Study of Proteus Syndrome and Related Congenital Disorders

The purpose of this project is to specifically delineate the phenotype and natural history
and to better understand the genetic etiology of Proteus syndrome (PS) and other overgrowth
disorders hypothesized to be in the AKT/PI3K pathway. As we have recently determined the
molecular cause of PS and the related disorder of fibroadipose overgrowth, our main
objectives moving forward include genotype-phenotype correlations, identifying quantifiable
phenotypic characteristics in patients and measuring changes in these characteristics over
time, developing potential biomarkers for future therapeutic research, and using our new
molecular insights to expand our understanding of both PS and related overgrowth disorders.
The natural history and specific phenotypic characteristics of patients with PS and selected
other overgrowth disorders will be determined by clinical assessment and longitudinal
followup of a cohort of patients. Subjects will be screened for eligibility using published
diagnostic criteria for PS; screening for AKT1 and other pathway gene mutations may be used
in patients with overlapping phenotypes. As well, we hope to identify and thoroughly
phenotype a cohort of patients with molecularly-confirmed AKT1 mutations who may be
candidates for future therapeutic intervention studies. The discovery of the AKT1 activating
mutation in patients with this disease provides us with a very attractive pathway toward
treatment for this devastating disorder. We also propose to expand our clinical ascertainment
to determine the full range of PS/AKT1 activating mutation phenotypes and to study other
overlapping conditions. The etiology of these disorders will be studied using candidate gene
analysis (primarily based on the PI3K/AKT pathway) and possibly exome and whole genome
sequencing (done under protocol 10-HG-0065).

- INCLUSION CRITERIA:

All patients who meet clinical diagnostic criteria for PS, or who have demonstrated AKT1
p.Glu17Lys mutations as well as their biological parents, are considered eligible for this
protocol. As well, we will generally offer an in-person evaluation at the NIHCC to patients
with PS whenever possible.

Patients with overgrowth that is not definitively PS (i.e., who do not appear to meet
clinical diagnostic criteria) and their biological parents may also be eligible to
participate in this study. Decisions to invite patients in this group to the NIHCC for an
in-person evaluation are made on a case-by-case basis where the patient s phenotype,
health, proximity to the NIH, and fit with our current research aims will all be taken into
account. In general, we will consider subjects who have one or more of the manifestations
from the PS clinical criteria as eligible.

There are no exclusions for race, age, or gender for participants.

EXCLUSION CRITERIA:

Patients with cancer but who do not have overgrowth or other non-tumor manifestations of PS
or non-PS overgrowth, whose tumors may harbor AKT1, PIK3CA, or other mutations, are not
eligible for this study. In general, patients who clearly meet diagnostic criteria for a
well-characterized overgrowth syndrome that is NOT PS are not eligible for this study.
Bannayan-Riley-Ruvalcaba syndrome and PHACES syndrome are examples of such entities. We
have no plans to enroll prisoners, fetuses, pregnant women, healthy volunteers, or lab
personnel. Some persons with PS and other overgrowth conditions are intellectually disabled
(ID) or developmentally delayed (probably ~10%). The consent issues are no different for
children with ID than developmentally appropriate children except that assent will be
judged by developmental level instead of age. Probands who are adults and
decisionally-impaired are eligible only if they have a legal guardian who has authority to
sign a consent form on their behalf. Patients who are medically fragile or unable to
tolerate travel to the NIHCC will not routinely be eligible for participation.

Since we enroll people of all ages, some of the women we enroll may become pregnant during
the course of the study. No imaging studies will be done on women if they are known to be
pregnant. No surgical procedures will be undertaken on pregnant women, and we will screen
all women of reproductive age with a pregnancy test prior to surgery, as per standard
surgical practice.

We will request permission to retain some information about prospective participants who
may not be immediately enrolled. As these participants will not immediately be signing a
consent form and joining the study, we propose to NOT count these participants in our
Inclusion Enrollment Reports until they have formally enrolled in the study (that is, they
have signed consent forms).