Introduction

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is a rare autosomal dominant disorder first described in 2003¹. It is caused by heterozygous mutations in RASA1 and EPHB4 genes, and associates multifocal capillary malformations (CMs) with an increased risk for fast-flow vascular malformations (FFVMs) (in the skin, muscle, bone, brain, and spine) that can be life-threatening².

Case report

A 6-year-old girl presented with telangiectasias on the lips as well as multiple (>10) erythematous to brownish irregular macules and patches (largest 5 × 2 cm on the posterior neck), some surrounded by a whitish peripheral halo, located on the face, neck, trunk and superior extremities (Fig. 1). They had no thrill or increased temperature. Lesions started to appear at 18 months of age, progressively increasing in number over time. There were no local or systemic complaints. She was otherwise healthy. Her father had similar cutaneous lesions, as well as her younger brother, paternal aunt, and paternal grandfather (Fig. 2). Genetic testing revealed a heterozygous mutation in the EPHB4 gene, confirming the diagnosis of CM-AVM type 2. She was then referred to cardiology and neurology and performed directed studies (ECG, echocardiography, brain MRI) that did not reveal associated arteriovenous malformations (AVMs). New cutaneous lesions compatible with CMs continue to appear, and the patient maintains regular dermatology and neurology follow-up. No treatment is planned for her cutaneous CMs at this time. Her father and brother were also evaluated with confirmation of the mutation in EPHB4 gene and exclusion of AVMs.

Figure 1 Multiple capillary malformations and lip telangiectasias in a 6-year-old girl. 

Figure 2 Pedigree showing the autosomal dominant inheritance of CM-AVM syndrome in this family. 

Discussion

CM-AVM is a rare autosomal dominant inherited disorder that has been reported in association with heterozygous mutations in the RASA1 gene, which encodes the protein RASp21, and more recently to EPHB4, that signals via RAS/MAPK/ERK1/2 and PI3K/AKT/mTORC1 pathways³. Loss-of-function mutations in EPHB4 cause a similar vascular disorder to RASA1 mutations. The terms CM-AVM 1 and CM-AVM 2 have been proposed for mutations in RASA1 and EPHB4, respectively. CM-AVM 2 seems to be rarer than type 1. In a recent Spanish multicentre study including 64 patients with CM-AVM, only 4 out of 57 that were tested had EPHB4 mutations (and 73% were positive for RASA1 mutations)⁴.

When caused by mutations in EPHB4 gene, the phenotype, CM-AVM type 2, mimics RASA1-related CM-AVM type 1 but also hereditary haemorrhagic telangiectasia (HHT)³,⁵. However, CM-AVM patients do not have frequent epistaxis, the hallmark of HHT³.

Both type 1 and 2 CM-AVM are characterized by multifocal atypical CMs and increased risk for FFVMs. Cutaneous lesions are present in all patients and are generally multiple, pinkish macules or patches, that can exhibit a brownish hue, hypotrichosis, and a perilesional whitish halo. A “herald patch” (one macule/patch significantly larger than the others) has been recently described in 75% of the 64 patients studied by a Spanish group and can be a useful diagnostic clue⁴. CMs may be present at birth but usually gradually appear in early childhood⁶. FFVMs can present in the skin, muscle, bone, brain or spinal cord and rarely are multiple⁴.

Patients with CM-AVM 2 often show a pale central region in the largest skin macules, and a higher prevalence of Bier spots and telangiectasias (especially on the lips but also in the perioral region and on the upper thorax) that CM-AVM 1. Moreover, there is a lower association with FFVMs than in CM-AVM 1 (18% vs. 31%), of which only 3% are cerebral (compared to 10% in CM-AVM 1)³,⁴. Therefore, CM-AVM 2 seems to have a better outcome than type 1⁴.

Evaluation of patients with multiple CMs is challenging because associated AVMs can be life threatening⁷. In addition to a complete family history and physical examination, other subspecialty evaluations may be necessary, especially neurology (to exclude potentially life-threating brain AVMs) and cardiology (since cardiac overload is a potential complication of FFVMs and may occur early in life)⁷. Valdivielso-Ramos et al. recently proposed brain and spinal MRI and genetic testing to all patients with ≥3 CMs, especially in familiar cases⁴.

The present case is a characteristic presentation of CM-AVM 2 syndrome, with progressive appearance of multifocal CMs, lip telangiectasias and a positive family history, without associated extracutaneous FFVMs. An increasing number of atypical skin CMs may be the only sign of CM-AVM and should alert the clinician to further investigate for potential life-threatening AVMs²,⁶. Moreover, close follow-up is warranted, even in patients with CM-AVM 2⁴.