Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults - PubMed (original) (raw)

Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults

Xiao-Ping Zhou et al. Am J Hum Genet. 2003 Nov.

Abstract

Lhermitte-Duclos disease (LDD), or dysplastic gangliocytoma of the cerebellum, is an unusual hamartomatous overgrowth disorder. LDD can be familial or, more commonly, sporadic. It has been only recently recognized that LDD may be associated with Cowden syndrome (CS). Over 80% of patients with CS carry germline mutations in PTEN. It remains unclear whether all cases of LDD, even without features of CS, are caused by germline PTEN mutation and whether somatic PTEN mutation occurs in sporadic LDD. We obtained paraffin-embedded LDD lesions from 18 unselected, unrelated patients and performed mutational analysis of PTEN. Overall, 15 (83%) of 18 samples were found to carry a PTEN mutation. All individuals with mutations were adult-onset patients, but the three without mutations were diagnosed at the ages of 1, 3, and 11 years. Germline DNA was available from six adult-onset cases, and all had germline PTEN mutations. Of these six, two had CS features, one did not have CS features, and three were of unknown CS status. Immunohistochemistry revealed that 75% of the LDD samples had complete or partial loss of PTEN expression accompanied by elevated phosphorylated Akt, specifically in the dysplastic gangliocytoma cells. These data suggest that the loss of PTEN function is sufficient to cause LDD. The high frequency and spectrum of germline PTEN mutations in patients ascertaining by LDD alone confirm that LDD is an important defining feature of CS. Individuals with LDD, even without apparent CS features, should be counseled as in CS.

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Figures

Figure 1

Loss of PTEN expression leads to elevated P-Akt levels detected by immunohistochemistry in LDD. a, Moderate to strong PTEN immunostaining intensity (brown) in the neurons of the granular-cell, Purkinje-cell, and molecular layers of adjacent normal cerebellar section. b, Loss of PTEN immunostaining in dysplastic ganglion cells of LDD. c, Markedly elevated P-Akt immunoexpression (brown) in the dysplastic neurons, predominantly in the cytoplasm. Sections were counterstained with methyl green (light blue) or hematoxylin (blue). Original magnification, 20×.

Figure 2

Spectrum of germline PTEN mutations detected in patients with LDD. A schematic of the nine-exon gene is displayed. Mutations (

_n_=16

) denoted above the bar were detected in this study. Mutations (

_n_=14

) underneath the bar were reported elsewhere.

References

Electronic-Database Information

1. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for CS, BRRS, PS, and PTEN/MMAC1/TEP1)

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Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults - PubMed (original) (raw)