sign in sign up
<<
Home , Cyclic neutropenia, Monocytosis, Neutropenia, Thrombocytopenia

Postgrad Med J: first published as 10.1136/pgmj.47.549.504 on 1 July 1971. Downloaded from Postgraduate Medical Journal (July 1971) 47, 504-510.

CLINICAL REVIEW

Haemocytic periodicity and periodic disorders: Periodic , , lymphocytosis and anaemia HOBART A. REImANN M.D. The Department ofMedicine, Hahnemann Medical College and Hospital, Philadelphia, Pennsylvania 19102 Summary involvement is either overt or clinically inapparent Evidence has accumulated of rhythmic numerical except for the numeric cellular oscillation. Periodicity oscillation of each of the cells either indepen- escapes detection unless cells are counted at short dently or in combinations. intervals in patients, n healthy genetic relatives or The cyclic changes originate in the marrow of some others. Serial counts have disclosed periodicity in normal persons and animals without causing illness, some patients regarded as cases of continuous, con- and can be induced experimentally. genital or hereditary neutropenia (Morley, Carew & In more than 100 reported instances, periodic oscilla- Baikie, 1967). tions of various cells were accompanied by respective Periodic neutropenia is heritable. Probably throm- episodes of the disorders named in the title. The dis- bocytopenia, and anaemia also areby copyright. orders may be transitory but usually recur throughout genetically transmissible. The disorders are not life and occasionally are fatal. All resist . always benign. Concurrent or Features in common suggest an interrelationship ofthe occasionally is fatal. Therapy generally is ineffectual; haemal disorders and other disparate heritable periodic the symptoms alone are meliorated, cellular cycles diseases. usually persist. This review stresses the periodicity of Theoretically, the rhythms are regulated by various haemocytes, their interrelated disorders and ubiquitous, inherent, intracellular bioclocks controlled frequent heritability as described in published cases hypothalamically or neurohumorally in relation to a and personally observed ones. Articles cited in feedback mechanism. Reactions to long cycles are of references recount detailed clinical features. greater clinical importance than disturbances arising http://pmj.bmj.com/ from the circadian rhythm. Periodic neutropenia Heredity Introduction Morley's studies, particularly his opportunity to After the establishment of periodic (cyclic) study five afflicted families, provided much informa- neutropenia as an entity in 1949 (Reimann & De tion. Twenty members had had overt disease, usually Berardinis, 1949) nearly fifty cases were added to the since infancy. also fluctuated rhythmi- forty-two cited in 1963 Because the in several (Reimann, 1963). cally symptomless members. Some of on October 2, 2021 by guest. Protected trouble originates in the marrow, the term periodic them had continuous neutropenia with cycles of myelodysplasia was proposed. The broad term further depression. The tempo ranged from 15 to 35 applies if the numbers of more than one kind of days, averaging 20. Synchronous and haemocyte oscillate synchronously or independently occurred often. Anaemia, and as they often do. When neutrophils, , mono- thrombocytopenia concurred episodically in three cytes, lymphocytes and erythrocytes alone oscillate, relatives. An autosomal dominant trait of high specific designation is appropriate. By including penetrance and variable manifestations character- periodic disorders related to the numeric fluctuation ized the afflicted families (Morley et al., 1967). of various haemocytes, the total number of reported Table 1 portrays thirty-seven primary cases cases involving the blood exceeds 100. Many un- accruing after forty-two previously recorded ones recognized ones, no doubt, exist. and includes a few I omitted in 1963. Table 2 shows Periodic haemocytic changes are either primary or ten cases regarded as secondary neutropenia, making are associated with mensis, and immuno- a total of eighty-nine in all. Of the seventy-nine suppressive therapy. In both circumstances, the primary ones, forty-two were in females, thirty-seven Postgrad Med J: first published as 10.1136/pgmj.47.549.504 on 1 July 1971. Downloaded from Clinical review 50S

TABLE 1. Periodic neutropenia Age at Perio- Thrombo- Author Sex Age onset dicity Mono- Lympho- cyto- Eosino- Familial Unusual (years) (years) (days) cytosis cytosis penia philia features Lorre & Denys F 8 3/12 23 + + + Rapid ESR (1960) Toro et al. (1960) M 2 4/12 19 (21 days + Thrombo- Sialorrhoea, after cytosis diarrhoea, seizures cortisone) Bray (1960) F 9 ? 21 Serious , steroids ineffective Gorlin & F 8 4 21 + Chaudry (1960) Malooly (by M 54 33 28 Mono- Prednisone letter) cyto- meliorated penia symptoms only Alestig (1961) F 58 54 14 Prednisone meliorated symptoms only. Spontaneous remission 1 year fever 40° C Telsey et al. F 14 4/12 ±21 and (1962) steroids ineffective Videbaek (1962) M 29 2 21 + + Fever 39 'C M 2 10/12 21 Fever 38 'C M 18 1 21; later 14 Wade & Stafford M 38 32 21-28 Splenectomy, pred-

(1963) nisone relieved by copyright. symptoms only Coutel, Morel & M 6 1 ±21 + Pulm. Thomet (1963) Smith (1964) M 20 6 14-20 Hypergamma- globulinaemia Journal of the F 22 16 ? Five episodes of American Medi- pancreatitis cal Association (1965) Simonsen (1966) F 21 17 ±21 Lympho- Abdominalgia, cyto- arthralgia penia Morley (1967) 7M Usually 15-35 Often 7 familial Periodic arthralgia http://pmj.bmj.com/ Twenty cases 13F child- in three hood Felitti (by letter) F 6 ? Died, Waldron-Shah F 35 8 21 + + + Doubtful Stethalgia, abdomi- (by letter) in several nalgia, arthralgia, relatives erythema, xero- stomia, diaphoresis, diarrhoea, oedema,

somnolence, pallor on October 2, 2021 by guest. Protected in males. They began in infancy in twenty-seven and were neutropenic or had recurrent oral ulcers with- after age 60 in three. Periodicity generally ranged out detected rhythm. Pregnancy suppressed, from 14 to 28 days, mostly 20 or 21. Monocytosis or worsened or had no effect on episodes. Cortico- , lymphocytosis or lymphocytopenia, steroids meliorated the symptoms in a few, but had eosinophilia and thrombocytopenia or thrombo- slight or no effect on the cellular cycles. Splenectomy cytosis characterized some instances. The recorded seldom was justified. As found in common with numbers depended upon whether cells were counted other disparate periodic disorders, synchronous during episodies or in the intervals. Published fever, sialorrhea, xerostomia, exanthems, arthrosis, reports do not always specify the timing. Serious abdominalgia and diarrhoea occasionally occurred. infections occasionally ensued and seven ended Similar to human disease, six grey Collie dogs had fatally. Familial involvement was evident in eleven heritable periodic neutropenia. Three had con- instances. In several groups, symptomless relatives current gingival and dermal ulcers, arthralgia and Postgrad Med J: first published as 10.1136/pgmj.47.549.504 on 1 July 1971. Downloaded from 506 Clinical review fever. Neutropenic episodes recurred every 8-13 ally concurred (Alexander. Dionigi & Meakins, days averaging 10 with compensatory monocytosis 1971). Morley & Stohlman using (Lund, Padgett & Ott, 1967). reduced the number of neutrophils in dogs and lowered neutropenia every 11-17 days (Morley & Complement anomaly in periodic neutropenia Stohlman, 1970). A hypothetic feedback control was Study of my patient E.C. disclosed the inhibitor discussed in detail (Morley, 1970). of C1 esterase reduced from a normal 5 6 units to 3-6 Patients with polycythemia or leukaemia and u and 4 u in two respective episodes, and to 4 u in an secondary periodic neutropenia listed in Table 2 all interval. His whole serum complement activity during were adults. The rhythm of neutropenia ranged from the two episodes measured 34 u and 58 u, and in the 30 to 120 days. Its amplitude probably was extended symptomless interval 44 u (normal 62 ± 19 u) to that length by the gravity of the underlying (Reimann, Coppola & Villegas, 1970). Splenectomy diseases or by therapy thereof. Thrombocytopenia failed to help the patient. Testosterone meliorated concurred in four. Episodes of neutropenia affected the symptoms for a time by preventing extreme aganunaglobulinemic children (Telsey, et al., 1962). neutropenia. It induced concurrent monocytosis, and lymphocytosis and increased the granulocytic Neutropenia andpancreatic disturbance reserve as demonstrated by the pyrogen stimulation Neutropenia and pancreatic dysfunction affected a test (Brodsky, Reimann & Dennis, 1965). child at 21-day intervals (Colebatch et al., 1965). In six other patients, a 'new' entity, in one instance Aysmptomatic and secondary periodic neutropenia familial, consisted of pancreatic insufficiency, Morley demonstrated symptomless neutropenia anaemia, neutropenia and occasional thrombo- at intervals of 14-23 days in eight of eleven normal cytopenia and . The tabulated data suggest men from unaffected families. Similar oscillation unnoticed recurrent episodes of neutropenia accompanied mensis in two normal women (Morley, (Shwachman et al., 1964). Bodian also commented 1966). The behavior indicates the existence of an on the combination of congenital pancreatic hypo- underlying inherent biorhythm and a feedback plasia, neutropenia and thrombocytopenia (Bodian,by copyright. mechanism affecting the formation of cells. This Sheldon & Lightwood, 1964). Fluctuation of the action in genetically susceptible persons provokes three factors appears in the tables of two of his disease (Reimann, 1948). In one of my patients with patients, but cell counts were too widely spaced to periodic polyserositis (Case 1, Reimann, 1948), detect regular periodicity. Elsewhere I described periods of symptomless neutropenia, monocytosis periodic pancreatosis without attention to neutro- and lymphocytosis occasionally recurred separately philic changes (Reimann, 1962). from episodes of her disease. After the deliberate impairment of immunity, Periodicity during haemal diseases Alexander demonstrated fluctuation of antibacterial In a polycythemic patient, the number of neutro- activity of neutrophils in cycles usually of 14-24 phils fluctuated every 15 days, the platelets every 27 http://pmj.bmj.com/ days in patients and monthly in dogs. The activity days, both within the normal range. A was independent of the number of neutrophils. cycle of another patient lasted 17 days (Morley, Injury and immunosuppressive therapy adversely 1969a). As noted by Morley and others, periodic affected but did not abolish the basic neutropenia occasionally accompanies - cycle. As in periodic neutropenia, infection occasion- toses (Morley, Baikie & Galton, 1967) (Table 2). In TABLE 2. Secondary periodic neutropenia on October 2, 2021 by guest. Protected Perio- Thrombo- Disease Sex Age Age at dicity Mono- cyto- (years) onset (days) cytosis penia Morley (1969a) Polycythemia M 68 8 15 + + Another patient had peri- 27-day odic reticulocytopenia at cycles 17-day intervals Morley, Baikie & Galton Myelogenous F 42 ? 50-55 + Modified by therapy (1967) leukaemia Leukaemia M 45 ? 30-35 + Modified by therapy Leukaemia F 60 57? 30 Modified by therapy Leukaemia M 37 35? 100-120 Modified by therapy Kennedy (1970) 5 patients 30-50 + Myelogenous leukaemia Postgrad Med J: first published as 10.1136/pgmj.47.549.504 on 1 July 1971. Downloaded from Clinical review 507

Kennedy's five patients with myelogenous leukaemia bleeding, each one worse until death from cerebral treated with hydroxyurea, leucocytes and platelets haemorrhage. Episodes came at predicted 21-day fluctuated in 30-50-day cycles (Kennedy, 1970). intervals. counts ranged from 0 to 500,000/ Rhythm may be obscured by therapy or by the mm3. Splenectomy and prednisone had failed to gravity of the primary disease. On the other hand, help (Wasastjerna, 1967). either therapy or the disease induces oscillation. Table 3 lists the six patients. The disorder began in middle age. Periodicity ranged from 21 to 39 Secondary lymphocytosis days. One patient had haemolytic anaemia. One Lymphocytosis occasionally accompanies normal died during an episode. Spenectomy and cortico- mensis (Minot, 1936). During lymphocytic leukaemia steroid therapy had no effect. in a patient, spells of fever, polyuria and facial oedema appeared at 5-10 day intervals. Four Asymptomatic and secondary periodic thrombo- months of observation disclosed a lymphocyte- cytopenia lymphoblast number of about 280,000 which dimin- Morley discovered a 21-35-day rhythmic oscilla- ished to normal during episodes. The 2%Y of seg- tion in the number of platelets in normal persons. In mented cells diminished slightly in unison. An occasional susceptible persons like these, bleeding attack of herpes zoster temporarily lengthened the may occur regardless of the degree of thrombo- rhythm to 15 and 17 days. On one occasion, with- cytopenia (Morley, 1969b). Rhythm may be over- drawal of spinal fluid promptly increased the number looked unless serial counts are made. If these are of lymphocytes and averted an expected febrile made on patients with essential thrombocytopenic episode. The event suggested central neural or neuro- purpura, rhythmic fluctuation of platelets may humoral regulation (Stacher & Bohnel, 1958). The become evident in some of them. Correct diagnosis idea was based on the experimental demonstration of obviates splenectomy which is ineffective for prompt leucocytosis after mechanical disturbance of periodic thrombocytopenia. the hypothalamic area. Although governed centrally, Thrombocytopenia and purpura also occur in

the effect presumably is mediated humorally on the rhythm with mensis (Pohle, 1939). In a woman aged by copyright. marrow (Rosenow, 1951). 46, episodes of epistaxis, menorrhagia and purpura recurred every 28 days for 8 years. Episodes usually Periodic thrombocytopenia coincided with mensis and also happened in the mid- Since Demmer's report, at least six primary cases period. Platelets varied in number from 10,000 to have been described (Demmer, 1920). In one instance, 300,000. The marrow contained nonfunctioning a man had episodes of bleeding for 42 years. His fluctuating in rhythm. Normal platelets diminished monthly to fewer than 50,000/ hormonal amounts remained constant. Because mm3 after reduction of megakaryocytes in the episodes recurred regularly after oophorectomy marrow. The numbers ofleucocytes and erythrocytes (Skoog, Lawrence & Adams, 1957), prior relation to

remained normal. Prednisone was ineffective mensis may have been coincidental. In another http://pmj.bmj.com/ (Engstrom, Lundquist & Soderstrom, 1966). A man, woman, happened at aged 37, had five episodes of thrombocytopenia and every other menstrual flow (Pepper, Liebowitz &

TABLE 3. Periodic thrombocytopenia Age Age at Periodicity Sex (years) onset (days) Symptoms Comment

Demmer (1920) M 61 55 28 Purpura Irregular synchronous lympho- on October 2, 2021 by guest. Protected cytosis. Death from nephritis Skoog et al. (1957) F 46 38 28 Epistaxis, menorrhagia, With and between mensis. purpura, mucosal lesions Persisted after oophorectomy Dameshek (by letter) F 42 27 Episodes of haemolytic Had prior splenectomy for anaemia, thrombocytopenic haemolytic anaemia purpura Wasastjerna (1967) M 37 33 21 Severe bleeding Died in predicted episode from cerebral haemorrhage. Sple- nectomy and steroids no help Engstrom et al. (1966) M 61 59 39 Purpura 'Absolutely regular sequence' Bernard & Caen M 54 12 Monthly Buccal ulcers, subcutaneous and splenec- haemorrhages tomy, no effect Candura (1960) Fourteen cases re- lated to mensis Postgrad Med J: first published as 10.1136/pgmj.47.549.504 on 1 July 1971. Downloaded from 508 Clinical review Lindsay, 1956). In the published case record, lower periodic neutropenia by Waldron-Shah (Table 1) is platelet counts appear without comment at about 20- pertinent. The patient has constant leucopenia with day intervals suggesting a circa 21-day periodicity. periods of neutropenia every 21 days 'predictable to Candura described two cases related to mensis and the day'. Other leucocytes increase reciprocally. cited reports of at least twelve others chiefly in During episodes, the usual oral ulcers appear. But in Italian and German journals (Candura, 1960). addition, there occur fever, severe abdominalgia and These are regarded here as secondary but if included stethalgia, arthralgia of elbows and knees, and in Table 3 would make a total number exceeding oedema of the eyelids, face, and hands. These twenty. More cases, no doubt, will be diagnosed features respectively characterize periodic poly- when serial counts are made. serositis, periodic arthrosis and periodic oedema. Regardless of known platelet participation, bleed- Myalgia, sialorrhea, xerostomia, erythema, somno- ing and purpura can be induced periodically in lence, blurred vision, diaphoresis, tachypnea, vomit- religious stigmatists presumably by wilful excite- ing and diarrhoea common to all periodic disorders ment ofthe autonomic neurovascular system (Agle & also concur at times in the episodes as autonomic Ratnoff, 1962). reactions. An electroencephalogram was normal. Because none of the symptoms predominate con- Periodic erythrocytic oscillation sistently, a basic diagnosis of periodic neutropenia A 7-year-old boy had 'congenital hypoplastic with composite symptoms is appropriate. anaemia and periodic erythrocytopenia' since It may be recalled that a patient with periodic infancy. At first, episodes came at 2-3-month polyserositis (Case 1, Reimann, 1948), cited above intervals, later about twice yearly. The marrow had occasional separate periods of neutropenia. As during episodes showed erythrocytic aplasia. The indicated in Table 1, Simonsen's neutropenic child was well between episodes and developed patient had abdominalgia and arthralgia. Some normally otherwise. An brother died from family members of Morley's group had arthralgia, anaemia (Gordon & Varadi, 1962). and Lorre's patient had synchronous sialorrhoea, A man who died at age 21 from Hodgkin's disease diarrhoea and seizures. Periodic neutropenia withby copyright. had had numerous episodes of anaemia with in- pancreatic disturbance was mentioned above. creased sedimentation-rate, lymphocytopenia and Systemic disturbance is obvious. fever. Two-week-long episodes alternated with Regarding periodic haemal disorders, several about 3 weeks of relative good health. Five episodes entities have emerged. According to the tables, were observed during 5 months in a hospital. primary periodic haemal disorders begin at any Because of brisk erytnropoiesis in the marrow, his time of life, occasionally are familial, have overlap- regarded the periodic anaemia as of ping features, resist therapy and occasionally are haemolytic origin (Ranl0v & Videbaeck, 1963). fatal. Evidence of similar periodicity emerges during Ashby observed 8-16-day cycles of haematopoesis unrelated diseases. Periodicity can also be induced in animals and changes in human erythrocyte experimentally in man and animals. Various haemal http://pmj.bmj.com/ numbers every 14 days (Ashby, 1948). In Morley's cells oscillate in number independently or in com- polycythemic patient, independent reticulocyte, binations. When independent, specific names may be and platelet cycles indicated that normal applied; for combinations, the term myelodysplasia homeostatic controls still were functional (Morley seems apropos. Synchronous increases in numbers 1969a). A 14-day oscillatory rhythm of ofcertain cells may be compensatory or specific. appeared in dogs. Bleeding and transfusion shifted The immediate site ofdisturbance is in the marrow. the oscillatory phases (Morley & Stohlman, 1969). Why the oscillatory rhythm varies in days, weeks or months, often precisely, in different patients and for on October 2, 2021 by guest. Protected Discussion different cells is unknown. Occasional temporal In the past 20 years, clinical interest in life-long association with mensis may indicate either hor- recurrent disorders in otherwise healthy persons has monal incitement or the synchronous effects of two increased. Many examples have been delineated and separate biorhythms. Morley's discovery of similar added to those described previously. They are in- haemocytic cycles in asymptomatic members of cluded in a proposed group of disparate noso- afflicted families, in normal persons, and in animals logically related entities. Common to all are herit- indicates the ubiquity of the rhythm. Exaggeration ability, precise or irregular periodicity, overlapping of oscillation or oscillation in susceptible persons features, menstrual suppression of episodes, resis- evokes periodic disease. tance to therapy and similar serum-complemental Alexander demonstrated depressed antibacterial defects (Reimann, 1963). action of neutrophils in the usual 14-24-day rhythm Considering the interrelation of periodic dis- in normal persons. At the nadir of action, infection orders, the case described to me as one of possible occurred in one person. Infections also occurred at Postgrad Med J: first published as 10.1136/pgmj.47.549.504 on 1 July 1971. Downloaded from Clinical review 509 the time in burned patients and in others treated with DEMMER, T. (1920) Morbus maculosis Werlhofii in Regel- immunosuppressive The behavior be massigen vier Wochenliche Schuben bei einen 60 Jahrigen drugs. may Mann nebst Untersuchungen uber Blutplattchen. Folia one variable factor favoring unexpected recurrent haematologica, 26, 74. infections. Long biorhythms as principles of life and ENGSTROM, K., LUNDQUIST, A. & SODERSTROM, N. (1966) reactions to them are of much more clinical im- Periodic thrombocytopenia or tidal platelet disgenesis in a portance than disturbances incident to the circadian man. Scandinavian Journal of Haematology, 3, 290. GORDON, R.R. & VARADI, S. (1962) Congenital hypoplastic rhythm. with periodic erythroblastopenia. Lancet, i, 296. Concerning the ultimate cause, no demonstrable GORLIN, R.J. & CHAUDRY, A.P. (1960) The oral manifesta- inborn-error of metabolism or endocrinal influence tions in chronic myelogenous during hydroxyurea participates. The circadian rhythm, extraneous geo- therapy. Blood, 35, 751. Journal of the American Medical Association (1965) Cyclic physical or cosmic influences have no bearing. neutropenia. 193, 752. Whether a complement disturbance observed in the KENNEDY, B.J. (1970) Cyclic leukocyte oscillations in chronic single case of periodic neutropenia is a characteristic myelogenous leukemia during hydroxyurea therapy. and relevant to the cause cannot be said without Blood, 35, 751. LORRE, J. & DENYS, P. (1960) Contribution A 1'6tude des further evidence. neutropenies cycliques. Acta Paediatrica Belgica, 14, 178. Theoretically, an inherent biorhythm excites the LUND, J.E., PADGETT, G.A. & OTT, R.L. (1967) Cyclic hypothalamic area, the effects of which are mediated neutropenia in grey Collie dogs. Blood, 29, 452. neurally. Pertinent to the blood, Richter postulated MINOT, G.R. (1936) Purpura hemorrhagica and lympho- local bioclocks or cytosis. type and intermittent menstrual type. the existence of Zeitgebers in cells American Journal of the Medical Sciences, 192, 445. of the marrow (Richter, 1960). An action-phase in MORLEY, A.A. (1966) A neutrophil cycle in healthy indi- the stem cells of each of the haematopoetic com- viduals. Lancet, ii, 1220. ponents may synchronize independently to cause MORLEY, A. (1969a) Blood-cell cycles in polycythaemia vera. Australasian Annals of , 18, 124. neutropenia, lymphocytopenia, thrombocytopenia, MORLEY, A.A. (1969b) A platelet cycle in normal individuals. reticulocytopenia or anaemia, or these in various Australasian Annals of Medicine, 18, 127. combinations. The bearing of the theories on the MORLEY, A.A. (1970) Periodic diseases, physiological feed-back proposal (Morley, 1970) is conjectural. rhythms and feedback control-a hypothesis. Australasian by copyright. Does feedback control the rhythm or the reverse? Annals of Medicine, 19, 244. MORLEY, A.A., BAIKIE, A.G. & GALTON, D.A.G. (1967) Morley, King-Smith & Stohlman (1970) discussed Cyclic as evidence for retention of normal the matter of haemal periodicity in detail concluding homeostatic control in chronic granulocytic leukaemia. that 'if many systems do show the same principles of Lancet, ii, 1320. control as does haemopoiesis, many periodic MORLEY, A.A., CAREW, J.P. & BAIKIE, A.G. (1967) Familial . British Journal of Haematology, 13, diseases may arise in similar fashion'. 719. MORLEY, A., KING-SMITH, A. & STOHLMAN, F. The oscil- References latory nature of hemopoesis. In: Hemopoetic Cellular AGLE, D.P. & RATNOFF, O.D. (1962) Purpura as a psycho- Proliferation (Ed. by F. Stohlman) pp. 3-14. Grune &

somatic entity. Archives , 109, 685. Stratton, Inc., New York. http://pmj.bmj.com/ ALESTIG, K. (1961) Cyclic treated with MORLEY, A. & STOHLMAN, F. (1969) Erythropoesis in the steroids. Acta medica Scandinavica, 169, 253 dog. The periodic nature of the steady state. Science, 165, ALEXANDER, J.W., DIONIGI, R. & MEAKINS, J.L. (1971) 1025. Periodic variation in the antibacterial function of human MORLEY, A. & STOHLMAN, F. (1970) Cyclophosphamide- neutrophils and its relation to . Annals ofSurgery. (In induced cyclical neutropenia. An animal model of a press.) human periodic disease. New England Journal ofMedicine, ASHBY, W. (1948) The span of life of the red . A 282, 643. resume. Blood, 3, 486. PEPPER, H., LIEBOWITZ, D. & LINDSAY, S. (1956) Cyclical BERNARD, J. & CAEN, J. (1962) Purpura thrombopenique et thrombocytopenic purpura related to the menstrual cycle. on October 2, 2021 by guest. Protected m~gacariocytop~nia cycliques mensuels. Nouvelle Review Archives of , 61, 1. Franfaise de HLmatologie, 2, 387. POHLE, S.F. (1939) The blood platelet count in relation to the BODIAN, M., SHELDON, W. & LIGHTWOOD, R. (1964) Con- menstrual cycle in normal women. American Journal ofthe genital hypoplasia of the exocrine pancreas. Acta Paedia- Medical 40. trica, 53, 282. Sciences, 197, BRAY, P.T. (1960) Cyclical neutropenia. Proceedings of the RANL0V, P. & VIDEBAEK, A. (1963) Cyclic haemolytic Royal Society of Medicine, 53, 1057. anaemia synchronous with Pel-Ebstein fever in a case of BRODSKY, I., REIMANN, H.A. & DENNIS, L.H. (1965) Treat- Hodgkin's disease. Acta medica Scandinavica, 174, 583. ment of cyclic neutropenia with testosterone. American REIMANN, H.A. (1948) Periodic diseases. Journal of the Journal of Medicine, 38, 802. American Medical Association, 136, 239. CANDURA, M. (1960) Su due casi di porpora intermittente REIMANN, H.A. (1962) Periodic pancreatosis. Journal of the mestruale piastrinopenica. Haematologia, 45, 457. Indian Medical Profession, 9, 4189. COLEBATCH, J.H., ANDERSON, C.M., SIMONS, M.J. & BURKE, REIMANN, H.A. (1963) Periodic Diseases, pp. 1-189. Black- V. (1965) Neutropenia and pancreatic disorders. Lancet, ii, well Scientific Publications, Oxford, and F. A. Davis, Co., 496. Philadelphia. COUTEL, Y., MOREL, H. & THOMET, G. (1963) Neutrop~nie REIMANN, H.A., & DE BERARDINIS, C.T. (1949) Periodic cyclique chez un enfant de 6 ans. Nouvelle Review Fran- (cyclic) neutropenia, an entity. A collection of 16 cases. faise deHmmatologie, 3, 482. Blood, 4, 1109. Postgrad Med J: first published as 10.1136/pgmj.47.549.504 on 1 July 1971. Downloaded from 510 Clinical review

REIMANN, H.A., COPPOLA, E.D. & VILLEGAS, G.R. (1970). SMITH, J.F. (1964) Cyclic neutropenia. Oral , Oral Complement system defects in periodic diseases. Annals Medicine and Oral Pathology, 18, 312. ofInternal Medicine, 73, 737. STACHER, A. & BOHNEL, J. (1958) Eigenartiges Krankheitsbild RICHTER C. (1960) Biological clocks in medicine and psy- einer zyklisch leukamischaleukimischen Lymphomatose. chiatry: Shock-phase hypothesis. Proceedings of the Wiener Klinische Wochenschrift, 70, 158. National Academy of Sciences, 46, 1506. TELSEY, B., BEUBE, F.E., ZEGARELLI, E.V. & KUTSCHER, A.H. (1962) Oral manifestations of cyclical neutropenia. Oral ROSENOW, G. (1951) The nervous humoral regulation of the Surgery, and Oral Pathology, 15, 540. leukocytes. Acta haematologica, 5, 1. TORO, A.H., ALLANDE, R.S. & MESA, S.A. (1960) Neutro- SHWACHMAN, H., DIAMOND, L.K., OSKI, F.A. & SHAW, K-T. penia ciclica. Reporte de un caso. Boletin Medical del (1964) The syndrome of pancreatic insufficiency and bone Hospital Infantil, 17, 215. marrow dysfunction. Journal of , 65, 645. VIDEBAEK, A. (1962) Cyclic neutropenia. Report of three SIMONSEN, E. (1966) Cyklisk agranulocytose. Nordisk Medi- cases. Acta medica Scandinavica, 172, 715. cine, 76, 1061. WADE, A.B. & STAFFORD, J.L. (1963) Cyclical neutropenia. SKOOG, W.A., LAWRENCE, J.S. & ADAMS, W.S. (1957) A meta- Oral Surgery, Oral Medicine, and Oral Pathology, 16, 1443. bolic study of a patient with idiopathic cyclical thrombo- WASASTJERNA, C. (1967) Cyclic thrombocytopenia of acute cytopenic purpura. Blood, 12, 844. type. Scandinavian Journal of Haematology, 4, 380. by copyright. http://pmj.bmj.com/ on October 2, 2021 by guest. Protected