Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review

Linda A J Hendricks; Janneke Schuurs-Hoeijmakers; Isabel Spier; Maaike L Haadsma; Astrid Eijkelenboom; Kirsten Cremer; Arjen R Mensenkamp; Stefan Aretz; Janet R Vos; Nicoline Hoogerbrugge

doi:10.1016/j.ejmg.2022.104533

Catch them if you are aware: PTEN postzygotic mosaicism in clinically suspicious patients with PTEN Hamartoma Tumour Syndrome and literature review

Eur J Med Genet. 2022 Jul;65(7):104533. doi: 10.1016/j.ejmg.2022.104533. Epub 2022 May 28.

Affiliations

¹ Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands; Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.
² Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands.
³ Institute of Human Genetics, Medical Faculty, University of Bonn, Germany; Center for Hereditary Tumor Syndromes, University Hospital Bonn, Germany.
⁴ Department of Pathology, Radboud university medical center, Nijmegen, the Netherlands.
⁵ Institute of Human Genetics, Medical Faculty, University of Bonn, Germany.
⁶ Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands; Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. Electronic address: Nicoline.hoogerbrugge@radboudumc.nl.

PMID: 35640862
DOI: 10.1016/j.ejmg.2022.104533

Abstract

PTEN germline variants cause PTEN Hamartoma Tumour Syndrome (PHTS). Of individuals fulfilling diagnostic criteria, 41-88% test negative for PTEN germline variants, while mosaicism could be an explanation. Here we describe two individuals with PTEN mosaicism. First, a 21-year-old female presented with macrocephaly and a venous malformation. Next generation sequencing analysis on her venous malformation identified the mosaic pathogenic PTEN variant c.493-2A>G (23%). This variant was initially missed in blood due to low frequency (<1%), but detected in buccal swab (21%). Second, a 13-year-old male presented with macrocephaly, language developmental delay, behavioral problems, and an acral hyperkeratotic papule. Targeted PTEN analysis identified the mosaic pathogenic variant c.284C>T (11%) in blood, which was confirmed via buccal swab. These two cases suggest that PTEN mosaicism might be more common than currently reported. PTEN mosaicism awareness is important to enable diagnosis, which facilitates timely inclusion in cancer surveillance programs improving prognosis and life expectancy.

Keywords: Cowden syndrome; Hamartoma syndrome, Multiple; Mosaicism; PTEN.

Publication types

Case Reports
Review

MeSH terms

Adolescent
Adult
Child
Developmental Disabilities
Female
Hamartoma Syndrome, Multiple* / diagnosis
Hamartoma Syndrome, Multiple* / genetics
Hamartoma Syndrome, Multiple* / pathology
High-Throughput Nucleotide Sequencing
Humans
Male
Megalencephaly*
Mosaicism
PTEN Phosphohydrolase / genetics
Young Adult

Substances

PTEN Phosphohydrolase
PTEN protein, human