Somatic Overgrowth & Related Syndromes

Genomics and Pathology Services (GPS) offers somatic variant analysis by next-generation sequencing for segmental overgrowth, skin lesions, vascular malformations, brain abnormalities, McCune Albright and related syndromes.

Results provide physicians with useful information to better manage difficult-to-diagnose patients.


Indications for Testing

Indications for testing include symptoms of any of the following:

  • Bannayan-Riley-Ruvalcaba syndrome (BRRS)
  • Cowden syndrome
  • Congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies (CLOVES)
  • Curry-Jones Syndrome
  • Epidermal nevi and seborrheic keratoses
  • Garcia-Hafner-Happle Syndrome
  • Hemimegalencephaly Klippel-Trenaunay syndrome (KTS)
  • Macrocephaly–capillary malformation (M-CM)
  • Maffuci Syndrome
  • McCune Albright Syndrome (MAS)
  • Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH)
  • Ollier Disease
  • Proteus syndrome
  • Schimmelpenning-Feuerstein-Mims

Test Order Options

Focused vs. Comprehensive Analysis – The gene content of each orderable test is not changing (see gene lists below), but we have changed the way in which we analyze the sequencing data. Since many of these DoSM share phenotypes related to overgrowth, vascular malformations, and/or skin lesions, we have found that reflexive reanalysis of an expanded set of genes known to be driving DoSM improves the diagnostic yield for compelling cases with initially negative findings. Based on this experience, we
believe that client-driven decisions at the time of ordering will result in a faster and more efficient diagnostic outcome. Our revised requisition now contains selectable options for sequence data analysis: 1) selection of a focused analysis will result in the evaluation of only the gene(s) included in the ordered subset. A negative result will trigger reporting of a negative finding (no pathogenic or likely pathogenic variants) or inconclusive finding (variants of unknown significance); 2) selection of comprehensive analysis includes an initial evaluation of the focused gene(s) only, and if a pathogenic or likely pathogenic (P/LP) variant is identified, the analysis ends and a report is generated. However, if no P/LP variants are initially identified from the ordered subset, then a comprehensive analysis automatically occurs, and any P/LP variants identified from our comprehensive list of 37 DoSM-associated genes is reported. If no P/LP variants are identified after comprehensive analysis, we generate a report with negative or inconclusive findings.

Available Tests and Gene Lists

**Focused panel gene lists are below. Please note that the Comprehensive Panel for each orderable focused subset includes all 37 genes on the larger Mosaicism Disorders Panel (AKT1, AKT2, AKT3, BRAF, CBL, FGFR1, FGFR2, FGFR3, GNA11, GNAS, GNAQ, HRAS, IDH1, IDH2, KRAS, MAP2K1, MAP2K2, MAP3K3, MTOR, NF1, NRAS, PDGFRB, PIK3CA, PIK3R1, PIK3R2, PTEN, PTPN11, RAF1,  RASA1, RIT1, SHOC2, SMO, SOS1, SPRED1, TEK, TSC1 and TSC2).

Somatic Overgrowth Panel – Focused

25 genes sequenced including AKT1, AKT2, AKT3, BRAF, FGFR1, GNA11, GNAQ, HRAS, IDH1, IDH2, KRAS, MAP2K1, MAP3K3, MTOR, NRAS, PDGFRB, PIK3CA, PIK3R1, PIK3R2, PTEN, RASA1, SMO, TEK, TSC1 and TSC2.

PIK3CA-Related Overgrowth Spectrum Disorders – Focused

1 gene sequenced PIK3CA.

McCune Albright Syndrome – Focused

1 gene sequenced GNAS.

Nevus Panel – Focused

12 genes sequenced including BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, HRAS, KRAS, MAP3K3, NRAS, PIK3CA and TEK.

Curry-Jones Syndrome – Focused

1 gene sequenced SMO.

Maffucci Syndrome Panel – Focused

2 genes sequenced including IDH1 and IDH2.

Rasopathies Panel – Focused

14 genes sequenced including BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1 and SPRED1.

Testing Methodology

All tests are performed using targeted hybridization capture coupled with next-generation sequencing (NGS) in our CAP accredited/CLIA certified clinical genomics labs for deep, comprehensive coverage of all coding exons of ordered genes.

Types of variation detected include single nucleotide variants (SNVs) small insertions and deletions (indels).

This test is routinely performed using formalin fixed paraffin embedded (FFPE) or fresh tissues and is able to detect alterations down to 1% allele fraction in affected tissues. A buccal swab may be considered in certain circumstances if affected tissue is not available, however sensitivity may be significantly limited. Please contact us prior to submitting buccal swabs for primary analysis.

Results and Interpretation

DNA sequence data are analyzed by GPS’ clinically validated bioinformatics pipeline to identify and annotate genetic variants associated with segmental overgrowth syndromes.

Variants are interpreted by a board-certified clinical genomicists in the context of the patient’s disease. Those that are most likely to account for the observed clinical phenotype based on evidence from the medical literature are highlighted.

Results are returned to the ordering physician in a concise report.

The turnaround time for NGS testing on the primary tissue is 3 weeks from the time a specimen arrives. Positive results are confirmed on blood by Sanger sequencing which may take an additional 4 weeks.

Specimen Requirements

**Primary specimen type required: tissue from the affected area.  Please call the laboratory for further information. In addition, 2-5 mL of peripheral blood in a lavender-top EDTA tube is requested to allow for comparative study.

Acceptable materials for submission include disease involved tissue in the form of a formalin fixed paraffin embedded (FFPE) tissue block, fresh tissue in transport or tissue culture media or buccal swab.

Tissue fixation protocols must be compatible with molecular testing; EDTA decalcification is acceptable, acid decalcification is not.

Kits for testing on peripheral blood and buccal cells are available upon request.

***Already extracted DNA can be accepted only with laboratory approval. The isolation of nucleic acids for clinical testing must have occurred in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or the CMS.

Request specimen kit  »

Clinical Utility

While many genetic disorders are caused by inherited DNA variants (germline), it is increasingly apparent that many rare disorders arise through genetic changes that occur during embryonic and fetal development in a subset of cells; so called somatic variants that are distributed according to the embryological segmental pattern.

Such is the case in disorders associated with somatic variation in the PI3K/AKT/mTOR pathway, a critical regulatory pathway for cellular proliferation, mobility and survival.

The phenotypic consequences of such somatic variation include fibroadipose overgrowth, vascular malformations, epidermal nevi, skeletal abnormalities, and megalencephaly, among other clinical findings. Somatic variation within the PI3K/AKT/mTOR pathway has been described in individuals diagnosed with M-CM, CLOVES, HMEG and Proteus syndrome, among others.

McCune-Albright is rare disorder characterized by a triad of clinical features including fibrous dysplasia, café au lait spots, and precocious puberty. Somatic variation within the GNAS gene, which encodes the stimulatory alpha subunit for a guanine nucleotide binding protein (G protein), results in the observed clinical features associated with McCune-Albright due to constitutive activation of adenylate cyclase.

Due to the somatic nature of these disorders testing is strongly recommended from affected tissue.

Next-generation sequencing provides clinicians with a powerful tool to manage patients with these diagnostically challenging disorders.