Gardner's syndrome

Gardner's syndrome (GS), a variant of FAP, is distinguished by the presence of prominent extracolonic lesions, such as desmoid tumors, osteomas, and cysts.

• In the member familial adenomatous polyposis (FAP) family, when these tumors arise, the family has traditionally been said to have Gardner's syndrome instead of FAP, since all the members of the family have the same mutation in the adenomatous polyposis coli (APC) gene.
  

In the early 1950s, Gardner described a kindred with intestinal characteristics of familial adenomatous polyposis (FAP), but also with a number of extra-colonic growths, including osteomas, epidermal cysts and fibromas.

The combination of these inherited colonic adenomatosis together with these extracolonic lesions has become known as Gardner's syndrome.

• FAP is characterized by 100’s to 1000’s of colonic adenomatous polyps that most often emerge in the second and third decades of life.
• The development of Colon cancer is inevitable if the colon is not removed.
• The polyposis is also usually observed in the stomach, duodenum, and small bowel, although the cancer risk in these locations is far less than in the colon.
• Shortly after discovery of the adenomatous polyposis coli (APC) gene, it became apparent that both FAP and Gardner’s syndrome arose from APC mutations.
• It is inherited as autosomal dominant, with near complete penetration of the gastrointestinal phenotype but with variable penetrance of the extraintestinal manifestations of the disease.
  
• Involvement of male and female is equal.
• New mutations have been represented by 20 to 30% of newly diagnosed cases.
• New cases may also arise from mosaic inheritance, which implies that a mutation occurred in parent's sperm or egg cells, but not in other cells of the body, so the parent did not have clinical disease.
• The number of the colonic polyp depends to some degree on where the mutation occurs in the APC gene.
• If the mutations occur in the center of the gene (often called the mutation cluster region), it give rise to dense polyposis, with 5000 or more colonic polyps when the disease is fully developed.
• If mutations occur proximal or distal to this central gene location, colonic polyps average approximately 1000 with full expression.
• Mutations in the extreme proximal or distal locations of the APC gene are associated with many fewer polyps (often less than 100). This clinical variation is referred to as attenuated FAP.
• Extraintestinal growths do not correlate with polyp density but have some correlation with mutation location.

The common extraintestinal manifestations associated with Gardner’s syndrome have been described in approximately 20 percent of patients with FAP.

• However, many more patients with FAP have these features if they undergo detailed physical and radiologic examinations.
• Thus, the difference between FAP and GS is somewhat semantic and GS is usually considered a subset of FAP.
• On the other hand, the term GS continues to be commonly applied, particularly in families that exhibit frequent and obvious extraintestinal lesions.

Extraintestinal benign lesions —

Gardner's syndrome is associated with several benign extraintestinal growths including:

• Osteomas
• Dental abnormalities
• Congenital hypertrophy of the retinal pigment epithelium
• Cutaneous lesions
• Desmoid tumors
• Adrenal adenomas
• Nasal angiofibromas

Osteomas

• Osteomas were originally described in the skull and mandible but more recently have been shown to involve other areas; they may be the only extracolonic manifestations.
• The bony tumors may be present for many years before the onset of intestinal symptoms they may appear denovo and continue to grow throughout the rest of life.
• Osteomas are found in about 20 percent of families with FAP and are the first described extracolonic lesions of GS.
• They are one to dozens in number and are of less than a millimeter to few centimeter in diameter.
• Radiologic examination of the mandible is a simple and noninvasive means to screen for young carriers of the FAP gene, but it is crucial to distinguish nonspecific sclerotic lesions in the mandible from true osteomas.
• Mandibular osteomas in FAP tend to be multiple, whereas nonspecific sclerotic bony lesions usually are single and located close to a diseased tooth.
• Because osteomas have no malignant potential, they are removed only for symptomatic or cosmetic reasons.

Dental abnormalities

• Dental abnormalities includ mandibular cysts, impacted teeth, and supernumerary teeths.
• They also appear before the development of colonic polyposis.
• Panoramic x-ray of jaw in FAP patients they are found in 90% of the cases but clinically their appearance is only 17% whereas 1 to 2 percent in general population.
• Again attention is needed only if there is a symptomatic or cosmetic problem.

Congenital hypertrophy of the retinal pigment epithelium

• Congenital hypertrophy of the retinal pigmented epithelium (CHRPE) has been reported in some families with FAP or Gardner's syndrome.
• More than 90% of patients with Gardner's syndrome have pigmented ocular fundus lesions (vs. 5% of controls), which are likely to be multiple (63% have four or more lesions) and are bilateral in 87% of those affected.
• The lesions are discrete, darkly pigmented, round, oval, or kidney shaped, ranging in size from 0.1 to 1.0 times the diameter of the disc.
• Pigmented ocular fundus lesions are found in approximately half of the unaffected but at-risk first-degree relatives and have been identified in infants as young as 3 months old, suggesting that they are probably congenital.
• The presence of multiple, bilateral lesions appears to be a reliable marker for gene carriage in FAP, and their absence predicts lack of carriage if carrier relatives show CHRPE.
• These marker lesions are asymptomatic curiosities that need not be sought in patients with an established diagnosis of FAP.
• Slit-lamp examination is usually required for detection.
• CHRPE is not known to cause clinical problems. CHRPE is observed with mutations between codons 311 and 1444, although this varies somewhat depending on the study.
• CHRPE perhaps reflects the most accurate genotype-phenotype correlation in FAP patients; these lesions occur in patients with APC gene mutations distal to exon 9 up through the proximal portion of exon 15.

Cutaneous lesions

Epidermal cysts:

• The association of epidermoid (sebaceous) cysts with FAP has been termed Oldfield's syndrome.
• As all other extraintestinal lesions they appear before puberty and also precedes polyposis.
• These cysts vary from few millimeters to many centimeters in size.
• They may appear any where on the surface of body but most frequently on the legs, face, scalp, and arms, in order of their occurrence.
• They are removed surgically if needed for cosmetic reasons.

Fibromas

• They appear on the cutaneous surfaces of the scalp, shoulders, arms, and back.
• They are few millimeter to few centimeter in size.

Lipomas

• There is an increase in the incidence of these lesions in Gardner’s Syndrome in compared to the general population.

Pilomatricomas
Desmoid tumors

• A particularly serious complication of the adenoma-tous polyposis syndromes is the development of diffuse mesenteric fibromatosis, also called desmoid tumors
• Desmoid tumors are usually benign fibromas that tend to infiltrate locally into adjacent tissue.
• They are rare in the general population (5 to 6 per million per year) but in FAP affect from 5 to 25 percent of patients.
• Studies have shown that the absolute risk of desmoids in patients with FAP is 2.56/1,000 person-years, with the comparative risk 852 times that of the general population.
• Usually, however, desmoid tumors become manifest from 1 to 3 years following surgery for polyposis.
• Desmoids can, however, occur in the absence of Gardner's syndrome.
• The peak incidence of desmoid occurrence in GS is between 28 and 31 years, although they may occur at any age.
• Independent predictors of their occurrence include APC gene mutations 3' of codon 1444, a family history of desmoids, female gender, and the presence of osteomas.
• Mutations between codons 1310 and 2011 are associated with a six-fold risk of desmoid tumors relative to the low-risk reference region (159 to 495).
• Although the lesion appears occasionally to emulate fibrosarcoma, metastasis does not occur.
• Local recurrence is the rule rather than the exception. The mass tends to develop in abdominal incisions, in the abdominal cavity (particularly the small bowel mesentery), and the retroperitoneum.
• Intra-abdominal desmoids may grow to massive sizes, sometimes occupying much of the abdominal cavity and encasing viscera.
• The condition may antedate the appearance of the polyposis by developing in an abdominal incision performed for another purpose (e.g., appendectomy).
• They may infiltrate adjacent structures, extend along facial planes, attach to and erode bones, and engulf and compress blood vessels, nerves, ureters, small bowel, and other hollow organs of the abdomen.
• Severe and sometimes fatal problems can arise especially if the mesenteric vessels or other hollow abdominal organs become obstructed.
• Clark and Phillips and others confirmed that intraabdominal desmoids behave unpredictably but are an important source of mortality in those with FAP.
• The authors also observed that signal intensity on magnetic resonance imaging reflects tumor cellularity, which may, in part, determine progression; this may aid in management of these individuals.
• Surgery (including colectomy) also appears to be an independent risk factor for desmoid disease in FAP, particularly with mutations in certain regions of the APC gene.
• Progression is often gradual and survival 10 years after the diagnosis is approximately 63 percent.
• Histologically, there may be some differences between fibroblastic growths in GS and sporadic desmoids.
• A distinctive fibroblastic growth, called Gardner associated fibroma, may be seen in young patients and appears to be the precursor lesion of desmoids in GS.
  o Desmoid tumors in GS are monoclonal growths, implying that they are true neoplasms.
  o Desmoids in FAP also arise from APC inactivation and subsequent accumulation of beta-catenin in cells.
  o In contrast, APC mutations are uncommon in sporadic desmoids.
  Adrenal adenomas
  o Adrenal adenomas in FAP harbor a somatic as well as germline APC mutation, indicating these tumors arise as part of FAP.
  o Most adrenal adenomas in Gardner’s Syndrome are found incidentally.
  o Their prevalence is 7 to 13 percent of patients with Gardner’s Syndrome whereas it is only 3 percent in the general population.
• Malignancy of the adrenal is rare in FAP.

Nasal angiofibromas

• They are described in some patients of Gardner’s Syndrome.

Extraintestinal malignant lesions
Patients with Gardener’s Syndrome have increased risk for the following malignancies:

• Upper Gastrointestinal Tumors (3 to 5 percent)
• Thyroid (2 percent)
• Pancreatic (2 percent)
• Gastric (0.6 percent)
• Central nervous system (<1>
• Hepatoblastoma (1.6 percent)
• Small bowel distal to the duodenum
• Possibly adrenal

Upper Gastrointestinal Tumors

• Periampullary carcinoma is a well-recognized disease that is associated with Gardner's syndrome.
• Twelve percent of patients in the St. Mark's Hospital series who survived for 5 years after colectomy developed carcinoma of the duodenum, ampulla of Vater, or pancreas.
• Sugihara and associates reviewed the literature and identified 29 such patients, with a mean age of 45 years.
• Eleven patients developed colorectal cancer, all of them having presented with symptoms before the periampullary malignancy.
• Gastrointestinal polyps and cancer have been frequently reported with this syndrome. Invasive upper gastrointestinal adenocarcinoma was found in 4.5% of patients with FAP as recorded in ten polyposis registries.
• Nederveen Cappel and associates calculated that the lifetime risk of developing duodenal cancer in FAP is 5%.
• The most frequent sites for upper gastrointestinal tumors are duodenum, followed by pancreatic ampulla and then stomach. J
• apanese studies reveal the incidence of gastric polyps to be as high as 70% with Gardner's syndrome, whereas the incidence of duodenal polyps approaches 100%.
• In Korea, where carcinoma of the stomach is the most common neoplasm, one survey identified 72 patients with FAP, three of whom (4.2%) were found to harbor gastric cancer.
• This is a much higher risk than would be anticipated from the general population in that country.
  

Periodic upper gastrointestinal radiologic investigation (optimally with double-contrast technique), or preferably endoscopy at intervals in all patients found to have FAP is recommended in order to diagnose and treat lesions at an earlier stage, before invasive carcinoma supervenes.

• This should be accomplished every 6 months to 4 years, depending on the polyp load.
• Their kindred should also be studied for the same.

Thyroid cancer

• Thyroid carcinoma has been reported to be associated with Gardner's syndrome.
• Unique about this observation is that the proliferative abnormalities of the syndrome as listed earlier are of mesenchymal origin, whereas thyroid tumors are not; this suggests a broader potential for the genetic defect.
• An association with thyroiditis has also been observed. Risk of thyroid cancer in Gardner’s syndrome is approximately 8 fold in comparison to normal population and occurs in about 12 percent on FAP patients.
• Average age of presentation is 33, presents as nodular growth, ultrasound is needed for screening, in addition to palpation.
• Histologically they are of papillary type and association of APC mutation in the 5’ end of exon 15 is documented.

Pancreatic cancer

• The risk of pancreatic cancer that is adenocarcinoma of pancreas in patients of FAP is 4 times to that of general population.
• It may present with any complication of ductal obstruction.

Hepatoblastoma

• This malignancy is 800 times more common in boys under age of 5 years in FAP children. But the risk of development remains up to 15 years.
• It has some association with mutation of APC at its 5’ end.

Miscellaneous Associations

Other conditions that are believed to represent manifestations of this syndrome include :

• carcinoid of the small bowel,
• adrenal cancer,
• adrenal adenoma,
• pheochromcytoma,
• skin pigmentation, and
• lymphoid polyposis.

There is, however, the possibility that the observations may merely be coincidental.