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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
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
