Proteus SyndromeNCT00001403
Study of Proteus Syndrome and Related Congenital Disorders
An observational study of Proteus Syndrome and PIK3CA Related Overgrowth Spectrum, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 month to 99 years
- Conditions the study is for
- Proteus Syndrome, PIK3CA Related Overgrowth Spectrum
- How many people
- 1,500 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Apr 1994to not given
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 month to 99 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: Patients with overgrowth syndromes.
Who may be able to join
- All patients who meet clinical diagnostic criteria for PS, or who have demonstrated AKT1 p.Glu17Lys variants 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.
Who cannot join
- 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 variants, 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).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
Official title: The Phenotype and Etiology of Proteus Syndrome
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 may be eligible for this study. 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 may be interviewed or complete questionnaires, or both, about how their disease affects them. Patients will provide a small blood sample for research.
Read the 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 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 variants may be used in patients with overlapping phenotypes. The discovery of the AKT1 activating variant 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 variants 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 variant 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.
- Keywords
- Sporadic, Mosaic, Growth Disorder, Progressive, Multiple Abnormalities, Natural History
- Medical subject headings
- Proteus Syndrome, Growth Disorders, Abnormalities, Multiple
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Proteus Syndrome | Patients with Proteus syndrome (PS) and other overgrowth disorders hypothesized to be in the AKT/PI3K pathway |
What is being measured
The primary outcome is the main question the study is designed to answer.
Molecular delineation of disorders under study
Determine causative genotypes of overgrowth disorders
Measured: ongoing
Determination of natural history of disorders under study
Determine natural history of a variety of overgrowth disorders
Measured: ongoing
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Nov 1999 (estimated)
- Study start27 Apr 1994
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Proteus SyndromeStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 1,500 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National Human Genome Research Institute (NHGRI)
- Sponsor type
- US National Institutes of Health
- Collaborators
- Children's National Research Institute, Uniformed Services University of the Health Sciences
- Responsible party
- Sponsor
- Investigators
- Leslie G Biesecker, M.D., Principal investigator, National Human Genome Research Institute (NHGRI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00001403
- Sponsor's protocol ID
- 940132
- Other IDs
- 94-HG-0132
- Status last verified
- 8 Sep 2026
- First submitted
- 3 Nov 1999
- Last updated
- 5 Nov 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Verling SD, Gaidici N, Biesecker LG, Darling TN, Ours CA. Clinical Characterization of Skin Findings on the Hands in Proteus Syndrome. Pediatr Dermatol. 2026 Jun 14. doi: 10.1111/pde.70281. Online ahead of print.
PubMed 42289769Keppler-Noreuil KM, Burton-Akright J, Kleiner DE, Sapp JC, Lindhurst MJ, Han CG, Biesecker LG, Gochuico BR. Phenotypic Features of Cystic Lung Disease in Proteus Syndrome: A Clinical Trial. Ann Am Thorac Soc. 2022 Nov;19(11):1871-1880. doi: 10.1513/AnnalsATS.202111-1214OC.
PubMed 35839129Ours CA, Sapp JC, Hodges MB, de Moya AJ, Biesecker LG. Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome. Cold Spring Harb Mol Case Stud. 2021 Dec 9;7(6):a006134. doi: 10.1101/mcs.a006134. Print 2021 Dec.
PubMed 34649967
Study at a glance
From the registry record, last updated by the sponsor on 5 Nov 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Phenotype and Etiology of Proteus Syndrome
- ClinicalTrials.gov ID
- NCT00001403
- Acronym / sponsor ID
- 940132
- Keywords
- Sporadic, Mosaic, Growth Disorder, Progressive, Multiple Abnormalities, Natural History
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 1,500 participants (estimated)
- Lead sponsor
- National Human Genome Research Institute (NHGRI)US National Institutes of Health
- Collaborators
- Children's National Research Institute, Uniformed Services University of the Health Sciences
- Study start
- 27 Apr 1994 (actual)
- First posted
- 4 Nov 1999 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 may be eligible for this study. 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 may be interviewed or complete questionnaires, or both, about how their disease affects them. Patients will provide a small blood sample for research.
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 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 variants may be used in patients with overlapping phenotypes. The discovery of the AKT1 activating variant 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 variants 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 variant 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.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Proteus Syndrome | – | –Patients with Proteus syndrome (PS) and other overgrowth disorders hypothesized to be in the AKT/PI3K pathway |
Who may qualify
- Ages
- 1 month to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- Patients with overgrowth syndromes.
Key inclusion criteria (7 listed)
- All patients who meet clinical diagnostic criteria for PS, or who have demonstrated AKT1 p.Glu17Lys variants 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.
Key exclusion criteria (3 listed)
- 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 variants, 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Molecular delineation of disorders under study
Time frame: ongoing
Determine causative genotypes of overgrowth disorders
Determination of natural history of disorders under study
Time frame: ongoing
Determine natural history of a variety of overgrowth disorders
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Nov 2026.
- Derived from this study: PubMed 42289769Verling SD, Gaidici N, Biesecker LG, Darling TN, Ours CA. Clinical Characterization of Skin Findings on the Hands in Proteus Syndrome. Pediatr Dermatol. 2026 Jun 14. doi: 10.1111/pde.70281. Online ahead of print.
- Derived from this study: PubMed 35839129Keppler-Noreuil KM, Burton-Akright J, Kleiner DE, Sapp JC, Lindhurst MJ, Han CG, Biesecker LG, Gochuico BR. Phenotypic Features of Cystic Lung Disease in Proteus Syndrome: A Clinical Trial. Ann Am Thorac Soc. 2022 Nov;19(11):1871-1880. doi: 10.1513/AnnalsATS.202111-1214OC.
- Derived from this study: PubMed 34649967Ours CA, Sapp JC, Hodges MB, de Moya AJ, Biesecker LG. Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome. Cold Spring Harb Mol Case Stud. 2021 Dec 9;7(6):a006134. doi: 10.1101/mcs.a006134. Print 2021 Dec.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
Related trials for Proteus Syndrome
Active, not recruitingPhase 2
MK-7075 (Miransertib) in Proteus Syndrome
Proteus Syndrome
Active, not recruitingPhase 2
A Study of the Safety and Tolerability in Participants With PIK3CA-related Overgrowth Spectrum or Proteus Syndrome Who Are Being Treated With Miransertib (MK-7075) in Other Studies (MK-7075-006)
PIK3CA-Related Overgrowth Spectrum (PROS)/Proteus Syndrome (PS)
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Leslie G Biesecker, M.D. principal investigator
National Human Genome Research Institute (NHGRI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Proteus Syndrome and PIK3CA Related Overgrowth Spectrum, run by National Human Genome Research Institute (NHGRI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 5 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Julie C Sapp ((301) 435-2832, sappj@mail.nih.gov), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Molecular delineation of disorders under study (time frame: ongoing). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00001403, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Nov 2026.