PEDIATRICS
Vol. 74 No. 4 October
1 984
527
Twin Transfusion
Syndrome
Causing
Cutaneous
Erythropoiesis
Joel
L. Schwartz,
MD, William
M. Maniscalco,
MD, Alfred
T. Lane,
MD,
and William
J. Currao,
MD
From the Dermatology Unit, Department of Medicine, and Neonatology Unit, Department
of Pediatrics, University of Rochester School of Medicine and Dentistry,
Rochester, New York
ABSTRACT. Two cases of twin transfusion syndrome are
described in which the donor twin exhibited blueberry
muffin-like macules and papules associated with
cuta-neous erythropoiesis. No evidence was found in either case for intrauterine viral infection, the most common
cause of cutaneous erythropoiesis. Cutaneous
erythropoi-esis is these two cases is considered to be due to
persist-ence or reactivation of fetal dermal erythropoiesis
sec-ondary to prolonged, severe intrauterine anemia.
Pedi-atrics 1984;1974:527-529; twin transfusion syndrome,
cu-taneous erythropoiesis, blueberry muffin skin lesions,
in-trauterine anemia.
Blueberry muffin skin lesions are 2- to 8-mm bluish-red or magenta-colored macules and papules. In the newborn, these lesions are seen in a variety of noninflammatory cellular infiltrating diseases, including the malignancies of congenital leu-kemia”2 and neuroblastoma.’ Cutaneous erythro-poiesis, of nonmalignant causes is most often as-sociated with intrauterine viral disease, especially rubella.4 In a single case reported in the literature,5 intrauterine anemia due to spherocytosis, has been associated with cutaneous erythropoiesis. We re-port two cases of twin transfusion syndrome in which prolonged intrauterine anemia in the donor twin was associated clinically with a blueberry muf-fin-like rash, and, histologically with cutaneous
erythropoiesis.
CASE REPORTS
Case I
Female twins were born to a 27-year-old gravida 1,
para 0, blood type A, Rh-positive mother at 37 weeks of
gestation. Maternal rubella titers were reported as
ade-quate. Pregnancy was not complicated by known viral exposures, maternal illness, or rash. After a normal labor and vaginal delivery, twin A, who weighed 2,380 g, was
noted to be plethoric. Twin B, a 1,200-g female infant,
was extremely pale and had generalized edema and
hepatomegaly. Also noted on twin B were bluish, papular
skin lesions, about 5 mm in diameter, distributed over the face and trunk. Twin B had Apgar scores of 2 (one
minute) and 4 (five minutes). She was immediately
in-tubated and received an emergency transfusion of 20 mL
whole blood. The hematocrit after the transfusion was
27% but no reticulocyte count was performed. A double-volume exchange transfusion with packed RBCs was performed which resulted in elevation of her hematocrit to 48%. She had persistent congestive heart failure and
severe metabolic acidosis, however, and died four hours
after birth. Twin B’s blood type was A, Rh positive. Twin
A had a central hematocrit ofSO%, but had an uneventful
course following a partial reduction transfusion. Findings
from an autopsy of twin B revealed generalized edema, severe cardiomegaly, and hepatomegaly. Widespread
ex-tramedullary hematopoiesis was observed in the kidneys,
adrenal glands, liver, spleen, and skin lesions. The hem-atopoietic cellular infiltrate in the skin was located in the
dermis and subcutaneous fat and consisted almost en-tirely of various stages of normoblasts, although a few
myeloid precursors were also seen. The placenta was monochorionic and diamnionic.
Case 2
Received for publication Aug 1, 1983; accepted Nov 15, 1983.
Reprint requests to (A.T.L.) Dermatology Unit, P0 Box 697, University of Rochester Medical Center, 601 Elmwood Aye,
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PEDIATRICS (ISSN 0031 4005). Copyright © 1984 by the American Academy of Pediatrics.
Twin A was a 1,720-g female infant transferred to
Strong Memorial Hospital Neonatal Intensive Care unit
at 16 hours of age for evaluation of a suspected congenital
infection. She was the product of a 36-week gestation
that was complicated by maternal urinary tract infection,
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TWIN TRANSFUSION SYNDROMEbut no known viral exposure or rash. Maternal rubella
titer indicated immunity at two weeks of gestation.
Se-rologic testing for syphilis was negative. Maternal blood type was A, Rh negative. Delivery was by cesarean section
because of breech presentation. Apgar scores were 1 (one
minute) and 8 (five minutes). Abnormalities on initial
physical examination included weight and length below the fifth percentile; the respiratory rate was 72/mm and
the heart rate was 138 beats per minute; magenta, non-blanching papules, approximately 5 mm in diameter, were most prominent on the face, trunk, and proximal
extrem-ities (see Figure). The patient was noted to have a grade
II systolic murmur heard best at the lower left sternal border. The liver was palpated 3 cm below the right costal
margin. Initial laboratory evaluation showed a hematocrit
of 32% (the other twin’s hematocrit was 86%); WBC count was 6,600/FL with 24 neutrophils and 19 band cells. The platelet count was 7,000/L; the reticulocyte
count was 17.6% with 540 nucleated RBCs/100 WBCs.
The infants’s blood type was A, Rh positive, with a
negative direct Coombs’ test. The patient received a
transfusion of packed RBCs and was transferred to
Strong Memorial Hospital for evaluation of a probable congenital infection. The other female twin had a birth
weight of 2,590 g and normal findings on physical ex-amination. After a reduction transfusion, she had an
uneventful hospital course.
Evaluation of twin A at Strong Memorial Hospital
confirmed her previously noted physical findings. The hematocrit was 30%, the WBC count was 10,700/1L, and
the platelet count was 70,000/tL, the reticulocyte count
was 11.5% and the nucleated RBCs were 340/100 WBCs.
Rubella titer was positive at a 1:64 dilution. Urine culture for cytomegalovirus was negative and toxoplasmosis titer was also negative. Epstein-Barr virus titer was not
ob-tamed. Blood and urine bacterial cultures were also
neg-ative. Findings from a chest roentgenogram showed car-diomegaly and a small pleural effusion on the right. The patient received another transfusion of packed RBCs and was treated with diuretic therapy with resultant
improve-ment in her respiratory symptoms. Repeated hematocrit levels after the transfusion were normal. The nucleated
Figure. Facial lesions photographed at 24 hours of age
(case 2).
RBC counts remained elevated, however. A skin biopsy
of a papular lesion was performed. After three days, the patient was returned to the community hospital where
her subsequent course was uneventful.
Pathologic evaluation of the placenta revealed a spec-imen weighing 1,130 g, diamnionic, monochorionic, and
consistent with twin-to-twin transfusion. The umbilical vessels were normal for both twins.
A3-mm punch biopsy was performed on a barely raised magenta papule on the posterior right thigh. The epider-mis and papillary dermis were normal. The deep dermis
and the septae of the subcutaneous fat were infiltrated with normoblasts. No platelet or myeloid precursors, nor any inflammatory cells were detected. Touch preparation
at the time of biopsy showed clumps of normoblasts in various stages of differentiation including
dyserythro-poietic cells.
DISCUSSION
Perfusion of monochorial twin placentas shows twin-to-twin vascular anastomoses with consider-able frequency.6 Unbalanced placental circulation,
favoring one of the twins over the other, is termed “the twin transfusion syndrome.” More than 10% of monochorial twin pregnancies exhibit the twin transfusion syndrome, which accounts in large
mea-sure for the greater fetal and neonatal risk in mon-ochorial than in dichorial twin gestation.7 The syn-drome can be diagnosed when there is obvious plethora in one twin and pallor in the other, to-gether with a hemoglobin difference of greater than
5 g/100 mL.
In twin live-born births, the majority of deaths are attributable to complications of prematurity. When the complications of prematurity are not too severe or can be controlled, the twin transfusion
syndrome itself tends to be a benign condition. The most common major complications-including con-gestive heart failure, hyperbilirubinemia, and res-piratory distress-are in the twin with polycythe-mia.7
The live-born donor twin is mostly at risk for the complications of anemia in the newborn. When anemia is present, a transfusion can be performed with good results. Most donor twins, however, are not anemic and do not require a transfusion.8 This
is attributable to the extraordinary erythropoietic potential of many tissues in the newborn, especially the liver and the spleen which function as major erythropoietic organs embryologically.9
The skin is also an organ of erythropoiesis during embryologic development. Beginning at the 8-mm stage, erythroblastic differentiation proceeds from undifferentiated dermal mesenchyme at perivascu-lar and periadnexal localization. This continues
until approximately the fifth month, when
myelo-poietic differentiation also begins in the dermis,
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ARTICLES
529
and erythroblastic elements seem to be phagocy-tized by developing leukocytes.’#{176}
Persistence of dermal erythropoiesis in the donor twin due to the stress of prolonged severe intra-uterine anemia is proposed as the pathophysiologic mechanism involved in the two cases detailed in this report. Congenital viral infections are an un-likely etiology, because in both cases, the recipient twin was not affected, and in both cases maternal rubella titers indicated immunity. In case 2, the anemia is unlikely to be due to Rh disease. The course was incompatible with isoimmune hemolytic anemia, the mother was primagravida, and, more-over, both twins had the same blood type yet only the donor twin was anemic. The thrombocytopenia in this case is not readily explained, but may be due to splenomegaly secondary to extramedullary erythropoiesis.
Not all donor twins from pregnancies compli-cated by the twin transfusion syndrome would be expected to exhibit blueberry muffin lesions of cu-taneous erythropoiesis. The erythropoietic stress would need to be both chronic and severe, corre-sponding to that subgroup of donor twins with a birth weight of less than 80% of their partner, and with the associated laboratory finding of reticulo-cytosis as seen in case 2.8
Persistence of dermal hematopoiesis due to intra-uterine anemia has previously been proposed as the pathophysiologic mechanism in a case of blueberry muffin rash associated with hereditary spherocy-tosis.5 There are, as yet, no reports of cutaneous hematopoiesis in other severe hereditary anemias, nor in erythroblastosis fetalis. Perhaps, in eryth-roblastosis fetalis, maternal anitbody destroys cir-culating human erythroid progenitor cells that might otherwise infiltrate and develop within the skin. However, the destruction of such progenitor cells would be expected to require expression of the rhesus antigen; such expression has not been dem-onstrated.” At the other end of the age spectrum, recurrence of dermal hematopoiesis has been doc-umented in several cases of myelofibrosis.’2” Whether this represents a response to prolonged, severe anemia from bone marrow failure, or a ma-lignant clone of cells is unclear.
In the neonate, the most common cause of blue-berry muffin lesions is cutaneous erythropoiesis, not due to intrauterine anemia, but rather due to intrauterine viral infection. This has been docu-mented both with congenital rubella’4 and with congenital cytomegalovirus infection.4 Blueberry muffin macules and papules can be seen in disorders other than cutaneous erythropoiesis, including con-genital leukemia2 and neuroblastoma.3 Because in-trauterine infection and malignancy are considered, skin biopsy of blueberry muffin lesions in the neo-nate should be performed.
ACKNOWLEDGMENTS
The authors thank Drs Jan E. Muhlbauer and Anthony Cecalupo for reviewing the pathology slides.
REFERENCES
1. Pierce MI: Leukemia in the newborn infant. J Pediatr
1959;54:691-706
2. Zussman, WV, Khan A, Shayesteh P: Congenital leukemia.
Cancer 1967;20:1227-1233
3. Hawthorne HC, Nelson JS, Witzleben CL, et al: Blanching
subcutaneous nodules in neonatal neuroblastoma. J Pediatr
1970;77:297-300
4. Brough AJ, Jones D, Page RH, et al: Dermal erythropoiesis in neonatal infants: A manifestation of intrauterine viral disease. Pediatrics 1967;40:627-635
5. Argyle JC, Zone JJ: Dermal erythropoiesis in a neonate.
Arch Dermatol 1981;117:492-494
6. Bhargava I, Chakravavty A: Vascular anastomoses in twin placentas and their recognition. Acta Anat 1975;93:471-480
7. Rausen AR, Seki W, Strauss L: Twin transfusion syndrome.
J Pediatr 1965;66:613-628
8. Tan KL, Tan R, Tan SH, et al: The twin transfusion
syndrome. Clin Pediatr 1979;18:111-114
9. Patten BM: Human Embryology. New York, McGraw-Hill, Inc, 1968, pp 503-509
10. Popoff L, Popoff N: L’hemopoiese cutanee an cours de la vie intra-uterine. Ann Dermatol Venereol 1958;85:157-167
1 1. Rearden A, Chiu P: Lack of rhesus antigen expression by human committed erythroid progenitors. Blood 1983;61:525-529
12. Kuo T, Uhlemann J, Reinhard EH: Cutaneous extramedul-lary hematopoiesis: Report of a case. Arch Derrnatol
1976;112:1302-1303
13. Ortonne JP, Jenne R, Perrot H: Myeloid metaplasia of the skin in two patients suffering from primary myelofibrosis. Arch Dermatol 1977;113:1459
14. Klein HZ, Markarian M: Dermal erythropoiesis in congen-ital rubella. Clin Pediatr 1969;8:604-607
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1984;74;527
Pediatrics
Joel L. Schwartz, William M. Maniscalco, Alfred T. Lane and William J. Currao
Twin Transfusion Syndrome Causing Cutaneous Erythropoiesis
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1984;74;527
Pediatrics
Joel L. Schwartz, William M. Maniscalco, Alfred T. Lane and William J. Currao
Twin Transfusion Syndrome Causing Cutaneous Erythropoiesis
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