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Study of Proteus Syndrome and Related Congenital Disorders

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ClinicalTrials.gov Identifier: NCT00001403
Recruitment Status : Recruiting
First Posted : November 4, 1999
Last Update Posted : May 26, 2023
Children's National Research Institute
Uniformed Services University of the Health Sciences
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) )

Brief Summary:

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.

Condition or disease
Proteus Syndrome PIK3CA Related Overgrowth Spectrum

Detailed Description:
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.

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Study Type : Observational
Estimated Enrollment : 1500 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: The Phenotype and Etiology of Proteus Syndrome
Actual Study Start Date : April 27, 1994

Proteus Syndrome
Patients with Proteus syndrome (PS) and other overgrowth disorders hypothesized to be in the AKT/PI3K pathway

Primary Outcome Measures :
  1. Molecular delineation of disorders under study [ Time Frame: ongoing ]
    Determine causative genotypes of overgrowth disorders

  2. Determination of natural history of disorders under study [ Time Frame: ongoing ]
    Determine natural history of a variety of overgrowth disorders

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Month and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Patients with overgrowth syndromes and, occasionally, unaffected family members for control and genetic studies.@@@

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.


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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00001403

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Contact: Julie Sapp (301) 435-2832 sappj@mail.nih.gov
Contact: Leslie G Biesecker, M.D. (301) 402-2041 lesb@mail.nih.gov

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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Human Genome Research Institute (NHGRI)
Children's National Research Institute
Uniformed Services University of the Health Sciences
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Principal Investigator: Leslie G Biesecker, M.D. National Human Genome Research Institute (NHGRI)
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Human Genome Research Institute (NHGRI)
ClinicalTrials.gov Identifier: NCT00001403    
Other Study ID Numbers: 940132
First Posted: November 4, 1999    Key Record Dates
Last Update Posted: May 26, 2023
Last Verified: February 23, 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Human Genome Research Institute (NHGRI) ):
Growth Disorder
Multiple Abnormalities
Natural History
Additional relevant MeSH terms:
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Proteus Infections
Proteus Syndrome
Pathologic Processes
Enterobacteriaceae Infections
Gram-Negative Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Hamartoma Syndrome, Multiple
Neoplasms, Multiple Primary
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Limb Deformities, Congenital
Musculoskeletal Abnormalities
Abnormalities, Multiple
Congenital Abnormalities