Postgrad Med J: first published as 10.1136/pgmj.63.741.573 on 1 July 1987. Downloaded from Postgraduate Medical Journal (1987) 63, 573-575

Epstein's syndrome: case report and survey ofthe literature

G.R. Standen, J. Saunders', J. Michael2 and A.L. Bloom Department ofHaematology, University Hospital of Wales, Heath Park, CardifCF4 4XN, 'Nevill Hall Hospital, Abergavenny, Gwent NP2 7EC and2Queen Elizabeth Medical Centre, Edgbaston, Birmingham BJ5 2TH, UK.

Summary: A diagnosis of Epstein's syndrome was made in a young female with congenital macrothrombopathic , a nephropathy and mild sensorineural deafness. Previous case reports ofthis rare disorder are briefly reviewed and attention is drawn to the frequent association between inherited thrombocytopenia and renal disease.

Introduction Alport's syndrome in its classical form is characterized as a dominant inherited disorder in which is associated with high tone sensorineural deafness. 2 Other rare abnormalities occasionally recognized in affected patients include polyneuropathy, hyper- prolinaemia and icthyosis3 and ocular defects such as retinitis pigmentosa, , lenticonus and sphero- phakia.4 In 1972, Epstein and co-workers5 described copyright. four patients from two kindreds who had hereditary nephritis and nerve deafness indistinguishable from Alport's syndrome in association with macrothrom- bopathic thrombocytopenia. In this report we describe the presentation and clinical course of a young female with this rare disorder.

Figure 1 Photomicrograph showing giant http://pmj.bmj.com/ Case report (arrow) in peripheral (Wright's stain, mag- nification x 1000). A 22 year old female was initially diagnosed as suffering from idiopathic thrombocytopenia at age 5 years following an uncomplicated fracture of the left femur. There was a history of easy bruising and recurrent epistaxis from birth and several episodes of negative. Because of the severe thrombocytopenia, otitis media in infancy. Further investigation of the platelet aggregation studies could not be performed. A on October 2, 2021 by guest. Protected thrombocytopenia at the age of 13 years showed bone marrow aspirate revealed normal to increased platelet counts of 12-20 x 109/1; bizarre giant forms numbers of megakaryocytes, many of which showed were recognized on the blood film (Figure 1). The abnormal morphology with peripherally localized, time was prolonged at 13 minutes and the condensed nuclei and poorly granular cytoplasm. prothrombin consumption index slightly increased at There was no evidence of platelet budding. 24%. Other coagulation tests including thrombin From the age of 14 years she suffered recurrent clotting time, one stage prothrombin time, kaolin urinary tract infections and when more fully inves- cephalin clotting time and the thromboplastin screen- tigated at the age of 18 years, microscopic haematuria ing test were normal. Serum immunoglobulins and and heavy (12.5 g/1) was recognized. On isohaemagglutinin titres were normal and the antinu- clinical examination she was normotensive with no clear factor and direct Coombs' test were peripheral oedema or abdominal masses palpable. The plasma urea was 2.6 mmol/l and an intravenous Correspondence: G.R. Standen, Ph.D. M.R.C.P. pyelogram was normal. At this time she also com- Accepted: 8 January 1987 plained of difficulty in hearing ip both ears associated C) The Fellowship of Postgraduate Medicine, 1987 Postgrad Med J: first published as 10.1136/pgmj.63.741.573 on 1 July 1987. Downloaded from 574 CLINICAL REPORTS with tinnitus, and audiometry demonstrated a mild, cataracts and cytoplasmic inclusions in symmetrical sensorineural deficit. A diagnosis of and eosinophils has been described." In addition, Epstein's syndrome was made on the basis of the there is one report ofa patient with nephritis, deafness macrothrombopathic thrombocytopenia, nephro- and macrothrombocytopenia in association with cys- pathy and sensory deafness. Both parents and two tic medianecrosis of the ascending aorta and malfor- siblings had normal platelet counts and morphology mation ofthe aortic valves.'2 However, acute relapsing and there was no evidence of renal disease or hearing pancreatitis has not been previously recognized as a disorder in the family. complication of Epstein's syndrome. Non-invasive At 21 years of age she was admitted with epigastric radiological investigations of the biliary tract in our pain of 5 days' duration which radiated to the back patient suggested that the pancreatitis was most likely and was associated with vomiting. There was no related to a coexistent chronic cholecystitis and we history of excessive alcohol intake'and she was taking suspect that this probably represents a chance associa- no . Apart from epigastric tenderness there tion. However, the possibility that the biliary and/or were no abnormal physical findings. The serum pancreatic pathology is in some way causally related to amylase was elevated at 1550 U/dl and serum bilirubin the underlying gene defect in this multisystem disorder increased at 47 lgmol/l (mainly direct). The serum cannot be entirely excluded. alkaline phosphatase was 91 IU/1, serum albumin 27 g/l, In the original report by Epstein and colleagues, the corrected calcium 2.34 mmol/I and glucose 4.7 mmol/l. platelet defect was characterized by giant forms with An abdominal ultrasound showed an oedematous abnormal ultrastructure and impaired function in pancreas but no pseudocyst formation. The gall terms of decreased glass adherence and diminished bladder wall was thickened but no calculi were aggregation in response to ADP, and adren- visualized in the biliary tree. Both kidneys were highly aline. Similar observations have been made in two echogenic and slightly irregular in contour. A diag- more recently described cases8' 9 and it has been nosis of acute pancreatitis was made which settled on suggested that the giant are derived from conservative treatment. A subsequent oral cholecys- abnormal megakaryocytes in which there is failure of

togram showed poor gall bladder contraction after a the demarcation membrane system.7 Normal plateletcopyright. fatty meal but was otherwise normal. One month after budding is impaired and the megakaryocytes undergo the initial episode, she suffered a mild recurrence ofthe degeneration and cytoplasmic fragmentation. The pancreatitis and recovery was again uncomplicated. survival of the macrothrombocytes in vivo has been Currently the serum creatinine is 77 limol/l with a reported to be normal8 and transfused random donor creatinine clearance of 106 ml/min. Heavy proteinuria platelets correct the prolonged bleeding time and persists (1Og/24 h) but the serum albumin has produce significant platelet increments.5 increased to 40 g/l. Neither endoscopic retrograde The renal pathology in Epstein's triad is indistingui- cholangiopancreatography nor renal biopsy have been shable from Alport's syndrome and consists ofscleros- feltjustifiable in view ofthe severe thrombocytopenia. ing and proliferative glomerulonephritis with mesan- http://pmj.bmj.com/ gial cell expansion, interstitial nephritis and fibrosis.5'6'8 Presentation with haematuria and proteinuria is Discussion typical and progression to end stage renal failure between the third and fifth decade frequently ensues. The association of inherited macrothrombopathic Despite the bleeding tendency, however, the feasibility thrombocytopenia, nephritis and sensorineural deaf- of renal transplantation has recently been documen- ness was first described by Epstein in 1972 and five ted.'° more recent reports in the American literature indicate A number of investigators have drawn attention to on October 2, 2021 by guest. Protected that this rare triad is a distinct clinical entity.6 10 In the association between nephritis and other types of common with the majority of previous cases, the familial thrombocytopenia including the May-Heg- platelet defect in the present patient was diagnosed at glin anomaly,'3 familial immune thrombocytopenia'4 an early age and preceded by some years the develop- and the Wiskott-Aldrich syndrome.'5"6 These disor- ment of the nephropathy and mild hearing deficit. ders have been broadly categorized as so-called Analysis of the small number of pedigrees reported 'thromborenal syndromes' but since their inheritance suggests that Epstein's syndrome is transmitted by patterns are variable and both the renal pathology and autosomal dominant inheritance.5' 6 If correct, the platelet defects are heterogeneous, the explanation for absence ofphenotypic abnormalities in the immediate this association remains obscure. Nevertheless, these family members of our patient indicates that her reports suggest that, in clinical practice, care should be disease resulted from a new . taken to exclude an associated nephropathy in any A single kindred in which affected individuals case of inherited thrombocytopenia. showed features of Epstein's triad accompanied by Postgrad Med J: first published as 10.1136/pgmj.63.741.573 on 1 July 1987. Downloaded from CLINICAL REPORTS 575

References 1. Cassady, G., Brown, K., Cohen, M. & De Maria, W. 111-117. Hereditary renal dysfunction and deafness Pediatrics 10. Alving, B.M., Tarassoff, P.G., Moore, J., Leissenger, 1965, 35: 967-979. C.A. & Fernandez-Bueno, C. Successful renal transplan- 2. Crawfurd, M. & Toghill, P.J. Alport's syndrome of tation for Epstein syndrome. Am J Hematol 1986, 21: hereditary nephritis and deafness. Q J Med 1968, 37: 111-113. 563-576. 11. Peterson, L.C., Venkateswara Rao, K., Crosson, J.T. & 3. Goyer, R.A., Reynolds, J., Burke, J. & Burkholder, P. White, J.G. Fechtner syndrome - a variant of Alport's Hereditary renal disease with neurosensory , syndrome with leukocyte inclusions and macrothrom- prolinuria and icthyosis. Am J Med Sci 1968, 256: 166- bocytopenia. Blood 1985, 65: 397-406. 179 12. Hansen, M.S., Behnke, O., Tinggaard Pedersen, N. & 4. Sohar, E. Renal disease, inner ear deafness and ocular Videbaek, A. Megathrombocytopenia associated with changes. Arch Intern Med 1956, 97: 627-630. glomerulonephritis, deafness and aortic cystic median- 5. Epstein, C.J., Sahud, M.A., Piel, C.F. et al. Hereditary ecrosis. Scand J Haematol 1978, 21: 197-205. macrothrombocytopathia, nephritis and deafness. Am J 13. Brivet, F., Girot, R., Barbanel, C., Gazengel, C., Med 1972, 52: 299-3 10. Maier, M. & Crosnier, J. Hereditary nephritis associated 6. Eckstein, J.D., Filip, D.J. & Watts, J.C. Hereditary with May-Hegglin anomaly. 1981, 29: 59-62. thrombocytopenia, deafness and renal disease. Ann 14. Spichten, H.P., Truniger, B., Mihatsch, M.J., Bucher, U., Intern Med 1975, 92: 639-645. Gudat, F. & Zollinger, H.U. Immuno-thrombocytopenia 7. Parsa, K.P., Lee, D.B.N., Zamboni, L. & Glassock, R.J. and IgA nephritis. Clin Nephrol 1980, 14: 304-308. Hereditary nephritis, deafness and abnormal throm- 15. Spitler, L.E., Wray, B.B., Mogerman, S., Miller, J.J., bopoiesis. Am J Med 1976, 60: 665-672. O'Reilly, R.J. & Lagios, M. Nephropathy in the Wisk- 8. Bernheim, J., Dechavanne, M., Bryon, P.A. et al. ott-Aldrich syndrome. Pediatrics 1980, 66: 391-398. Thrombocytopenia, macrothrombocytopenia, nephritis 16. Standen, G.R., Lillicrap, D.P., Matthews, N. & and deafness. Am J Med 1976, 61: 145-150. Bloom, A.L. Inherited thrombocytopenia, elevated 9. Clare, N.M.,Montiel, M.M., Lifschitz, M.D. & Ban- serum IgA and renal disease: Identification as a variant nayan, G.A. Alport's syndrome with macrothrom- of the Wiskott-Aldrich syndrome. Q J Med 1986, 59:

bopathic thrombocytopenia. Am J Clin Pathol 1979, 72: 401-408. copyright. http://pmj.bmj.com/ on October 2, 2021 by guest. Protected