A Clinical, Molecular Genetic and Coagulation study in patients with Klippel-Trenaunay Syndrome and related entities

Klippel-Trenaunay syndrome (KTS) is a congenital malformation syndrome
characterised by combinations of vascular malformations (capillary, venous,
lymphatic malformations), and localized disturbed growth of bone and soft
tissues. Clinical presentation varies extensively. Occurrence is usually
sporadic. The recognition of KTS is important because of its possible
thrombotic complications. The pathogenesis of KTS is still unclear.
In an earlier part of the present study the clinical characteristics of 100
persons with KTS have been studied, radiological studies of blood vessels have
been performed, and coagulation studies performed in a subset of patients.
Molecular analysis was done in all patients and included a large set of genes
involved in growth and blood vessel formation. No significant abnormality has
been found.
Recently mutations have been found in AKT1 in patients with Proteus syndrome
[Biesecker et al, N Engl J Med, in the press]. Proteus syndrome resembles KTS
to a great extend both in tissues involved and distribution of manifestations;
the difference is that Proteus syndrome patients are more severely affected.
AKT1 is known to be involved in colon cancer and several other cancers in case
of loss-of-function mutations. In Proteus syndrome gain-of-function mutations
have been found. Importantly the mutations were not detectable in lymphocytes
but only in other tissues.

Detection of mutations in AKT1 in patients with KTS

The study will be performed in two steps:
- first, in 5 adult patients buccal swabs and skin biopsies will be studied
for mutations. Patients are already participating in the earlier part of the
study
- the second step depends on the results of the first step: if mutations will
be detectable both in buccal tissue and fibroblasts, a series of 25 patients
will be investigated using buccal swabs only. If mutations will be detectable
only in fibroblasts, a series of 25 patients will be investigated using skin
biopsies. Blood samples of all participating patients are already available and
will be studied for mutations as well. All patients are already participating
in the earlier part of the study.

buccal swabs: no risk
skin biopsy: very limited risk for infection and keloid formation. No pain if
biopsy is performed under local anaesthesia. Only the formation of a scar of
3mm in diameter located at the inner part of the lower arm is a permanent
sequella. As the benefit for the group of findings genes is considerable, and
possibly even the patients themself may have benefit of the results of the
biopsy if pharmacogenomics allows more directed thera[py, we consider it
acceptable to perform a skin biopsy in a small series of patients.