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Abstract

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

Capillary malformation–arteriovenous malformation (CM-AVM) syndrome is an autosomal dominant disorder caused by mutations in RASA1. Multifocal, small, round-to-oval, pinkish-to-red cutaneous capillary malformations are seen in more than 90% of people with RASA1 mutations. These RASA1-associated cutaneous capillary malformations (CMs) can accompany internal or cutaneous arteriovenous malformation (AVM) or arteriovenous fistula to constitute CM-AVM syndrome. The cutaneous capillary malformations in CM-AVM syndrome are unusual in that some lesions have high-flow characteristics (according to Doppler or a white halo). We describe the histopathologic and corresponding ultrasound and Doppler findings in a CM from a patient with clinical CM-AVM syndrome and show that an arterial component is not present in the dermis or the most superficial portions of the subcutaneous fat but that there is ultrasound evidence that an AVM resides in the underlying adipose tissue.

Although cutaneous capillary malformations (CMs) are common, those associated with RASA1 mutations are characteristically multifocal, small, round to oval, and pinkish to red [2]. The CMs may be solitary in a small minority of cases [2], and some CMs have a small white halo, suggesting vascular steal (high flow with direct arteriovenous shunting), and others have fast flow according to Doppler [3]. CMs may be the only finding in some affected individuals [4], but arteriovenous malformations (AVMs) or arteriovenous fistulas (AVFs) were seen in 18.5% of the 140 reported patients with RASA1 defects in a study by Revencu et al [2], including 7.1% with intracerebral AVMs or AVFs. These fast-flow AVMs or AVFs are detectable with magnetic resonance imaging (MRI), Doppler, or angiography; potentially serious complications can include bleeding and neurologic problems. Symptomatic AVMs or AVFs may present at birth or during the first year of life; a study of 101 patients with confirmed RASA1 mutations found six intracranial AVMs or AVFs, five of which presented with various symptoms before the first year of life [2]. Parkes Weber syndrome (a cutaneous stain, underlying AVF, and resultant overgrowth of the affected limb) is seen in some families with CM-AVM syndrome [3], and patients with Parkes Weber syndrome have been shown to have RASA1 mutations [1, 2, 5]. Herein we report the histopathologic and ultrasound characteristics of a CM in a patient with CM-AVM syndrome. We know of only one article in the literature that has mentioned the histopathology of a CM in CM-AVM; it presented a photomicrograph of a skin biopsy and noted dilated capillaries in the papillary dermis [5].

Case Report

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

A 7-year-old African American boy with a history of perianal vitiligo and positive tuberculin test was referred for evaluation of numerous asymptomatic pink patches that had developed over the preceding 3 months. He had been born with several similar-appearing pink macules and patches and had recently developed many more lesions on his trunk, upper and lower extremities, and face. He had no history of neurologic problems or AVMs and his parent, sibling, and distant relative history was negative for AVM, cerebral hemorrhage, and neurologic problems. His mother and numerous maternal aunts had similar skin lesions, all asymptomatic. His only medication was prophylactic isoniazid for the positive tuberculin test. On physical examination, he had 24 pink-to-red oval-to-round macules and patches ranging in size from 3 to 20 mm in largest diameter, clinically consistent with small CMs. Most blanched incompletely with diascopy, whereas a brownish discoloration remained in a few. Several of the lesions exhibited arterial flow with a handheld Doppler, and a few of the lesions had a blanched halo surrounding them. There was a 4.5-cm × 1.5-cm incompletely blanchable dark red patch over the midline lumbosacral back. This congenital lesion also demonstrated fast flow with Doppler. None of the lesions produced a thrill or felt warmer than the adjacent skin on palpation. There was a 4-cm, white, round depigmented perianal patch consistent with vitiligo. The lip, oropharynx, eye, and neurologic examination were normal. MRI of the brain and lumbar spine with and without contrast failed to demonstrate any structural or vascular anomalies. The family refused an MRI of the cervical and thoracic spine.

A punch biopsy including a small portion of superficial subcutaneous fat was performed on a representative 1.5-cm red patch on the right posterior arm that had demonstrated fast flow with Doppler interrogation (Fig. 1). Histopathologic findings were of minimally dilated dermal vessels (Fig. 2A). The vessels in the middermis were slightly larger than the vessels in the upper dermis, where no discernible dilation was present. No erythrocytes were visible in the vessel lumens. The vessels were lined by a single layer of endothelial cells, and muscular walls were not visible. Staining for smooth muscle actin highlighted the vessel pericytes (Fig. 2B), but there was no prominent muscular layer. D2-40 and CD31 staining were largely unremarkable; background lymphatics were positive with D2-40, and all vessels were positive with CD31. No prominent increase in vessel density was apparent. We obtained multiple sections through the biopsy block and could not find notable differences between the sections.

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Figure 1. A representative 1.5-cm red patch on the right posterior arm.

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Figure 2. Capillary stain. (A) A punch biopsy specimen shows minimally dilated vessels in the dermis lined by a single layer of endothelial cells (hematoxylin and eosin, original magnification 10×). (B) Smooth muscle actin staining highlights the pericytes (original magnification 4×).

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Three lesions, including the biopsied lesion on the right arm demonstrating fast flow with Doppler interrogation in the office, were evaluated using ultrasound and color Doppler. Ultrasound indicated a well-defined, mixed, predominantly hyperechoic lesion beneath each CM within the subcutaneous tissues, with no large vascular lakes or channels identified (Fig. 3A). Color Doppler examination revealed an arterial waveform, consistent with a mixed AVM beneath the cutaneous marks (Fig. 3B).

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Figure 3. Radiologic examination. (A) Ultrasound image of the biopsy site in the right posterior arm demonstrates a well-defined, mixed, predominantly hyperechoic lesion within the subcutaneous tissues. No large vascular lakes or channels are identified. (B) Doppler examination of the right posterior arm lesion demonstrates an arterial waveform consistent with a mixed AVM.

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Discussion

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References

The histopathologic findings of the CM from our patient with CM-AVM syndrome have some characteristics of a CM, with minimally dilated vessels lined by a single layer of endothelial cells. It is also conceivable that the vessels represented in the biopsy are dilated dermal vessels above a deeper vascular lesion, which findings on ultrasound and Doppler examination of a mixed AVM directly below this dermal stain in the subcutaneous tissue would support.

The presence of vascular steal, the absence of typical histologic CM findings, and ultrasound evidence of a subcutaneous AVM suggest that the pink patches in CM-AVM syndrome are a manifestation of an underlying AVM and not that of a capillary malformation. The clinical characteristics of the biopsied capillary stain from our patient are compatible with a stain over an AVM. The histopathology of AVM, even in the quiescent phase, is different from that of a CM; the early stage of an AVM shows thickened vessel walls with a prominent smooth muscle actin–positive muscular layer [6]. Vessels may show an exaggerated branching pattern, high density, or both [6]. Generally there are no erythrocytes in the lumens. The absence of erythrocytes is thought to be compatible with fast flow [6], although the earliest stage of an AVM is likely to manifest histopathologically as minimally dilated microvasculature, as in hereditary hemorrhagic telangiectasia [7]. Although we cannot state with certainty that the lesions we studied are representative of all skin lesions in CM-AVM, the evidence supports that all pink stains are manifestations of AVMs. These lesions appear to be harmless cutaneous manifestations of the CM-AVM syndrome, but are potential signs of a serious AVM or AVF.

Although CM-AVM syndrome has come to greater attention since the RASA1 gene mutation was reported in 2003, it is still an underrecognized syndrome. Clinicians treating patients with AVM or AVF have generally paid little attention to small cutaneous marks. There is evidence that the prevalence of CM-AVM syndrome may be high in children with AVMs. In a study of 30 families with children who experienced cerebral hemorrhage due to AVM, CMs were found in both the cerebral hemorrhage patients and their relatives in three families; in nine additional families CMs were not found in the cerebral hemorrhage patients themselves but were present in their relatives [8]. AVMs or AVFs may remain undetected until a potentially fatal hemorrhage, and the identification of the characteristic CMs of CM-AVM syndrome can alert clinicians to look for asymptomatic AVMs or AVFs and perhaps ultimately prevent hemorrhagic episodes.

References

  1. Top of page
  2. Abstract
  3. Case Report
  4. Discussion
  5. References