A dyadic genotype–phenotype approach to diagnostic criteria for Proteus syndrome

Abstract

Phenotype‐based diagnostic criteria were developed for Proteus syndrome in 1999 and updated in 2006. Subsequently, the causative mosaic gene alteration was discovered, the c.49G>A p.E17K variant in AKT1. As well, a number of overlapping overgrowth disorders attributable to mosaic PIK3CA variants have now been characterized, leading to the designation of PIK3CA‐related overgrowth spectrum (PROS). Finally, ongoing work to better characterize Proteus syndrome has led to identification of additional features of that disorder that could be useful in diagnostic criteria. We have taken the opportunity of these discoveries to re‐evaluate the Proteus syndrome diagnostic criteria. Here we propose a new set of diagnostic criteria that establishes a weighted, point‐based system for the phenotypic attributes and then integrates that with the potential molecular test results to result in one of two designations: AKT1‐related Proteus syndrome or AKT1‐related overgrowth spectrum. A patient whose only manifestation is an AKT1 c.49G>A‐positive tumor would receive neither of these designations. Here we review the rational basis of diagnostic criteria and argue that a unitary diagnostic entity is a distinct gene‐phenotype dyad and that this should be the model for all mendelian disorders. The gene‐alone or phenotype‐alone approach is inadequate to rigorously delineate a unitary diagnostic entity.

Allelic heterogeneity of Proteus syndrome

“…This individual unambiguously met the 2006 clinical criteria for Proteus syndrome -he has nearly all manifestations of the disorder (Biesecker 2006). Recently, we have updated these simple clinical criteria to incorporate an integrated clinical-molecular scoring system (Sapp et al 2019). In this scheme, clinical manifestations are scored on a point scale from -10 to +28 points, with positive points for attributes of Proteus syndrome and negative points for attributes associated with PIK3CA-related overgrowth spectrum.…”

Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth

“…Clinical features of the syndrome include asymmetric skeletal growth, connective tissue nevi, epidermal nevi, vascular malformations, and dysregulated adipose tissue (lipomas, lipohyperplasia, fatty overgrowth, and partial lipohyperplasia) (51). Overlapping disorders, such as CLOVES, under the umbrella of PROS prompted the creation of a new diagnostic scoring system for PS (52). Five points are attributed for cerebriform connective tissue nevus, disproportionate overgrowth, and organ/visceral overgrowth.…”

“…Two points are attributed for bullae or cysts of the lungs, dysregulated adipose tissue, linear verrucous epidermal nevus, vascular malformations, deep vein thrombosis/pulmonary embolism, and certain facial features, such as dolichocephaly and a low nasal bridge. Single points are attributed for specific tumors including genital cystadenomas, parotid monomorphic adenoma, and meningiomas (52). Points are subtracted for features, such as substantial prenatal extracranial overgrowth and ballooning overgrowth (52).…”

Prenatal diagnosis of Proteus syndrome: Diagnosis of an AKT1 mutation from amniocytes

“…She had significant airway stridor and progressive respiratory distress secondary to seizure burden, and died at 6 months of age from respiratory failure. With the prenatal mosaic AKT1 variant from cultured amniocytes, development of the characteristic cerebriform connective tissue nevi, and other features including progressive asymmetric overgrowth, the patient met diagnostic criteria of Proteus syndrome based on the criteria proposed by Sapp, Buser, Burton‐Akright, Keppler‐Noreuil, and Biesecker (2019).…”