Parkes Weber syndrome associated with two somatic pathogenic variants in RASA1

• Published in: Cold Spring Harbor molecular case studies 2020-08, Vol.6 (4), p.a005256
• Main Authors: Flores Daboub, Josue A., Grimmer, Johanes Fred, Frigerio, Alice, Wooderchak-Donahue, Whitney, Arnold, Ryan, Szymanski, Jeff, Longo, Nicola, Bayrak-Toydemir, Pinar
• Format: Article
• Language: English
• Subjects: Autosomal dominant inheritance; Deoxyribonucleic acid; DNA; Endothelium; Enlargement; Heredity; Magnetic resonance imaging; Muscles; Research Report; Soft tissues; Tissues; Ultrasound
• ISSN: 2373-2865; 2373-2873
• DOI: 10.1101/mcs.a005256

Parkes Weber syndrome is associated with autosomal dominant inheritance, caused by germline heterozygous inactivating changes in the RASA1 gene, characterized by multiple micro arteriovenous fistulas and segmental overgrowth of soft tissue and skeletal components. The focal nature and variable expressivity associated with this disease has led to the hypothesis that somatic “second hit” inactivating changes in RASA1 are necessary for disease development. We report a 2-yr-old male with extensive capillary malformation and segmental overgrowth of his lower left extremity. Ultrasound showed subcutaneous phlebectasia draining the capillary malformation; magnetic resonance imaging showed overgrowth of the extremity with prominence of fatty tissues, fatty infiltration, and enlargement of all the major muscle groups. Germline RASA1 testing was normal. Later somatic testing from affected tissue showed two pathogenic variants in RASA1 consistent with the c.934_938del, p.(Glu312Argfs*14) and the c.2925del, p.(Asn976Metfs*20) with variant allele fractions of 3.6% and 4.2%, respectively. The intrafamilial variability of Parkes Weber syndrome involving segmental overgrowth of soft tissue, endothelium, and bone is strongly suggestive of a somatic second-hit model. There are at least two reports of confirmed second somatic hits in RASA1 . To our knowledge, this is the first report of an individual with two somatic pathogenic variants in the RASA1 gene in DNA from a vascular lesion.