Published online April 3, 2006
PEDIATRICS
Vol. 117
No. 4
April 2006, pp.
e810-e813
(doi:10.1542/peds.2005-1936)
Multifocal Lymphangioendotheliomatosis With Thrombocytopenia: A Rare Cause of Gastrointestinal Bleeding in the Newborn Period
Kurt D. Piggott, MD,
Phillip A. Riedel, MD and
Howard I. Baron, MD
University of Nevada School of Medicine, Sunrise Children's Hospital, Las Vegas, Nevada
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ABSTRACT
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Severe gastrointestinal bleeding in the newborn period is a serious but uncommon phenomenon that has a broad differential diagnosis. In the following case report we describe a rare phenomenon in which a newborn presents with severe hematemesis, hematochezia, and thrombocytopenia that are resistant to repeated platelet and packed red blood cell transfusions. Previous cases have been reported, but none of the patients described presented within the first 8 days of life. The early age of presentation and refractory nature of this disease entity to multiple therapies make it a diagnostic and therapeutic dilemma for all physicians involved in the care of newborns.
Key Words: gastrointestinal bleeding • newborn • thrombocytopenia • multifocal lymphangioedotheliomatosis with thrombocytopenia
Abbreviations: GI, gastrointestinal
Severe gastrointestinal (GI) bleeding in the newborn period is a serious but uncommon phenomenon. The differential diagnosis includes coagulopathies such as hemorrhagic disease of the newborn, milk protein allergy, sepsis, inherited bleeding disorders, necrotizing enterocolitis, intussusception, and vascular anomalies. In 2004, North et al1 reported 3 patients with multifocal, congenital skin and GI tract vascular anomalies. These lesions were remarkably similar, and all were associated with bleeding. Histologic findings on skin biopsy led to the proposed name "multifocal lymphangioendotheliomatosis with thrombocytopenia."
GI bleeding was seen in all 3 previously described patients. One of these patients had profound thrombocytopenia at birth that required platelet transfusion. However, none of these patients experienced GI bleeding within the first 2 weeks of life. Here we report a patient who experienced GI bleeding in the first 8 days of life with similar characteristics to those described by North et al.
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CASE REPORT
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The patient was an 8-day-old Hispanic female born at 38 weeks' gestation by normal spontaneous vaginal delivery. She was the product of a pregnancy complicated only by preterm labor. She was discharged on the second day of life with an uneventful neonatal course. Her diet on discharge consisted of Enfamil with iron, which she was tolerating without complication.
On the day of readmission the patient passed gross blood per rectum. She was otherwise healthy and feeding well and experienced no fever or vomiting. There was no family history of bleeding disorders. On presentation to the emergency department, the patient appeared pale and mildly lethargic. Physical examination revealed a 2-cm area of bruising on the right labia majora and some scattered petechiae on the lower extremities. The remainder of the examination was unremarkable, including no hepatosplenomegaly.
A nasogastric tube was placed and returned a small amount of fresh blood. Initial laboratory investigations revealed a hematocrit level of 16%, a platelet count of 15000/mm3, prothrombin time of 15.8 seconds, and activated partial thromboplastin time of 46 seconds. Intravenous immunoglobulin, platelets, and packed red blood cells were transfused, and the patient underwent a barium enema and upper-GI series, the results of which were normal. Antibiotics were empirically started and discontinued after 48 hours of negative cultures. Ranitidine, sucralfate, and recombinant factor VIIa were started at that time. The patient was placed nil per os, and clinical improvement was seen after transfusion. On day 4 of admission, the bruising of the labia began to resolve. However, multiple cutaneous lesions began appearing on the back and extremities. These lesions appeared as erythematous, red-brown, flat papules that in some cases contained central pallor. Some of the lesions that appeared bright red blanched with pressure, whereas the darker, red-brown lesions did not. The lesions increased in number over a period of days. They ranged in size from 3 to 8 mm (Fig 1). Results from a Meckel's scan and an abdominal ultrasound were normal. Feeding was initiated and was soon followed by the appearance of frank blood in the stool. Aminocaproic acid and methylprednisolone were started, and recombinant factor VIIa was stopped. Endoscopy was performed and revealed multiple punctate, hemangiomatous, red macules with hemorrhagic mucosa (Fig 2). Vincristine and octreotide acetate were added. Endoscopy was repeated later because of an episode of profound hematemesis associated with hypotension that required emergent endotracheal intubation. Endoscopy results were nearly identical, with no active site of bleeding identified. The patient's platelet count and hematocrit level continued to decline, and she required multiple transfusions of platelets and packed red blood cells throughout her hospital stay. Outside telephone consultation resulted in a change in management. The above-mentioned medications were stopped, and transfusion of packed red blood cells, platelets, and fresh-frozen plasma was reserved for active bleeding only. Methylprednisolone 2 mg/kg per day was also started with an expected duration of treatment of 6 to 9 months.
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FIGURE 1 Red-brown cutaneous lesions that are characteristic of multifocal lymphangioendotheliomatosis with thrombocytopenia.
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FIGURE 2 Retroflexed view of the cardia of the stomach showing hemangiomatous lesions with hemorrhagic mucosa.
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A punch biopsy of the skin lesions was performed. Microscopy was consistent with multifocal lymphangioendotheliomatosis. The biopsy demonstrated a delicate network of thin-walled vessels within the dermis and extending into the subcutaneous tissue. The dilated vessels were lined by endothelial cells that in many areas appeared hobnailed. In some areas, endothelial hobnailing was fairly prominent, and small endothelial tufts protruded into vascular lumina (Fig 3). CD31 and CD34 immunostains performed at our center highlighted the lesional endothelial cells. D2-40 and LYVE-1 immunostains (performed by P.E. North, MD) also showed focal staining of these endothelial cells.
The patient showed significant clinical improvement including only a mild drift downward in hemoglobin and persistently hemoccult-negative stools. In addition, she had excellent growth and tolerance of feedings and was discharged from the hospital. She had good follow-up as an outpatient and remained symptom-free for 
1 month. She then presented to the emergency department with hematemesis and was readmitted with a hematocrit level of 14% and a platelet count of 60000/mm3. Once again, packed red blood cells, platelets, and recombinant factor VIIa were transfused. After 2 weeks as an inpatient receiving multiple transfusions, the patient was placed on vincristine. She has been stable over a 2-month period on vincristine and methylprednisolone, as well as ranitidine and sucralfate, and is being managed as an outpatient. There was total resolution of her skin lesions at discharge, and there was no recurrence over this 2-month period.
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DISCUSSION
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Multifocal lymphangioendotheliomatosis with thrombocytopenia has been characterized by multifocal cutaneous and GI tract vascular lesions resulting in severe GI tract bleeding in infancy. A number of other multifocal vascular skin disorders presenting in childhood have been described.2–5 However, none of these disorders have the combination of multifocal cutaneous and GI tract lesions with thrombocytopenia.
The factor that makes this case unique is the age of the patient at presentation. This report adds another disease entity to the differential diagnosis of bleeding in the newborn period. The complications of this disorder and the disorder's apparent resistance to repeated blood and platelet transfusions exemplify its seriousness and complexity.
The pathogenesis of this disorder is unknown. It seems to be a congenital disorder with no familial pattern of inheritance. No patient described to date has had an affected relative, nor was there any family history of bleeding disorders.
The cutaneous and GI lesions present in this disorder have raised questions as to whether they are of vascular or lymphatic origin or possibly both. All 3 patients described by North et al had vascular lesions displaying histologic features consistent with lymphatic endothelial origin and low-grade proliferative activity. Lesional vessels present in these patients were immunoreactive for LYVE-1, a lymphatic endothelial cell–specific marker in normal tissues including skin and in tumor-associated lymphatic vessels.1 This pathologic feature in combination with clinical findings led to the suggested name multifocal lymphangioendotheliomatosis with thrombocytopenia. The alternative possibility of a vascular origin to the lesions raises the question as to whether drugs that prevent or slow vascular proliferation, such as thalidomide, might be helpful in the treatment of this disorder.6
Other cutaneous lesions have been described with a similar histopathologic appearance to those in our patient. However, these previously described lesions were all found to be solitary.7,8 Our patient, along with the 3 patients described by North et al, has skin lesions that are unique in their clinical and histologic appearance and are also more numerous than those seen in other conditions.
All 4 patients mentioned in this discussion experienced multiple episodes of GI bleeding. All patients also experienced recurrent, fluctuating thrombocytopenia that was unresponsive to multiple transfusions. These findings seem to be more consistent with a consumptive process than an autoimmune phenomenon.
The complications of this newly described entity prove to be a new challenge to general pediatricians and subspecialists. Although we are learning more about this disease, it is clear that there is much we do not understand in regard to its treatment and prognosis. Long-term steroid therapy combined with reserving transfusions only for active bleeding has resulted in clinical improvement in our patient. However, much more study is needed to understand the pathogenesis, prognosis, and long-term outcome of this disorder. This brings to light the need for additional research and information sharing in this area so that we all may gain a better understanding of this new clinical entity.
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ACKNOWLEDGMENTS
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We thank Victor Fox and the Vascular Anomalies Group at Children's Hospital of Boston for recommendations regarding the management of our patient and Edith Schmidt, MD, and Ronald Kline, MD, for contributions to this case report.
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FOOTNOTES
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Accepted Oct 13, 2005.
Address correspondence to Howard I. Baron, MD, University of Nevada School of Medicine, Sunrise Children's Hospital, 3196 S Maryland Pkwy, Suite 309, Las Vegas, NV 89109. E-mail: hbaron{at}juno.com
The authors have indicated they have no financial relationships relevant to this article to disclose.
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