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Hereditary spherocytosis and sickle cell trait in the Negro
T h e J o u r n a l o/ P E D I A T R I C S
589
Hereditary qoberocytosis and sickle cell trait in the Negro Four cases o[ hereditary spherocytosis associated with sickle cell trait in a Negro family are reported. The salient diagnostic [eatures o[ spherocytosis with hemoglobin S trait are described and the importance is mentioned o[ considering this combination as a possibility in the Negro presenting with hemoglobin AS and evidence o[ hemolytic disease.
Salud Rodriguez, M.D., Sanford Leikin, M.D., "~ William H. Bullock, M.D., and Clifford Booker, M.D. WAStIINGTON~
D. C.
W I T It T ~ E detection of m o r e cases of h e r e d i t a r y spherocytosis in the Negro, it is probable t h a t increasing numbers of patients will be f o u n d w i t h this red cell defect in association with an a b n o r m a l hemoglobin. Since the first r e p o r t of h e r e d i t a r y spherocytosis c o m b i n e d with sickle cell trait by S m i t h a n d Conley, 1 8 additional cases have been described in the literature. 2-6 I n 1959 Cohen a n d associates ~ studied 3 generations of an A m e r i c a n N e g r o family a n d f o u n d 2 individuals with h e r e d i t a r y spherocytosis a n d sickle cell trait a n d one with this combination a n d w h a t was considered to be thalassemia. Recently, W h i t a k e r a n d co-workers 6 r e p o r t e d the first case of h e r e d i t a r y spherocytosis associated with sickle cell trait a n d cholelithiasis. From the Children's Hospital of the District o/Columbia and the Department o[ Pediatrics, George Washington University School of Medicine, and the Departments o[ Pediatrics and Medicine, Howard University School o[ Medicine. "X'Address, Children's Hospital o] the District o[ Columbia, 2125 13th Street, N. W., Washington, D. C. 20009.
T h e purpose observations on c o m b i n a t i o n of sickle cell trait of an A m e r i c a n
of this p a p e r is to r e p o r t 4 a d d i t i o n a l patients with a h e r e d i t a r y spherocytosis a n d a p p e a r i n g in 3 generations Negro family.
CASE REPORT A 9-year-old Negro girl entered the Children's Hospital of the District of Columbia on Jan. 4, 1964. One week prior to admission she had developed a skin eruption over the thighs and lower abdomen. This was followed 5 days later by fever associated with lethargy, pallor, icterus, and left-sided abdominal pain. The day prior to admission she complained of weakness, the passage of dark urine, and anorexia. Vomiting occurred on the morning of admission. The past history of the patient revealed that she was the product of a full-term pregnancy and uncomplicated delivery. Jaundice was noted shortly after birth and intermittently during her infancy. She was seen in the Outpatient Clinic of Children's Hospital at the age of 4 years and again at 5 years because of respiratory infections. A mild anemia was detected on each occasion, and some microspherocytes and in-
59 0
Rodriguez
April 1966
creased polychromasia were noted on the peripheral blood smear. O n admission to the hospital in 1964 she a p p e a r e d acutely ill. H e r vital signs were as follows: t e m p e r a t u r e 100.4 ~ F.; pulse, 80 per minute; respirations, 20 per minute; a n d blood pressure, 100/60. T h e skin a n d mucous membranes were pale a n d the sclerae icteric. H e a l i n g p y o d e r m a was present on the thighs a n d lower abdomen. T h e r e was mild n u c h a l rigidity. Slight tenderness was present over the left u p p e r a b d o m i n a l q u a d r a n t , a n d the spleen a n d liver were palpable 3.5 and 4 cm., respectively, below the costal margins. T h e p e r t i n e n t laboratory findings are shown in T a b l e I and recorded below: white blood count, 17,000 per cubic millimeter with 71 per cent granulocytes, 12 per cent monocytes, and 17 per cent lymphocytes. T h e platelet count was 130,000 per cubic millimeter. T h e m e a n corpuscle volume was 86 per cubic micron; m e a n corpuscular hemoglobin 31 per micromicrogram; and m e a n corpuscular h e m o g l o b i n concentration, 36 per cent. Polychromasia and microspheroeytes were present on the smear but no sickle forms were seen (Fig. 1). Direct a n d indirect Coombs tests were negative. Alkaline phosphatase was 2.6 units; thymol turbidity, 2 units; and blood urea nitrogen 17 mg. per cent. S e r u m electrolyte concentrations, u r i n a r y findings, a n d the cerebrospnial fluid were within n o r m a l limits. T h e chest x-ray was normal, and roentgen study of the gallbladder revealed no stones. T h e patient was given two transfusions of
packed erythrocytes a n d s y m p t o m a t i c therapy. T h e hemoglobin level rose to 11.4 Gm. per cent, and the platelet count r e t u r n e d to n o r m a l limits. T h e child was discharged on the twentieth hospital day to be followed in the outpatient clinic. Six m o n t h s later she was a d m i t t e d for elective splenectomy. Except for a mild hemolytic crisis which did not require hospitalization, she had d o n e well in the interim. She was given one packed cell transfusion prior to surgery. T h e spleen after removal weighed 4 0 grams and measured 17 by 12 by 4 cm. T h e surface was slightly lobulated and the capsule was smooth and a p p e a r e d grayish purple. O n section the p a r e n c h y m a was reddish purple, fairly firm, and markedly congested. Microscopically, there was a m a r k e d decrease in lymphopoiesis. T h e sinusoids were empty and lined with p r o m i n e n t reticuloendothelial cells. T h e intersinusoidal
Fig. 1. Peripheral blood smear of III-1 showing microspherocytes and absence of sickle forms.
T a b l e I. H e m a t o l o g i c f i n d i n g s of t h e p e d i g r e e
Subject
Hemoglobin
Hema-
(Gin.~ 100 ml.)
tocrit (%)
Reticulocytes (%)
Sickle preparation
Red blood cetl osrno,tic [rap.ility
Hemoglobin
paper electror
Bilirubin (mg./lO0 ml.) Total
I Indirect I Direct
I-1 8.6 28 12.5 Positive Increased AS 3.7 3.1 0.6 II-1 16.0 52 0.1 Negative Normal AA 1.0 0.7 0.3 II-2 9.8 20 2.9 Positive Increased AS 4.6 3.8 0.8 II-3 ~ 4.0 13 6.3 Positive Decreased AS 2.0 1.7 0.3 II-4 4 to 7 Positive Normal II-5 13.8 38 Negative Normal AA II-6 8.4 27 8.4 Positive Increased AS III-1 4.2 12 8.4 Positive Increased AS 5.0 4.3 0.7 III-2 12.8 45 0.4 Negative Normal AA 0.2 0.1 0.1 III-3 12.0 42 0.5 Positive Normal AS 0.2 0.1 0.1 III-4 7.5 26 73 Negative Increased AA § studies were performed 2 months posttransfusion. Examinations performed at an earlier date when all transfused cells had been eliminated revealed 5 per cent hemoglobin F, the remainder being hemoglobin S. We are deeply indebted to Dr. Paul McCurdy for providing this latter information.
Volume 68 Number 4
areas were congested and some cells with suggestive sickling were noted. The patient did well and was discharged on the sixth postoperative day with a hemoglobin level of 11 Gm. per cent and hematocrit level of 33 per cent. FAMILY
STUDIES
The laboratory data on the following individuals is reported in Table I. The family pedigree is shown in Fig. 2. I-1. The maternal grandfather, age 58, Negro, had mild intermittent jaundice and splenomegaly, but is living a normal, active life. Spherocytes and increased polychromasia without sickle forms were seen on his peripheral blood smear. His serum glutamic oxaloacetic transaminase, alkaline phosphatase, and thymol turbidity were within normal limits. I-2. According to the hospital record of III-4, the maternal grandmother had the sickle cell trait. No specific studies are recorded. She had not permitted examinations of her blood by the present investigators. IIol. The father of the proposita, age 31, Negro, was in good health and had no abnormal physical findings. II-2. Mother of the propo.sita, age 33, Negro, had had jaundice with cholelithiasis since 1958. On physical examination pallor, icterus, and splenomegaly were present. A peripheral blood smear revealed spherocytes and increased polychromasia but no sickle forms. Her serum glutamic oxaloacetic transaminase was 500 units; thymol turbidity, 3 units; and alkaline phosphatase, 5.6 units. Subsequent to our examination she was admitted to another hospital because of a hemolytic crisis and pain in the left upper
III
X-
Not investigated
Fig. 2. Pedigree of the family of III-i.
Spherocytosis and sickle cell trait
59 1
quadrant of the abdomen. Radiologic investigation revealed gallstones. She underwent splenectomy and cholecystectomy without difficulty. Follow-up studies 4 months later revealed a hemoglobin level of 13 Gm. per cent and total bilirubin of 1.0 mg. per 100 ml. II-3. An aunt of the proposita, age 31, Negro, had requir~ed numerous transfusions for sickle cell anemia. On physical examination, icterus and a palpable spleen were the only prominent findings. Target cells and sickle forms, as well as increased polychromasia, were present in a peripheral blood smear. Her direct and indirect Coombs tests were negative and no atypical antibodies were detected in her serum. II-4. Another aunt of the proposita, Negro, died in October, 1938, at the age of 12 years. The diagnosis at that time was sickle cell anemia and heart failure. She had been previously hospitalized on 4 occasions, as follows: (1) January, 1931, Anemia, heart murmur, and hepatosplenomcgaly; (2) February, 1931, Tonsillectomy; (3) April, 1931, Splenectomy; microscopically, the spleen showed overt sickling; and (4) April, 1938, Osteomyelitis of the right femur. During this admission her hemoglobin ranged from 4 to 7 Gm. per cent and the icterus index from 7 to 13.5 units. Three osmotic fragilities were reported as normal. Sickle forms were noted on the peripheral blood smear. II-5. Caucasian male, husband of II-6, was clinically well and on investigation exhibited no hematologic abnormality. II-6. Aunt of the proposita, Negro, had had intermittent jaundice throughout her life. She was first seen by us at the age of 26 years because of intermittent right upper quadrant pain. She was moderately icteric and her spleen
5 9 2 Rodriguez
was palpable 4 cm. below the left costal margin. Macrocytes, spherocytes, ovalocytes, and increased polychromasia were found on the peripheral blood smear, but no sickle forms were seen. II-7. Unavailable for study. II-8. Unavailable for study. II-9. Unavailable for study. We were informed, however, that she was anemic. III-1. The proposita. III-2. Sister of the proposita, aged 11, Negro, was in good health and had no abnormal physical findings. III-3. Brother of the proposita, aged 12, Negro, was in good health and had no abnormal physical findings. III-4. Cousin of the proposita, one year of age, was jaundiced shortly after birth. There was no evidence of blood incompatibility but numerous spherocytes were found in the blood smear. An exchange transfusion was performed. She has, subsequently, been clinically well. DISCUSSION
The fact that hemoglobin S is limited to the Negro race and that hereditary spherocytosis affects mainly Caucasians makes the finding of hemoglobin S and spherocytosis in combination both interesting and of practical significance. Actually, within the last 10 years it has become apparent that hereditary spherocytosis in the Negro is not as rare as was once thought. By 1959 44 cases had been accumulated7 including two in African Bantus. 8 We have recently observed another case, and it is highly likely that more will be discovered. This makes the possibility of finding more Negro patients having both hereditary spherocytosis and an abnormal hemoglobin more likely. This report brings t h e total number of cases of congenital spherocytic hemolytic anemia in association with hemoglobin AS to 13. Of these 13, 3 of the cases had cholelithiasis, 2 of which are reported herein. At present there is no specific therapy for patients with hemolytic disease due to abnormal hemoglobins, whereas hemolysis due to hereditary spherocytosis is almost uniformly corrected by splenectomy. It is, therefore, of importance to include a consideration of hereditary spherocytosis in Negro
April 1966
patients with hemolytic disease even in the presence of a positive sickle preparation. The severity of the hemolytic process as evidenced by the hemoglobin level, reticulocyte count, or bilirubin level in this group of patients is not dissimilar from that of other hemoglobinopathies, particularly homozygous S disease. Splenomegaly is rare after the age of 3 to 4 years in homozygous S disease, but it is found at all ages in patients with congenital spherocytosis. In cases of congenital spherocytosis in association with sickle trait, spherocytes are present in the peripheral blood smear and there is an absence of sickle forms. In homozygous S disease sickle forms and target cells are invariably present. The concomitant increased erythrocyte osmotic fragility of spherocytosis precludes most of the common helnoglobinopathies. Hemoglobin electrophoresis is, however, very important in differentiating hemolytic disease due to hereditary spherocytosis from that caused by an abnormal hemoglobin. The information which was presented on I-2 was acquired from the hospital chart of II-4. No further studies on I-2 are available. It is unfortunate that specific laboratory studies could not be obtained to substantiate that the patient had sickle cell trait. II-3, however, had homozygous S disease as evidenced by p a p e r electrophoresis. Moreover, there was good evidence that II-4 probably had homozygous S disease despite the fact that she died before the use of hemoglobin electrophoresis in the differentiation of the hemoglobinopathies. Sickle forms were noted on her peripheral blood smear without the presence of spherocytes, and red cell fragilities were normal on 3 occasions. These facts indicated that I-2 had the sickle gene. It has been proposed that the genes for sickling (fi-S chain production) and spherocytosis are nonallelic, s T h e independent assortment that one finds in this kindred of individuals with hemoglobin A alone, hemoglobin AS without spherocytosis, hemoglobin A with spherocytosis, as well as homozygous S, would support this hypothesis. These find-
Volume 68 Number 4
Spherocytosis and sickle cell trait
ings would also indicate t h a t these genes are on different chromosomes or far a p a r t on the same chromosome.
ease, Bull. Johns Hopkins Hosp. 94: 289, 1954. de Torregrosa, M. V., Ortiz, A., and Vargas, D.: Sickle cell spherocytosis associated with hemolytic anemia, Blood 11: 260, 1956. Jones, B., and Klingberg, W. G.: Hemoglobin S hereditary spherocytosis, J. PEDIAT. 54: 375, 1959. Martin, W. W., Jr., Krough, R. H., and Branche, G. C., Jr.: Hereditary spherocytosis--sicklemia in the Negro; a case report and study of a Negro family having multiple instances of hereditary spherocytosis, Blood 14: 668, 1959. Cohen, F., Zuelzer, W. W., Neel, J. V., and Robinson, A. R.: Multiple inherited erythrocyte abnormalities in an American Negro family. Hereditary spherocytosis, sickting and thalassemia, Blood 14: 816, 1959. Whitaker, J. A., Windmiller, J., Viette, T., and Sartain, P.: Hereditary spherocytosis associated with sickle cell trait and cholelithiasis, J. PEDIAT. 63: 65, 1963. Kline, A. H., and Holman, G. H.: Hereditary spherocytosis in the Negro, Am. J. Dis. Child. 94: 609, 1957. Matz, J.: Hereditary spherocytosis in the Bantu, South African M. J. 33: 1034, 1959.
SUMMARY
F o u r cases of h e r e d i t a r y spherocytosis associated with sickle cell t r a i t in a N e g r o f a m i l y are r e p o r t e d . S p l e n e c t o m y was perf o r m e d in 3 of the subjects with alleviation of the anemia. T w o h a d gallstones for which cholecystectomy was performed. T h e salient diagnostic features of spherocytosis with h e m o g l o b i n S t r a i t are described a n d the i m p o r t a n c e is m e n t i o n e d of considering this c o m b i n a t i o n as a possibility in the N e g r o p r e s e n t i n g with h e m o g l o b i n AS a n d evidence of h e m o l y t i c disease. O n the basis of this s t u d y it is suggested t h a t the genes for spherocytosis a n d sickling are nonallelic a n d a r e not cIosely linked. REFERENCES
1. Smith, E. W., and Conley, C. L.: Clinical features of genetic variants of sickle cell dis-
2. 3. 4.
5.
6.
7. 8.
593
589
Hereditary qoberocytosis and sickle cell trait in the Negro Four cases o[ hereditary spherocytosis associated with sickle cell trait in a Negro family are reported. The salient diagnostic [eatures o[ spherocytosis with hemoglobin S trait are described and the importance is mentioned o[ considering this combination as a possibility in the Negro presenting with hemoglobin AS and evidence o[ hemolytic disease.
Salud Rodriguez, M.D., Sanford Leikin, M.D., "~ William H. Bullock, M.D., and Clifford Booker, M.D. WAStIINGTON~
D. C.
W I T It T ~ E detection of m o r e cases of h e r e d i t a r y spherocytosis in the Negro, it is probable t h a t increasing numbers of patients will be f o u n d w i t h this red cell defect in association with an a b n o r m a l hemoglobin. Since the first r e p o r t of h e r e d i t a r y spherocytosis c o m b i n e d with sickle cell trait by S m i t h a n d Conley, 1 8 additional cases have been described in the literature. 2-6 I n 1959 Cohen a n d associates ~ studied 3 generations of an A m e r i c a n N e g r o family a n d f o u n d 2 individuals with h e r e d i t a r y spherocytosis a n d sickle cell trait a n d one with this combination a n d w h a t was considered to be thalassemia. Recently, W h i t a k e r a n d co-workers 6 r e p o r t e d the first case of h e r e d i t a r y spherocytosis associated with sickle cell trait a n d cholelithiasis. From the Children's Hospital of the District o/Columbia and the Department o[ Pediatrics, George Washington University School of Medicine, and the Departments o[ Pediatrics and Medicine, Howard University School o[ Medicine. "X'Address, Children's Hospital o] the District o[ Columbia, 2125 13th Street, N. W., Washington, D. C. 20009.
T h e purpose observations on c o m b i n a t i o n of sickle cell trait of an A m e r i c a n
of this p a p e r is to r e p o r t 4 a d d i t i o n a l patients with a h e r e d i t a r y spherocytosis a n d a p p e a r i n g in 3 generations Negro family.
CASE REPORT A 9-year-old Negro girl entered the Children's Hospital of the District of Columbia on Jan. 4, 1964. One week prior to admission she had developed a skin eruption over the thighs and lower abdomen. This was followed 5 days later by fever associated with lethargy, pallor, icterus, and left-sided abdominal pain. The day prior to admission she complained of weakness, the passage of dark urine, and anorexia. Vomiting occurred on the morning of admission. The past history of the patient revealed that she was the product of a full-term pregnancy and uncomplicated delivery. Jaundice was noted shortly after birth and intermittently during her infancy. She was seen in the Outpatient Clinic of Children's Hospital at the age of 4 years and again at 5 years because of respiratory infections. A mild anemia was detected on each occasion, and some microspherocytes and in-
59 0
Rodriguez
April 1966
creased polychromasia were noted on the peripheral blood smear. O n admission to the hospital in 1964 she a p p e a r e d acutely ill. H e r vital signs were as follows: t e m p e r a t u r e 100.4 ~ F.; pulse, 80 per minute; respirations, 20 per minute; a n d blood pressure, 100/60. T h e skin a n d mucous membranes were pale a n d the sclerae icteric. H e a l i n g p y o d e r m a was present on the thighs a n d lower abdomen. T h e r e was mild n u c h a l rigidity. Slight tenderness was present over the left u p p e r a b d o m i n a l q u a d r a n t , a n d the spleen a n d liver were palpable 3.5 and 4 cm., respectively, below the costal margins. T h e p e r t i n e n t laboratory findings are shown in T a b l e I and recorded below: white blood count, 17,000 per cubic millimeter with 71 per cent granulocytes, 12 per cent monocytes, and 17 per cent lymphocytes. T h e platelet count was 130,000 per cubic millimeter. T h e m e a n corpuscle volume was 86 per cubic micron; m e a n corpuscular hemoglobin 31 per micromicrogram; and m e a n corpuscular h e m o g l o b i n concentration, 36 per cent. Polychromasia and microspheroeytes were present on the smear but no sickle forms were seen (Fig. 1). Direct a n d indirect Coombs tests were negative. Alkaline phosphatase was 2.6 units; thymol turbidity, 2 units; and blood urea nitrogen 17 mg. per cent. S e r u m electrolyte concentrations, u r i n a r y findings, a n d the cerebrospnial fluid were within n o r m a l limits. T h e chest x-ray was normal, and roentgen study of the gallbladder revealed no stones. T h e patient was given two transfusions of
packed erythrocytes a n d s y m p t o m a t i c therapy. T h e hemoglobin level rose to 11.4 Gm. per cent, and the platelet count r e t u r n e d to n o r m a l limits. T h e child was discharged on the twentieth hospital day to be followed in the outpatient clinic. Six m o n t h s later she was a d m i t t e d for elective splenectomy. Except for a mild hemolytic crisis which did not require hospitalization, she had d o n e well in the interim. She was given one packed cell transfusion prior to surgery. T h e spleen after removal weighed 4 0 grams and measured 17 by 12 by 4 cm. T h e surface was slightly lobulated and the capsule was smooth and a p p e a r e d grayish purple. O n section the p a r e n c h y m a was reddish purple, fairly firm, and markedly congested. Microscopically, there was a m a r k e d decrease in lymphopoiesis. T h e sinusoids were empty and lined with p r o m i n e n t reticuloendothelial cells. T h e intersinusoidal
Fig. 1. Peripheral blood smear of III-1 showing microspherocytes and absence of sickle forms.
T a b l e I. H e m a t o l o g i c f i n d i n g s of t h e p e d i g r e e
Subject
Hemoglobin
Hema-
(Gin.~ 100 ml.)
tocrit (%)
Reticulocytes (%)
Sickle preparation
Red blood cetl osrno,tic [rap.ility
Hemoglobin
paper electror
Bilirubin (mg./lO0 ml.) Total
I Indirect I Direct
I-1 8.6 28 12.5 Positive Increased AS 3.7 3.1 0.6 II-1 16.0 52 0.1 Negative Normal AA 1.0 0.7 0.3 II-2 9.8 20 2.9 Positive Increased AS 4.6 3.8 0.8 II-3 ~ 4.0 13 6.3 Positive Decreased AS 2.0 1.7 0.3 II-4 4 to 7 Positive Normal II-5 13.8 38 Negative Normal AA II-6 8.4 27 8.4 Positive Increased AS III-1 4.2 12 8.4 Positive Increased AS 5.0 4.3 0.7 III-2 12.8 45 0.4 Negative Normal AA 0.2 0.1 0.1 III-3 12.0 42 0.5 Positive Normal AS 0.2 0.1 0.1 III-4 7.5 26 73 Negative Increased AA § studies were performed 2 months posttransfusion. Examinations performed at an earlier date when all transfused cells had been eliminated revealed 5 per cent hemoglobin F, the remainder being hemoglobin S. We are deeply indebted to Dr. Paul McCurdy for providing this latter information.
Volume 68 Number 4
areas were congested and some cells with suggestive sickling were noted. The patient did well and was discharged on the sixth postoperative day with a hemoglobin level of 11 Gm. per cent and hematocrit level of 33 per cent. FAMILY
STUDIES
The laboratory data on the following individuals is reported in Table I. The family pedigree is shown in Fig. 2. I-1. The maternal grandfather, age 58, Negro, had mild intermittent jaundice and splenomegaly, but is living a normal, active life. Spherocytes and increased polychromasia without sickle forms were seen on his peripheral blood smear. His serum glutamic oxaloacetic transaminase, alkaline phosphatase, and thymol turbidity were within normal limits. I-2. According to the hospital record of III-4, the maternal grandmother had the sickle cell trait. No specific studies are recorded. She had not permitted examinations of her blood by the present investigators. IIol. The father of the proposita, age 31, Negro, was in good health and had no abnormal physical findings. II-2. Mother of the propo.sita, age 33, Negro, had had jaundice with cholelithiasis since 1958. On physical examination pallor, icterus, and splenomegaly were present. A peripheral blood smear revealed spherocytes and increased polychromasia but no sickle forms. Her serum glutamic oxaloacetic transaminase was 500 units; thymol turbidity, 3 units; and alkaline phosphatase, 5.6 units. Subsequent to our examination she was admitted to another hospital because of a hemolytic crisis and pain in the left upper
III
X-
Not investigated
Fig. 2. Pedigree of the family of III-i.
Spherocytosis and sickle cell trait
59 1
quadrant of the abdomen. Radiologic investigation revealed gallstones. She underwent splenectomy and cholecystectomy without difficulty. Follow-up studies 4 months later revealed a hemoglobin level of 13 Gm. per cent and total bilirubin of 1.0 mg. per 100 ml. II-3. An aunt of the proposita, age 31, Negro, had requir~ed numerous transfusions for sickle cell anemia. On physical examination, icterus and a palpable spleen were the only prominent findings. Target cells and sickle forms, as well as increased polychromasia, were present in a peripheral blood smear. Her direct and indirect Coombs tests were negative and no atypical antibodies were detected in her serum. II-4. Another aunt of the proposita, Negro, died in October, 1938, at the age of 12 years. The diagnosis at that time was sickle cell anemia and heart failure. She had been previously hospitalized on 4 occasions, as follows: (1) January, 1931, Anemia, heart murmur, and hepatosplenomcgaly; (2) February, 1931, Tonsillectomy; (3) April, 1931, Splenectomy; microscopically, the spleen showed overt sickling; and (4) April, 1938, Osteomyelitis of the right femur. During this admission her hemoglobin ranged from 4 to 7 Gm. per cent and the icterus index from 7 to 13.5 units. Three osmotic fragilities were reported as normal. Sickle forms were noted on the peripheral blood smear. II-5. Caucasian male, husband of II-6, was clinically well and on investigation exhibited no hematologic abnormality. II-6. Aunt of the proposita, Negro, had had intermittent jaundice throughout her life. She was first seen by us at the age of 26 years because of intermittent right upper quadrant pain. She was moderately icteric and her spleen
5 9 2 Rodriguez
was palpable 4 cm. below the left costal margin. Macrocytes, spherocytes, ovalocytes, and increased polychromasia were found on the peripheral blood smear, but no sickle forms were seen. II-7. Unavailable for study. II-8. Unavailable for study. II-9. Unavailable for study. We were informed, however, that she was anemic. III-1. The proposita. III-2. Sister of the proposita, aged 11, Negro, was in good health and had no abnormal physical findings. III-3. Brother of the proposita, aged 12, Negro, was in good health and had no abnormal physical findings. III-4. Cousin of the proposita, one year of age, was jaundiced shortly after birth. There was no evidence of blood incompatibility but numerous spherocytes were found in the blood smear. An exchange transfusion was performed. She has, subsequently, been clinically well. DISCUSSION
The fact that hemoglobin S is limited to the Negro race and that hereditary spherocytosis affects mainly Caucasians makes the finding of hemoglobin S and spherocytosis in combination both interesting and of practical significance. Actually, within the last 10 years it has become apparent that hereditary spherocytosis in the Negro is not as rare as was once thought. By 1959 44 cases had been accumulated7 including two in African Bantus. 8 We have recently observed another case, and it is highly likely that more will be discovered. This makes the possibility of finding more Negro patients having both hereditary spherocytosis and an abnormal hemoglobin more likely. This report brings t h e total number of cases of congenital spherocytic hemolytic anemia in association with hemoglobin AS to 13. Of these 13, 3 of the cases had cholelithiasis, 2 of which are reported herein. At present there is no specific therapy for patients with hemolytic disease due to abnormal hemoglobins, whereas hemolysis due to hereditary spherocytosis is almost uniformly corrected by splenectomy. It is, therefore, of importance to include a consideration of hereditary spherocytosis in Negro
April 1966
patients with hemolytic disease even in the presence of a positive sickle preparation. The severity of the hemolytic process as evidenced by the hemoglobin level, reticulocyte count, or bilirubin level in this group of patients is not dissimilar from that of other hemoglobinopathies, particularly homozygous S disease. Splenomegaly is rare after the age of 3 to 4 years in homozygous S disease, but it is found at all ages in patients with congenital spherocytosis. In cases of congenital spherocytosis in association with sickle trait, spherocytes are present in the peripheral blood smear and there is an absence of sickle forms. In homozygous S disease sickle forms and target cells are invariably present. The concomitant increased erythrocyte osmotic fragility of spherocytosis precludes most of the common helnoglobinopathies. Hemoglobin electrophoresis is, however, very important in differentiating hemolytic disease due to hereditary spherocytosis from that caused by an abnormal hemoglobin. The information which was presented on I-2 was acquired from the hospital chart of II-4. No further studies on I-2 are available. It is unfortunate that specific laboratory studies could not be obtained to substantiate that the patient had sickle cell trait. II-3, however, had homozygous S disease as evidenced by p a p e r electrophoresis. Moreover, there was good evidence that II-4 probably had homozygous S disease despite the fact that she died before the use of hemoglobin electrophoresis in the differentiation of the hemoglobinopathies. Sickle forms were noted on her peripheral blood smear without the presence of spherocytes, and red cell fragilities were normal on 3 occasions. These facts indicated that I-2 had the sickle gene. It has been proposed that the genes for sickling (fi-S chain production) and spherocytosis are nonallelic, s T h e independent assortment that one finds in this kindred of individuals with hemoglobin A alone, hemoglobin AS without spherocytosis, hemoglobin A with spherocytosis, as well as homozygous S, would support this hypothesis. These find-
Volume 68 Number 4
Spherocytosis and sickle cell trait
ings would also indicate t h a t these genes are on different chromosomes or far a p a r t on the same chromosome.
ease, Bull. Johns Hopkins Hosp. 94: 289, 1954. de Torregrosa, M. V., Ortiz, A., and Vargas, D.: Sickle cell spherocytosis associated with hemolytic anemia, Blood 11: 260, 1956. Jones, B., and Klingberg, W. G.: Hemoglobin S hereditary spherocytosis, J. PEDIAT. 54: 375, 1959. Martin, W. W., Jr., Krough, R. H., and Branche, G. C., Jr.: Hereditary spherocytosis--sicklemia in the Negro; a case report and study of a Negro family having multiple instances of hereditary spherocytosis, Blood 14: 668, 1959. Cohen, F., Zuelzer, W. W., Neel, J. V., and Robinson, A. R.: Multiple inherited erythrocyte abnormalities in an American Negro family. Hereditary spherocytosis, sickting and thalassemia, Blood 14: 816, 1959. Whitaker, J. A., Windmiller, J., Viette, T., and Sartain, P.: Hereditary spherocytosis associated with sickle cell trait and cholelithiasis, J. PEDIAT. 63: 65, 1963. Kline, A. H., and Holman, G. H.: Hereditary spherocytosis in the Negro, Am. J. Dis. Child. 94: 609, 1957. Matz, J.: Hereditary spherocytosis in the Bantu, South African M. J. 33: 1034, 1959.
SUMMARY
F o u r cases of h e r e d i t a r y spherocytosis associated with sickle cell t r a i t in a N e g r o f a m i l y are r e p o r t e d . S p l e n e c t o m y was perf o r m e d in 3 of the subjects with alleviation of the anemia. T w o h a d gallstones for which cholecystectomy was performed. T h e salient diagnostic features of spherocytosis with h e m o g l o b i n S t r a i t are described a n d the i m p o r t a n c e is m e n t i o n e d of considering this c o m b i n a t i o n as a possibility in the N e g r o p r e s e n t i n g with h e m o g l o b i n AS a n d evidence of h e m o l y t i c disease. O n the basis of this s t u d y it is suggested t h a t the genes for spherocytosis a n d sickling are nonallelic a n d a r e not cIosely linked. REFERENCES
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