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 neutropenia, thrombocytopenia, 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 blood 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, lymphocytopenia 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 therapy. always benign. Concurrent infection or bleeding 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. Neutrophils 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 monocytosis and haemocyte oscillate synchronously or independently fever occurred often. Anaemia, eosinophilia and as they often do. When neutrophils, platelets, 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, lymphomas 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 infections, 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 Splenectomy 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. abscess 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, peritonitis 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- monocytopenia, 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 cyclophosphamide (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 purpura. 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