IllnessOvergrowth, segmental - PIK3CA; differential diagnosis

NGS +

[Sanger]

The PIK3CA-related overgrowth spectrum includes a number of clinical findings whose main features are congenital or early childhood segmental/focal overgrowth with or without cellular dysplasia. These include hemi-megalencephaly, fibroadipose hyperplasia and congenital lipomatous overgrowth, vascular malformations, epidermal nevi and skeletal or spinal anomalies (CLOVES syndrome). The syndrome includes overgrowth of adipose tissue in the abdomen, often with a reddish mole on the skin and abnormalities of the blood vessels, skin and bones. As in Klippel-Trenaunay syndrome, megalencephaly-capillary abscess formation and epidermal nevus, PIK3CA mutations occur somatically as a mosaic. Proteus syndrome is important in the differential diagnosis albeit a rare disorder with usually asymmetric overgrowth of bone, skin and other tissues. Newborns with Proteus syndrome rarely have symptoms. The overgrowth becomes evident at 6-18 months of age and continues to increase lateron. The pattern of overgrowth varies widely, but can affect almost any part of the body. The bones of the limbs, skull and spine are often affected. The disease can also cause a variety of skin growths, especially cerebriform connective tissue naevi. Vascular and adipose tissue may also grow excessively in Proteus syndrome. These patients may have neurological symptoms including mental retardation, seizures and visual disturbances as well as prominent facial features, various benign tumors and deep vein thrombosis. Proteus syndrome results from AKT1 somatic mutations. Mutations in the PTEN gene do not result in Proteus syndrome; instead, patients suffer from PTEN hamartoma tumor syndrome with segmental overgrowth, lipomatosis, arteriovenous malformations and epidermal naevi (SOLAMEN syndrome or segmental Cowden syndrome type 2). The complex differential diagnosis for the abovementioned and similar disorders includes a number of additional genes as well. Altogether the molecular genetic diagnostic yield of this comprehensive gene panel is unknown; it depends largely on the quality of the patient's clinical workup. Therefore, a negative DNA test result may not exclude the clinical diagnosis.

References: https://www.ncbi.nlm.nih.gov/books/NBK153722/

https://www.ncbi.nlm.nih.gov/books/NBK99495 /

https://www.ncbi.nlm.nih.gov/books/NBK396098/

https://www.ncbi.nlm.nih.gov/books/NBK1488/

• Alias: PIK3CA-related overgrowth syndrome
• Allelic: Basal cell carcinoma, somatic (RASA1)
• Allelic: Breast cancer, somatic (AKT1, PIK3CA)
• Allelic: CLAPO syndrome, somatic (PIK3CA)
• Allelic: CLOVE syndrome, somatic (PIK3CA)
• Allelic: Colorectal cancer, somatic (AKT1, PIK3CA)
• Allelic: Cowden syndrome 1 [Bannayan-Riley-Ruvalcaba] (PTEN)
• Allelic: Cowden syndrome 5 (PIK3CA)
• Allelic: Cowden syndrome 6 (AKT1)
• Allelic: Diabetes mellitus, type II (AKT2)
• Allelic: Focal cortical dysplasia, type II, somatic (MTOR)
• Allelic: Gastric cancer, somatic (PIK3CA)
• Allelic: Hepatocellular carcinoma, somatic (PIK3CA)
• Allelic: Keratosis, seborrheic, somatic (PIK3CA)
• Allelic: Lhermitte-Duclos syndrome (PTEN)
• Allelic: Macrodactyly, somatic (PIK3CA)
• Allelic: Nevus, epidermal, somatic (PIK3CA)
• Allelic: Nonsmall cell lung cancer, somatic (PIK3CA)
• Allelic: Ovarian cancer, somatic (AKT1, PIK3CA)
• Beckwith-Wiedemann syndrome [MONDO:0016475] (NLRP2)
• Beckwith-Wiedemann syndrome [panelapp] (PADI6)
• Capillary malformation-arteriovenous malformation 1 (RASA1)
• Central conducting lymphatic anomaly [panelapp] (ARAF)
• Cutaneous and hepatic vascular lesions [panelapp] (GJA4)
• Hypoinsulinemic hypoglycemia with hemihypertrophy (AKT2)
• Macrocephaly/autism syndrome (PTEN)
• Megalencephaly-capillary malformation-polymicrogyria syndrome, somatic (PIK3CA)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1 (PIK3R1)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (AKT3)
• Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3 (CCND2)
• Preimplantation embryonic lethality 2 (PADI6)
• Proteus syndrome, somatic (AKT1)
• Smith-Kingsmore syndrome (MTOR)