Patient case: 45-year-old female with Meningioma. Genetic variant: NF2 (K322), AKT1(E17K). Other conditions: None.

Clinical trial: Study of Proteus Syndrome and Related Congenital Disorders

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.

Detailed description: 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).

Eligibility: -  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).

Relevance to patient case: possibly relevant