Clinical Genetics 1977: 11: 163-170
Familial occurrence of histiocytosis E. FRISELL, B. BJORKSTBN,G. HOLMGRENAND T. A N G S ~ O M
Department of Pediatrics and Pathology, University of Umel, Sweden The clinical and histological findings of four children with lethal histiocytosis are reported. The children belonged to t w o sibships and originated from a Swedish geographical isolate. Consanguinity between the parents was established for one of the sibships, belonging to a pedigree in which malignant disease occurred in two generations. The observations indicate that the type of histiocytosis investigated is caused by homozygosity for a single recessive gene. The association between histiocytosis and malignancy is discussed. Received 26 November I975, revised 21 September, accepted f o r publication 29 September I976
The histiocytoses are a group of diseases characterized by the infiltration or proliferation of histiocytic cells within the tissues of the body (Leiken 1975). They include a number of disorders described in the literature under different names: histiocytosis X, reticuloendotheliosis, eosinophilic granuloma, Hand-Schiiller-Christian disease, Letterer-Siwe disease, histiocytic medullary reticulosis and disseminated lipogranulomatosis (Vogel & Vogel 1972, Leiken 1975, Nesbit & Krivit 1975). Familial occurrence of histiocytosis has been reported under different names, e.g. familial haemophagocytic reticulosis (Farquhar et al. 1958) and familial reticuloendotheliosis (Omenn 1965). These and several other reports suggest that genetic factors may play a role in the pathogenesis of generalized histiocytosis. We describe the clinical and autopsy findings in four siblings in two sibships who died from histiocytosis. This report provides additional evidence that histiocytosis may be genetically determined.
Case Reports
Case 1, MB, the oldest of three siblings, was referred to hospital at 2 months of age with pallor, tachypnoea, and hepato-splenomegaly. On admission, anaemia and pancytopenia were found. The blood smear showed a marked anisocytosis, poikilocytosis and polychromasia (Table 1). There was a normal proportion of plasma cells. Bone marrow smears were hypocellular with reduced erythropoesis and myelopoesis. This girl received repeated blood transfusions, antibiotics and corticosteroids, but her condition deteriorated. The peripheral white blood cell count fell to 900/mm3 with only 7 per cent neutrophils, and bone marrow aspirate revealed a total bone marrow aplasia. During the following weeks, she suffered from recurrent episodes of diarrhoea, developed petechiae, jaundice (bilirubin concentration 8 mg/100 ml), and a haemorrhagic necrosis 4 cm in diameter on the thigh. There was a progressive en-
164
FRISELL, BJORKSTEN, HOLMGREN AND ANGSTROM
Table 1
Clinical, familial and laboratory data on Cases 1-4 Case No. Initials
1 MB
LB
3 UL
4 RL
1 month 8 months
2 weeks
3 months
2 months
2 months 2 months
Familial occurrence Consanguinity
+ +
+ +
+
+
probably
probably
Clinical symptoms Irritability Fever Pallor Tachypnoea Petechiae Hopato-splenomegaly Enlarged lymph nodes
+ + + + + + +
+ + + + + + +
-
+ +
Laboratory data Anisocytosis, poikilocytosis and polychromasia i n peripheral blood
+
Bone marrow smears: Hypocellular with reduced erythropoiesis and myelopoiesis
+
2 ~
Age at admission Age at death
Haemoglobin g1100 rnl R BC/1O W Reticulocytes/l 000 RBC WBCIu' Neutrophils, % Platelets Bleeding time Coagulation time Serumbilirubin mgil00 m i ESR, mm/h
2 months
11.74.7 2.e-1.4
-
-
+
+ +
+
+
+
9.c3.2 3.61 .O
13.1-5.8 3.8-1.8 147 4,200-840 8
-
0-40
10,70&1,200
Case 2, LB, a younger brother of Case I, was admitted t o hospital at the age of 1 month with a temperature of 39.4"C and bronchopneumonia. T h e liver and spleen were palpable 6 and 8 cm, respectiveIy, below the costal margins, and the superficial lymph nodes were enlarged (Fig. 1). He had multiple petechiae on the abdomen. A necrotic area 1-2 c m in diameter developed near the anus. Bacterial cultures from spinal fluid and urine were negative. On admission he had anaemia and neu-
-
+
+
2,600-900 7 normal normal normal 2.74 20
largement of the spleen. T h e child died after 1 month in hypovolaemic shock.
+ +
9
46,000 normal normal 0,64 4
21.000
normal normal 2.7 2
7.8 2.8 10 3,300 20 normal normal normal not examined 23
tropenia. A blood smear showed poikilocytosis, anisocytosis and nucleated red cells. The bone marrow smear was hypocellular with reduced erythropoiesis and myelopoiesis. The picture was similar to that found in his sister, MB, and repeated studies of the bone marrow during the course of disease showed the same abnormalities. T h e marrow cells had a normal XY karyotype. Leukocyte agglutinins could not be demonstrated. Serum iron and total iron binding capacity were normal. There were no signs of haemolytic or megaloblastic anaemia. H e was treated with antibiotics and after
F A M I L I A L O C C U R R E N C E O F H I S T IO C Y T O S l S
165
and anaemia recurred with progressive enlargement of the lymph nodes. T h e child died after 8 months of illness.
Fig. 1. Case 2 at the age of 6 months.
1 week his general condition had improved, Hepatosplenomegaly diminished, and he was discharged in good general condition with healed skin lesions, but was readmitted 1 week later because of fever and diarrhoea. T h e liver and spleen were again markedly enlarged and gradually came to occupy the greater part of the abdomen. In addition to petechiae and necrosis, small purplish-red infiltrates appeared on the anterior of the thorax, as well as small yellow papules on the back. During the following weeks he developed progressive anaemia and neutropenia and, for this reason, splenectomy was performed 5 months after admission. Following splenectomy the bone marrow showed more active erythropoiesis, whereas the myelopoiesis was still reduced. The bone marrow, however, was still dominated by lymphoreticular cells. One month after the splenectomy, the child's condition deteriorated, and fever
Case 3, GL, a 2-week old boy, the oldest of three siblings, was admitted because of fever, progressive anaemia, thrombocytopenia, hyperbilirubinemia and hepatosplenomegaly (Table 1).A peripheral blood smear showed marked anisocytosis, poikilocytosis and neutropenia. Bone marrow investigation revealed cellular hypoplasia similar t o that found in MB and LB. The boy received repeated transfusions of blood and fibrinogen, but his clinical condition deteriorated. Peripheral leukocytes fell to 840/mm? with 8 per cent neutrophils and the marrow displayed an almost total aplasia. He had recurrent episodes of diarrhoea. There was a progressive enlargement of the spleen and an increase in serum bilirubin concentration to 2.7 mg/100 ml. T h e child died of septicaemia at the age of 2 months. Case 4, RL, a 2-month old boy, a younger brother of Case 3 was admitted because of fever, anaemia, neutropenia, and hepatosplenomegaly. T h e bone marrow was hyperplastic with increased erythropoiesis, but normal granulopoiesis. The boy died 6 days after admission of splenic rupture following needle biopsy.
Autopsy Findings in the Four Patients Hepatosplenomegaly and enlarged lymph nodes were seen in all four children. Most organs showed a massive, mainly perivascular, cellular infiltration of lymphocytes and histiocytes of varying degrees of maturity, including macrophages showing erythrophagocytosis (Table 2). Some of the cells were atypical and impossible to classify (Fig. 2). There were isolated small necrotic areas in the cellular infiltrates. Sections of liver, spleen, lymph nodes and bone mar-
166
FRISELL, BJORKSTEN, HOLMGREN AND ANGSTROM
FAMILIAL OCCURRENCE OF HlSTlOCYTOSlS Table 2
Histiocytic infiltration in different organs seen in cases 1-4 at autopsy Case No. Initials
ME
Central nervous system Lymph nodes Spleen Liver Bone marrow Kidney Pancreas Lungs
+ + + + + + +
1
+
2 LE
+
+ + + + + + +
3 UL
RL
a)
a)
+ + + + + + -
4
+ + + + + +
-
a) Not investigated.
row were stained with fat stain and with PAS stain with negative results. The bone marrow in Cases 1-3 showed varying degrees of aplasia. The marrow was dominated by erythropoietic cells. The myelopoiesis was highly reduced and no mature granulocytes could be identified. Numerous lymphocytes and histiocytes were seen as well as macrophages with erythrophagocytosis (Fig. ZD). In Case 4, however, the bone marrow was hyperplastic and there were increased numbers of reticuloendothelial cells, some of which showed erythrophagocytosis. The bone marrow findings in this boy may be explained by the short duration of disease prior to his death. Family History
Genealogical investigations of Cases 1 and 2 have shown that the paternal and maternal lines converge in a couple born, respectively in 1702 and 1700, nine generations removed from the index case (Fig. 3).
167
This couple and all the other persons included in the pedigree (except for X: 1-3) were born in the northern part of the county of Vasterbotten, and continued to reside there. There was consanguinity within both the paternal and maternal lines, as shown in Figure 3. An autosomal mode of inheritance might be suggested for this family, based on pedigree analysis. The mother is living and well at the time of this report. The father developed a squamous cell carcinoma of the lip at the age of 35 and 1 year later, systemic lupus erythematosus (SLE). He died at the age of 43. At the age of 70, the paternal grandfather developed chronic lymphatic leukemia and died 3 years later from general dissemination of the disease. The ancestors of the parents of Cases 3 and 4 were from the same part of a county in northern Sweden as the parents of Cases 1 and 2 , but genealogical investigation back to the 18th century did not reveal any common ancestry (Fig. 4). An autosomal recessive mode of inheritance might also be suggested for this family. Laboratory Investigations Twelve relatives of Cases 1 and 2 were examined with respect to total and differential leukocyte counts, bone marrow morphology and serum proteins. The father and the paternal grandfather had elevated gammaglobulin (30-33.6 per cent of the total serum proteins). Discussion
Familial occurrence of histiocytosis has
Fig. 2. Case 1. High-power photomicrographs of liver (A), spleen (B), abdominal lymph node (C) and bone marrow (D). H 8 E x 260. A : Infiltration of lymphocytes and histiocytes into portal area of the liver. 8: Infiltration into the sinusoids of the spleen of lymphocytes and histiocytes including macrophages with erythrophagocytosis. Some cells have atypical nuclei and are hard to classify. C: The normal architecture of abdominal lymph node i s obliterated and replaced by cellular infiltrates of the same type as in the liver and the spleen. D: Bone marrow with a few preserved granulopoietic cells and infiltration of lymphocytes and large histiocytic cells.
FRISELL, BJURKSTEN, HOLMGREN AND ANGSTRUM
168
Fig. 3. Pedigree 1 with Cases 1 and 2. Common ancestors
I
are traced back to the 18th century. II
111 IV V
VI VII
Vlll
IX
61
I
1
I
b2
0 3
6 L
05
/ t
68
n9
L
01
X
$7
?6
Case 1
.3
02
Case 2
Pedigree 1
f 0
pr Obari d
male
female
r ~ i ~ d e~v eyl o p e d
been described under different names. Nelson et al. (1961) described three cases of “generalized lymphohistiocytic infiltration” in a family. T h e histological preparations from LB closely resemble those from Nelson’s patients (Nelson, personal communication). Nelson, also pointed out the close resemblance between his cases and three infants with “familial hacniophagocytic reticulosis“ previously piiblishcd by Farquhar et al. (t95S). Consanguinity between parents of siblings with histiocytosis has been reported by Falk Er. Gellei (1957) and Omenn (1965); the latter found 12. children with histiocytosis in six sibships in an extraordinarily inbred family. In these reports, as well as in 1;itcr ones, (MacMahon et al. 1963,
d I sease
Schoeck et al. 1963. Miller 1966, Bell et al. 1968. McClure et al. 1974), the clinical picture was similar to that in our patients. Genetic factors have also been suggested by Glass Rr Miller (196S), who found an
T
m
Case 3
C.ise 4
Pedlgrre 2 Fig. 4. Pedigree 2 with Cases 3 and 4
FAMILIAL OCCURRENCE OF HlSTlOCYTOSlS
accumulation of deaths in the first 2 years of life in the families of patients with histiocytosis. Felletta et al. (1973) described a similar syndrome in 17 boys from two generations of a Latin American family. In this family there was an X-linked mode of inheritance, but the histological findings were different. There was a widespread infiltration of bizarre mononuclear and plasma cells and a lack of phagocytosis and histiocytes. Juberg et al. (1970) concluded that at least some instances of histiocytosis result from a single autosomal recessive gene with slightly reduced penetrance. In our patients, consanguinity was established between the parents of the children, MB and LB (Fig. 3). Although we could not show common ancestry for the parents of the brothers BL and RL, their families have been living for several generations in the same part of a sparsely populated county in northern Sweden as the former family. T h e pedigrees are consistent with autosomal recessive inheritance. Our data suggest that homozygosity for a single gene may explain at least one form of the histiocytosis syndrome. Several pathogenetic mechanisms may cause the disease and also account for differences in the clinical picture. The common pattern of progressive spread and the involvement of multiple organ systems suggest that idiopathic generalized variants of histiocytosis represent a neoplastic process (Vogel 6: Vogel 1972). Recently Warnke et al. (1975) presented 29 cases. mostly adults with nislignant histiocytosis. Their patients represent not only well-documented cases of neoplastic disease, but the histological findings were indistinguishable from those of a child with "familial haemophagocytic reticulosis." In view of this. the development of malignancy in the father and paternal grandfather of M B and LB is of interest. It could
169
be either that the heterozygotic state may be associated with malignancy while the homozygous condition may lead to histiocytosis or that a single gene with variable penetrance is instrumental. Corticosteroids and antibiotics did not influence the course of the disease in our patients. Splenectomy was beneficial for only 1 month in patient LB. This agrees with previous experience in similar cases (Nelson et al. 1961, MacMahon et al. 1963). Successful treatment of histiocytosis with antimetabolite drugs has been reported (Crocker 1973, V i r l g et al. 1974). Nesbit & Krivit (1975) recently recommended combination therapy f o r generalized histiocytosis, including prednisone and vinblastine sulfate over a period of 4 months if there is an initial clinical response.
References
Bell, R. J. M., A. J. E. Brafield, N. D. Barnes Br N. E. France (1968). Familial haemophagocytis reticulosis. A r c h Dis. Childh. 43, 601-606. Crocker, A. C. (1973). The histiocytosis syndromes. Currerit Pediatric Therapy, ed. Gellis, S. S. &B. M. Kagan. Philadelphia, W. B. Saunders, pp. 375-376. Falk, W. & B. Gellei (1957). The familial occurrence of Letterer-Siwe Disease. Acta paediat. Uppsala 46, 4714180. Falletta, J. M., D. J. Fernbach, D. B. Singer, M. A. South, B. H. Landing, C. W. Heath, N. A. Shore Br F. F. Barrett (1973). A fatal X-linked recessive reticuloendothelial syndrome with hyperglobulinemia. J . Pedior. 83, 549-556. Farquhar. J. W., A. R. hlacgregor B: J. Richmond (1958). Familial haemophagocytic reticulosis. Brit. med. J . 2, 1561-1561. Glass. A. G. & R. W. hfiller (1968). U S . mortality from Letterer-Siwe disease, 196064. Pediatrics 42, 364-367. Leiken. S. (1975). The histiocytoses. Pediar. Atftl. 4, 85-98. AlcClure. P., P. Stracham Br E. Saunders (1974). Hypofibrinopenemia and thronibocytopenia in familial hemophagocytic reticulosis. J . P~di(7t.85, 67-70.
170
FRISELL, BJORKSTEN, HOLMGREN AND ANGSTROM
MacMahon, H. E., M. Bedizel & C. A. Ellis (1963). Familial erythrophagocytic lymphohistiocytosis. Pediatrics 32, 868-879. Miller, D. R. (1966). Familial reticuloendotheliosis: Concurrence of disease in five siblings. Pediatrics 38, 986-995. Nelson, P., A. Santamaria, R. L. Olsen & N. C. Nayak (1961). Generalized lymphohistiocytic infiltration. A familial disease not previously described and different from Letterer-Siwe and Chediak-Higashi syndrome. Pediatrics 27, 931-950. Nesbit, M. E. & W. Krivit (1975). Histiocytosis. Cancer in Children, Clinical Management, ed. Bloom, H. J. G., J. Lemerle, M. K. Neidhardt & P. A. Voute. Berlin, Springer, pp. 193-199. Juberg, R. C., H. W. Kloepfer & H. A. Oberman (1970). Genetic determination of acute disseminated histiocytosis X (Letterer-Siwe syndrome). Pediatrics 45, 753-765. Omenn, G. S. (1965). Familial reticuloendctheliosis with eosinophilia. New Engl. J . Med. 273, 421-432.
Schoeck, V. W., R. D. A. Peterson & R. A. Good (1963). Familial occurrence of Letterer-Siwe Disease. Pediatrics 32, 1055-1063. Virag, I., D. Boda, I. Altorjay & L. Praefort (1974). Die Vinblastin Behandlung der malignen Krankenheiten des Kinderalters (Vinblastin Treatment in Childhood Malignancies). Mschr. Kinderheilk. 122, 111-714. Vogel, J. M. & P. Vogel (1972). Idiopathic histiocytosis: A discussion of eosinophilic granuloma. The Hand-Schuller-Christian syndrome and the Letterer-Siwe syndrome. Sernain. Hernatol. 9, 349-369. Warnke, R. A., H. Kim & R. F. Dorfman (1975). Malignant histiocytosis (histiocytic medullary reticulosis). I. Clinicopathological study of 29 cases. Cancer 35, 215-230. Address: G. Holmgren, M.D., Ph.D. Departtnerrt of Pediatrics University Hospital o f Vine; S-901 85 Utried Sweden
Familial occurrence of histiocytosis E. FRISELL, B. BJORKSTBN,G. HOLMGRENAND T. A N G S ~ O M
Department of Pediatrics and Pathology, University of Umel, Sweden The clinical and histological findings of four children with lethal histiocytosis are reported. The children belonged to t w o sibships and originated from a Swedish geographical isolate. Consanguinity between the parents was established for one of the sibships, belonging to a pedigree in which malignant disease occurred in two generations. The observations indicate that the type of histiocytosis investigated is caused by homozygosity for a single recessive gene. The association between histiocytosis and malignancy is discussed. Received 26 November I975, revised 21 September, accepted f o r publication 29 September I976
The histiocytoses are a group of diseases characterized by the infiltration or proliferation of histiocytic cells within the tissues of the body (Leiken 1975). They include a number of disorders described in the literature under different names: histiocytosis X, reticuloendotheliosis, eosinophilic granuloma, Hand-Schiiller-Christian disease, Letterer-Siwe disease, histiocytic medullary reticulosis and disseminated lipogranulomatosis (Vogel & Vogel 1972, Leiken 1975, Nesbit & Krivit 1975). Familial occurrence of histiocytosis has been reported under different names, e.g. familial haemophagocytic reticulosis (Farquhar et al. 1958) and familial reticuloendotheliosis (Omenn 1965). These and several other reports suggest that genetic factors may play a role in the pathogenesis of generalized histiocytosis. We describe the clinical and autopsy findings in four siblings in two sibships who died from histiocytosis. This report provides additional evidence that histiocytosis may be genetically determined.
Case Reports
Case 1, MB, the oldest of three siblings, was referred to hospital at 2 months of age with pallor, tachypnoea, and hepato-splenomegaly. On admission, anaemia and pancytopenia were found. The blood smear showed a marked anisocytosis, poikilocytosis and polychromasia (Table 1). There was a normal proportion of plasma cells. Bone marrow smears were hypocellular with reduced erythropoesis and myelopoesis. This girl received repeated blood transfusions, antibiotics and corticosteroids, but her condition deteriorated. The peripheral white blood cell count fell to 900/mm3 with only 7 per cent neutrophils, and bone marrow aspirate revealed a total bone marrow aplasia. During the following weeks, she suffered from recurrent episodes of diarrhoea, developed petechiae, jaundice (bilirubin concentration 8 mg/100 ml), and a haemorrhagic necrosis 4 cm in diameter on the thigh. There was a progressive en-
164
FRISELL, BJORKSTEN, HOLMGREN AND ANGSTROM
Table 1
Clinical, familial and laboratory data on Cases 1-4 Case No. Initials
1 MB
LB
3 UL
4 RL
1 month 8 months
2 weeks
3 months
2 months
2 months 2 months
Familial occurrence Consanguinity
+ +
+ +
+
+
probably
probably
Clinical symptoms Irritability Fever Pallor Tachypnoea Petechiae Hopato-splenomegaly Enlarged lymph nodes
+ + + + + + +
+ + + + + + +
-
+ +
Laboratory data Anisocytosis, poikilocytosis and polychromasia i n peripheral blood
+
Bone marrow smears: Hypocellular with reduced erythropoiesis and myelopoiesis
+
2 ~
Age at admission Age at death
Haemoglobin g1100 rnl R BC/1O W Reticulocytes/l 000 RBC WBCIu' Neutrophils, % Platelets Bleeding time Coagulation time Serumbilirubin mgil00 m i ESR, mm/h
2 months
11.74.7 2.e-1.4
-
-
+
+ +
+
+
+
9.c3.2 3.61 .O
13.1-5.8 3.8-1.8 147 4,200-840 8
-
0-40
10,70&1,200
Case 2, LB, a younger brother of Case I, was admitted t o hospital at the age of 1 month with a temperature of 39.4"C and bronchopneumonia. T h e liver and spleen were palpable 6 and 8 cm, respectiveIy, below the costal margins, and the superficial lymph nodes were enlarged (Fig. 1). He had multiple petechiae on the abdomen. A necrotic area 1-2 c m in diameter developed near the anus. Bacterial cultures from spinal fluid and urine were negative. On admission he had anaemia and neu-
-
+
+
2,600-900 7 normal normal normal 2.74 20
largement of the spleen. T h e child died after 1 month in hypovolaemic shock.
+ +
9
46,000 normal normal 0,64 4
21.000
normal normal 2.7 2
7.8 2.8 10 3,300 20 normal normal normal not examined 23
tropenia. A blood smear showed poikilocytosis, anisocytosis and nucleated red cells. The bone marrow smear was hypocellular with reduced erythropoiesis and myelopoiesis. The picture was similar to that found in his sister, MB, and repeated studies of the bone marrow during the course of disease showed the same abnormalities. T h e marrow cells had a normal XY karyotype. Leukocyte agglutinins could not be demonstrated. Serum iron and total iron binding capacity were normal. There were no signs of haemolytic or megaloblastic anaemia. H e was treated with antibiotics and after
F A M I L I A L O C C U R R E N C E O F H I S T IO C Y T O S l S
165
and anaemia recurred with progressive enlargement of the lymph nodes. T h e child died after 8 months of illness.
Fig. 1. Case 2 at the age of 6 months.
1 week his general condition had improved, Hepatosplenomegaly diminished, and he was discharged in good general condition with healed skin lesions, but was readmitted 1 week later because of fever and diarrhoea. T h e liver and spleen were again markedly enlarged and gradually came to occupy the greater part of the abdomen. In addition to petechiae and necrosis, small purplish-red infiltrates appeared on the anterior of the thorax, as well as small yellow papules on the back. During the following weeks he developed progressive anaemia and neutropenia and, for this reason, splenectomy was performed 5 months after admission. Following splenectomy the bone marrow showed more active erythropoiesis, whereas the myelopoiesis was still reduced. The bone marrow, however, was still dominated by lymphoreticular cells. One month after the splenectomy, the child's condition deteriorated, and fever
Case 3, GL, a 2-week old boy, the oldest of three siblings, was admitted because of fever, progressive anaemia, thrombocytopenia, hyperbilirubinemia and hepatosplenomegaly (Table 1).A peripheral blood smear showed marked anisocytosis, poikilocytosis and neutropenia. Bone marrow investigation revealed cellular hypoplasia similar t o that found in MB and LB. The boy received repeated transfusions of blood and fibrinogen, but his clinical condition deteriorated. Peripheral leukocytes fell to 840/mm? with 8 per cent neutrophils and the marrow displayed an almost total aplasia. He had recurrent episodes of diarrhoea. There was a progressive enlargement of the spleen and an increase in serum bilirubin concentration to 2.7 mg/100 ml. T h e child died of septicaemia at the age of 2 months. Case 4, RL, a 2-month old boy, a younger brother of Case 3 was admitted because of fever, anaemia, neutropenia, and hepatosplenomegaly. T h e bone marrow was hyperplastic with increased erythropoiesis, but normal granulopoiesis. The boy died 6 days after admission of splenic rupture following needle biopsy.
Autopsy Findings in the Four Patients Hepatosplenomegaly and enlarged lymph nodes were seen in all four children. Most organs showed a massive, mainly perivascular, cellular infiltration of lymphocytes and histiocytes of varying degrees of maturity, including macrophages showing erythrophagocytosis (Table 2). Some of the cells were atypical and impossible to classify (Fig. 2). There were isolated small necrotic areas in the cellular infiltrates. Sections of liver, spleen, lymph nodes and bone mar-
166
FRISELL, BJORKSTEN, HOLMGREN AND ANGSTROM
FAMILIAL OCCURRENCE OF HlSTlOCYTOSlS Table 2
Histiocytic infiltration in different organs seen in cases 1-4 at autopsy Case No. Initials
ME
Central nervous system Lymph nodes Spleen Liver Bone marrow Kidney Pancreas Lungs
+ + + + + + +
1
+
2 LE
+
+ + + + + + +
3 UL
RL
a)
a)
+ + + + + + -
4
+ + + + + +
-
a) Not investigated.
row were stained with fat stain and with PAS stain with negative results. The bone marrow in Cases 1-3 showed varying degrees of aplasia. The marrow was dominated by erythropoietic cells. The myelopoiesis was highly reduced and no mature granulocytes could be identified. Numerous lymphocytes and histiocytes were seen as well as macrophages with erythrophagocytosis (Fig. ZD). In Case 4, however, the bone marrow was hyperplastic and there were increased numbers of reticuloendothelial cells, some of which showed erythrophagocytosis. The bone marrow findings in this boy may be explained by the short duration of disease prior to his death. Family History
Genealogical investigations of Cases 1 and 2 have shown that the paternal and maternal lines converge in a couple born, respectively in 1702 and 1700, nine generations removed from the index case (Fig. 3).
167
This couple and all the other persons included in the pedigree (except for X: 1-3) were born in the northern part of the county of Vasterbotten, and continued to reside there. There was consanguinity within both the paternal and maternal lines, as shown in Figure 3. An autosomal mode of inheritance might be suggested for this family, based on pedigree analysis. The mother is living and well at the time of this report. The father developed a squamous cell carcinoma of the lip at the age of 35 and 1 year later, systemic lupus erythematosus (SLE). He died at the age of 43. At the age of 70, the paternal grandfather developed chronic lymphatic leukemia and died 3 years later from general dissemination of the disease. The ancestors of the parents of Cases 3 and 4 were from the same part of a county in northern Sweden as the parents of Cases 1 and 2 , but genealogical investigation back to the 18th century did not reveal any common ancestry (Fig. 4). An autosomal recessive mode of inheritance might also be suggested for this family. Laboratory Investigations Twelve relatives of Cases 1 and 2 were examined with respect to total and differential leukocyte counts, bone marrow morphology and serum proteins. The father and the paternal grandfather had elevated gammaglobulin (30-33.6 per cent of the total serum proteins). Discussion
Familial occurrence of histiocytosis has
Fig. 2. Case 1. High-power photomicrographs of liver (A), spleen (B), abdominal lymph node (C) and bone marrow (D). H 8 E x 260. A : Infiltration of lymphocytes and histiocytes into portal area of the liver. 8: Infiltration into the sinusoids of the spleen of lymphocytes and histiocytes including macrophages with erythrophagocytosis. Some cells have atypical nuclei and are hard to classify. C: The normal architecture of abdominal lymph node i s obliterated and replaced by cellular infiltrates of the same type as in the liver and the spleen. D: Bone marrow with a few preserved granulopoietic cells and infiltration of lymphocytes and large histiocytic cells.
FRISELL, BJURKSTEN, HOLMGREN AND ANGSTRUM
168
Fig. 3. Pedigree 1 with Cases 1 and 2. Common ancestors
I
are traced back to the 18th century. II
111 IV V
VI VII
Vlll
IX
61
I
1
I
b2
0 3
6 L
05
/ t
68
n9
L
01
X
$7
?6
Case 1
.3
02
Case 2
Pedigree 1
f 0
pr Obari d
male
female
r ~ i ~ d e~v eyl o p e d
been described under different names. Nelson et al. (1961) described three cases of “generalized lymphohistiocytic infiltration” in a family. T h e histological preparations from LB closely resemble those from Nelson’s patients (Nelson, personal communication). Nelson, also pointed out the close resemblance between his cases and three infants with “familial hacniophagocytic reticulosis“ previously piiblishcd by Farquhar et al. (t95S). Consanguinity between parents of siblings with histiocytosis has been reported by Falk Er. Gellei (1957) and Omenn (1965); the latter found 12. children with histiocytosis in six sibships in an extraordinarily inbred family. In these reports, as well as in 1;itcr ones, (MacMahon et al. 1963,
d I sease
Schoeck et al. 1963. Miller 1966, Bell et al. 1968. McClure et al. 1974), the clinical picture was similar to that in our patients. Genetic factors have also been suggested by Glass Rr Miller (196S), who found an
T
m
Case 3
C.ise 4
Pedlgrre 2 Fig. 4. Pedigree 2 with Cases 3 and 4
FAMILIAL OCCURRENCE OF HlSTlOCYTOSlS
accumulation of deaths in the first 2 years of life in the families of patients with histiocytosis. Felletta et al. (1973) described a similar syndrome in 17 boys from two generations of a Latin American family. In this family there was an X-linked mode of inheritance, but the histological findings were different. There was a widespread infiltration of bizarre mononuclear and plasma cells and a lack of phagocytosis and histiocytes. Juberg et al. (1970) concluded that at least some instances of histiocytosis result from a single autosomal recessive gene with slightly reduced penetrance. In our patients, consanguinity was established between the parents of the children, MB and LB (Fig. 3). Although we could not show common ancestry for the parents of the brothers BL and RL, their families have been living for several generations in the same part of a sparsely populated county in northern Sweden as the former family. T h e pedigrees are consistent with autosomal recessive inheritance. Our data suggest that homozygosity for a single gene may explain at least one form of the histiocytosis syndrome. Several pathogenetic mechanisms may cause the disease and also account for differences in the clinical picture. The common pattern of progressive spread and the involvement of multiple organ systems suggest that idiopathic generalized variants of histiocytosis represent a neoplastic process (Vogel 6: Vogel 1972). Recently Warnke et al. (1975) presented 29 cases. mostly adults with nislignant histiocytosis. Their patients represent not only well-documented cases of neoplastic disease, but the histological findings were indistinguishable from those of a child with "familial haemophagocytic reticulosis." In view of this. the development of malignancy in the father and paternal grandfather of M B and LB is of interest. It could
169
be either that the heterozygotic state may be associated with malignancy while the homozygous condition may lead to histiocytosis or that a single gene with variable penetrance is instrumental. Corticosteroids and antibiotics did not influence the course of the disease in our patients. Splenectomy was beneficial for only 1 month in patient LB. This agrees with previous experience in similar cases (Nelson et al. 1961, MacMahon et al. 1963). Successful treatment of histiocytosis with antimetabolite drugs has been reported (Crocker 1973, V i r l g et al. 1974). Nesbit & Krivit (1975) recently recommended combination therapy f o r generalized histiocytosis, including prednisone and vinblastine sulfate over a period of 4 months if there is an initial clinical response.
References
Bell, R. J. M., A. J. E. Brafield, N. D. Barnes Br N. E. France (1968). Familial haemophagocytis reticulosis. A r c h Dis. Childh. 43, 601-606. Crocker, A. C. (1973). The histiocytosis syndromes. Currerit Pediatric Therapy, ed. Gellis, S. S. &B. M. Kagan. Philadelphia, W. B. Saunders, pp. 375-376. Falk, W. & B. Gellei (1957). The familial occurrence of Letterer-Siwe Disease. Acta paediat. Uppsala 46, 4714180. Falletta, J. M., D. J. Fernbach, D. B. Singer, M. A. South, B. H. Landing, C. W. Heath, N. A. Shore Br F. F. Barrett (1973). A fatal X-linked recessive reticuloendothelial syndrome with hyperglobulinemia. J . Pedior. 83, 549-556. Farquhar. J. W., A. R. hlacgregor B: J. Richmond (1958). Familial haemophagocytic reticulosis. Brit. med. J . 2, 1561-1561. Glass. A. G. & R. W. hfiller (1968). U S . mortality from Letterer-Siwe disease, 196064. Pediatrics 42, 364-367. Leiken. S. (1975). The histiocytoses. Pediar. Atftl. 4, 85-98. AlcClure. P., P. Stracham Br E. Saunders (1974). Hypofibrinopenemia and thronibocytopenia in familial hemophagocytic reticulosis. J . P~di(7t.85, 67-70.
170
FRISELL, BJORKSTEN, HOLMGREN AND ANGSTROM
MacMahon, H. E., M. Bedizel & C. A. Ellis (1963). Familial erythrophagocytic lymphohistiocytosis. Pediatrics 32, 868-879. Miller, D. R. (1966). Familial reticuloendotheliosis: Concurrence of disease in five siblings. Pediatrics 38, 986-995. Nelson, P., A. Santamaria, R. L. Olsen & N. C. Nayak (1961). Generalized lymphohistiocytic infiltration. A familial disease not previously described and different from Letterer-Siwe and Chediak-Higashi syndrome. Pediatrics 27, 931-950. Nesbit, M. E. & W. Krivit (1975). Histiocytosis. Cancer in Children, Clinical Management, ed. Bloom, H. J. G., J. Lemerle, M. K. Neidhardt & P. A. Voute. Berlin, Springer, pp. 193-199. Juberg, R. C., H. W. Kloepfer & H. A. Oberman (1970). Genetic determination of acute disseminated histiocytosis X (Letterer-Siwe syndrome). Pediatrics 45, 753-765. Omenn, G. S. (1965). Familial reticuloendctheliosis with eosinophilia. New Engl. J . Med. 273, 421-432.
Schoeck, V. W., R. D. A. Peterson & R. A. Good (1963). Familial occurrence of Letterer-Siwe Disease. Pediatrics 32, 1055-1063. Virag, I., D. Boda, I. Altorjay & L. Praefort (1974). Die Vinblastin Behandlung der malignen Krankenheiten des Kinderalters (Vinblastin Treatment in Childhood Malignancies). Mschr. Kinderheilk. 122, 111-714. Vogel, J. M. & P. Vogel (1972). Idiopathic histiocytosis: A discussion of eosinophilic granuloma. The Hand-Schuller-Christian syndrome and the Letterer-Siwe syndrome. Sernain. Hernatol. 9, 349-369. Warnke, R. A., H. Kim & R. F. Dorfman (1975). Malignant histiocytosis (histiocytic medullary reticulosis). I. Clinicopathological study of 29 cases. Cancer 35, 215-230. Address: G. Holmgren, M.D., Ph.D. Departtnerrt of Pediatrics University Hospital o f Vine; S-901 85 Utried Sweden
