This retrospective study was undertaken to characterise the types of vascular anomalies that occur in patients with a PTEN
mutation, thereby expanding the phenotype of PHTS. Macrocephaly and penile freckling are well‐known features.5
All of our patients who had their head circumference measured were macrocephalic, and all male patients who were fully examined had penile freckling. Previous studies of PTEN
‐positive BRRS patients had documented macrocephaly in all patients, but penile freckling had been noted in only 67–85% of patients.6,27
This study was not designed to examine the prevalence of the various clinical features seen in patients with a PTEN
mutation. Nevertheless, it is of note that at least 8 of 26 (31%) patients had thyroid involvement in the form of multinodular goitre, thyroid adenoma or thyroid cancer. Similarly, 8 of 26 patients had gastrointestinal polyps, none of which was found to be malignant. Some authors have reported an association between PTEN
mutation and autism,11,28
and our findings support these observations.
The terminology for the extracranial vascular anomalies in these patients is controversial. Although radiologically these lesions have features of fast‐flow vascular malformations, histopathologically, they appear to be disordered growths of blood vessels, adipose and fibrous tissue, with a low level of proliferation. Therefore, we elected to use the generic term “anomaly” to describe these lesions, recognising that further radiological, histopathological and molecular studies should provide a more precise nosology.
We identified vascular anomalies in 54% of our patients with a PTEN mutation, although none of them had haemangiomas or other “pure” vascular tumours. This relatively high frequency could be due to selection bias, as the Vascular Anomalies Center, Children's Hospital Boston, is a major referral centre. Moreover, it is likely that asymptomatic patients will not be tested for the mutation. For example, two of our patients were found to have the mutation only after their children had been diagnosed with PHTS.
In the patients who underwent angiography, the deep vascular anomalies were all fast‐flow with some degree of arteriovenous shunting. There was a spectrum of findings, ranging from infiltration of the affected tissue with fine, tortuous arterial and venous channels and a tissue blush, to direct arteriovenous fistulae with massive enlargement of the proximal draining veins (termed arteriovenous or arteriolovenous). We believe that the angioarchitecture in these vascular anomalies is relatively unique, characterised by the unusual segmental dilatation of the draining veins. In contrast, arteriovenous anomalies in patients without a PTEN mutation exhibit diffuse, smooth dilatation of the draining veins. Moreover, cross‐sectional imaging (MRI, CT and ultrasonography) showed that the intramuscular vascular anomalies in our patients disrupted the muscular architecture and had excessive disorganised ectopic fat. Non‐syndromic intramuscular AVMs are usually associated with symmetrical overgrowth of the affected muscle, without an eccentric mass effect, and are not accompanied by excess adipose tissue. Involvement of multiple non‐contiguous sites, seen in 57% of the PTEN positive patients, is also very uncommon in patients with non‐syndromic AVM.
DVAs are usually considered normal anatomical variants of no clinical significance. Nonetheless, the fact that 8 of 9 of our patients who had brain MRI with contrast were found to have DVAs is striking. Further brain imaging studies are needed to determine the true prevalence and significance of DVAs in these patients. Cavernous vascular malformations are known to occur in association with DVAs, as noted in one of our patients,29
but the pathogenesis of these two entities appears to be different.30
This study was not designed to examine the neuroanatomical characteristics of patients with PTEN mutations. Nonetheless, it is noteworthy that, other than Arnold–Chiari I malformation in 2 patients (one of whom only had a cervical spine MRI), no other structural brain abnormalities were seen in the 14 patients who underwent a brain MRI for a variety of indications, including global developmental delay or mental retardation.
Heterozygous deletion of PTEN
in mouse endothelial cells increases the sensitivity of the cells to various vascular growth factors, resulting in enhanced angiogenesis and growth of tumours.31
These murine studies could explain the predisposition to vascular anomalies in our patients. Other experiments in mice have also shown that anti‐angiogenic therapy can diminish adipose tissue,32
suggesting that the ectopic fat in vascular anomalies may be due to the increased angiogenesis caused by a PTEN
gene encodes a lipid phosphatase that mediates cell‐cycle arrest and apoptosis. PTEN has two key domains, an N‐terminal phosphatase domain encoded by exons 1–6, and a C‐terminal domain encoded by exons 6–9, which is involved in protein–protein interactions.33
Marsh et al.9,10
reported that mutations in exons 5, 7 and 8 of the PTEN
gene together accounted for 63–75% of the pathogenic mutations, with 31–50% of all mutations occurring in exon 5. In contrast, only 50% of our patients had mutations in exons 5, 7 and 8. Moreover, 23% of our patients had mutations in exon 6, compared with only 6–13% in previous reports (table 4).9,10
Exon 6 lies at the interface between the phosphatase domain and the N‐terminal domain involved in the binding of phospholipids. It is a highly conserved region, and mutations in that region result in reduction in the activity of the phophatase against phosphatidylinositol‐(3,4,5)‐triphosphate (PI(3,4,5)P3
). This suggests an important role for exon 6 in the binding of PI(3,4,5)P3
Table 4Distribution and types of mutations in PTEN identified by previous studies and in our study
R173 in exon 6 is one of the eight most commonly mutated residues in patients with PTEN‐related tumours, suggesting that the integrity of the interface is important for the function of PTEN. It is therefore interesting that of our six patients with mutations in exon 6, two had both thyroid carcinoma and intestinal polyps, one had both multiple thyroid nodules and intestinal polyps, and another had thyroid carcinoma with only a solitary thyroid nodule. In contrast, the only patient in our series with a mutation in R173 had neither thyroid carcinoma nor thyroid nodules and did not have intestinal polyps.
This study has documented a high frequency of deep vascular anomalies in patients with a PTEN mutation. These extracranial vascular anomalies are almost all fast‐flow and have consistent, unusual features, including multifocality (involvement of multiple non‐contiguous sites), musculoskeletal location, ectopic adipose tissue and drainage into disproportionately dilated veins. Multifocality is not a feature of non‐syndromic AVM. Clinicians who care for these patients should consider regular monitoring for vascular anomalies. MRI, with MRA, is appropriate for the initial evaluation of a suspicious lesion.
In conclusion, our study suggests that all patients who present with fast‐flow vascular anomalies or who have multiple DVAs on brain MRI should have their head circumference measured, and male patients should also be examined for penile freckling. Those who are macrocephalic or have penile freckling should be considered candidates for PTEN testing. MRI should be used to evaluate symptomatic mass lesions. Multiple fast‐flow vascular anomalies, the presence on MRI of ectopic fat with disruption of the architecture of the affected muscles, and angiographic finding of disproportionate dilation of the immediate draining veins appear to be the typical features of these lesions. These radiological features should also prompt consideration for PTEN testing. A molecular diagnosis of PTEN mutation is critical because these patients have an increased risk of malignancy, even when they are relatively young, as suggested by our three patients who developed thyroid carcinoma in their early teenage years. Timely identification of these patients also facilitates the diagnosis of asymptomatic carriers and enables physicians to institute appropriate surveillance for thyroid, breast and endometrial cancers for all people found to have a PTEN mutation.