Overview

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.

Eligibility

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