H Hoehn

University of Wuerzburg, Würzburg, Bavaria, Germany

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Publications (156)760.97 Total impact

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    ABSTRACT: Fanconi anemia (FA) is an inherited bone marrow failure syndrome due to defective DNA inter-strand cross-link repair. Hematopoietic stem cell transplantation (HSCT) is curative for pancytopenia, but may not prevent the development of non-hematological malignancies. We describe a 26-year-old male patient with FA and Marfan syndrome who in 1994 underwent successful HSCT with bone marrow stem cells from his human leukocyte antigen (HLA)-identical sister. In 2006, three lesions in the liver were detected and resected. The three lesions all showed activation of the β-catenin pathway and were histologically characterized by a highly differentiated steatotic hepatocellular carcinoma (HCC) with remnants of the underlying adenoma from which it arose, a hepatocellular adenoma with foci of well-differentiated HCC, and a cholestatic adenoma. Risk factors for the emergence of HCC included FA itself, the use of androgens for a period of 3 years preceding HSCT and toxicity of the conditioning regimen. Because of the danger of developing additional HCC, liver transplantation was proposed, taking into consideration that immunosuppression would increase the risk of other malignancies. By using part of the liver of the sister, who already acted as bone marrow donor 13 years earlier, immunosuppression could be avoided. Liver transplantation was performed in 2007 without complication. Five years after liver transplantation the patient is doing well. This case is twofold special being the first case reporting FA co-occurring with Marfan syndrome and being the first reported case of FA treated for HCC by liver transplantation from a HLA-identical sibling donor without the use of immunosuppression.
    Hepatology Research 05/2013; 43(9). DOI:10.1111/hepr.12043 · 2.74 Impact Factor
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    ABSTRACT: Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.
    Human Genetics 07/2010; 128(1):103-11. DOI:10.1007/s00439-010-0832-5 · 4.82 Impact Factor
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    ABSTRACT: Although still incomplete, we now have a remarkably detailed and nuanced picture of both phenotypic and genotypic components of the FA spectrum. Initially described as a combination of pancytopenia with a limited number of physical anomalies, it was later recognized that additional features were compatible with the FA phenotype, including a form without detectable malformations (Estren-Dameshek variant). The discovery of somatic mosaicism extended the boundaries of the FA phenotype to cases even without any overt hematological manifestations. This clinical heterogeneity was augmented by new conceptualizations. There was the realization of a constant risk for the development of myelodysplasia and certain malignancies, including acute myelogenous leukemia and squamous cell carcinoma, and there was the emergence of a distinctive cellular phenotype. A striking degree of genetic heterogeneity became apparent with the delineation of at least 12 complementation groups and the identification of their underlying genes. Although functional genetic insights have fostered the interpretation of many phenotypic features, surprisingly few stringent genotype-phenotype connections have emerged. In addition to myriad genetic alterations, less predictable influences are likely to modulate the FA phenotype, including modifier genes, environmental factors and chance effects. In reviewing the current status of genotype-phenotype correlations, we arrive at a unifying hypothesis to explain the remarkably wide range of FA phenotypes. Given the large body of evidence that genomic instability is a major underlying mechanism of accelerated ageing phenotypes, we propose that the numerous FA variants can be viewed as differential modulations and compression in time of intrinsic biological ageing.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 06/2009; 668(1-2):73-91. DOI:10.1016/j.mrfmmm.2009.05.006 · 3.68 Impact Factor

  • Cellular oncology: the official journal of the International Society for Cellular Oncology 02/2008; 30(6):507. DOI:10.3233/CLO-2008-0452 · 4.17 Impact Factor

  • Cellular oncology: the official journal of the International Society for Cellular Oncology 02/2008; 30(5):461-2. DOI:10.3233/CLO-2008-0449 · 4.17 Impact Factor
  • H. Höhn ·

    Medizinische Genetik 12/2007; 19(4):463-464. DOI:10.1007/s11825-007-0064-9 · 0.13 Impact Factor
  • K Neveling · A Bechtold · H Hoehn ·
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    ABSTRACT: We discuss examples of the rare human genetic instability syndromes as they present themselves at the chromosome, telomere, and nuclear envelope level. Destabilization of the nuclear envelope due to mutations in the Lamin A/C gene lead to global impairments of the chromatin structure and gene expression with the fatal consequences observed in the Hutchinson-Gilford juvenile progeria syndrome. Patients with Dyskeratosis congenita have defective telomerase function. These patients exhibit a number of progeroid features, suggesting a causal connection between short telomeres and premature ageing. The most prominent example of the chromosomal instability syndromes is the Werner adult progeria syndrome where impaired helicase and exonuclease functions cause a multitude of (albeit superficial) similarities with the normal ageing process. A less well-know example is Fanconi anemia (FA) a multisystem disorder caused by biallelic mutations in one of at least 13 different genes which include the BRCA2 breast cancer gene. Unlike cells from any other human disorder, FA cells are uniquely sensitive to oxidative stress. In a situation of defective DNA repair, oxidative stress leads to accumulation of (unrepaired) DNA damage. Oxidative stress is the likely culprit of bone marrow failure, risk of neoplasia, and features of premature ageing in FA, rendering this rare disease into the only known human model of the free radical theory of ageing.
    Zeitschrift für Gerontologie + Geriatrie 11/2007; 40(5):339-48. DOI:10.1007/s00391-007-0483-x · 0.81 Impact Factor
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    ABSTRACT: FANCD2 is an evolutionarily conserved Fanconi anemia (FA) gene that plays a key role in DNA double-strand-type damage responses. Using complementation assays and immunoblotting, a consortium of American and European groups assigned 29 patients with FA from 23 families and 4 additional unrelated patients to complementation group FA-D2. This amounts to 3%-6% of FA-affected patients registered in various data sets. Malformations are frequent in FA-D2 patients, and hematological manifestations appear earlier and progress more rapidly when compared with all other patients combined (FA-non-D2) in the International Fanconi Anemia Registry. FANCD2 is flanked by two pseudogenes. Mutation analysis revealed the expected total of 66 mutated alleles, 34 of which result in aberrant splicing patterns. Many mutations are recurrent and have ethnic associations and shared allelic haplotypes. There were no biallelic null mutations; residual FANCD2 protein of both isotypes was observed in all available patient cell lines. These analyses suggest that, unlike the knockout mouse model, total absence of FANCD2 does not exist in FA-D2 patients, because of constraints on viable combinations of FANCD2 mutations. Although hypomorphic mutations arie involved, clinically, these patients have a relatively severe form of FA.
    The American Journal of Human Genetics 06/2007; 80(5):895-910. DOI:10.1086/517616 · 10.93 Impact Factor
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    ABSTRACT: Chromosome breakage analysis following exposure of cultured cells to DNAcrosslinking agents has long been considered the ’gold standard’ for the confirmation or exclusion of Fanconi anemia (FA). Cells containing DNA damage are arrested and accumulate, with a 4c DNA content, near the S/G2-phase border of the cell cycle. As manifestation of their impaired DNA damage response, FA cells typically express elevated G2-phase cell fractions which can easily be measured by flow cytometry. In our experience with more than 3,000 such analyses, at most 1 in 10 blood samples submitted for the exclusion or confirmation of FA yields a positive result. Compared to traditional chromosome breakage analysis, cell cycle testing is less demanding and offers the advantage of speed and low cost. We prefer flow cytometric cell cycle testing for the initial screening of patients, in whom unexplained thrombocytopenia, macrocytic aplastic anemia or other clinical findings require the exclusion of FA. In addition to its application in diagnostic screening, we here show that cell cycle analysis has become a valuable tool for the determination of clastogen sensitivity (such as required within the context of complementation studies), for the precise definition of cell cycle checkpoints, and for the quantitative determination of compartment-specific cell cycle delay or cell cycle arrest. Cell cycle analysis not only provides a reliable test system for the initial confirmation or exclusion of FA, but also serves as a highly informative tool for the comprehensive characterization of the FA cellular phenotype.
    Monographs in human genetics 05/2007; 15. DOI:10.1159/000102552
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    ABSTRACT: One out of four to five patients with Fanconi anemia experience a reversion or attenuation of their constitutional mutations during their lifetime. If the reversion event takes place in a bone marrow stem cell or in an early precursor cell of hematopoiesis, peripheral blood cell counts may gradually recover, leading to improved quality of life. At the beginning of this process, MMC testing will reveal a mixture of MMC sensitive and MMC resistant blood lymphocytes, but after several years MMC sensitive cells (the original FA-cells) may be completely replaced by the progeny of the reverted progenitor cell such that the confirmation of FA requires testing of patient fibroblasts. Molecular analysis reveals the presence of the disease causing biallelic mutations in fibroblast-derived DNA whereas MMC-resistant blood cells show only a single defective allele, explaining their phenotypic reversion. The mechanisms leading to revertant mosaicism include intragenic mitotic recombination (crossing over and gene conversion), back mutation, and compensatory second site mutations. Evidence for each of these mechanisms has been obtained in mosaic FA-patients, but their molecular details are not fully understood. Compound heterozygosity facilitates some of these mechanisms, but reversions have also been observed in homozygous patients. Patients belonging to subtypes FA-A, FA-C, FA-D1, FA-D2 and FA-L have developed revertant mosaicism, with subtypes FA-A and FA-D2 being most frequently involved. Even though the phenomenon of revertant mosaicism has been well documented in FA, there still are many questions: we do not know whether the progeny of a single reverted blood stem or progenitor cell would be able to sustain lifelong hematopoiesis, whether revertant mosaicism provides protection against hematopoietic malignancy, or whether it would be possible to deliberately increase the rate of somatic reversions in order to improve chances for ’natural gene therapy’. Prospective and long-term follow-up studies are needed to answer these questions.
    Monographs in human genetics 05/2007; 15. DOI:10.1159/000102554
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    ABSTRACT: DNA Ligase IV deficiency syndrome is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV gene (LIG4). The clinical phenotype shows overlap with a number of other rare syndromes, including Seckel syndrome, Nijmegen breakage syndrome, and Fanconi anemia. Thus the clinical diagnosis is often delayed and established by exclusion. We describe a patient with pre- and postnatal growth retardation and dysmorphic facial features in whom the diagnoses of Seckel-, Dubowitz-, and Nijmegen breakage syndrome were variably considered. Cellular radiosensitivity in the absence of clinical manifestations of Ataxia telangiectasia lead to the diagnosis of DNA ligase IV (LIG4) deficiency syndrome, confirmed by compound heterozygous mutations in the LIG4 gene. At age 11, after a six year history of progressive bone marrow failure and increasing transfusion dependency the patient was treated with matched sibling donor hematopoietic stem cell transplantation (HSCT) using a fludarabine-based conditioning regimen without irradiation. The post-transplantation course was uneventful with rapid engraftment leading to complete and stable chimerism. Now at age 16, the patient has gained weight and is in good clinical condition. HSCT using mild conditioning without irradiation qualifies as treatment of choice in LIG4-deficient patients who have a matched sibling donor.
    Orphanet Journal of Rare Diseases 02/2007; 2(1):5. DOI:10.1186/1750-1172-2-5 · 3.36 Impact Factor
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    ABSTRACT: Bladder carcinomas frequently show extensive deletions of chromosomes 9p and/or 9q, potentially including the loci of the Fanconi anemia (FA) genes FANCC and FANCG. FA is a rare recessive disease due to defects in anyone of 13 FANC genes manifesting with genetic instability and increased risk of neoplasia. FA cells are hypersensitive towards DNA crosslinking agents such as mitomycin C and cisplatin that are commonly employed in the chemotherapy of bladder cancers. These observations suggest the possibility of disruption of the FA/BRCA DNA repair pathway in bladder tumors. However, mutations in FANCC or FANCG could not be detected in any of 23 bladder carcinoma cell lines and ten surgical tumor specimens by LOH analysis or by FANCD2 immunoblotting assessing proficiency of the pathway. Only a single cell line, BFTC909, proved defective for FANCD2 monoubiquitination and was highly sensitive towards mitomycin C. This increased sensitivity was restored specifically by transfer of the FANCF gene. Sequencing of FANCF in BFTC909 failed to identify mutations, but methylation of cytosine residues in the FANCF promoter region was demonstrated by methylation-specific PCR, HpaII restriction and bisulfite DNA sequencing. Methylation-specific PCR uncovered only a single instance of FANCF promoter hypermethylation in surgical specimens of further 41 bladder carcinomas. These low proportions suggest that in contrast to other types of tumors silencing of FANCF is a rare event in bladder cancer and that an intact FA/BRCA pathway might be advantageous for tumor progression.
    Cytogenetic and Genome Research 02/2007; 118(2-4):166-76. DOI:10.1159/000108297 · 1.56 Impact Factor
  • K. Neveling · A. Bechtold · H. Hoehn ·

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    M. Digweed · H. Hoehn · K. Sperling ·
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    ABSTRACT: The recessive disease Fanconi anemia (FA) is a prototype chromosome instability syndrome which shows a high level of spontaneous and induced chromosomal aberrations in combination with a significantly increased cancer risk. Thus, the underlying defect must be directly or indirectly involved in a fundamental cellular task of long-lived mammalian cells, the maintenance of genomic integrity. In addition to the delineation of the FA clinical and cellular phenotypes, prominent milestones in FA research include proof of extensive genetic heterogeneity, identification of (so far) 12 disease genes, and elucidation of the FA pathway involved in the repair of crosslinks at arrested replication forks. What is referred to as the FA/BRCA pathway represents only part of a complex network of protein-protein interactions which is far from being understood. The ultimate milestone in FA research would be the achievement of an individualized and curative therapy. Currently, hematopoietic stem cell transplantation is a promising but still high-risk therapy, and gene therapy is still at the experimental stage. Nonetheless, in a significant proportion of patients, a kind of ’natural gene therapy’ can be observed which results from intragenic recombination or from compensating second site mutations. The elucidation of these somatic events and their underlying mechanisms can be considered a milestone in genetic research. The remarkable progress in FA research during the last 10-15 years was fostered by the foundation of FA patient support groups in many countries. These support groups are gratefully acknowledged as important motivational milestones in FA research.
    Monographs in human genetics 01/2007; 15. DOI:10.1159/000102546
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    ABSTRACT: The International Registry of Werner syndrome (www.wernersyndrome.org) has been providing molecular diagnosis of the Werner syndrome (WS) for the past decade. The present communication summarizes, from among 99 WS subjects, the spectrum of 50 distinct mutations discovered by our group and by others since the WRN gene (also called RECQL2 or REQ3) was first cloned in 1996; 25 of these have not previously been published. All WRN mutations reported thus far have resulted in the elimination of the nuclear localization signal at the C-terminus of the protein, precluding functional interactions in the nucleus; thus, all could be classified as null mutations. We now report two new mutations in the N-terminus that result in instability of the WRN protein. Clinical data confirm that the most penetrant phenotype is bilateral ocular cataracts. Other cardinal signs were seen in more than 95% of the cases. The median age of death, previously reported to be in the range of 46-48 years, is 54 years. Lymphoblastoid cell lines (LCLs) have been cryopreserved from the majority of our index cases, including material from nuclear pedigrees. These, as well as inducible and complemented hTERT (catalytic subunit of human telomerase) immortalized skin fibroblast cell lines are available to qualified investigators.
    Human Mutation 07/2006; 27(6):558-67. DOI:10.1002/humu.20337 · 5.14 Impact Factor
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    ABSTRACT: Nijmegen breakage syndrome (NBS) patients and carriers are predisposed to malignancy and are often treated with X-irradiation. In the present study, the single-cell gel electrophoresis (Comet) assay was used to examine radiation-induced DNA damage and repair in peripheral blood mononuclear cells from NBS patients (n=13) and carriers (n=36) of six unrelated families. Cells from apparently healthy donors (n=10) and from breast cancer patients with normal clinical radiosensitivity (n=10) served as controls. Cells were irradiated with 5 Gy of X-rays and assayed for initial DNA damage and for residual DNA damage after 40 min of repair; the kinetics of DNA repair also was estimated. In addition, the nuclear area of unirradiated cells was extracted from the Comet data. The initial radiation-induced DNA fragmentation indicated that cells from members of two out of six NBS families were significantly more sensitive to X-irradiation than cells from the controls. Cells from four NBS families had longer DNA repair half-time values, while cells from five NBS families had significantly increased residual DNA damage following repair. The mean nuclear area of unirradiated cells processed in the Comet assay was 1.3-fold higher in cells from all NBS families than in the controls (P<0.05). Notably, the Comet assay parameters (initial and residual DNA damage and the repair kinetics) of irradiated NBS cells predicted the carrier status of the majority (86%) of blindly tested individuals. The prediction of NBS status was higher if the nuclear area of unirradiated cells was used as the endpoint. The results of this study suggest that the impaired radiation response of NBS cells should be taken into account if radiotherapy of NBS patients and carriers is required.
    Environmental and Molecular Mutagenesis 05/2006; 47(4):260-70. DOI:10.1002/em.20202 · 2.63 Impact Factor
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    ABSTRACT: Ataxia telangiectasia (AT) is an autosomal recessive multisystem disorder with increased radiosensitivity and cancer susceptibility. The responsible gene (ATM) consists of 66 exons and a coding region of 9171 bp which precludes direct sequencing as a screening assay for confirmation or exclusion of the clinical suspicion of AT. Peripheral blood mononuclear cells of 330 patients referred for the exclusion of AT were exposed to ionizing radiation (IR) and incubated for 72 h in the presence of phytohemagglutinin. Using bivariate BrdU-Hoechst/ethidium bromide flowcytometry, the following cell cycle parameters were ascertained: (1) proportion of non-proliferating (G0,G1) cells as a measure of mitogen response, (2) proportion of first-cycle G2-phase cells relative to the growth fraction (G2/GF) as a measure of radiosensitivity. Of the cases tested, 94.2% could be unequivocally assigned either to the AT-negative or the AT-positive group of patients. Of the AT-positive cases, 11 were confirmed by ATM mutation analysis. Nineteen cases presented with non-conclusive results, mostly due to poor mitogen response; however, a combination of cell-cycle data with serum AFP concentrations led to the exclusion of AT in all but two of the uncertain cases. Substitution of ionizing radiation by the radiomimetic bleomycin was additionally tested in a small series of patients. We conclude that cell-cycle testing complemented by serum AFP measurements fulfills the criteria as a rapid and economical screening procedure for the differential diagnosis of juvenile ataxias.
    European Journal of Pediatrics 05/2006; 165(4):250-7. DOI:10.1007/s00431-005-0037-4 · 1.89 Impact Factor
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    ABSTRACT: To explore the potential of flow cytometry in the prenatal exclusion or confirmation of Fanconi anemia (FA). Indications for prenatal diagnosis were (1) FA-negative family history, but suspicious ultrasound findings such as radial ray aplasia, (2) FA-positive family history, but without knowledge of the affected gene and/or mutation. Amniotic fluid (AF) cell cultures and umbilical cord (UC) blood cultures were assayed for typical cell cycle changes (G2-phase accumulations) without and with mitomycin C (MMC) treatments using single- and dual-parameter (BrdU-Hoechst) flow cytometry. Single-parameter flow cytometry correctly identified 2 positive and 9 negative cases on the basis of MMC sensitivity of cultivated AF cells. Likewise, 8 negative and 2 positive cases were correctly predicted using bivariate flow cytometry of 72-hour UC blood cultures. In contrast, bivariate flow cytometry applied to AF cells grown in the presence of bromodeoxyuridine (BrdU) yielded false-positive and false-negative results. Single-parameter flow cytometry of AF cell cultures and bivariate flow cytometry of UC cell cultures have the potential to correctly predict the affected status in cases at risk for FA, whereas bivariate flow cytometry proved unreliable when applied to BrdU-substituted AF cell cultures. Cases with a low a priori risk (e.g. sonographic finding of radial ray abnormalities and negative family history) would benefit most from flow cytometry as a rapid and economical prenatal screening procedure.
    Fetal Diagnosis and Therapy 02/2006; 21(1):118-24. DOI:10.1159/000089061 · 2.94 Impact Factor
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    R Kalb · K Neveling · I Nanda · D Schindler · H Hoehn ·
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    ABSTRACT: Fanconi anemia (FA) is a rare recessive disease that reflects the cellular and phenotypic consequences of genetic instability: growth retardation, congenital malformations, bone marrow failure, high risk of neoplasia, and premature aging. At the cellular level, manifestations of genetic instability include chromosomal breakage, cell cycle disturbance, and increased somatic mutation rates. FA cells are exquisitely sensitive towards oxygen and alkylating drugs such as mitomycin C or diepoxybutane, pointing to a function of FA genes in the defense against reactive oxygen species and other DNA damaging agents. FA is caused by biallelic mutations in at least 12 different genes which appear to function in the maintenance of genomic stability. Eight of the FA proteins form a nuclear core complex with a catalytic function involving ubiquitination of the central FANCD2 protein. The posttranslational modification of FANCD2 promotes its accumulation in nuclear foci, together with known DNA maintenance proteins such as BRCA1, BRCA2, and the RAD51 recombinase. Biallelic mutations in BRCA2 cause a severe FA-like phenotype, as do biallelic mutations in FANCD2. In fact, only leaky or hypomorphic mutations in this central group of FA genes appear to be compatible with life birth and survival. The newly discovered FANCJ (= BRIP1) and FANCM (= Hef ) genes correspond to known DNA-maintenance genes (helicase resp. helicase-associated endonuclease for fork-structured DNA). These genes provide the most convincing evidence to date of a direct involvement of FA genes in DNA repair functions associated with the resolution of DNA crosslinks and stalled replication forks. Even though genetic instability caused by mutational inactivation of the FANC genes has detrimental effects for the majority of FA patients, around 20% of patients appear to benefit from genetic instability since genetic instability also increases the chance of somatic reversion of their constitutional mutations. Intragenic crossover, gene conversion, back mutation and compensating mutations in cis have all been observed in revertant, and, consequently, mosaic FA-patients, leading to improved bone marrow function. There probably is no other experiment of nature in our species in which causes and consequences of genetic instability, including the role of reactive oxygen species, can be better documented and explored than in FA.
    Genome dynamics 02/2006; 1:218-42. DOI:10.1159/000092510
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    Cytogenetic and Genome Research 02/2005; 109(4):415-79. DOI:10.1159/000084205 · 1.56 Impact Factor

Publication Stats

4k Citations
760.97 Total Impact Points


  • 1981-2013
    • University of Wuerzburg
      • • Institute for Human Genetics
      • • Department of Biochemistry
      • • Institute for Molecular Infection Biology
      Würzburg, Bavaria, Germany
  • 2000
    • United States Department of Agriculture
      Washington, Washington, D.C., United States
  • 1990
    • Universität Hamburg
      • Institute for Occupational and Maritime Medicine
      Hamburg, Hamburg, Germany
  • 1972-1989
    • University of Washington Seattle
      • Department of Pathology
      Seattle, Washington, United States