Cerebral Cavernous Malformations: The Importance of Cutaneous Manifestations.

Sir,

A 77-year-old man presented with multiple asymptomatic lesions that had appeared progressively over the previous 20 years. He was not aware of any history of cerebrovascular accidents or vascular malformations in his family. Physical examination showed dozens of blue-purple dome-shaped lesions with a soft consistency on the chest, abdomen, back, and right thigh [Figure 1].

Figure 1

Multiple blue-purple nodules of varying sizes on the thorax (a), abdomen (b), back (c), and right thigh (d)

Histopathologic study showed nodular dermal lesions featuring dilated congested blood vessels with different sized lumen and a flat endothelial lining [Figure 2a and b]. Immunohistochemical study was positive for CD31 and negative for D2-40 and WT-1 [Figure 3]. These findings were consistent with vascular malformations.

Figure 2

Biopsy findings of cutaneous venous malformation. (a) Nodular dermal lesion featuring dilated, congested vessels with lumen of varying sizes (hematoxylin-eosin, ×40). (b) Higher magnification view showing vascular lumen separated by fine collagen bands (hematoxylin-eosin, ×200)

Figure 3

Immunohistochemical study. (a) Vascular structures are positive for CD31 (v100), and (b) negative for D2-40 staining (×200) and WT-1 (×100)

Because of the onset in her adulthood of vascular lesions gradually increasing in number, we proposed a brain magnetic resonance imaging (MRI) study, which showed multiple hypointense well-defined lesions consistent with cavernomas [Figure 4a and b]. Cavernoma in the left cerebellar hemisphere showed a mixed single intensity due to bleeding [Figure 4c]. Cavernoma in the right cerebral peduncle showed a typical “popcorn-like” appearance [Figure 4d].

Figure 4

Magnetic resonance imaging (MRI) scan showing multiple hypointense infratentorial and supratentorial lesions (a, b). Note bleeding in the lesion in the left cerebellar hemisphere (white arrow). (c) A “popcorn-like” image in the right cerebral peduncle with a mixed signal intensity core and a peripheral rim of hypointense signal intensity (black arrow) (d)

Cutaneous and radiologic findings were consistent with cerebral cavernous malformations (CCM). The genetic study identified a heterozygous c.1267C>T (p.Arg423*) mutation in exon 13 of CCM1/KRIT1, confirming the diagnosis. This pathogenic variant, which has been previously described, leads to a premature stop codon and consequently a truncated protein.[1]

CCM are characterized by multiple vascular malformations mostly located within the central nervous system but can also involve the skin, retina, or other organs. CCM can occur sporadically or in an autosomal dominant fashion, with variable penetration. Familial CCM include families with several members affected, or a single patient affected but with multiple vascular malformations as in our case. Three genes have been associated with CCM: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10).[23]

Venous cerebral malformations or cavernomas are asymptomatic in up to 40% of cases. Clinical manifestations tend to appear between the third to fifth decade including seizures, headache, and neurological deficits. MRI is the diagnostic technique of choice. A calcified so-called popcorn image is considered pathognomonic for this syndrome.[4]

Cutaneous vascular malformations are seen in 10% of CCM patients, being KRIT1 the most frequently mutated gene in these cases. Hyperkeratotic capillary-venous malformations are the most common and the most specific type of CCM. They are strongly associated with KRIT1 mutation. These lesions are irregularly shaped purple-black hyperkeratotic plaques with an outer bluish ring. Capillary malformations tend to be congenital and manifest as a port wine stain or punctate lesions. Venous malformations may be solitary or multiple. Multiple venous malformations tend to affect adults, as in our case. Capillary and venous malformations are mostly seen in patients with a PDCD10 mutation. Angiokeratomas have also been described in CCM.[45]

The progressive development of multiple vascular cutaneous lesions calls for an exhaustive history to investigate a past or family history of cutaneous or cerebral vascular malformations and neurological manifestations. Depending on the findings, it may then be necessary to order a brain MRI or a CCM genetic study to enable early diagnosis and facilitate appropriate treatment and genetic counseling where necessary.[35]

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The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.