Vascular malformation rupture in a patient affected by Costello syndrome

Discussion

Considering the rarity of CS, many specialists taking care of this type of patients may have limited experience and some manifestations might go unnoticed. Evidence-based treatment guidelines are lacking and clinical recommendations are often based on expert opinion.7

Once histology confirmed we had faced an acute event of VM rupture, we investigated potential causes. The most common triggering events are hormonal changes and local trauma: the first one is predominant during puberty and, concerning the second one, direct trauma on the same site where the VM ruptured was not present in the patient’s history. Thus, we considered that the VM might have been intrinsically unstable from the structural point of view and that it might had ruptured spontaneously. Although in literature is well known the frequency and type of cardiovascular diseases and malformations present in CS patients,10 to the best of our knowledge, the presence of VMs and especially the occurrence of VM rupture has not been reported.

However, there are two crucial points: first, the CM-AVM syndromes—characterised by vascular (mostly capillary) malformations on face and limbs11—belong to the group of RASopathies, as CS; and, second, the various mutations of the RAS/MAPK pathway finally contribute to altered cell growth and cellular proliferation.12

In general, except for CM-AVM syndromes, the differentiation between the other RASopathies may be challenging. In particular, Noonan and CFC are very reminiscent of CS and differential diagnosis can be difficult, particularly in infancy. However, phenotypic differences become more evident as the patient advances in age. For example, postnatal growth deficiencies and feeding difficulties—although usually less severe—are some of the CFC syndrome features overlapping with CS, together with nystagmus and hypotonia. However, facial and cutaneous dysmorphisms of CFC syndrome are different (i.e., thinner lips, sparse or absent eyebrows, presence of severe atopic dermatitis, absence of papillomata) from CS and, importantly, malignant tumours have not been reported in CFC patients. Concerning Noonan syndrome, short stature in infants and congenital heart defects may be very similar to CS but, at older ages, Noonan syndrome presents with pathognomonic features and disorders (i.e., typical facies, coagulation defects, lymphatic dysplasia, normal or near normal adult height) which are absent in CS.7

Nonetheless, RAS mutations affecting VSMC and endothelial cell (EC) populations might specifically promote instability of the vascular wall structure. VSMCs are the most prominent cell type in the vessel wall, specifically located within the tunica media, where they are surrounded by elastic (mostly) and collagen fibres. In a non-diseased context, VSMCs have a physiological contractile phenotype and they are the main mediators of vascular resistance changes.13 14 The tunica media, thanks to its just mentioned main components (i.e., VSMCs, elastic and collagen fibres), is the layer deputed to architectural support and, consequently, structural stability. Although the effects of specific HRAS mutations in VSMCs have not been clearly described, some studies suggest that alterations of the RAS signalling cascade in this cell population significantly impair cell cycle and cellular proliferation,15 16 possibly, ultimately, weakening structural stability. ECs, instead, live in the tunica intima, the innermost layer of the vessel wall, and they are predominantly deputed to the regulation of vessel permeability and the production of vasoactive mediators. A structurally intact, healthy endothelium has well-known physiological antithrombotic properties17 and, in addition, plays an extremely important role in angiogenesis.18 Similarly to VSMCs, ECs experience lower proliferation rates and altered cell cycle characteristics in case of RAS pathway alterations. For example, it has been reported that R-Ras activation promotes microtubule stability in ECs, via interactions with the protein kinase B (AKT), ultimately stimulating cell proliferation and angiogenesis.19 Notably, Serban et al described a specific contribution of HRAS—the causative gene of CS—in promoting angiogenesis.20

Therefore, considering the known link between the RAS genes with both CS and vascular stability (considering RAS functions in both VSMCs and ECs), we hypothesised that a correlation between CS and vascular events might exist as well. Moreover, considering the above-mentioned molecular functions of the RAS genes, VMs related to CS might also be more susceptible to rupture.

One main limitation of our experience is certainly that of not having performed a genetic analysis of the surgical specimen. CS is, indeed, inherited as an autosomal dominant disorder; however, to date, most cases arise from de novo pathogenic variants, thus siblings are considered to be at low risk. Even though vertical transmission has been reported, these cases are rare, and usually present with an attenuated phenotype.1 In fact, our patient had a negative family history for CS but this would not make the diagnosis less likely. Furthermore, all clinical features—some already present at the time of diagnosis, others developed subsequently—are pathognomonic and further support CS diagnosis, even though we could not effectively evaluate the genetic test performed during his first year of life. For example, facial dysmorphism (epicanthus, strabismus, flattened nose, macroglossia) is very typical.5 The patient also presented a typical combination of musculoskeletal deformities such as foot heel cord contractures, for which he was submitted to surgical lengthening procedures, severe scoliosis and stiff lumbar column, treated with surgical arthrodesis and also hand ulnar deviation (figure 1).6 Furthermore, feeding difficulties became so severe that it became necessary to position a feeding tube from his 1st–5th year of age, as it is often necessary for most CS patients.7 Consistently with the above-mentioned information, the patient presented oncological and cardiac problems typically associated with CS as well. Concerning the first one, at about 20 years of age, he was diagnosed with abdominal rhabdomyosarcoma, very typical of CS patients,21 and submitted to surgical resection and both chemotherapy and abdominal radiotherapies. Specifically, he received four cycles of adjuvant chemotherapy (for a total of about 3 months’ duration) with vincristine, ifosfamide, adriblastine and actinomycin D. Subsequently, therapy was continued with vincristine and irinotecan, though we could not retrieve official documentation concerning the duration of the latest treatment. For maintenance therapy, that lasted 7 months, vinorelbine and cyclophosphamide were chosen. Subsequently, he experienced multiple lung recurrences from the abdominal rhabdomyosarcoma. The first one was treated with surgical lung atypical resection and chemotherapy (2 weeks’ duration cycle with ifosfamide, to be repeated every 4 weeks). The second lung recurrence presented 4 years later, and it was treated with both surgical resection and chemotherapy (ifosfamide in elastomeric pump for 5 months). More recently (7 years later the first diagnosis of rhabdomyosarcoma), he developed bladder polyps (preventively removed considering the risk of progression to bladder carcinoma). Bladder cancer is extremely uncommon in young people, while CS patients have a higher risk.21 Moreover, since childhood, he has been periodically developing HPV-negative papillomas in the perianal region, ultimately treated during the last year. For what concerns cardiac issues, the most common are hypertrophic cardiomyopathy and arrhythmias.22 Although typical hypertrophic cardiomyopathy was excluded and normal systolic function was confirmed, echocardiography revealed diastolic abnormalities of the left ventricles with sigmoid interventricular septum. Recent clinical documentation also revealed he has been developing tachyarrhythmias, currently under pharmacological therapy.

Many elements confirm the diagnosis of CS in this patient, thus strongly indicating the importance of reporting this case for an adequate investigation of future similar cases.

In conclusion, CS patients could have a higher risk of developing structurally unstable VMs and, in the presence of acute development of a painful and pulsatile mass, VM rupture should be suspected.