versus a sex chromosome numerical aneuploidy. Emphasis should be placed on autosomes known to be associated with phenotypic abnormalities. These new guidelines, which cover both flask and in situ methods, should result in more effective prenatal cytogenetic diagnosis and reduced patient anxiety.

Amniocentesis↗
PubMed1991

Triple autosomal trisomy in a pregnancy at risk for Bloom's syndrome.

Cytogenetic analysis of the products of conception in a pregnancy at risk for Bloom's syndrome (BS) documented the karyotype 49,XX, +2, +8, +11. Autosomal triple trisomy has previously been reported in abortuses but is exceedingly rare. Other interesting but previously unreported observations made during the present study were the following: BS in a Brazilian individual, the first instance of BS diagnosed in South America; transmission of the BS mutation in Jews that are non-Ashkenazi; a medulloblastoma in the propositus, the first malignant brain tumor reported in BS; and, as in all previously examined pregnancies at risk for BS, non-homozygosity for the BS mutation.

Abortion, Spontaneous↗
PubMed1991

Identification of a missense mutation in an adult-onset patient with glycogenosis type II expressing only one allele.

The lysosomal enzyme acid alpha glucosidase (GAA) or acid maltase is deficient in glycogen storage disease type II. We sought to determine the molecular basis for the disease in an adult-onset patient, unusual for very low enzyme activity similar to that seen with the infantile-onset form and with a previously reported defect in phosphorylation. We constructed cDNA and genomic DNA libraries from the patient's cell line (GM 1935) and determined the nucleotide sequence of the coding region. There were three base-pair substitutions in one allele (C1935 to A; G2446 to A and C2780 to T), all predicting amino acid changes (Asp-645 to Glu; Val-816 to Ile and Thr-927 to Ile). To determine which of the three base-pair substitutions resulted in loss of enzyme activity, we next utilized primer-directed mutagenesis and transient gene expression in an SV40-immortalized GAA-deficient fibroblast cell line. Only the construct containing the G2446 to A mutation (Val-816 to Ile) lost GAA enzyme activity, while the other two substitutions (including the Thr-927 to Ile change that predicts a loss of a potential site for N-linked glycosylation and mannose phosphorylation) each resulted in enzyme activity equal to the control. Analysis of RFLPs in genomic DNA, as well as sequence analysis for the three base-pair alterations, indicated that the patient was a genetic compound. We next digested PCR-amplified cDNA (reverse-transcribed from RNA) with Aat II to detect the base-pair 1935 substitution and found that virtually all of the mRNA was derived from the allele with the three base-pair substitutions.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1990

Mesomelic dysplasia with absence of fibulae and hexadactyly: Nievergelt syndrome or new syndrome?

Mesomelic dysplasia is a form of short-limb dwarfism characterized by disproportionate shortness of the middle segment of all limbs. Included in this category of skeletal disorders is the Nievergelt syndrome, which typically manifests a rhomboidal shape of the tibiae and fibulae, an unusual foot deformity, radioulnar synostosis, and dysplasia of the elbow and knee joints. We describe a patient with mesomelic dysplasia with findings suggestive of the Nievergelt syndrome and with absence of fibulae and hexadactyly.

Abnormalities, Multiple↗
PubMed1990

Trisomy 12 mosaicism detected by mid-trimester amniocentesis.

Trisomy 12 mosaicism was found in about 15 per cent of cultured amniocytes obtained from a 32-year-old white female at 17.6 weeks of gestation. Termination of pregnancy was elected and multiple tissues were obtained for chromosome analysis. Of 158 cells examined, only 1 cell in placenta was found with an extra number 12 chromosome. Pathological examination of the fetus did not reveal significant physical abnormalities. This report illustrates the difficulty of confirming trisomy 12 mosaicism which has been detected on prenatal diagnosis. The presence of trisomy 12 in one placental cell obtained from the curettage specimen suggests the possibility of confined placental mosaicism in this case.

Adult↗
PubMed1989

Duplication of 16q and deletion of 15q.

A patient with distal arthrogryposis, congenital dislocations of the hips, a prominent forehead, epicanthal folds, thin lips, and a poorly defined philtrum was found to have a deletion of 15q and a duplication of 16q. Her mother, maternal grandmother, and great grandmother had a balanced t(15q-, 16q+). The gene for adenine phosphoribosyl transferase was assignable to the 16q22----16qter area that was duplicated.

Adenine Phosphoribosyltransferase↗
PubMed1985

Further regional localization of the genes for human acid alpha glucosidase (GAA), peptidase D (PEPD), and alpha mannosidase B (MANB) by somatic cell hybridization.

We have further regionally localized the gene for human acid alpha glucosidase (GAA) to 17q21----q23 by examination of hybrid clones derived from a fusion between human fibroblasts carrying a 17/19 balanced translocation (17pter----17q23::19p13.3----19pter; 19qter----p13.3::17q23----17qter) and a mouse line deficient in thymidine kinase. These hybrids were constantly maintained in HAT selective media in order to select for the presence of the human thymidine kinase gene on the intact chromosome 17 (17q21-q22) or the 17/19 (17pter----17q23::19p13.3----19pter) translocation chromosome. We detected human GAA by rocket immunoelectrophoresis, using a human specific heterologous antibody raised against human acid alpha glucosidase (GAA) (Honig et al. 1984). Three secondary clones, which contained the 17/19 translocation and no intact chromosome 17 or 19, were still positive for GAA. Two of these secondary clones contained the distal portion of the 17/19 translocation chromosome, with a break in the band 17q21 (probably at 17q21.2), attached to a mouse chromosome. Combined with earlier results (Weil et al. 1979; Nickel et al. 1982; Honig et al. 1984), the gene for GAA can be assigned to 17q21.2----17q23. Additionally, these clones were negative for human peptidase D (PEPD), alpha mannosidase B (MANB), and phosphohexose isomerase (PHI). Combined with previous results (Ingram et al. 1977; Bruns et al. 1979), these results exclude the genes for PEPD and MANB from 19pter----19p13.3 and confirm the exclusion of the gene for PHI from this segment of chromosome 19 (Wilson et al. 1984; Ingram et al. 1977).

Animals↗
PubMed1984

Confirmation of the regional localization of the genes for human acid alpha-glucosidase (GAA) and adenosine deaminase (ADA) by somatic cell hybridization.

We have confirmed the localization of human acid alpha-glucosidase (GAA) to 17q21----q25 and of adenosine deaminase (ADA) to 20q13----20qter by examination of hybrid clones derived from a fusion between a human cell line carrying a 17/20 balanced translocation (17pter----17q25::20q13----20qter;20pter-- --20q13::17q25----17qter) and a mouse line deficient in thymidine kinase. These hybrids were constantly maintained in HAT selective media in order to select for the presence of the human thymidine kinase gene on the intact chromosome 17 (17q21----22) or the 17/20 (17pter----17q25::20q13----20qter) translocation chromosome. We detected human GAA by rocket immunoelectrophoresis, using a heterologous antibody raised against human acid alpha-glucosidase. A clone which contained the 17/20 translocation and no intact chromosome 17 was still positive for GAA. This finding confirms the exclusion of GAA from 17q25----17qter reported by Nickel et al. (1982). Combined with earlier results (Weil et al. 1979), GAA can be assigned to 17q21----17q25. A clone which contained only the 17/20 translocation chromosome and no intact chromosome 20 contained ADA. This confirms the previous localization of ADA to 20q13.2----qter by gene dosage studies (Philip et al. 1980).

Adenosine Deaminase↗
PubMed1983

Acquired partial deletions of the long arm of chromosome 5 in hematologic disorders.

We have analyzed the data on 105 patients reported with a deletion of part of the long arm of chromosome 5 in the presence of hematologic disease. The major conditions associated with this abnormality are refractory anemia, polycythemia vera, and acute myelogenous leukemia, as well as the occasional occurrence of several other problems.

Anemia, Aplastic↗