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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
From the Pediatric Hemato-Oncology Department and the
Institute of Hematology, the Chaim Sheba Medical Center, Tel-Hashomer,
Tel-Aviv, Israel; Research Center on Pathophysiology of
Heamostasis, Catholic University of Medicine, Rome, Italy;
Department of Pediatrics, University of California, San Francisco, CA;
Department of Medicine, Castrovillari Hospital, Castrovillari,
Italy; and Institut for Immunology and Transfusion Medicine,
Ernst-Moritz- Arndt-University, Greifswald, Germany.
Families with 3 different syndromes characterized by
autosomal dominant inheritance of low platelet count and giant
platelets were studied. Fechtner syndrome is an autosomal-dominant
variant of Alport syndrome manifested by nephritis, sensorineural
hearing loss, and cataract formation in addition to
macrothrombocytopenia and polymorphonuclear inclusion bodies. Sebastian
platelet syndrome is an autosomal-dominant macrothrombocytopenia
combined with neutrophil inclusions that differ from those found in
May-Hegglin syndrome or Chediak-Higashi syndrome or the Dohle bodies
described in patients with sepsis. These inclusions are, however,
similar to those described in Fechtner syndrome. Other features of
Alport syndrome, though, including deafness, cataracts, and nephritis,
are absent in Sebastian platelet syndrome. Epstein syndrome is
characterized by macrothrombocytopenia without neutrophil inclusions,
in addition to the classical Alport manifestations Autosomal-dominant giant platelet disorders are
rare. The most prevalent diseases that belong to this entity are
May-Hegglin anomaly, Fechtner syndrome, Sebastian platelet syndrome,
and Epstein syndrome. Fechtner syndrome, first described in 1985 by
Peterson et al,1 is an autosomal-dominant variant of
Alport syndrome manifested by nephritis, sensorineural hearing loss,
cataract formation, macrothrombocytopenia, and polymorphonuclear
inclusion bodies. Two other large families were described so far with
this syndrome. The second Fechtner family was described by
Gershoni-Baruch2 in 1988. In this family, the affected
members had impaired liver function and hypercholesterolemia in
addition to the other ailments. The third Fechtner family was described
by Rocca et al3 in 1993.
In 1990, Greinacher et al4 described the Sebastian
platelet syndrome (SPS), a new variant of hereditary,
autosomal-dominant macrothrombocytopenia combined with the presence of
neutrophil inclusions that differed from those found in patients with
May-Hegglin anomaly,5 Chediak-Higashi syndrome, and Dohle
bodies found in patients with sepsis.6,7 They are similar
to those found in patients with Fechtner syndrome.1-3
However, other features of Alport syndrome, including high-frequency
deafness, congenital cataracts, and chronic interstitial nephritis, are
absent in patients with SPS.
In 1972, Epstein described 2 families with a syndrome of
macrothrombocytopenia, nephritis, and high-frequency sensorineural hearing loss inherited in an autosomal-dominant mode.8
Renal and hearing abnormalities were indistinguishable from those seen in classic Alport syndrome.
Because the disease-causing gene of the Israeli Fechtner syndrome was
recently located by us on the long arm of chromosome 229
and because the gene for the May-Hegglin anomaly (macrothrombocytopenia and inclusion bodies in the neutrophils, which differ from those found
in Fechtner syndrome) was recently located to the same
area,10,11 we used markers from that area to establish a
genetic linkage of the same interval to the Italian Fechtner, Sebastian
platelet, and Epstein syndromes.
The study included 4 families affected by Fechtner
syndrome, SPS, and Epstein syndrome. The first family (Figure
1) is the original family described by
Rocca et al3 in 1993. The second family (Figure
2) is the originally described family
with SPS syndrome,4 and the third family (Figure
3) is new. The fourth family (Figure
4) is the original family described by
Epstein in 1972.8 All the affected patients in the first
family with Fechtner syndrome had macrothrombocytopenia,
polymorphonuclear inclusion bodies, and various combinations of
nephropathy, eye abnormalities, and sensorineural hearing loss. Some
patients from this family were recruited in Italy; peripheral blood
smears were the source for DNA analysis in others.
All the affected patients in families 2 and 3 had macrothrombocytopenia
and polymorphonuclear inclusion bodies. There were no nephropathy or
eye abnormalities in the families. However, as described in the
original report, one patient has a hearing problem, possibly acquired
from work in a noisy factory. The patients were recruited in Germany.
All the affected patients in the Epstein family had
macrothrombocytopenia, nephritis, and deafness. The patients were
recruited in the United States.
The study was approved by the institutional review board, and informed
consent was obtained from all participants. Each subject underwent complete physical and ophthalmologic examinations, hearing test, complete blood count, kidney and liver function tests, and Giemsa
staining under a light microscope for the study of
polymorphonuclear inclusion bodies.
Genotyping
Linkage analysis
The markers used for linkage analysis in the study were those that were found to be linked with Fechtner syndrome on chromosome 22q11-13.9 Figure 1 shows typing results for the Italian Fechtner family, with 8 chromosome 22 markers. Recombinant events in patients II-4, III-2, III-8, IV-1, and IV-2 established D22S693 and D22S282 as the centromeric and telomeric boundaries of the interval containing the disease-causing gene, respectively. Figure 2 shows typing results for SPS family A, with 8 chromosome 22 markers. Figure 3 shows typing results for SPS family B, with 10 chromosome 22 markers. Two recombinant events in affected family members III-2 in family A and III-1 in family B, and one such recombination in a healthy member II-1 in family A, established D22S693 and D22S282 as the centromeric and telomeric boundary of the interval, respectively. Figure 4 shows typing results for the Epstein family. Two recombination events were noted in the Epstein family, one in marker D22S429 in patient III-1. This marker is centromeric to D22S693, which is the centromeric boundary of the interval according to linkage analysis of the Fechtner and SPS families and, therefore, does not refine the interval. Another recombination was noted in D22S284, which is centromeric to D22S282, found to be the telomeric boundary of the interval according to linkage analysis in both Fechtner and SPS syndromes. An arithmetic summary of the 2-point LOD scores, calculated
separately according to the typing of the 4 different families, is shown in Table 1. Four markers showed
a LOD score of more than 2.76. A maximal 2-point LOD score
(Zmax) of 3.41 was obtained with the marker D22S683 at a
maximal recombination fraction of 0.00. Thus, the disease-causing gene
maps to a 16-cM interval between markers D22S284 and D22S693.
According to established physical maps, this interval spans 3.37 Mb
(Figure 5).
Autosomal-dominant giant platelet syndromes have similar clinical characteristics and an autosomal-dominant mode of inheritance. This prompted us to look first at the markers on the interval on chromosome 22q11-13 that were recently found by us9 and others10,11 to be linked with a high LOD score to Fechtner syndrome as candidate markers for genetic linkage with these diseases. We analyzed Italian Fechtner, Sebastian platelet, and Epstein syndromes together for the same reasons. In the families described above, we demonstrated that the disease-causing gene maps to chromosome 22q11-13. Four markers on the long arm of chromosome 22 yielded a LOD score greater than 2.76. One marker conveyed a maximal LOD score of 3.41. Haplotype analysis placed the disease-causing gene in a 3.37-Mb interval between D22S284 and D22S693. The high LOD score and the clinical similarity between these syndromes support the notion that this interval indeed contains the disease-causing gene in all 3 syndromes. Our work sheds more light on the genetics of giant platelet
syndromes that are actually a part of the Alport-like syndromes. An
updated comparison between the Alport-like families
The fact that all giant platelet syndromes map to the same area and probably stem from the same genetic defect may theoretically be explained in 3 ways: the interval may contain more than one gene or it may contain contiguous genes that may be mutated or deleted in these diseases; different mutations may occur in the same gene; different modifier genes may be affected that modulate the effect of the same mutation. Among the most attractive candidate genes to be mutated in the giant
platelet syndromes is the gene encoding for glycoprotein 1b- Another possible candidate gene to be mutated in the giant platelet syndromes is a collagen type IV gene because this is a structural gene that governs the composition of the basement membrane in the glomerulus, lens capsule, and inner ear, known to be the tissues involved in Alport syndrome. However, several of the syndromes mentioned (SPS and May-Hegglin) have no clinical features in common with Alport syndrome, and the role of basement membrane in the maturing process of megakaryocytes and platelet biogenesis is not established. A gene that affects platelet biogenesis is more attractive. That this candidate gene is sometimes involved in tissue alterations may be explained, for example, by mutations that lead to deleterious accumulation of the mutated protein in renal epithelial cells, lens capsule, or inner ear and in megakaryocytes, whereas mutations leading to the absence of protein would affect platelet biogenesis only. The cloning of the gene involved in the autosomal-dominant giant platelet syndromes may deepen our understanding with regard to genetic and nongenetic diseases of the tissues involved in these syndromes. Moreover, these syndromes comprise the biologic model to study the linkage between megakaryocytopoiesis and platelet production, a still unresolved question in hematopoiesis.
This work was performed in partial fulfillment of the requirements for a PhD degree of Amos Toren, Sackler Faculty of Medicine, Tel-Aviv University.
Submitted May 12, 2000; accepted July 10, 2000.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Amos Toren, Pediatric Hemato-Oncology Department and the Institute of Hematology, The Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel; e-mail: amost{at}post.tau.ac.il.
1.
Peterson LC, Rao KV, Crosson JT, White JG.
Fechtner syndrome: a variant of Alport's syndrome with leukocyte inclusions and macrothrombocytopenia.
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1985;65:397-406 2. Gershoni-Baruch R, Baruch Y, Viener A, Lichtig C. Fechtner syndrome: clinical and genetic aspects. Am J Med Genet. 1988;31:357-367[Medline] [Order article via Infotrieve]. 3. Rocca B, Laghi F, Zini G, Maggiano N, Landolfi R. Fechtner syndrome: report of a third family and literature review. Br J Haematol. 1993;85:423-426[Medline] [Order article via Infotrieve]. 4. Greinacher A, Nieuwenhuis HK, White JC. Sebastian platelet syndrome: a new variant of hereditary macrothrombocytopenia with leukocyte inclusions. Blut. 1990;61:282-288[Medline] [Order article via Infotrieve]. 5. Hegglin R. Gleichzeitige konstitutionelle Veränderungen an Neutrophilen und Thrombozyten. Helv Med Acta. 1945;12:439-440. 6. Cawley JC, Hayhoe FG. The inclusions of the May-Hegglin anomaly and Dohle bodies of infection: an ultrastructural comparison. Br J Haematol. 1972;22:491-496[Medline] [Order article via Infotrieve]. 7. Dohle V. Leukozyteneinschlusse bei scharlach. Zentralbl Bakteriol Microbiol Hyg. 1912;61:63-68. 8. Epstein CJ, Shaud MA, Piel CF, et al. Hereditary macrothrombocytopenia, nephritis and deafness. Am J Med. 1972;52:299-310[Medline] [Order article via Infotrieve]. 9. Toren A, Amariglio N, Rozenfeld-Granot G, et al. Genetic linkage of autosomal dominant Alport syndrome with leukocyte inclusions and macrothrombocytopenia (Fechtner syndrome) to chromosome 22q11-13. Am J Hum Genet. 1999;65:1711-1717[Medline] [Order article via Infotrieve]. 10. Kunishima S, Kojima T, Tanaka T, et al. Mapping of a gene for May-Hegglin anomaly to chromosome 22q. Hum Genet. 1999;105:379-383[Medline] [Order article via Infotrieve]. 11. Martignetti J, Heath KE, Harris J, et al. The gene for May-Hegglin anomaly localizes to a <1-MB region on chromosome 22q12.3-13.1. Am J Hum Genet. 2000;66:1449-1454[Medline] [Order article via Infotrieve].
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Miller SA, Dykes DD, Plesky HF.
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© 2000 by The American Society of Hematology.
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  V. Rodriguez, W. L. Nichols, J. E. Charlesworth, and J. G. White Sebastian Platelet Syndrome: A Hereditary Macrothrombocytopenia Mayo Clin. Proc., November 1, 2003; 78(11): 1416 - 1421. [Abstract] [PDF]
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 S. Prakash, K. W. Chung, S. Sinha, M. Barmada, D. Ellis, R. E. Ferrell, D. N. Finegold, P. S. Randhawa, A. Dinda, and A. Vats Autosomal Dominant Progressive Nephropathy with Deafness: Linkage to a New Locus on Chromosome 11q24 J. Am. Soc. Nephrol., July 1, 2003; 14(7): 1794 - 1803. [Abstract] [Full Text] [PDF]
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C. Arrondel, N. Vodovar, B. Knebelmann, J.-P. Grunfeld, M.-C. Gubler, C. Antignac, and L. Heidet Expression of the Nonmuscle Myosin Heavy Chain IIA in the Human Kidney and Screening for MYH9 Mutations in Epstein and Fechtner Syndromes J. Am. Soc. Nephrol., January 1, 2002; 13(1): 65 - 74. [Abstract] [Full Text] [PDF]
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 B. Knebelmann, F. Fakhouri, and J.-P. Grunfeld Hereditary nephritis with macrothrombocytopenia: no longer an Alport syndrome variant Nephrol. Dial. Transplant., June 1, 2001; 16(6): 1101 - 1103. [Full Text] [PDF]
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| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
deafness,
cataracts, and nephritis
,
recently found to be deleted in another macrothrombocytopenic state,
Bernard-Soulier syndrome.