Volume 92 Number 6

B r i e f clinical a n d laboratory observations

6. Hatch FE, Azar SH, Ainsworth TE, Nardo JM, and Culbertson JW: Renal circulatory studies in young adults with sickle cell anemia, J Lab Clin Med 76:632, 1970. 7. Statius vanEpps LW, Pinedo-Veels C, DeVries GH, and DeKonig J: Nature of the concentrating defect in sickle-cell nephropathy, Lancet 1:450, 1970. 8. Barreras L, Diggs LW, and Lipscomb A: Plasma volume in sickle cell disease, South Med J 59:456, 1966.

Classical Fanconi anemia in a family with hypoplastic anemia Frederick P. Li, M.D.,* and Nancy Upp Potter, R.N., Boston, Mass.

IN 1 947, Estren and D a m e s h e k 1 described five siblings who developed hypoplastic anemia at 6 to 10 years of age; the proband was the sole survivor. No birth defects were found in these five children or in nine other healthy siblings. The authors suggested that the patients had a genetic disease distinct from Fanconi anemia. Recent follow-up of the family slaeds new light on the diagnosis.

9. Hatch FE, Cultertson JW, and Diggs LW: .Nature of the renal concentrating defect in sickle cell disease, J Clin Invest 46:336, 1967. 10. Barron DH: The pressure gradient and pulse in the vascular system, in Ruch TC, and Fulton JF, editors: Medical physiology and biophysics, ed 19, Philadelphia, 1960, WB Saunders Company.

the thumbs and first metacarpals, webbing between the second and third toes, and retarded growth during childhood. At 10 years of age, she developed aplastic anemia. Laboratory studies showed a hemoglobin of 2.2 gm/dl, platelet count of 10,000/ mm 3, and white count of 2,300/ram 3 with 46% neutrophils, 52% lymphocytes, 1% eosinophils, and 1% monocytes. A bone marrow aspirate was hypocellular. Chromosome analysis of the peripheral blood revealed no aneuploidy, and the frequency of breaks and rearrangements was not recorded. Autopsy after a fatal subarachnoid hemorrhage showed a hypocellular marrow and one additional anomaly: incomplete fissuring of both lungs. The final diagnosis was Fanconi anemia. The father of the proband (Patient 7) developed carcinoma of the larynx at age 77 years, and his mother (Patient 4) died with colon cancer at age 84. No blood dyscrasia or cancer has developed in the nine surviving siblings of the proband (Patients 16-24) or their mother (Patient 8). The four siblings of the child with Fanconi anemia (Patients 26 to 29) are healthy except for a heart murmur in Patient 28. The family has refused additional studies. COMMENT

CASE REPORTS After the publication, the proband (Patient 15) had a complete clinical remission of hypoplastic anemia (Fig. 1). Fourteen years later (age 24), he had normal peripheral blood-counts at the time of hospitalization for pleurisy. However, he developed cough, weight loss, and intermittent hemoptysis at 28 years of age. The platelet count was 18,000/mm 3, and the other peripheral blood counts were normal. The patient did not respond to corticosteroid therapy, and died one month later with pneumonia and pulmonary hemorrhage. The bone marrow at autopsy showed almost no megakaryocytes and slight diminution of other cellular elements. A child (Patient 25) in the paternal side of the family developed aplastic anemia in 1968. Her parents were second cousins; the child's coefficient of inbreeding is 0.016. In addition, each parent was a cousin of the five siblings with hypoplastic anemia. Born at term, the child's weight (2.1 kg) and length (46 cm) were below the third percentile, and head circumference (33 cm) was below the tenth percentile. She had bilateral absence of From the Clinical Epidemiology Branch, National Cancer Institute; and the Sidney Farber Cancer Institute. Supported in part by the Amy Potter Fund. *Reprint requests: 35 Binney St., Boston, MA. 02115.

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9 1978 The C. V. Mosby Co.

Several studies have described constitutional aplastic anemia as a heterogeneous group o f pancytopenias in childhood.2. 3 This diagnosis encompasses the following clinical conditions: (1) classical Fanconi anemia with associated birth defects, (2) congenital amegakaryocytic thrombocytopenia with pancytopenia later in childhood, and (3) familial hypoplastic anemia without demonstrable congenital anomalies? -~ The present family has been cited frequently as an example of the last condition? -7 However, the new data on this family suggest that the affected siblings carried at least one gene for Fanconi anemia. The homozygous state for Fanconi anemia in Patient 25 is very likely due to inbreeding. U n d e r this assumption, the probability of carrying a gene for Fanconi anemia would be 1.0 in Patients 3 to 6, and 0.5 in the father of the siblings (Patient 7). Furthermore, hypoplastic anemia in five of the 14 siblings could be explained by inheritance of this gene, and an additional defect from the mother (Patient 8). Maternal influences may have limited gene expression in the siblings to the hematologic component of the syndrome. Alternatively, the maternal gene may be

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Brief clinical and laboratory observations

The Journal of Pediatrics June 1978

after a complete remission of hypoplastic anemia. Followup of other survivors of hypoplastic anemia is needed to define the course of the disease after apparently successful therapy. We thank Dr. John Mulvihill for comments on the manuscript.

REFERENCES

_

25

26,27 28,29

[]

MALE

(~

FEMALE

HYPOPLASTIC ANEMIA

(~ CLASSICAL FANCONI ANEMIA [ ~ = ~ CONSANGUINITY



NINE PERSONS, EITHER SEX

~

PROBAND

Fig. 1. Abridged pedigree of the family. allelic to that for classic Fanconi anemia, i.e., the affected siblings are double heterozygotes. The chance of two unrelated, rare inherited hematologic disorders in the family is small. Mortality from aplastic anemia is highest in the first year after diagnosis of the disease." Thereafter, patients are at high risk of death from acute nonlymphocytic leukemia, 3'~ liver tumors after androgen therapy,'`" or recurrence of marrow aplasia. In the present family, Patient 15 died with severe thrombocytopenia 18 years

Hemoglobin A2 in early childhood P. Angelova-Gateva and M. Marinova,* Sofia, Bulgaria

THE PHYSIOLOGIC F U N C T I O N of hemoglobin A~ is not fully understood. Most authors agree that normal values for Hgb A2 are about 2.3 to 4% of the total hemoglobin, or about 459 m g / d l in adults. '' ~ Because of increased interest in the use of Hgb A2 values for the evaluation of iron deficiency in childhood and to determine the physiologic patterns during early

From the Medical Academy, Research Institute of Pediatrics Biochemical Laboratory.

1. Estren E, and Dameshek W: Familial hypoplastic anemia of childhood, Am J Dis Child 73:671, 1947. 2. Shahidi NT, and Diamond LK: Testosterone-induced remission in aplastic anemia of both acquired and congenital types, N Engl J Med 264:953, 1961. 3. O'Gorman Hughes DW: Aplastic anaemia in childhood, Med J Aust 1:519, 1974. 4. Hirschman RJ, Shulman NR, Abuelo JG, and Whang-Peng J: Chromosomal aberrations in two cases of inherited aplastic anemia with unusual clinical features, Ann Intern Med 71:107, 1969. 5. Sarna G, Tomasulo P, Lotz MJ, et al: Multiple neoplasms in two siblings with a variant form of Fanconi's anemia, Cancer 36:1029, 1975. 6. Zaizov R, Matoth Y, and Maroon Z: Familial aplastic anaemia without congenital malformations, Acta Paediatr Scand 58:151, 1969. 7. Killander A, Lundmark KM, and Sjolin S: Idiopathic aplastic anaemia in children, Acta Paediatr Scand 58:10, 1969. 8. Swift M: Fanconi's anaemia in the genetics of neoplasia, Nature 230:370, 1971. 9. Li FP, Alter BP, and Nathan DG: The mortality of acquired aplastic anemia in children, Blood 40:153, 1972. 10. Mulvihill JJ, Ridolfi RL, Schultz FR, Borzy MS, and Haughton PBT: Hepatic adenoma in Fanconi anemia treated with oxymetholone, J PEDIATR87:122, 1975.

childhood we studied Hgb A2 levels in children 14 days to 3 years of age, and compared them with adult v a l u e s Y I MATERIAL

Abbreviation Used Hgb: hemoglobin AND METHODS

A group of 154 children from 14 days to 3 years of age and 16 adults between 20 and 40 years of age were studied. We determined the total hemoglobin value by the method of Crosby and Cannan,`" the fetal Hgb by the method of Singer, and the A2 and A~~ by separation on cellogel (Chemetron) in 1.10M phosphate bufer, p H = 8. The hemoglobin concentration was obtained from capillary blood erythrocytes drawn in physiologic saline with pH = 7.4 (in 0.01M phosphate buffer) washed three times and hemolyzed in water with chloroform. 2' `" The children studied were reared in a nursery, were clinically healthy, and had had no illness for two weeks

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Classical Fanconi anemia in a family with hypoplastic anemia.

Volume 92 Number 6 B r i e f clinical a n d laboratory observations 6. Hatch FE, Azar SH, Ainsworth TE, Nardo JM, and Culbertson JW: Renal circulato...
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