PTEN HAMARTOMA TUMOUR SYNDROME...PTEN HAMARTOMA TUMOUR SYNDROME Stefan Aretz Institute of Human...

PTEN HAMARTOMA TUMOUR SYNDROME

Stefan Aretz

Institute of Human Genetics

Center for Hereditary Tumour Syndromes

University Hospital Bonn

Germany

Hereditary Cancer Genetics, Lugano, 26.4.2019

DISCLOSURE OF INTEREST

I have no conflict of interest to declare

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

PTEN HAMARTOMA TUMOR SYNDROME (PHTS)

Cowden

syndrome

(CS)

Bannayan-

Riley-Ruvalcaba

syndrome

(BRRS)

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

CAUSATIVE GENES

OMIMOnline Mendelian Inheritance in Man®

An Online Catalog of Human Genes and Genetic Disorders

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

*

* Germline KLLN promoter hypermethylation

Multigene panel testing

CS: TUMOUR SPECTRUM

• Mucocutaneous lesions (99%)

• Hamartomatous intestinal polyps (60-90%)

• Breast cancer

• Non-medullary thyroid cancer

• Endometrial cancer

• Adult cerebellar dysplastic gangliocytoma(Lhermitte-Duclos-Disease – LDD)

• Renal cell carcinoma

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

CS - MUCOCUTANEOUS LESIONS

trichilemmomaspapillomatous papules

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

POLYP HISTOLOGY

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

GANGLIONEUROMATOUS POLYPOSIS (GP)

• Very rare disorder

• Ganglioneuromas:

• benign neuroectodermal tumor

• originate from sympathetic nerve system

• Composed of ganglion cells, Schwann

cells, connective tissue, nerve fibers

• Malignant transformation of

ganglioneuromas unknown

• CS, MEN2b or NF1

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

INTERNATIONAL COWDEN CONSORTIUM

CLINICAL DIAGNOSTIC CRITERIA

Blumenthal, EJHG 2008

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

GeneReviews: www.ncbi.nlm.nih.gov/gtr/

NCCN: www.nccn.org

BANNAYAN-RILEY-RUVALCABA SYNDROME (BRRS)

Subcutaneous tumour

Erkek et al., Dermatopathology 2005

Lipomas Penile freckling

Diagnosis: no consensus criteria Based on presence of cardinal features

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

BANNAYAN-RILEY-RUVALCABA SYNDROME (BRRS)

Subcutaneous tumour

Erkek et al., Dermatopathology 2005

Lipomas Penile freckling

• Macrocephaly

• Developmental delay

• Pigmented macules of the glans penis

• Lipomas

• Intestinal hamartomatous polyposis

Diagnosis: no consensus criteria Based on presence of cardinal features

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

CRANIOFACIAL DYSMORPHIC FEATURES

Parisi et al., JMG 2001; Merks et al., JMG 2003

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

BANNAYAN-RILEY-RUVALCABA SYNDROME (BRRS)

CFC 64 cm

CFC 64 cm

CFC 62 cmIII:1

II:4II:3

I:1 I:2

II:1 II:2

Reutter et al. 2009

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

PEDIATRIC CLINICAL CRITERIA PTEN SCREENING

Tan et al., AJHG 2011

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

PROTEUS SYNDROME (PS) / PROTEUS-LIKE SYNDROME

• complex, highly variable disorder

• progressive segmental or patchy overgrowth / disfigurement (skeleton, skin, adipose, central nervous systems)

• Modest or no manifestations at birth, rapid progresses beginning in toddler period till childhood

• Cerebriform connective tissue nevi (CCTN)

• caused by somatic mosaicism for specific de novo pathogenic variant c.49G>A in AKT1

• Mosaic distribution of lesions

• Sporadic occurrence

• Progressive course

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

JUVENILE POLYPOSIS OF INFANCY

◆ Severe course

early-onset, rectal bleeding, anemia, hypoproteinemia, diarrhea,

abdominal pain, develomental delay

◆ Mikrodeletion syndrome 10q22-q23 (BMPR1A + PTEN)

◆ Symptoms of both JPS and BRRS / PHTS

◆ So far sporadic cases only

◆ Sub-colectomy, mTOR inhibitors (Sirolimus)

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

SURVEILLANCE CS

Blumenthal, EJHG 2008

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019

PHTS: SUMMARY AND CONCLUSIONS

• Multi-system disorder with broad tumour spectrum

and several differential diagnoses

• Clinical diagnosis often challenging, many families

probably remain undiagnosed

• Might be genetically heterogeneous

• Multidisciplinary team, specialised centres

• Research tasks: more sensitive and more simple

clinical criteria

Aretz – Institute of Human Genetics Bonn PTEN Hamartoma Tumour Syndrome Lugano, 26.04.2019