Hereditary Eosinophilia: Report of a Family and Review of the Literature J

Hereditary Eosinophilia: Report of a Family and Review of the Literature J. LAWRENCE NAIMAN, FRANK A. OSKI, FRED H. ALLEN, JR., AND LOUIS K. DIAMOND

Department of Pediatrics, Harvard Medical School, the Hematology Division of the Medical Service, the Children's Hospital Medical Center, and the Blood Grouping Laboratory of Boston SINCE 1909 (Gaugain), there have been numerous reports of familial occur- rence of persistent eosinophilia in the absence of known causal factors. These have generally been called "constitutional" or "familial" eosinophilia. In- cluded in this category are a few reports of cases in which there was evidence of allergy or parasitic infestation, two conditions commonly occurring in families and causing eosinophilia. A number of families remain, however, in which extensive investigation has failed to reveal such a basis for the eosinophilia. In these families, the distribution of eosinophilia has suggested autosomal dominant inheritance. In this report, these cases are designated "hereditary eosinophilia," to distinguish them from cases of familial eosinophilia associated with an environmental condition affecting the family. The purpose of this report is to describe a family with three generations of eosinophilia of unknown etiology and to review critically the literature on this subject in an effort to decide which of the reported families may correctly be classified as "hereditary eosinophilia." Case Report The propositus, a ten year old white male, was first admitted to the Chil- dren's Hospital Medical Center on November 9, 1961, for investigation of chronic eosinophilia and abdominal pain of recent onset. Eosinophilia of 20 per cent had been discovered first at age of 21/2 years oil routine blood count prior to elective herniorrhaphy. At six years of age, the patient was found to have eosinophilia of 25 per cent prior to mastoidec- tomy for chronic otitis media and mastoiditis. There had been no history of eczema, asthma, hives, food or drug sensitivities, or other manifestations of allergy. Vague left upper abdominal pain was first noted six weeks before admission. This had no relation to meals, time of day, or bowel habits. The pain was crampy, lasted a few minutes, and occasionally subsided after vomiting. The patient was in a local hospital for 22 days, where X rays of the chest,

Received August 26, 1963. Supported in part by grants HTS-5255 and H-2405 from the National Institutes of Health, U. S. Public Health Service. 195 AMERICAN JOURNAL OF HUMAN GENETICS, VOL. 16, No. 2 (JUNE), 1964 196 HEREDITARY EOSINOPHILIA sinuses, kidneys, and upper and lower gastrointestinal tract were reported to be normal. Eosinophilia as high as 45 per cent was found at this time. Repeated stool examinations were negative for ova and parasites. Shortly after discharge, he again complained of intermittent hypogastric pain. In the week before admission to the Children's Hospital Medical Center, he developed a mild nonproductive cough. He had never had fever, night sweats, or weight loss, and his general health had remained good. The father, aged 54 years, had severe emphysema without antecedent asthma. The patient's mother, eleven sibs, a niece, and a nephew were in good health. None had any symptoms suggestive of allergy or parasitic infestation. The paternal aunt and grandfather were both well and without history of allergic symptoms. They had not had contact with the propositus or his family for several years. Physical examination of the patient gave normal results. In particular, there was no skin rash, hepatosplenomegaly, or lymphadenopathy. Laboratory findings included the following: hemoglobin, 13.5 g/100 ml; hematocrit, 41.5 per cent; red blood cell count, 5,000,000/mm3; reticulocytes, 2.6 per cent. Red cell indices were normal. The platelet count was 340,000/ mm'. White cell count was 7,200/mm5 with 26 per cent mature neutrophils, 7 per cent band forms, 23 per cent eosinophils, 15 per cent small lymphocytes, 16 per cent atypical lymphocytes, and 13 per cent monocytes. An absolute eosinophil count by the direct method was 1,250/mm3. The eosinophils in blood smears were of normal appearance. There were no abnormalities of red cell morphology. Urinalysis, liver function tests, and serum protein electrophoresis were normal. Several stools were negative for ova and parasites. The patient's blood group was B, Rh+ and the anti-A titer was 1:32. Skin tests with Old Tuberculin and with Trichinella antigen were negative. Stool guaiac tests were negative. An X ray of the chest and a flat film of the abdomen were normal. During his brief hospitalization, the boy remained well and did not com- plain of further abdominal pain. Following discharge and until the time of this report (June 1963) he has continued in good health. The eosinophilia has persisted. Family Studies The kindred is illustrated in Fig. 1, and the results of blood counts and blood typing are shown in Table 1. All members were well at the time of these examinations. The absolute eosinophil counts were determined by the direct method where possible (Wintrobe, 1961). In the few exceptions, the absolute count was calculated from the total white cell count and differential eosinophil count of 300 cells on a coverslip smear of peripheral blood. Adults with counts greater than 400/mm3 were considered to have eosinophilia. A value of 440/mm5 was used to classify children. Counts were repeated during a period of 1%s years on many of the relatives and, in particular, on those whose eosinophil counts were close to the upper limit of normal. Fluctuations were observed in individual family members; these were on NAINIAN. OSKI, ALLEN, AND DIAMIOND) 197

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Fic. 1 Pedigree ol Famly W. HeredSitoy esonoplolis Thc genotype is suggested for each indiidual ith respect to tho RI, fators Where is cannot be deteimined by tests only the phenotype is gives. sine or the other side of tire tippee limit ofi norinal, aiel tlseieforee final deci- sion regarding selection of a patieit's classification was based on an average of moltiple saloes in these indeteeminate cases. Diurnal vaeiations (Uhbeband, 1958) may esplain some of this vaeiation, since conditions of the field study did not permit esammfation of all of the ieiohees of this laige family at the same time of day. Alhotgh decisions weeetrased on moltiple coonts, it is ecsognized that theee is a eontinnoos spectlum of eosinophil coons in this family and that the dinision into inormal and abnormal is qoite arbitrary in a few cases. This unfortonate cire mstance diminishes the importance of the linhage analysis. Linkoge Anolysis This pedigree is infoinats ae on the psosible linkoge of thefosinophilia ros and fire of the blood grop loci. With respect to the ABO locns, only type 0 persons in generation III are informatioe. The one type 0 person, 111i9l is nonhecombinanei With respect to the aIN locus Ite1and IIr2 are either both recombinant oi both nonrecombinantc Ini1i2h the Rh, gene is coopted withaosinophiliathe gene. There are sis nonrecombinan offspring snd foui recombinant. 112 is also heteiozygsos at the Duffy and P tori hot the phase of coopling is nnhnown. In the case of Duffy, the recombinont. nonrecombinant iatio is 6.4 (or 4re)s o the case of P, it is) 1 (or 1.3). In the case of the Duffy and Rfh loci, the data do not support linkage. Information from the other loci is inadequate. 198 HEREDITARY EOSINOPHILIA

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DISCUSSION Criteria for Eosinophilia From the present family and similar ones described in the literature, the entity of "hereditary eosinophilia" may be defined in terms of the following diagnostic criteria: 1. Significant eosinophilia. In most reports, the eosinophils were stated as an absolute number calculated indirectly from the total white blood cell count. By this method, the upper 95 per cent confidence limit in normal adults varies from 250/mm3 to 400/MM3 in the literature (Osgood et al., 1939). It should be stressed that the indirect count of eosinophils is far less accurate than the direct counting method and makes all counts in the indeterminate range difficult to interpret. For the present analysis of the literature, an eosinophil count of 400/mm3 has been selected as the level above which significant eosinophilia is considered to exist. In those reports in which the white cell count was not stated, an eosinophil level by differential count of 6 per cent or more was considered significant. In children who show a trend toward slightly higher eosinophil counts, reference has been made to the table of normal values at various ages compiled from the literature by Broun et al. (1961). For analysis of the present family, eosinophil numbers were calculated both from the differential count of 300 cells on a coverslip smear and, where possible, as an absolute number by the more accurate direct method (Wintrobe, 1961). A level of 440/mm3 by the latter method was considered significant, based on statistical analysis of the results obtained in healthy young adults by Muehreke, Eckert, and Kark (1952). The range of two standard deviations found by these authors extended from 72 to 440 cells/mm3. Comparable studies of the absolute eosinophil count (direct method) in normal children haste not been reported. The limited observations of Hain (1951) in 18 normal children (ages not stated) showed a range of 109- 359/mm3. Since most studies using the less accurate indirect method of counting indicate higher eosinophil counts in children than in adults, it was felt that a level of 440/mm3 (direct method) would be a "safe" upper limit of normal for separation of the children in the present family. Until further studies permit establishment of a more statistically significant upper limit of the normal in children, the aforementioned criterion of eosinophilia must remain tentative. Although only one child (Itt-12) had an eosinophil count near this limit, the importance of the linkage analysis is thereby lessened. 2. Familial incidence, with more than one generation being affected. This criterion excludes eosinophilia due to recessive inheritance and also excludes a large number of cases in which allergy or parasitic infestation are the causal factors. In fact, these conditions were common among the reported families in which only one generation was affected. 3. Absence of recognized causal factors. Careful investigation should exclude the usual etiologic conditions such as allergy or parasitic infestation which may occur within families. 200 HEREDITARY EOSINOPHILIA

TABLE 2. REPORTS OF HEREDITARY EosINOPHILIA

No..of N.. of members Rangehof Year Author genertion affected/studied % 1909 Gaugain 2 4!4 10-19 1923 Bastai 2 3/3 27-33 1926 Cirio 2 4/6 8-70 1930 Armand-DeLille 2 6/9 7-52 1931 Dalla Palma 2 31/50 6-75 1931 Cattaneo 3 6/7 12-39 1932 Molteni 2 6/8 6-24 1933 Stewart Family P 2 8/8 15-32 Family L 2 7/9 7-22 Family M 2 4/5 6-42 Family B 2 2/5 16-33 1939 Malmberg 2 4/5 6-26 1940 Terakado 2 2/2 29-52 1941 Vegh 2 13/18 6-80 1950 DiGuglielmo 2 5/6 6-38 1952 Unghvary 3 4/4 11-16 1957 Schultheiss 3 3/4 12-18 1963 Present authors 3 7/14 7-23 Total 119/167 Review of Cases Which Meet These Criteria Seventeen families which satisfy the above criteria were noted in the literature. These are summarized in Table 2. From an analysis of the reported cases, the following conclusions may be drawn: Heredity. Application of the criteria of two affected generations eliminates cases of eosinophilia which might be inherited as an autosomal recessive trait. Of the 119 affected cases reported, there were 58 males and 61 females, a ratio which favors autosomal inheritance. Further evidence against sex- linked inheritance is the existence of two pedigrees showing father to son transmission (Dalla Palma, 1931; Molteni, 1932). The absence of reports of single generation pedigrees of eosinophilia in which causal conditions were satisfactorily excluded suggests that a recessive inheritance, if it exists at all, is not common. However, reluctance to report such cases because of the seeming lack of genetic interest may explain the preponderance of dominant inheritance pedigrees in the literature. In two reports (Dalla Palma, 1931; Stewart, 1933), both parents in a family had eosinophilia and they were not known to be related. Neel (1953) has questioned "the extent to which unrecognized familial endemics of one kind or another may be responsible" for the familial con- centrations of eosinophilia. This criticism may apply in particular to some of the older reports in which limitations of knowledge and investigative tech- niques may have precluded detection of some of the more recently described parasitic infestations, such as visceral larva migrans. However, the predomi- nance of the latter condition in small children and the association with pica, NAINIAN, OSKI, ALLEN, ANT) DIANIONi) 201 leokocytosis with extreme eosinophilia, and hepatomegaly argue against such a condition being a factor in many of the reported families with eosinophilia. At the present time such reports can be accepted as probable examples of hereditary eosinophilia, much of the evidence coming from the strong pattern of transmission between generations. This is especially evident in the present family and in those reported by Dalla PaTina (1931), Cattaneo (1931) and Schultheiss and Schultheiss (1957), in each of which three generations were affected. Age of onset. The presence of several affected infants under one year of age among the reported families suggests the eosinophilia is present from early infancy. The youngest affected infant was two months of age. Concurrent clinical conditions. Although illnesses were frequent among the propositi and were the occasion for examination of the blood and sub- sequent family investigation, these were in all probability unrelated and coincidental. The persistence of eosinophilia after disappearance of symptoms and its presence among healthy relatives supports this conclusion. The few remaining reports of "familial eosinophilia" in the literature have been discounted as instances of true hereditary transmission. In each there was adequate cause for the eosinophilia. Allergic symptoms were frequent in the families reported by Klinkert (1911), Bowman (1941), Gray and Shaw (1949) and Nowotna-Walcowa (1953). In the Mexican family reported by Atmar (1940), the proposita, a 25 year old woman, was subjected to liver biopsy which revealed numerous foci of dense eosinophilic infiltration. Zuelzer and Apt (1949), in reviewing this case, likened the lesions to those found in his cases of visceral larva migrans, a condition known to produce marked eosinophilia. The leukocytosis of 42,700 and X-ray evidence of pulmonary infiltration in this case support the latter diagnosis. In the family reported by Stefanini and Karaca (1963), only one generation was affected, and the data were insufficient to exclude underlying disease, especially suspected since splenomegaly was an associated finding. Eosinophilia. The degree of eosinophilia nearied among different families and among members of any one family. Values oner 50 per cent were present in 5 of the 18 families. In affected individuals, wide fluctuations in the level of eosinophilia were occasionally noted. These were usually associated with infections. Gaugain (1909), Bastai (1923), and Vegh (1941) observed transient increases during infections, whereas Stewart (1933) reported a fall in eosinophils from 42 per cent to normal levels in a 3 year old boy during an attack of pneumonia. One of the affected members of the family reported here (III-8) showed a fall in eosinophils from 580/mm3 to 99/mm' after tonsillectomy. These opposite effects are difficult to reconcile. The total while cell count was normal or only slightly elevated in all of the reported cases, a point of value in differentiating this condition from eosinophilia due to parasitic infestation in which leukocytosis is common. The eosinophils are described as normal in appearance on blood smear. Bone marrow examinations were performed in four cases; eosinophil precur- sors were normal in three but increased in the fonrth. 202 HEREDITARY EOSINOPHILIA The only reports of associated hematologic anomalies were those of Unghvary and Schultheiss (1955) and Schultheiss and Schultheiss (1957). In each of these families, a mild degree of ovalocytosis was present in the members affected with eosinophilia. There have been no previous studies of blood groups among the reported cases of hereditary eosinophilia. In the present family, extensive blood group testing failed to yield evidence favoring linkage of any of the blood groups to hereditary eosinophilia. Hereditary eosinophilia appears to represent a benign anomaly probably due to a disordered regulation of production of eosinophils. Elucidation of the precise mechanism will depend on further advances in our understanding of the physiologic regulation of the level of eosinophils in normal persons. All cases of unexplained eosinophilia deserve family studies with this possi- bility in mind. If significant eosinophilia is found in more than one generation, it is essential to intensify efforts to exclude coincidental allergy and parasitic infestation as possible etiologic factors. Only in such circumstances does a diagnosis of hereditary eosinophilia appear justified.

SUMMARY A ten year old boy was found to have had eosinophilia of unknown etiology since early childhood. Investigation of his family revealed a similar finding in several well members, with a total of three generations affected. An autosomal dominant mode of inheritance was evident. Blood group testing failed to establish linkage with any of the blood group genes. The term "hereditary eosinophilia" is given for this condition, to distinguish it from cases of familial eosinophilia secondary to allergy or parasitic infestation. From the literature, another 17 families were found which could be included in this category. The common features are analyzed and discussed.

ACKNOWLEDGMENT We wish to thank Miss Patricia Greer for technical assistance. REFERENCES ARMAND-DELILLE, P. F., HURST, A. F., AND SORAPURE, V. E. 1930. Familial eosinophilia. Guo's Hosp. Reps. 80: 248-252. ATmAR, R. C. 1940. Familial eosinophilia. J. Amer. Med. Assoc. 115: 449-450. BASTAI, P. 1923. Della eosinoftlia costituzionale. Haesatologica 4: 23-58. BoWMAo, J. E. 1941. Familial eosinophilia. Penn. Med. J. 44: 1445-1446. BRoUN, G. 0. et al., 1961. In Bloed and Other Bode Fluids, D. S. Dittmer. Washington, D. C.: Federation of American Societies for Experimental Biology, pp. 125-126. CATTANEo, L. 1931. Contributo allo studio delr eosinofilia costituzionale. Haenatologica 12: 263-271. Couo, L. 1926. Sopra un caso di cosidetta eosinofiha costituzionale. Riforea Med. 42: 219-222. DALLA PALMA, M. 1931. Sulla eosinofilia fatigliare. PolFilinico, Sez. Med. 38: 605-619. DIGUGLsELmo, R., CoRTn, L., AND CAPPELLo, F. 1950. Ipereosinofilia costituzionale familiare ereditaria. Haematologcia 34: 799-814. GAUGAIN, M. 1909. Un cas d'eosinophilie familiare. Sem. Med. 29: 329. NAIMAN, OSKI, ALLEN, AND IJIAMOND 203

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