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 determine the natural history and etiology of Proteus syndrome. The natural history and the phenotypic range will be determined by clinical assessment and longitudinal follow-up of a cohort of patients. Subjects will be screened for eligibility using published diagnostic criteria for Proteus syndrome. The determination of the molecular etiology of this disorder will be difficult. It is extremely rare, affected patients have a shortened lifespan, and the disorder is sporadic. Thus the typical approach of positional cloning is not useful. The etiology of this disorder will be studied using various comparative molecular biology techniques including cDNA arrays, genomic arrays, subtractive techniques, testing of candidate genes, and other appropriate techniques. We will also test for dysregulation of growth controlling hormones and binding proteins in vivo.

Note is made that although this protocol is currently structured to recruit only subjects with Proteus syndrome, it was previously used for a more general group of sporadic birth defect syndromes. The original goals for that group have been accomplished, which was the determination of the frequency of submicroscopic chromosomal rearrangements and uniparental disomy. That group of patients (and unaffected parents) is no longer being recruited but the specimens are retained. These specimens will be tested for appropriate candidate genes if, and when, that opportunity should arise.

• Growth Disorder
• Mental Retardation
• Multiple Abnormalies

• Rosenberg M, Hui L, Ma J, Nusbaum HC, Clark K, Robinson L, Dziadzio L, Swain PM, Keith T, Hudson TJ, Biesecker LG, Flint J. Characterization of short tandem repeats from thirty-one human telomeres. Genome Res. 1997 Sep;7(9):917-23.
• Biesecker LG, Rosenberg M, Dziadzio L, Ledbetter DH, Ning Y, Sarneso C, Rosenbaum K. Detection of a subtle rearrangement of chromosome 22 using molecular techniques. Am J Med Genet. 1995 Sep 25;58(4):389-94. Review.
• Biesecker LG, Peters KF, Darling TN, Choyke P, Hill S, Schimke N, Cunningham M, Meltzer P, Cohen MM Jr. Clinical differentiation between Proteus syndrome and hemihyperplasia: description of a distinct form of hemihyperplasia. Am J Med Genet. 1998 Oct 2;79(4):311-8.

• INCLUSION CRITERIA:

For Proteus Patients

All affected subjects should have the following general criteria: mosaic distribution of lesions, progressive course, and sporadic occurrence.

In addition, they should have either 1 from A, 2 from B or 3 from C.

A. Cerebriform connective tissue nevus.

B. Epidermal nevus, Disproportionate overgrowth, specific tumors before the age of 30 years (bilateral. ovarian cystadenomas or monomorphic parotid adenoma).

C. Dysregulated adipose tissue, Vascular malformations, Lung cysts, Facial phenotype.

The Proteus mail-in and Proteus case review subjects must meet the same eligibility standards as those who come to the clinical center and this will be determined by the review of the materials.