Gardner syndrome

Key Points at a Glance

Highlights of This Disease

• Gardner syndrome (GS) is a subtype of familial adenomatous polyposis (FAP) caused by APC gene mutations, characterized by extracolonic manifestations (osteomas, desmoid tumors, epidermal cysts).
• Congenital hypertrophy of the retinal pigment epithelium (CHRPE) is present in 74% of FAP patients and is the earliest extracolonic sign, existing from birth.
• If left untreated, colorectal polyps lead to colorectal cancer in 50% of patients by age 40 and in nearly all patients by age 60.
• The presence of three or more osteomas strongly suggests GS and may be detected up to 17 years before the diagnosis of FAP.
• De novo mutations are found in 20–30% of cases, and the condition can occur even without a family history.
• Genotype-phenotype correlation is clear, and risk stratification is possible based on the mutation site.
• Ophthalmologic examination is an important opportunity for early detection of GS.

1. What is Gardner syndrome?

Gardner syndrome (GS) is a phenotypic variant of familial adenomatous polyposis (FAP). In addition to colorectal adenomatous polyposis, it is characterized by extracolonic manifestations such as osteomas, soft tissue tumors (desmoid tumors), and epidermal cysts. It follows an autosomal dominant inheritance pattern.

The causative gene is the APC (adenomatous polyposis coli) gene, located on chromosome 5q21. It is caused by germline mutations, with a 50% probability of transmission to offspring. The prevalence is estimated at 1 in 100,000 to 160,000 individuals⁴⁾.

FAP has the following subtypes ¹⁾.

• Classic FAP: More than 100 polyps in the colon
• Attenuated FAP (AFAP): Characterized by relatively few polyps, fewer than 30
• Gardner syndrome: Accompanied by extracolonic manifestations (osteomas, desmoid tumors, epidermal cysts, etc.)
• Turcot syndrome: Colorectal polyposis associated with brain tumors

FAP accounts for about 1% of all colorectal cancers ¹⁾. Colorectal polyps appear around age 10 and can number from hundreds to tens of thousands. Without treatment, 50% develop colorectal cancer by age 40, and nearly all by age 60. De novo mutations are found in about 20–30% of cases ¹⁾⁵⁾.

Q Can Gardner syndrome occur even if there is no family history of colorectal polyposis?

A

De novo mutations in the APC gene occur with a frequency of approximately 20–30%, so the condition can develop even without a family history¹⁾⁵⁾. It is important to note that the absence of a family history does not rule out GS.

2. Main symptoms and clinical findings

Gardner Syndrome image

Adrian Babel; Eric K Chin; David RP Almeida. Diagnostic implications of Gardner Syndrome, case report of a familial adenomatous polyposis (FAP) variant, for eye care professionals. Int J Surg Case Rep. 2024 Feb 10; 116:109379. Figure 1. PMCID: PMC10943999. License: CC BY.

Initial fundoscopic examination OD revealed small to large round CHRPE-like lesions without holes, tears, or macular involvement in multiple retinal quadrants consistent with PO-FLs (oval, fish-tail depigmentation at lesion margin).

Subjective symptoms

Colorectal polyps are usually asymptomatic, and detection is often delayed. When symptoms do appear, they mainly include the following.

• Abdominal pain, diarrhea, rectal bleeding: Occur as polyps enlarge or ulcerate
• Jaw swelling: Patients may visit a dentist complaining of a mass due to osteoma (jawbone, paranasal sinuses), leading to a diagnosis of GS²⁾
• Subcutaneous mass: Palpable as epidermal cysts or soft tissue tumors

Clinical Findings

Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE)

CHRPE (congenital hypertrophy of the retinal pigment epithelium) is the earliest extracolonic manifestation of GS and is present from birth ¹⁾.

• Frequency: Found in 74% of FAP patients (1.2–4.4% in the general population) ¹⁾
• Location: Most common in the mid-peripheral retina
• Appearance: Flat, well-defined pigmented lesions with internal lacunae (depigmented spots)
• GS-associated CHRPE features: Bilateral, multiple quadrants, pea-shaped, irregular borders

However, GS cannot be ruled out even if CHRPE is not present ²⁾.

Osteoma

• Frequency: Found in 60–80% of FAP patients¹⁾
• Common sites: Skull, jawbone, paranasal sinuses
• Diagnostic significance: Three or more osteomas strongly suggest GS¹⁾
• Early sign: Osteomas may be detected an average of 17 years before FAP diagnosis¹⁾

Osteoma

Frequency: 60–80% of FAP patients

Common sites: Jaw bones, paranasal sinuses, skull

Diagnostic significance: Three or more strongly suggest GS. May precede FAP diagnosis by 17 years

CHRPE

Frequency: 74% of FAP patients

Features: Bilateral, multiple, pea-shaped. The earliest sign present from birth

Note: GS cannot be ruled out even without CHRPE

Epidermal cyst

Frequency: Approximately 70%

Common site: Head and neck

Characteristics: Appears from a young age, often multiple

Desmoid tumor

Frequency: 12–15% of FAP patients

Common sites: Abdomen (37–50%), followed by shoulder girdle/chest wall

Note: Second only to colorectal cancer as a cause of death in FAP patients. Mortality rate 10–50%

Dental abnormalities

Found in 30–75% of FAP patients¹⁾. Impacted teeth and supernumerary teeth (11–27% in FAP patients vs. 0–4% in the general population) are observed¹⁾.

Risk of extracolonic malignancies

The risk of various malignant tumors other than colorectal cancer also increases.

Cancer type	Lifetime risk
Thyroid cancer	FAP 2–12%, Gardner type 10%
Small bowel cancer	4–12%
Pancreatic cancer	Approximately 1%

(Source: Reference 1)¹⁾

Q Does the presence of CHRPE always indicate Gardner syndrome?

A

Sporadic CHRPE is found in 1.2–4.4% of the general population, so the presence of CHRPE alone cannot confirm GS. GS-associated CHRPE is characterized by bilateral, multiple, pea-shaped lesions with irregular borders. Conversely, GS cannot be ruled out even if CHRPE is absent²⁾.

3. Causes and Risk Factors

The cause of GS is a germline mutation in the APC gene (5q21). Most mutations are frameshift or nonsense mutations, resulting in a truncated (loss-of-function) APC protein.

There is a clear correlation between mutation site and phenotype¹⁾.

Mutation site	Associated phenotype
Codons 311–1444	CHRPE
Codons 767–1578	Osteoma
Exon 1399 and beyond	Desmoid (800-fold risk)
Codon 1309	Early colorectal cancer at age 20

The mutation cluster region (MCR) spans codons 1250 to 1464 ¹⁾, with the most common mutation at codon 1309 (approximately 10% of all cases), followed by codon 1061 (approximately 5%) ¹⁾. The age of onset of colorectal cancer also varies by mutation site: around age 20 for codon 1309, around age 30 for codons 168–1580, and around age 52 for other sites ¹⁾.

About genetic counseling

Gardner syndrome follows an autosomal dominant inheritance pattern, with a 50% probability of passing the gene to offspring. If familial occurrence is identified, consider referral to a genetic specialist and genetic counseling. Since de novo mutations are possible, genetic testing is useful even in the absence of a family history.

Q If a family member has the condition, when should children be tested?

A

Molecular genetic testing of the APC gene can be performed from early childhood. Colonoscopy is often recommended starting around age 10. If an APC mutation is known in the family, it is important to confirm the presence or absence of the mutation through genetic testing.

4. Diagnosis and testing methods

For a definitive diagnosis, molecular genetic testing of the APC gene is performed. Next-generation sequencing (NGS) panel testing is recommended ¹⁾.

Ophthalmic Examination

• Dilated fundus examination: Essential for detecting CHRPE. Excellent for confirming bilateral and multiple lesions.
• OCT (Optical Coherence Tomography): Evaluates irregular thickening of the retinal pigment epithelium and obscuration of the IS/OS line.
• Fluorescein angiography (FAG): Confirms fluorescence blockage in the lesion area and hyperfluorescence of lacunae.

Systemic Examination

• Colonoscopy: Evaluate the number, morphology, and distribution of polyps²⁾
• Panoramic X-ray and CBCT: Detect osteomas of the jaw and paranasal sinuses¹⁾²⁾
• Thyroid ultrasound: Performed for thyroid cancer screening ²⁾
• Upper gastrointestinal endoscopy: Evaluation of duodenal and small intestinal polyps

Differential Diagnosis

• Solitary CHRPE: Also found in the general population, but often solitary and unilateral.
• Classic FAP: Differentiation from cases without prominent extracolonic manifestations is necessary
• Turcot syndrome: APC mutation or MMR gene mutation with brain tumor

Q Can genetic testing provide a definitive diagnosis?

A

Molecular genetic testing of the APC gene provides a basis for confirming the diagnosis of GS, but mutations may not be detected in some patients. The detection rate has improved with the use of NGS panel testing ¹⁾. Genetic test results should be interpreted in combination with clinical findings.

5. Standard Treatment

Ophthalmology (CHRPE)

CHRPE itself does not become malignant and has no effect on visual function. Ophthalmic intervention is unnecessary, and only periodic observation is performed.

Colorectal Treatment

Pharmacotherapy

It is used before surgery or in mild cases to suppress polyp growth.

• NSAIDs (sulindac): Reported to reduce the number of polyps
• COX-2 inhibitors (celecoxib): Effective in suppressing polyp growth

Medication alone cannot eliminate the risk of colorectal cancer.

Prophylactic Colectomy

Colectomy is recommended by age 25, ideally performed between 16 and 20 years of age²⁾. The main surgical procedures are the following three types²⁾.

Total Proctocolectomy with Permanent Ileostomy

Features: The most definitive procedure. No colorectal epithelium remains.

Advantages: Maximally reduces the risk of colorectal cancer.

Disadvantages: Requires a permanent stoma, affecting quality of life

Restorative Proctocolectomy with Ileal Pouch-Anal Anastomosis

Features: Surgical procedure that preserves intestinal continuity

Advantages: Avoids a permanent stoma

Disadvantages: Risk of urinary and sexual function complications

Total Colectomy with Ileorectal Anastomosis

Features: Minimally invasive, suitable for young patients

Advantages: Relatively less surgical invasiveness

Disadvantages: Continuous surveillance of the remaining rectum is required

Treatment of Desmoid Tumors

Desmoid tumors are histologically benign but highly locally invasive and prone to recurrence. Treatment requires a multidisciplinary approach ⁴⁾⁵⁾.

• Pharmacotherapy: Tamoxifen, NSAIDs, imatinib, sorafenib ³⁾
• Chemotherapy in children: Combination of vinblastine and methotrexate⁵⁾
• Surgery: Aim for R0 resection, but recurrence rates of 25–60% have been reported³⁾

Surveillance

Continue the following surveillance even after colectomy²⁾.

• Annual thyroid ultrasound and abdominal ultrasound (liver)
• Regular proctoscopy if the rectum is preserved
• Upper endoscopy (duodenal polyp evaluation)

Important notes on desmoid tumors

Desmoid tumors are the second leading cause of death in FAP patients after colorectal cancer, with reported mortality rates of 10–50% ¹⁾. Intra-abdominal desmoids may progress by involving the intestines and blood vessels, and surgical cases are often difficult. Regular imaging is important for early detection.

Q If a polyp is found, is surgery needed immediately?

A

It depends on the number of polyps and the degree of dysplasia. For a small number of polyps, medication with NSAIDs or COX-2 inhibitors may be used for observation. However, if 20 or more polyps or high-grade dysplastic polyps are found, prophylactic resection is recommended. The ideal timing for surgery is considered to be between 16 and 20 years of age ²⁾.

6. Pathophysiology and detailed pathogenesis

APC protein is a tumor suppressor consisting of 2800 amino acids. Its main domain structures include an oligomerization region, armadillo repeats, a β-catenin binding region, an axin binding region, and a microtubule binding region ¹⁾.

APC mutations cause constitutive activation of the Wnt signaling pathway. Normal APC protein phosphorylates β-catenin, promoting its degradation by the proteasome. In APC mutations, this function is lost, leading to accumulation of β-catenin in the cytoplasm, which forms a complex with TCF/LEF transcription factors in the nucleus and promotes transcription of cell proliferation genes.

Most mutations are frameshift or nonsense mutations, resulting in truncated (loss-of-function) APC protein ¹⁾.

In sporadic desmoid tumors, CTNNB1 (β-catenin gene) mutations are found in over 75% of cases, involving a similar pathway ³⁾.

CHRPE arises as a localized abnormal proliferation of retinal pigment epithelium. The areas of abnormal retinal pigment epithelium proliferation show concentrated and hypertrophied pigment, creating a characteristic appearance in contrast to the surrounding lacunae (depigmented areas). There is almost no malignant potential and no effect on visual function.

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7. Latest Research and Future Prospects (Investigational Reports)

For Patients: Please Read Carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Risk Stratification Using NGS Panel Testing

Next-generation sequencing (NGS) panel testing has improved the accuracy of identifying mutation sites in the APC gene ¹⁾. Risk stratification based on genotype-phenotype correlations is advancing, and the development of personalized surveillance and treatment strategies according to mutation sites is expected ¹⁾.

Novel Treatments for Desmoid Tumors

Litchinko et al. (2022) reported a rare case of a large desmoid tumor (170 mm) arising in the pancreas ³⁾. Multidisciplinary management was performed, highlighting the difficulty of surgical indication and timing in pancreatic desmoids. The efficacy of sorafenib as pharmacotherapy is attracting attention, and its application to cases where surgical resection is difficult is being considered.

The application of high-intensity focused ultrasound (HIFU) as a non-invasive treatment for desmoids is also under investigation ³⁾.

Multidisciplinary management of pediatric desmoids

Albuquerque et al. (2025) reported a case of pediatric desmoid tumor requiring shoulder joint functional reconstruction ⁵⁾. A multidisciplinary approach including preoperative chemotherapy with vinblastine plus methotrexate achieved functional preservation and tumor control. Desmoids of the shoulder girdle and chest wall account for 37–50% of cases, indicating the importance of functional reconstruction in pediatric patients.

Diaz et al. (2025) reported a GS case presenting surgical dilemmas including invasive basal cell carcinoma and total knee arthroplasty complications, demonstrating the need for multidisciplinary management of rare complications ⁴⁾. With a prevalence of 1 in 100,000–160,000, the importance of personalized medicine is increasing.

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8. References

1. Antohi C, Haba D, Caba L, et al. Novel Mutation in APC Gene Associated with Multiple Osteomas in a Family and Review of Genotype-Phenotype Correlations of Extracolonic Manifestations in Gardner Syndrome. Diagnostics. 2021;11(9):1560. doi:10.3390/diagnostics11091560.
2. Kozan R, Taşdöven İ, Seven TE, Aydemir S, Doğan Gün B, Cömert M. Gardner’s syndrome: Simultaneous diagnosis and treatment in monozygotic twins. Turkish journal of surgery. 2022;38(4):413-417. doi:10.47717/turkjsurg.2022.4218. PMID:36875267; PMCID:PMC9979555.
3. Litchinko A, Brasset C, Tihy M, Amram ML, Ris F. Large Desmoid Tumor of the Pancreas: A Report of a Rare Case and Review of the Literature. The American journal of case reports. 2022;23:e937324. doi:10.12659/AJCR.937324. PMID:36378606; PMCID:PMC9676065.
4. Q Carlos Diaz, Victor H Argueta, Pedro Chajon, Andrea Argueta. Surgical dilemmas in Gardner syndrome: infiltrative basal cell carcinoma and total knee prosthesis failure. Journal of Surgical Case Reports. 2025;2025(5). doi:10.1093/jscr/rjaf285.
5. Albuquerque M, Constantino C, Martins P, et al. Functional shoulder girdle reconstruction in paediatric desmoid tumour. J Surg Case Rep. 2025;10:rjaf830.