Gorlin Syndrome and Cowden Syndrome
論文ID: 2023-0010-IR
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論文ID: 2023-0010-IR
Gorlin syndrome and Cowden syndrome are hereditary diseases that are characterized by multiple malignancies, cutaneous symptoms, and various other abnormalities. Both disorders are caused by a mutation of the gene that regulates cell proliferation and growth, resulting in tumorigenesis. Representative mutations are mutation in the patched 1 gene (PTCH1) in Gorlin syndrome and mutation in the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene in Cowden syndrome. Making a diagnosis of these diseases in the early years of life is important because detection of malignancies at an early stage is linked to improved prognosis. Both Gorlin syndrome and Cowden syndrome have cutaneous findings in the early phase in childhood, and the role of dermatologists is therefore important. These diseases are generally diagnosed by clinical criteria, but some patients who do not meet the criteria need genetic examinations including a genetic diagnostic panel and next-generation sequencing. The most important treatment and management are detection and resection of malignancies in the early stage, and targeted therapies have recently been used for treatment of tumors and other symptoms in these diseases. Although evidence of the effectiveness of targeted therapies has been limited, they are promising therapeutic options and further clinical trials are needed in the future.
Gorlin syndrome (GS), also known as Gorlin Goltz syndrome, nevoid basal cell carcinoma (BCC) or basal cell naevus syndrome, was first reported in 1960 by Gorlin and Goltz.1 GS is an autosomal dominant hereditary disease that affects multiple organs and causes diverse abnormalities and neoplasms.2,3 Representative characteristics of GS are multiple BCCs, odontogenic keratocysts of the jaw, palmoplantar pits, and skeletal abnormalities.4 The incidence of GS has been reported to be 1 in 31,000 to 1 in 256,000 with a male-to-female ratio of 1:1.5 GS is caused by a mutation of the Hedgehog signaling pathway, and although more than 100 mutations have been reported, common mutations are those in patched 1 (PTCH1), PTCH2, and suppressor of fused homolog (SUFU) genes.2 In the Hedgehog signaling pathway, PTCH1 suppresses smoothened (SMO) activity and reduces cell proliferation.4 Therefore, under the condition of loss of function in PTCH1, SMO activity is increased, and a downstream gene such as a gene in the GLI family is also activated and cell proliferation is promoted. SUFU regulates GLI activity, and SUFU mutation therefore upregulates GLI and cell proliferation.4 In this way, the Hedgehog signaling pathway is associated with the development and tumorigenesis of GS, and mutations in the pathway cause diverse abnormalities and neoplasms.
Symptoms and diagnosisSymptoms of GS are characterized by developmental defects and tumorigenesis.6 Rib anomalies, palmoplantar pits, falx calcification, and macrocephaly are common developmental defects, and BCCs, odontogenic keratocysts, medulloblastoma, cardiac fibroma, and ovarian fibroma are characteristic tumors.6 The prevalence of each of these symptoms depends on the mutation in GS. For example, the frequency of medulloblastoma is 2% in patients with a PTCH1 mutation, but the frequency is 33% in patients with an SUFU mutation.2
Making a diagnosis of GS is important for treating cancer in the early phase and to prevent the occurrence of BCCs by avoiding exposure to ultraviolet light or radiation.3 Most cases of GS have been diagnosed by clinical diagnostic criteria.7 Two major criteria or one major criterion and two minor criteria are needed for a diagnosis of GS. The major and minor criteria are shown in Table 1.7
| Major criteria | |
| 1 | More than two BCCs or one BCC under the age of 20 years |
| 2 | Odontogenic keratocysts of the jaw (histopathologically proven) |
| 3 | Three or more palmar or plantar pits |
| 4 | Bilamellar calcification of the falx cerebri |
| 5 | Bifid, fused, or markedly splayed ribs |
| 6 | First degree relative with GS |
| Minor criteria | |
| 1 | Macrocephaly determined after adjustment for height |
| 2 | Congenital malformations: cleft lip or palate, frontal bossing, coarse face, moderate or severe hypertelorism |
| 3 | Other skeletal abnormalities: Sprengel deformity, marked pectus deformity, marked syndactyly of the digits |
| 4 | Radiological abnormalities: bridging of the sella turcica, vertebral anomalies such as hemivertebrae, fusion or elongation of the vertebral bodies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands or feet |
| 5 | Ovarian fibroma |
| 6 | Medulloblastoma |
Two major criteria or one major criterion and two minor criteria are needed for a diagnosis of GS.
For a dermatologist, multiple BCCs and palmoplantar pits are useful diagnostic features of GS. Palmoplantar pits occur in approximately 65% of adults with GS.4 A previous study showed that patients with GS who have skeletal anomalies tend to have higher frequencies of BCCs, odontogenic keratocysts, and ovarian fibromas.8 Therefore, recognition of skeletal anomalies in the early phase of childhood is important for assessing the risk of tumorigenesis in GS. Although the clinical diagnostic criteria are helpful for making a diagnosis of GS, some patients with GS may not meet the criteria. For these patients, genetic examinations including a genetic diagnostic panel and next-generation sequencing are useful for making a diagnosis of GS.2,4,9
TreatmentMultiple BCCs are one of the most common symptoms of GS. BCCs rarely metastasize to lymph nodes or distant organs. However, BCCs may invade into deep tissues such as muscle or bone if adequate treatment is not provided. Surgical resection is generally the first option for treatment of BCCs. However, some patients with GS have many BCCs, making surgical resection of all lesions difficult or onerous. In such cases, other therapeutic options are needed. Given that exposure to ultraviolet light causes BCCs in patients with GS, protection against ultraviolet light is important. In patients with advanced BCC, radiation therapy is a useful option. However, radiation exposure also causes BCCs in patients with GS and radiation therapy is a contraindication for treatment of BCCs in GS. Other options for multiple BCCs in GS include CO2 laser treatment, cryotherapy, topical 5-fluorouracil ointment, topical imiquimod, and photodynamic therapy.4 These treatments should be performed before the tumor enlarges, and careful follow-up is therefore important for patients with GS.
Odontogenic keratocysts are also common neoplasms in patients with GS. Although odontogenic keratocysts are generally asymptomatic, they can be symptomatic when they cause infection. If they are symptomatic, surgical treatment is the first option.4However, odontogenic keratocysts in patients with GS have a high frequency of recurrence after surgical treatment.10
Medulloblastoma is a malignant tumor with an age of onset of 2–3 years in GS.6 The first option for treatment for medulloblastoma is surgery with chemotherapy and radiation therapy.11 However, given that radiation therapy causes BCCs and squamous cell carcinoma in GS patients, radiation therapy should be avoided or replaced with non-confocal radiation techniques that conserve the skin.11
A Hedgehog pathway inhibitor was first approved by the Food and Drug Administration in the USA for treatment of advanced BCC in 2012.12 Hedgehog pathway inhibitors, including vismodegib and sonidegib, inhibit SMO in the Hedgehog signaling pathway and inactivate cell proliferation.13,14 Treatment with a Hedgehog pathway inhibitor is a promising therapeutic option for BCCs in GS patients.15 However, most patients who receive treatment with a Hedgehog pathway inhibitor have high frequencies of adverse events including muscle spasms, alopecia, taste loss, and weight loss.5,16 Therefore, it has been necessary to interrupt treatment or reduce the dose of the Hedgehog pathway inhibitor in many patients.15,16 Resistance to vismodegib has also been reported in GS patients.15 A topical Hedgehog pathway inhibitor is now being tested in a clinical trial, and treatment that combines safety and durability of the effect is needed for treatment of GS in the future.
Cowden syndrome (CS) is an autosomal dominant hereditary disease characterized by macrocephaly, mucocutaneous findings, multiple hamartomas, and malignancies.17,18 CS was first reported by Lloyd and Denis in 1963, and the name of the syndrome came from the family name of the first described patient.19 CS is caused by a mutation in the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene and is a representative disease of PTEN hamartoma tumor syndrome.20PTEN hamartoma tumor syndrome includes CS, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and PTEN-related Proteus-like syndrome.18 The incidence of CS has been reported to be 1 in 100,000 to 1 in 250,000 individuals.17,20 Clinical features of CS are typically presented in the second to third decade of life and the average age of diagnosis is 39 years.21 The PTEN gene regulates activation of the PI3 K-Akt-mTOR pathway, which affects cell growth and survival.22 Therefore, the loss of PTEN function leads to upregulation of the PI3 K-Akt-mTOR pathway and causes the development of hamartomas and tumorigenesis.23
Symptoms and diagnosisMucocutaneous lesions, including trichilemmoma, acral keratosis, and oral papillomatosis, are the most common features in patients with CS.21 However, the frequencies of symptoms in CS are variable and making a diagnosis is generally difficult. Eng and Yehia reported clinical diagnostic criteria for PTEN hamartoma tumor syndrome including CS, and the National Comprehensive Cancer Network has also updated the clinical criteria.24,25 The criteria proposed by Eng and Yehia are shown in Table 2.24
| Pathological criteria | |
| 1 | Adult Lhermitte-Duclos disease, defined as the presence of a cerebellar dysplastic gangliocytoma |
| 2 | Mucocutaneous lesions including trichilemmomas (facial), acral keratoses, papillomatous lesions, and mucosal lesions |
| Major criteria | |
| 1 | Breast cancer |
| 2 | Epithelial thyroid cancer (non-medullary), especially follicular thyroid cancer |
| 3 | Macrocephaly (occipital frontal circumference ≥97th percentile) |
| 4 | Endometrial carcinoma |
| Minor criteria | |
| 1 | Other thyroid lesions (e.g., adenoma, multinodular goiter) |
| 2 | Intellectual disability (IQ ≤75) |
| 3 | Hamartomatous intestinal polyps |
| 4 | Fibrocystic disease of the breast |
| 5 | Lipomas |
| 6 | Fibromas |
| 7 | Genitourinary tumors (especially renal cell carcinoma) |
| 8 | Genitourinary malformation |
| 9 | Uterine fibroids |
| To make a diagnosis of CS, patients must meet one of the following criteria: | |
| 1 | Pathognomonic mucocutaneous lesions including one of the following: six or more facial papules, of which three or more must be trichilemmomas, cutaneous facial papules and oral mucosal papillomatosis, oral mucosal papillomatosis and acral keratosis, six or more palmoplantar keratoses |
| 2 | Two or more major criteria |
| 3 | One major and three or more minor criteria |
| 4 | Four or more minor criteria |
| To make a diagnosis of CS in a family in which one individual has met the above criteria, one of the following criteria must be met: | |
| 1 | A pathognomonic criterion |
| 2 | Any one of the major criteria with or without minor criteria |
| 3 | Two minor criteria |
| 4 | History of Bannayan-Riley-Ruvalcaba syndrome |
Mucocutaneous manifestations of CS are important because these symptoms tend to be the first signs of CS.22 Therefore, dermatologists have to understand the mucocutaneous findings of CS including trichilemmoma, acral keratosis, oral papilloma, and mucocutaneous neuroma.22 Oral and perioral regions are also frequently affected in patients with CS, and the role of oral healthcare providers is also important for an early diagnosis of CS.26 Recent genetic tests, such as comprehensive genomic profiling, also enable detection of the PTEN mutation and its variants.27 Given that some patients with CS do not meet the clinical criteria, genomic profiling is also important for making a diagnosis of CS and PTEN hamartoma tumor syndrome.
TreatmentDetection of the cancer as early as possible is important for the treatment and management of CS.24 Patients with CS have increased risks for cancers, including thyroid, breast, colon, endometrial, and various other cancers.24,28 Given that the first option for treatment of these cancers is surgery, detection of the cancer at an early stage is necessary. It has been reported that the youngest patient with thyroid cancer in CS was a 7-year-old patient, and making a diagnosis of CS in the early years of life is also important.24 Regular follow-up examinations, which may include the use of ultrasonography, computed tomography, magnetic resonance imaging, or colonoscopy, are needed for management of CS.24 It has been reported that radiation therapy as adjuvant therapy for breast cancer caused undifferentiated pleomorphic sarcoma in a patient with CS.29 However, another report has described the successful use of stereotactic radiotherapy in a CS patient with meningiomas.30 Because of the risk of secondary malignancy in CS, radiation therapy should be performed with a minimal dose, and highly conformal and stereotactic techniques should be used with consideration of the risks and benefits.30
For patients with CS, treatment with sirolimus, an oral mTOR inhibitor, has been reported as the targeted therapy.23 Everolimus, another mTOR inhibitor, has also been reported as treatment for neurocognitive symptoms in PTEN hamartoma tumor syndrome patients.31 Although the numbers of patients in these studies were small and evidence of the effectiveness of treatment was limited, the targeted therapies were well tolerated and promising. Further clinical trials are needed in the future.
As described above, Gorlin syndrome and Cowden syndrome are rare diseases. By establishing a registry for rare diseases, it is possible to obtain information about the natural history, progression, risks, and outcomes of the disease as well as genetic information. Study data were collected and managed using the Research Electronic Data Capture (REDCap) platform hosted at the Osaka Metropolitan University Graduate School of Medicine.32,33 REDCap is a secure, web-based software platform that is designed to support data capture for research studies. It provides the following capability: 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources. We established registries for GS and CS with the aim of improving the understanding of these diseases.
We thank Prof. Takashi Hashimoto (Osaka Metropolitan University) for providing the opportunity to study these diseases.
The authors declare no conflict of interest.
