Friday, March 12, 2010

Mosaicism – What is it? Who’s affected? Why does it matter?

This is a long, complex report. Please ask questions and for clarification!

This is a patient-view report. Please remember, I’m a Peutz-Jeghers syndrome patient not a medical professional and am not giving medical advice. My advice is to get good medical advice, hopefully from a genetics professional. This report contains speculations on the importance of mosaicism in PJS, based on its importance in FAP (familial adenomatous polyposis). Because PJS mosaicism hasn’t been described in the medical literature, even a genetic counselor may not be familiar with the topic. You are welcome to share this report with your health care provider, just make sure to say it’s a literature based report, not medical prescribing.

Let’s consider genetic mosaicism in PJS. Though it hasn’t been described in the PJS literature, in the summer 0f 2009 two people have reported mosaicism in self or PJS family member. Mosaicism is a genetic mutation that affects only some cells or portions of a person’s body…so instead of having the PJS gene (LKB1/STK11) mutated in every cell of the body, including the blood, only portions of the body are affected.

The reported presence of mosaicism in two PJS families calls into question many of our former beliefs about who’s affected and with whom the disorder began in any particular family. Before 1997 when the PJS gene was found on chromosome 19, genetic counselors took a family history to determine which family members were affected with spots and polyps. Since 1997 genetic testing has become more common and as techniques have improved, it’s possible to test first the proband (someone known to be affected), then if a mutation has been found, at-risk family members. Mosaicism makes genetic testing more difficult because mutations may not be found in the blood, but still be present in portions of the body. If the germ-line is affected, the disorder can be passed onto children, even if the parent has no signs of spots, polyps or a positive genetic test by blood sample.

A person with a mosaic mutation may have a milder or patchy involvement, negative DNA blood test or milder symptoms of the disorder (ref. 1). It’s thought that mosaic mutations are formed in the embryo after fertilization, but before birth. Depending on when and where the mutations take place, different parts of the body are affected.

An important distinction is made between somatic mosaicism and germ-line mosaicism. Somatic mutations can affect any portion of the body, while germ-line mutations specifically affect the gonads (ovaries in females, testicles in males). Germ-line mutations can be passed onto more than one offspring. (references 1, 2)

Mosaicism has been reported in several other autosomal dominant inherited cancer syndromes with a high degree of new mutations. These include familial adenomatous polyposis (FAP), retina blastoma, tuberous sclerosis types 1 & 2, neurofibromatosis type 1 and von Hippel-Lindau disease.

I focused my reading on FAP, because it’s closest to PJS (GI tract polyps and increased cancer risk).

Mosaicism calls into question new (de novo or sporadic) diagnoses of genetic diseases in a family member. The parents, siblings and offspring of someone affected with a genetic condition may need genetic counseling (and possible testing to rule out mosaicism).

In FAP, a seemingly unaffected parent of an affected child was found to have a germ-line mutation of the FAP gene, APC. (ref. 3) The authors note,  “parents who test negative for the mutation should be counseled abut the small possibility of having another affected child due to gonadal mosaicism. Likewise, all siblings of the affected individual should be offered genetic testing or undergo colonoscopic evaluation (if genetic counseling is not pursued), even if neither of the parents is affected.” (ref. 3)

I’ve no idea whether this advice applies to PJS people. Interestingly, the authors also work with PJS people at Huntsman Cancer Institute in Salt Lake City, Utah.

Aretz et al noted, “A de novo APC mutation was assumed when one of the following criteria was fulfilled: 1) both of the patient’s parents were healthy until at least 70 years of age; 2) both parents had negative colonoscopies at an age of >50 years. A de novo mutation was regarded as being confirmed if the APC mutation identified in the child could be excluded in the blood samples of both parents.” (4) These authors didn’t specifically address germ-line mutations or siblings. They do note, “children of parents with mosaicism…may present with a more severe phenotype and earlier onset than that observed in the mosaic aren’t, which has implications for determining appropriate start to surveillance. The parents of apparently de novo FAP cases should be carefully examined since one of them may be mildly affected due to FAP mosaicism.” (4)

Hes et al provide a decision tree that is too small for me to read, the caption reads, “Decision tree for an apparently sporadic patient with colorectal adenomas. Children, siblings and parents of apparently de novo patients with an identified APC mutation are eligible for DNA testing. Parents without a detectable germline mutation remain at risk because the possibility of somatic mosaicism, manifesting in colorectal cells cannot be ruled out. The risk of germline APC mutations for siblings and parents of an apparently de novo patient with a mosaic APC mutation is very unlikely. Their children have a <50% risk of inheriting a germline APC mutation.” (5) They also note, “Given the low but tangible number of occurrences of gonadal mosaicism and the possibility that a low percentage mosaicism may remain undetected, we advise DNA testing of siblings of patients in which polyposis coli apparently arose de novo.” (5)

If a parent or family member of a person with FAP has had polyps or cancer, DNA from those tissues may be genetically tested to reveal a mutation. (5)

And the authors of a 1999 article on mosaicism in FAP state, “Our findings have relevance to counseling regarding recurrence risk to siblings of “sporadic” FAP patients who do not appear to carry the APC mutation as assessed by conventional methods.” (6)

I hope that reports of mosaicism in PJS are soon published and that the authors adequately describe the issues so that genetic counselors can guide affected families. Mosaicism in PJS ushers in a new era of genetic counseling and testing. What we used to know about new cases of PJS in a family has changed. And even the definition of PJS may change with reports of mosaicism.

Warm regards,



(2) Hall JG.
 Review and hypotheses: somatic mosaicism: observations related to clinical genetics.
Am J Hum Genet. 1988 Oct;43(4):355-63. Review.
PMID: 3052049
Free full-text

(3) Schwab AL, Tuohy TM, Condie M, Neklason DW, Burt RW.
 Gonadal mosaicism and familial adenomatous polyposis.
Fam Cancer. 2008;7(2):173-7. Epub 2007 Nov 18.
PMID: 18026870
Hes FJ, Nielsen M, Bik EC, Konvalinka D, Wijnen JT, Bakker E, Vasen HF, Breuning MH, Tops CM.
 Somatic APC mosaicism: an underestimated cause of polyposis coli.
Gut. 2008 Jan;57(1):71-6. Epub 2007 Jun 29.
PMID: 17604324

(4) Aretz S, Stienen D, Friedrichs N, Stemmler S, Uhlhaas S, Rahner N, Propping P, Friedl W.
 Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP).
Hum Mutat. 2007 Oct;28(10):985-92.
PMID: 17486639

(5) Hes FJ, Nielsen M, Bik EC, Konvalinka D, Wijnen JT, Bakker E, Vasen HF, Breuning MH, Tops CM.
 Somatic APC mosaicism: an underestimated cause of polyposis coli.
Gut. 2008 Jan;57(1):71-6. Epub 2007 Jun 29.
PMID: 17604324

(6) Farrington SM, Dunlop MG.
 Mosaicism and sporadic familial adenomatous polyposis.
Am J Hum Genet. 1999 Feb;64(2):653-8.
PMID: 9973305
Free full-text

(7) more on mosaicism

(8) more on autosomal dominance

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