INTRODUCTION — Gardner, in the early 1950s, described a kindred with intestinal characteristics of familial adenomatous polyposis (FAP), but also with a number of extracolonic growths, including osteomas, epidermal cysts and fibromas [1]. Dental abnormalities, desmoid tumors and other lesions were later recognized as additional manifestations of the underlying genetic defect [2,3]. The constellation of inherited colonic adenomatosis together with these extracolonic lesions has become known as Gardner syndrome (GS).

This topic review will discuss each of the extraintestinal manifestations of FAP that historically have defined GS. Gastric, duodenal, and colonic polyp and cancer issues are discussed in a separate section on FAP. Genetic testing is now also available for FAP and GS since both arise from mutations of the same gene [4]. It should be noted that GS is now considered a subcategory of FAP, characterized by the extraintestinal manifestations to be reviewed below that occur in addition to the intestinal polyposis of FAP. Issues related to genetic testing are also presented in the section on FAP. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "Familial adenomatous polyposis: Screening and management of patients and families".)

DEFINITIONS — Shortly after discovery of the adenomatous polyposis coli (APC) gene, the gene responsible for familial adenomatous polyposis (FAP), it became apparent that both FAP and Gardner syndrome (GS) arose from APC mutations [2,3]. FAP is characterized by hundreds to thousands of colonic adenomatous polyps that most often emerge in the second and third decades of life. Colon cancer is inevitable if the colon is not removed. 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. Inheritance is autosomal dominant with near complete penetrance of the gastrointestinal phenotype but with variable penetrance of the extraintestinal manifestations of the disease [5].

GS cannot be separated from FAP when considering studies that describe its overall prevalence. Estimates for the prevalence of the combined syndromes vary from 1 in 6850 to 1 in 31,250 people (2.29 to 3.2 cases per 100,000 persons) [6-8]. Prevalence appears fairly constant throughout the world with men and women affected equally. Twenty to 30 percent of newly diagnosed cases, ie, those not belonging to previously identified families, appear to represent new mutations [6]. 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 [9].

It was once believed that GS patients exhibited fewer and more distinct colonic polyps. However, continued study has demonstrated that the gastrointestinal polyp and cancer phenotypes, although variable, are identical for both GS and FAP. Colonic polyp number depends to some degree on where the mutation occurs in the APC gene [10]. Mutations in the center of the gene (often called the mutation cluster region) give rise to dense polyposis, with 5000 or more colonic polyps [11] 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, or in certain areas of exon nine, are associated with many fewer polyps (often less than 100). This clinical variation is referred to as attenuated FAP. Extraintestinal growths also occur in the attenuated form of FAP, do not correlate with polyp density but have some correlation with mutation location [2,11,12].

The common extraintestinal manifestations associated with GS 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 [2]. Thus, the difference between FAP and GS is somewhat semantic and GS is usually considered a subset of FAP [2]. On the other hand, the term GS continues to be commonly applied, particularly in families that exhibit frequent and obvious extraintestinal lesions.

BENIGN EXTRAINTESTINAL LESIONS — Gardner syndrome (GS) is associated with several benign extraintestinal growths including:

●Osteomas and dental abnormalities

●Cutaneous lesions

●Desmoid tumors

●Congenital hypertrophy of the retinal pigment epithelium

●Adrenal adenomas

●Nasal angiofibromas

Osteomas and dental abnormalities — Osteomas, the first described extracolonic lesions of GS, are found in about 20 percent of families with familial adenomatous polyposis (FAP). They are benign bone growths found most commonly on the skull and mandible but may occur on any bone of the body [1,6,13-15]. The size ranges from less than a millimeter to several centimeters in diameter, and they number from one to dozens. These lesions may occur in children before colonic polyposis is present, and may continue to appear and grow throughout life. They have no malignant potential but may occasionally be of cosmetic concern.

Dental abnormalities of GS include unerupted teeth, supernumerary teeth, dentigerous cysts, and odontomas [1,16-18]. Osteomas and dental abnormalities may precede the development of colonic polyposis. The prevalence of clinically apparent lesions is estimated at 17 percent in FAP compared to 1 to 2 percent in the general population. Radiopaque jaw lesions not apparent on physical examination are evident by panoramic dental radiographs in up to 90 percent of FAP patients [19]. Surgical or orthodontic management is needed when lesions are associated with cosmetic or dental problems [20]. There is some correlation of bone, cutaneous and desmoid tumor occurrence with location of mutation in the distal or 3' portion of the APC gene [2,21]. (See 'Desmoid tumors' below.)

Cutaneous lesions — Epidermoid cysts, fibromas, lipomas, and pilomatricomas can all occur in GS [2,3,22-26]. All of the cutaneous lesions can cause cosmetic problems.

●Epidermoid cysts are most common on the legs, face, scalp, and arms, in that order, but they may be found anywhere on the surface of the body [22]. Their size ranges from millimeters to several centimeters. While they are also common in the general population, in GS they often appear before puberty and may precede the onset of polyposis. Epidermoid cysts in GS, similar to sporadic epidermoid cysts, are surgically removed when needed, usually for cosmetic reasons [27].

●Fibromas range in size from millimeters to centimeters and occur on the cutaneous surfaces of the scalp, shoulders, arms, and back. Fibromas appear to be the cutaneous equivalent of desmoid tumors.

●Lipomas are so common in the general population that they are not a helpful diagnostic feature of GS, and there is even some question as to whether there is actually an increased incidence of these lesions in GS compared to the general population.

●Pilomatricomas are common in children, but are a rare association with GS [28]. When present in GS, they may be millimeters to centimeters in size and are often multiple. A family history to rule out GS is indicated when pilomatricomas are present in children. These lesions are surgically removed.

None of the cutaneous lesions progress to malignancy.

Desmoid tumors — Desmoid tumors (also referred to as desmoid fibromatosis) represent a somewhat different disease in GS than in the general population. (See "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone".) They are rare in the general population (5 to 6 per million per year) [29] but in FAP affect from 5 to 25 percent of patients [30-32]. The risk of finding FAP in patients who develop a desmoid without a prior history of FAP is 4.8 percent [33]. 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 [10,34], a family history of desmoids [32,34,35], female gender, and the presence of osteomas [36]. 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 [32,37-39].

When extraintestinal lesions are present in any member of an FAP family, the family has traditionally been said to have GS, since all members of the family segregate the same APC mutation. Desmoids may be the first manifestation of GS. Families have also been reported that exhibit desmoids as the only manifestation of an APC mutation.

Desmoid tumors can arise in all musculoaponeurotic structures throughout the body but are most common in the abdomen where they begin as mesenteric plaque like lesions that may progress to mesenteric fibromatosis and finally to desmoid tumors [40,41]. About one-half of abdominal desmoids occur intra-abdominally while the other one-half are found in tissues of the abdominal wall [31,42,43]. Approximately one-third of abdominal desmoids cause pain. In a series of 38 patients, the most common presenting feature was small bowel obstruction (58 percent) [44].

Desmoid tumors are considered to be benign because they do not metastasize. The tumors may enlarge gradually or stop growing. Surgery appears to stimulate their growth; an increased frequency of the lesions is observed following abdominal surgery [45-47]. Pregnancy may slow desmoid growth in some of these patients [48].

Although benign, desmoid behavior can cause substantial morbidity and mortality [49]. They may infiltrate adjacent structures, extend along fascial planes, attach to and erode bones, and engulf and compress blood vessels, nerves, ureters, small bowel, and other hollow organs of the abdomen especially with the occurrence of mesenteric fibromatosis. Fistula formation with and between hollow organs and with skin also occur [50] and bowel perforation has been reported [51]. Severe and sometimes fatal problems can arise especially if the mesenteric vessels or other hollow abdominal organs become obstructed [52]. Intra-abdominal desmoids may grow to massive sizes, sometimes occupying much of the abdominal cavity and encasing viscera (image 1). Desmoid tumors are a common cause of mortality after colectomy [53]. Mortality is as high as 10 to 50 percent in patients who have a desmoid tumor. However, progression is often gradual and survival 10 years after the diagnosis is approximately 63 percent [31,40,45].

GS associated desmoids are histologically indistinguishable from sporadic desmoids, although 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 [54,55]. Desmoid tumors in GS are monoclonal growths, implying that they are true neoplasms [56]. Desmoids in FAP also arise from APC inactivation and subsequent accumulation of beta-catenin in cells [57]. In contrast, APC mutations are uncommon in sporadic desmoids, which usually arise from beta-catenin gene mutations (CTNNB1 gene) [58-61].

The specific location of mutations within the APC gene correlates with the occurrence of desmoid tumors, although desmoids can occur with mutations in any APC gene location [10]. Desmoid tumors occur more frequently when mutations are in the 3' end of the APC gene, specifically distal to codon 1444 [10,36,41]. One study showed desmoid tumors to be more common with APC mutations between codons 1444 to 1578 [62] and in another study between codons 543 to 713 and 1310 to 2011 [63]. 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) [12]. However, the specific phenotype varies with mutations within these regions [64,65]. A study of 269 patients found that tumors were present in 20 percent of patients with mutations 5' to codon 1444 compared with 49 percent of patients with mutations 3' to that codon [64]. In addition, desmoid tumors were present in 61 percent of patients with mutations between codons 1445 and 1580 compared with 18 percent of patients with mutations at sites 3' to that region. (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy", section on 'Adenomatous polyposis coli (APC) mutations'.)

The molecular events that lead to desmoid tumor formation in patients with APC mutations are incompletely understood. However, increasing evidence points to involvement of the APC gene and beta-catenin (both components of the Wnt signaling pathway) in the molecular pathogenesis of desmoids both in Gardner syndrome as well as in sporadic desmoids [41,59,61]. (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy".)

Treatment — Screening for desmoid tumors is not routinely recommended. Imaging is indicated for physical exam findings, symptoms that may indicate a desmoid issue, or prior to colectomy in patients at increased risk for desmoids. Treatment of desmoid tumors is indicated only when they cause symptoms, there is imminent risk to adjacent structures, or they create cosmetic concerns. Surgery is generally performed initially for extra-abdominal desmoids [59]. By contrast, a more conservative approach is usually recommended for intra-abdominal and abdominal wall desmoids (such as with sulindac or increasing doses of tamoxifen) [41,66]. Tyrosine kinase inhibitors have also been suggested as possible treatment agents in combination with nonsteroidal anti-inflammatory medicines [67]. In patients who do not respond or who lose response, options include chemotherapy [41] (similar to that used for sarcomas), radiation therapy, and/or surgery [68]. Intestinal perforation with chemotherapy for desmoids has been reported [69]. When combination chemotherapies are used, those including doxorubicin have been associated with the most favorable outcomes [70]. The biological agent imatinib has shown significant utility with progression-free survival of 66 percent at 12 months and objective tumor response in three of 51 patients [71]. Other biological agents are now also under study. Finally, total enterectomy with intestinal transplantation is now an option for the most extreme cases [72]. The choice and order among these should be guided by a multidisciplinary team, all of whom should have experience with this difficult tumor [41,59,70,73-76]. Desmoid recurrence is frequent following surgery, particularly those in the abdomen [77]. It is recommended that patients with desmoid tumors be referred to specialty centers in view of the difficulty in treatment and the multispecialty approach needed for optimal outcome [78]. (See "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy" and "Familial adenomatous polyposis: Screening and management of patients and families", section on 'Desmoid tumors'.)

Congenital hypertrophy of the retinal pigment epithelium — Multiple and bilateral patches of congenital hypertrophy of the retinal pigment epithelium (CHRPE), also called pigmented ocular fundus lesions, are a common manifestation of GS [79]. 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. The presence of bilateral or multiple (more than four) lesions is specific (94 to 100 percent) but only moderately sensitive (58 to 84 percent) for GS [80]. These lesions may exhibit an association with disorder of the cilia [81].

CHRPE lesions appear to be congenital and have been detected in patients as young as three months. Slit-lamp examination is usually required for detection. CHRPE is observed with mutations between codons 311 and 1444, although this varies somewhat depending on the study [2,10,12]. CHRPE is not known to cause clinical problems, although one case of malignant transformation was reported [82].

Adrenal adenomas — Adrenal adenomas have been reported in 7 to 13 percent of patients with GS (compared with approximately 3 percent in the general population) [83]. Most adrenal masses in GS are found incidentally (as they are in the general population), are non-functioning and should be managed using similar principles [84,85]. (See "Evaluation and management of the adrenal incidentaloma".) Adrenal adenomas in FAP harbor a somatic as well as germline APC mutation, indicating these tumors arise as part of FAP [86,87]. Malignancy of the adrenal is rare in FAP.

Nasal angiofibromas — Nasal angiofibromas have been described in some patients with GS [88] and mutational studies indicate they are part of the syndrome [89].

EXTRACOLONIC MALIGNANCIES — Patients with Gardner syndrome (GS) are at increased risk for several extra-colonic malignancies. The following malignancies (and proportions of affected patients with GS) have been described in various studies:

●Duodenal and periampullary (3 to 5 percent)

●Thyroid (2 percent)

●Pancreatic (2 percent)

●Gastric (0.6 percent)

●Central nervous system (<1 percent)

●Hepatoblastoma (1.6 percent)

●Small bowel distal to the duodenum (rare)

●Adrenal (rare)

Thyroid — Benign thyroid masses occur in almost 50 percent of FAP patients, and 2.6 percent are found to have thyroid cancers [90,91]. The cancer risk is increased approximately eight-fold compared with the general population (RR 7.6, 95% CI 2.5 to 17.7) [92]. The mean age of diagnosis is 33 years [91]. There is elevated risk of FAP-associated thyroid cancer in females, in persons with thyroid nodules, and in those with a relative affected with this malignancy [90,93]. In a study from Japan, the risk of thyroid cancer was near 14 percent in FAP patients with an 8:1 female to male ratio [93]. The histology of thyroid cancer in FAP is predominantly papillary, commonly with a cribriform pattern. Thyroid cancer is associated with APC mutations in the 5' end of exon 15 [94]. The thyroid in FAP/GS patients is frequently nodular; as a result, ultrasound screening, in addition to palpation, should be used for thyroid surveillance in these patients [91]. (See "Overview of the clinical utility of ultrasonography in thyroid disease".)

Pancreatic — The risk of pancreatic adenocarcinoma in GS has been estimated to be increased more than fourfold compared with the general population (RR 4.46, 95% CI 1.2 to 11.4) [92]. In addition, duct obstruction has been described from benign and malignant tumors, sometimes giving rise to pancreatic cysts [95].

Hepatoblastoma — Hepatoblastoma occurs in 0.75 to 1.6 percent of children with FAP. The risk of hepatoblastoma in children with FAP is 800-fold greater than in the general population [96]. It occurs more commonly in boys and has some association with APC mutations in the 5' end of the gene [2]. This cancer usually occurs in the first five years of life but some risk remains up to 15 years. In one study of children with hepatoblastoma, 14 percent were found to have germline pathogenic APC gene mutations [97]. The authors thus recommended that all children with hepatoblastoma malignancies undergo germline APC testing for FAP.

Central nervous system (CNS) — CNS malignancies, mostly medulloblastoma, are rare in FAP but show a distinct relationship [98,99]. When CNS tumors are present, the condition is actually called Turcot syndrome. It is estimated that the risk for medulloblastoma in FAP is 92-fold greater than in the general population.

Neoplasms of the gallbladder and bile ducts — Adenomatous change and cancer have been described in the gallbladder and bile ducts both of which may lead to biliary obstruction [100-103]. Neoplasms in these locations are unusual and their precise frequency is not known.

SCREENING FOR EXTRAINTESTINAL MALIGNANCIES AND DESMOIDS — Consensus has not been achieved on optimal strategies for screening patients with Gardner syndrome (GS) for extraintestinal malignancies and desmoids. However, general screening recommendations for colonic and extracolonic malignancies have been suggested for patients with familial adenomatous polyposis (FAP) and should be applied to those with GS. (See "Familial adenomatous polyposis: Screening and management of patients and families".)

In addition:

●The thyroid should probably be subject to physical examination and ultrasound annually, starting at age 10 to 12 years. There is some difference of opinion in this regard, with one study suggesting annual thyroid ultrasound in those with nodules, but an interval of two years in persons with a normal baseline study until nodules are detected [104].

●It is generally suggested that other possible extraintestinal cancer sites should be evaluated only if symptoms occur or if these cancers have occurred in relatives. This recommendation is provisional and not accepted by all investigators in this area. A recent FAP study from the Netherlands found that screening for cancers in other than colon, duodenum, and thyroid did "not contribute significantly to the survival of patients with FAP" [53].

●Patients should be questioned regularly regarding neurologic symptoms. In addition, a periodic head MRI is recommended if any family member has had CNS malignancy. The appropriate frequency is not known, but intervals of one to three years have been discussed, depending on the family history and presence of any possible related symptoms.

●Every six month liver palpation, together with liver function tests, abdominal ultrasound exam, and alpha fetoprotein levels, should be considered to screen for hepatoblastoma, especially during the first five years of life [105,106]. This can be safely discontinued after age 15, and probably after age 10. The risk of occurrence of this tumor in neonates and children provides a rationale for performing genetic testing in the first year of life to determine which persons should be considered for screening. Although formal recommendations have not been given in this regard, genetic testing may be useful in patients if liver screening is to be anticipated. There is not yet consensus among experts on whether hepatoblastoma screening should be done for all FAP/GS patients, and thus depends on individual physician and parental concern as well as family history.

●Biliary evaluation should be performed only for symptoms or abnormal liver function tests. Upper endoscopy every one to three years, with side viewing capability is indicated for screening the stomach and duodenum in view of the risk of advanced duodenal polyposis and cancer [107]. It appears that there is even some risk of gastric cancer [108,109]. Obvious papillary abnormalities will be observed with this screening. Reasonably good endoscopic and surgical outcomes after finding advanced polyposis and/or duodenal cancer appear to justify these screening approaches [110,111].

Screening is not routinely undertaken for desmoids, but evaluation should be pursued for palpable masses or symptoms. On the other hand, it is reasonable to obtain an abdominal computed tomography with oral contrast every three years beginning at age 20 to 25 [102]. Particular attention should also be given to the biliary tree, gallbladder, pancreas, small bowel, and adrenal glands whenever abdominal imaging is performed.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hereditary colorectal cancer syndromes".).

SUMMARY AND RECOMMENDATIONS

●Gardner syndrome refers to the constellation of inherited colonic adenomatosis polyposis (familial adenomatous polyposis, FAP) together with a number of extracolonic lesions. (See 'Introduction' above.)

●Gardner syndrome arises from a mutation in the adenomatous polyposis coli (APC) gene. As in FAP, the number of colonic polyps is related to the locus of the mutation in the APC gene. (See 'Definitions' above.)

●Several benign extraintestinal growths are associated with Gardner syndrome, including osteomas and dental abnormalities, cutaneous lesions, desmoid tumors, congenital hypertrophy of the retinal pigment epithelium, adrenal adenomas, and nasal angiofibromas. (See 'Benign extraintestinal lesions' above.)

●Patients with Gardner syndrome are at increased risk for extracolonic malignancies, including neoplasms of the thyroid, pancreas, liver, CNS, gallbladder, biliary tract, duodenum, and stomach. (See 'Extracolonic malignancies' above.)

●Patients with Gardner syndrome should be screened for certain extracolonic malignancies. Desmoid tumors, including intra-abdominal, abdominal wall, and extra-abdominal, are a common feature of Gardner syndrome, similar to FAP, and may result in significant morbidity and even mortality. Screening for these tumors is usually indicated if signs or symptoms occur and a multidisciplinary approach is indicated in their treatment. (See 'Screening for extraintestinal malignancies and desmoids' above and "Familial adenomatous polyposis: Screening and management of patients and families".)

ACKNOWLEDGMENT — We are saddened by the death of Paul Rutgeerts, MD, who passed away in September 2020. UpToDate gratefully acknowledges Dr. Rutgeerts' work as our Section Editor for Gastroenterology.