Clinical reportProteus syndrome: Report of a case with AKT1 mutation in a dental cyst
Introduction
The syndrome was first described in 1979 by Cohen and Hayden, who reported two cases [Cohen and Hayden, 1979]. In 1983, Wiedemann et al. described four children with similar findings and named the disorder Proteus syndrome, which refers to the mythical Greek god of the sea who was able to change his appearance to escape capture [Wiedemann et al., 1983]. In 1987, Happle et al. suggested a genetic cause and postulated that this disorder should result from somatic mosaicism, lethal in the non-mosaic state [Happle, 1987]. Referring to the highly variable phenotypes, mosaic distribution of lesions, sporadic occurrence, the reports of discordant monozygotic twins and the birth of unaffected children of affected parents, authors confirmed the hypothesis that PS is caused by a postzygotic mutation [Brockmann et al., 2008, Cohen, 1989, Cohen, 1993, Cohen, 2002, Happle, 1987]. The association of PS with mutations in the PTEN tumor suppressor gene was reported by Zhoue et al. [Zhou et al., 2001] and Smith et al. [Smith et al., 2002]. In 2011, Lindhurst et al. performed exome sequencing of DNA samples from affected and unaffected tissues of patients with PS and identified a recurrent somatic activating mutation in AKT1 [Lindhurst et al., 2011, Wieland et al., 2013]. Of 29 patients with PS, 26 carried a heterozygous mutation in the oncogene AKT1 (c.49G > A, which predicts a substitution of glutamic acid to lysine at amino acid 17 -p.Glu17Lys). This gene encodes a kinase, known to mediate cell proliferation and apoptosis. This mutation that activates AKT1 through phosphorylation, was already reported in various cancerous tissues and underlies the proliferative mechanism [Carpten et al., 2007]. Consistent with this, the up-regulation of AKT1 phosphorylation occurred in some tissues of patients with PS and could explain overgrowth and tumour susceptibility by activation of the phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway [Vivanco and Sawyers, 2002]. In addition to the recurrent activating AKT1 mutation, other genetic alterations (chromosomal instability, CNV or SNV affecting tumor suppressor genes or other oncogenes) are probably required to promote cancer development. Molecular genetic testing for AKT1 c.49G > A mutation in the affected tissues may confirm the diagnosis in individuals with clinical criteria and establish the diagnosis in individuals with ambiguous or mild clinical findings [Biesecker and Sapp, 2012].
Section snippets
Craniofacial and oral abnormalities
Cohen described a facial phenotype in the PS which can be associated with craniofacial distortion or abnormalities [Cohen, 1993]. Craniofacial disfigurement is progressive, less common than skeletal abnormalities of the limbs and spine and often due to focal overgrowth of membrane bones, which produced exostosis and/or overgrowth of condylar cartilage, which resulted in dentofacial deformity and malocclusion.
Case report
The patient was a 7-year-old girl born to unrelated healthy parents. At 22nd weeks' gestation, ultrasound and magnetic resonance imaging demonstrated ventriculomegaly leading to amniocentesis for foetal karyotyping. No chromosomal abnormality was detected. Normal vaginal delivery was at 40 weeks' gestation, with an Apgar score 10/10, weight 3340 g (50th centile), height 46 cm (2nd centile) and head circumference 37 cm (97th centile). Psychomotor development was normal until 2 years of age
Discussion and conclusion
Proteus syndrome is a rare congenital hamartomatous condition that is characterized by disproportionate and progressive mosaic overgrowth of skin, bones, muscles, adipose tissues, viscera and by a predisposition to pulmonary embolism. Multisystem involvement and great clinical variability of the disorder make its diagnosis challenging and misdiagnosis is probably common. The diagnosis depends of clinical examination, imaging studies and genetic tests for AKT1 c.49G > A mutation in affected and
Conflict of interest
No authors have relevant conflicts of interests to report.
Consent
Written consent was obtained from the parents of our patient for publication of this case report.
Acknowledgement
We thank Bernadette Gastaldello for technical assistance in molecular analysis.
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2019, European Journal of Medical GeneticsCitation Excerpt :PS becomes apparent in early infancy (between 6 and 18 months of age) and then rapidly progresses in childhood. After adolescence, it appears to stabilise or progress less rapidly (Valéra et al., 2015; Marsh et al., 2008). It is characterised by the excessive and asymmetric overgrowth of soft tissues, skin and bones.
Ophthalmic manifestations and treatments of proteus syndrome: a case report and systematic review
2023, European Review for Medical and Pharmacological SciencesPostmortem Diagnosis of the Proteus Syndrome by Next Generation Sequencing of Affected Brain Tissue
2022, Academic Forensic Pathology
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Marie-Cécile Valéra and Fréderic Vaysse contributed equally to this work.