A girl with CLOVES syndrome with a recurrent PIK3CA somatic mutation and pancreatic steatosis

Abstract

CLOVES syndrome is characterized by congenital lipomatous overgrowth, vascular malformation, epidermal nevi, and scoliosis/spinal malformation. It is caused by somatic mosaicism of gain-of-function variants of PIK3CA . Here, we describe a novel case of a 5-year-old Japanese girl with CLOVES and concurrent pancreatic steatosis. She had a recurrent somatic mutation in PIK3CA (NM_006218.3: c.1357G>A, p.Glu453Lys), elevated HbA1c levels, and pancreatic steatosis. This case indicates that pancreatic screening is critical for PIK3CA- related disorders.

A Review on Cutaneous and Musculoskeletal Manifestations of CLOVES Syndrome

“… 7 The term “CLOVES” is an acronym denoting congenital lipomatous overgrowth, vascular malformations, epidermal nevi and spinal (scoliosis) and/ or skeletal anomalies. 1 , 2 , 8–13 …”

“…CLOVES syndrome is currently categorized as a disorder within the canopy of PIK3CA -Related Overgrowth Spectrum (PROS) ( Box 1 ). 3 , 5 , 8 , 11 , 15 , 19–30 The syndrome harbors postzygotic activating somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) gene mapped to chromosome 3q26.32, which encodes a 110-kD catalytic α subunit of PI3K (phosphoinositide 3-kinase). 1 , 8 , 11 , 13 , 23 , 24 , 31 , 32 PI3K is a lipid kinase that converts phosphatidylinositol (4,5)-bisphosphate to phosphatidylinositol (3,4,5)- triphosphate and regulates cell proliferation, growth, and survival.…”

“… 3 , 5 , 8 , 11 , 15 , 19–30 The syndrome harbors postzygotic activating somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) gene mapped to chromosome 3q26.32, which encodes a 110-kD catalytic α subunit of PI3K (phosphoinositide 3-kinase). 1 , 8 , 11 , 13 , 23 , 24 , 31 , 32 PI3K is a lipid kinase that converts phosphatidylinositol (4,5)-bisphosphate to phosphatidylinositol (3,4,5)- triphosphate and regulates cell proliferation, growth, and survival. 13 A complex signaling pathway paves the way for activation of AKT1 (protein kinase B), and subsequently drives enhanced cell proliferation through mTOR1 (mammalian target of rapamycin).…”

“… 6 , 13 Activating mutations of PIK3CA commence in uncontrolled growth of predominantly mesoderm-derived (eg, adipose tissue, vascular and lymphatic tissues, muscle, bone) and neuroectoderm-derived tissues (eg, skin, brain cephalic connective tissue). 1 , 3 , 6 , 8 , 18 , 23 , 27 , 32–35 The overgrowth is segmental, patchy, asymmetric, and confined to body parts affected by the mutation. 1 , 14 , 32 …”

“… 5 , 24 Phenotypic expressivity and malformation severity might vary. 1 , 5 , 8 As compared with other PROS disorders, CLOVES syndrome presents with a pleiotropic, divergent and a more severe constellation of findings. 3 …”