The Phenotype and Etiology of Proteus Syndrome

  • participants needed
  • sponsor
    National Human Genome Research Institute (NHGRI)
Updated on 18 September 2022


This study will examine rare congenital disorders that involve malformations and abnormal growth. It will focus on patients with Proteus syndrome, whose physical features are characterized by overgrowth, benign tumors of fatty tissue or blood vessels, asymmetric arms or legs, and large feet with very thick soles. The study will explore the genetic and biochemical cause and course of the disease, the changes in symptoms over time, and the effects of the disease on patients.

Patients with Proteus syndrome and their parents may be eligible for this study. Parents will be studied, when possible, for comparison of molecular findings. Study candidates will have a medical history and physical examination, including X-rays and possibly other imaging tests, such as computerized tomography (CT), magnetic resonance imaging (MRI) and ultrasound. Other tests and examinations may be done if needed.

Those enrolled in the study will have will be interviewed or complete questionnaires, or both, about how their disease affects them. (Parents will be asked about their feelings about having a child with a rare disorder.) Patients will provide a small blood sample for research and may be asked to undergo biopsies from a normal area of skin and from a tumor.


The purpose of this project is to specifically delineate the phenotype and natural history and genetic etiology of Proteus syndrome (PS) and other overgrowth disorders hypothesized to be in the PI3K/AKT 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 follow-up of patients, which includes patients who have been exposed to therapeutic agents, such as an AKT inhibitor. 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. The discovery of the AKT1 activating mutation in patients with this disease provides an attractive target for directed treatment for this devastating disorder. This protocol aims to aid in identifying individuals with molecularly-confirmed AKT1 mutations who may be candidates for pharmacologic interventional studies. 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, performed as part of protocol 10-HG-0065.

Condition Proteus Syndrome, PIK3CA Related Overgrowth Spectrum
Clinical Study IdentifierNCT00001403
SponsorNational Human Genome Research Institute (NHGRI)
Last Modified on18 September 2022


Yes No Not Sure

Inclusion Criteria

All patients who meet clinical diagnostic criteria for PS, or who have demonstrated AKT1
p.Glu17Lys mutations 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
As these disorders are usually apparent at or soon after birth, and appear to evolve at
least into the third decade of life, early assessment and long-term follow-up are
necessary. We have already learned that PS has a high pediatric mortality rate. PS and
other overgrowth disorders are progressive and for some individuals, may warrant more
frequent observation during youth and adolescence. Therefore, it would not be practicable
or ethical to exclude children from enrollment
Patients with overgrowth that is not definitively PS (i.e., who do not appear to meet
clinical diagnostic criteria) 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
There are no exclusions for race, age, or gender for participants
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
Enrollment of adults with impaired decision-making capacity is scientifically justified
because PS is an ultra-rare disorder where 10-15% of patients have significant cognitive
impairment and gaining a better understanding of this aspect of the phenotype (as well as
the other concerns adult patients may present with) is critical to advancing our knowledge
of this disorder. Progression of overgrowth, particularly the fibroadipose overgrowth in
CLOVES syndrome, is a significant issue in many adults with this condition and
understanding the trajectory of overgrowth throughout the lifespan is an important goal of
this study
This protocol enrolls participants of all ages which includes women of child-bearing age
We recognize that women may become pregnant during the course of this study. While we have
not documented a case of a female with Proteus syndrome becoming pregnant it is important
to gather clinical data if such a case occurs in order to better understand the natural
history of Proteus syndrome and related disorders
Since we enroll people of all ages, some of the women we enroll may become pregnant during
the course of the study. No radiation imaging studies will be done on women if they are
known to be pregnant. We will screen all women of reproductive age with a pregnancy test
prior to surgery, as per standard surgical practice

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
will not enroll prisoners, 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. Patients 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
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)
routinely be eligible for participation
We will not enroll neonates (newborns less than one month old)
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