Table 3.

Autosomal Dominant Genetic Cancer Syndromes Showing Signs and Symptoms that Overlap with Peutz-Jeghers Syndrome

Gene(s)SyndromeClinical Features
OverlappingDistinguishing
BMPR1A
SMAD4 		Juvenile polyposis syndrome (JPS) 1GI polyps usually by age 20 yrs: hamartoma +++; adenoma +
Cancers: CRC; gastric; upper GI; pancreatic		In JPS: juvenile polyp histology different from PJS: hamartomas w/nl epithelium w/a dense stroma, an inflammatory infiltrate & smooth surface w/dilated, mucus-filled cystic glands in the lamina propria; HHT in those w/SMAD4-JPS 3; no pigmentary abnl (MM); no ovarian or testicular tumors
15q15.3q22.1 duplication 2
BMPR1A
SMAD4		Hereditary mixed polyposis syndrome (HMPS) (OMIM 601228)Polyps: juvenile hamartoma +; adenoma +; serrated +
Cancers: CRC		In HMPS: no pigmentary abnl; no ovarian or testicular tumors
PTEN PTEN hamartoma tumor syndrome (PHTS)Polyps: hamartoma +++; adenoma +; ganglioneuroma +
Cancers: breast; CRC		In PHTS: different pigmentary abnl - freckles of glans penis & keratoses; extraintestinal manifestations more pronounced than intestinal polyposis: trichilemmoma, lipomas, macrocephaly, breast fibrosis; thyroid, kidney, & endometrial cancer
PRKAR1A Carney complex (CC)Polyps: ± adeno
Hyperpigmented lesions: facial +; mucosal +
Cancers: large-cell calcifying Sertoli cell tumor		In CC: myxomas of heart, skin, breast, oropharynx, & female genital tract; thyroid nodules; acromegaly; thyroid cancer, primary pigmented nodular adrenocortical disease, & schwannomas
APC Familial adenomatous polyposis (See APC-Associated Polyposis Conditions.)Polyps: adenoma +++
Cancers: CRC; GI		In FAP: desmoid tumors, osteomas, CHRPE, brain tumors; no ovarian or testicular tumors
EPCAM
MLH1
MSH2
MSH6
PMS2 		Lynch syndrome Polyps: adenoma +
Cancers: CRC; gastric; ovarian		In Lynch syndrome: sebaceous adenoma; addl cancers incl endometrial, renal pelvis & ureter; no testicular tumors

CC = Carney complex; CHRPE = congenital hypertrophy of the retinal pigment epithelium; CRC = colorectal cancer; FAP = familial adenomatous polyposis; GI = gastrointestinal; HHT = hereditary hemorrhagic telangiectasia; JPS = juvenile polyposis syndrome; MM = melanocytic macules; PJS = Peutz-Jeghers syndrome

1.

The term "juvenile" refers to the type of polyp, not the age of onset of polyps.

2.

HMPS can be caused by either a BMPR1A pathogenic variant or a duplication of 15q15.3q22.1 that leads to increased expression of GREM1 [Jaeger et al 2012]. Some families with mixed hereditary polyposis syndrome have SMAD4 pathogenic variants [Valle et al 2019].

3.

JPS may occur with hereditary hemorrhagic telangiectasia (HHT); or the combined entity of JPS-HHT. The JPS-HHT overlap syndrome has been reported in 22% of individuals with JPS due to a SMAD4 pathogenic variant (SMAD4-JPS) [Aretz et al 2007]. In a cohort 41 families with SMAD4-JPS, nearly all affected individuals had overlap syndrome [O'Malley et al 2012].

From: Peutz-Jeghers Syndrome

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