Nevoid basal cell carcinoma syndrome with a novel PTCH1 variant: Genetic testing and literature review in a case report

Abstract

Nevoid basal cell carcinoma syndrome is a rare autosomal dominant hereditary disorder characterized with almost complete penetrance and multiple clinical manifestations. A 31-year-old female presented with a 31-year history of black papules on her face, neck, trunk, and upper limbs. Over time, these lesions increased in size and number, demonstrating an invasive nature. Histopathological analysis of the skin lesions revealed basaloid cells arranged in a palisading pattern within the dermis and extensive basophilic changes in the superficial dermis. Whole-exome sequencing identified a somatic PTCH1 mutation c.3080G>A (p.Trp1027Ter), confirming the diagnosis of nevoid basal cell carcinoma syndrome. An integrated treatment approach was employed, including surgical interventions and carbon dioxide laser therapy. As nevoid basal cell carcinoma syndrome affects multiple organ systems, it requires multidisciplinary management. Understanding and recognizing the clinical presentations and underlying genetic mutations can provide insights into its pathogenesis and guide effective management strategies.

Introduction

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder with an autosomal dominant inheritance pattern, and characterized by complete penetrance and variable expressivity. ¹ It is primarily caused by germline mutations in the genes PTCH1/2 or SUFU, which are integral to the Sonic hedgehog (Shh) molecular pathway. ² NBCCS is characterized by the presence of multiple nevoid basal cell carcinomas (BCCs), odontogenic cysts, brain sickle calcifications, and skin lesions on the palms and soles of the feet. ³ Herein, we report the case of a 31-year-old female patient presenting with a multifocal mass predominantly on her face. Based on her medical history, auxiliary examinations, and genetic testing, the final diagnosis of NBCCS was established. In particular, to the best of our knowledge, this report presents the first description of a novel PTCH1 somatic nonsense variant (c.3080G>A, p.Trp1027Ter), which has not been previously reported in the literature, thereby expanding the known mutational spectrum of NBCCS. We believe that this addition clearly communicates the unique scientific contribution of this case report. Favorable clinical outcomes have been achieved through surgical excision combined with carbon dioxide laser therapy. Furthermore, to enhance the understanding of NBCCS and increase clinicians’ recognition of this disorder, a literature review was also conducted.

Case report

A female patient in her early 30s presented to the Fifth People’s Hospital of Hainan Province, Haikou, China, in July 2023, with a 31-year history of black papules on her face, neck, trunk, and both upper limbs. The papules gradually increased in number and more recently accompanied by ulcers. On physical examination, the patient exhibited facial asymmetry with widened orbital distance. Oral examination revealed a cleft palate. Scattered black papules and maculopapular rashes, ranging from the size of millet to soybean, were observed on her face, neck, torso, and both upper limbs. These lesions had a rough surface, clear boundaries, and uneven pigment distribution. Some were eroded and ulcerated. Several dotted depressions were evident in the palms of both hands. No enlarged lymph nodes were observed upon palpation (Figure 1). The patient provided a written informed consent to the publication of the case information. This study was approved by the institutional ethics committee.

Figure 1.

Clinical manifestations of the patient. (a) The patient’s face was asymmetric and the orbital distance was widened. Multiple black papules of variable sizes on the face. (b) Nasal septum deviation and cleft palate can be seen in the mouth; (c and d) dyskeratotic palmar and sole pitting.

No obvious abnormalities were found in laboratory examination. Dermoscopy revealed a dark brown background with large blue-gray oval nests, multiple blue-gray globules, leaf-like structures, wheel-like structures, dendritic vessels, central ulcer formation, multiple patterns, and no pigmented mesh. A biopsy of facial skin lesions showed that the epidermis was atrophied and thinned, and superficial erosion was evident. At the bottom and periphery of the erosion, a tumor mass composed of basal-like cells connected with the normal epidermis could be seen. The size of the tumor cells was consistent, the surrounding cells were palisade, the central cells were serous, and the superficial dermis was extensively basophilic (Figure 2). Plain computed tomography (CT) scans of the head and maxillofacial region revealed multiple calcifications in the cerebral falx and tentorium cerebelli, a hallmark radiological feature of NBCCS. Additional findings included a localized defect in the left maxilla, irregular adjacent soft tissue, and left deviation of the nasal septum. Three-dimensional CT reconstruction of the whole thoracic spine revealed a bifid T2 vertebra, consistent with the skeletal anomalies characteristic of NBCCS. Genetic testing of lesional skin tissue identified a heterozygous PTCH1 mutation (c.3080G>A; p.Trp1027Ter). Per American College of Medical Genetics and Genomics (ACMG) guidelines, this variant was classified as likely pathogenic (pathogenic very strong 1 (PVS1) + pathogenic moderate 2 (PM2)_Supporting) based on the null effect and absence from population databases.

Figure 2.

Histological features of the biopsy of the papules on the patient’s face. (a) The tumor mass composed of basal-like cells was seen in the dermis, which was connected with the epidermis, and the boundary between the tumor mass and the surrounding tissue was clear. (HE, 100×). (b) The cells around the tumor mass show peripheral palisading, and the central cells are arranged disorderly. The dermal papilla and hair follicle structure are visible (HE, 400×). HE: hematoxylin and eosin.

A diagnosis of NBCCS was established based on the clinical presentation, histological features, and genetic testing. Surgical resection was performed for larger rashes on the head and face, and a carbon dioxide pulse laser was used for smaller rashes. The patient recovered well after surgery and has been followed up for more than 3 months. No new rashes have been observed, and further follow-up is ongoing. We have deidentified all patient details.

The patient provided written informed consent for the publication of any accompanying photos and case details. The Hospital Ethics Committees of the Fifth People’s Hospital of Hainan Province approved publication of the case details.

Discussion

NBCCS is a rare autosomal dominant genetic disorder with an incidence of 1 in 256,000 to 1 in 57,000. ⁴ This syndrome was first described by White in 1894. In 1960, Gorlin and Goltz first proposed the multi-basal cell triad, namely BCC, keratocystic odontogenic tumor (KCOT), and skeletal deformity. ⁵ NBCCS is composed of multiple BCCs and jaw keratocysts, palmar keratosis and intracranial ectopic calcification, facial malformations (deformed eyes, cleft lip and palate, and severe eye malformations), skeletal system abnormalities, and multiple organ developmental disorders. ⁶ Risk factors for this disorder include excessive sun exposure, radiation exposure, immunosuppression, and vitamin D deficiency. ³ The European consensus-based interdisciplinary guideline for diagnosis and treatment of BCC (update 2023) traditionally classifies BCC into superficial, nodular, morpheic, and ulcerated subtypes. However, the latest framework proposes a pragmatic two-tier division of “easy-to-treat” (>90% of cases) and “difficult-to-treat” (including all locally advanced (laBCCs)), further refined by the European Association of Dermato-Oncology (EADO) into five groups based on tumor characteristics, location, and patient factors. ⁷

Most NBCCS cases are associated with mutations in the tumor suppressor gene PTCH1, which may inhibit the activation of the Shh signaling pathway by encoding the Shh protein receptor and affect its role in cell differentiation, cell proliferation, and neuronal development. ⁸ Additionally, some studies suggest that the pathogenesis of NBCCS is related to the regulation of various gene products in the Shh signaling pathway, such as BOC, SUFU, GLI family, and SMO^9,10 (Table 1). Patients with NBCCS exhibit chromosomal instability under stress. In addition, the presence of PTCH1 mutations in fibroblasts makes it highly sensitive to ionizing radiation and ultraviolet (UV)-mediated cytotoxicity through reactive oxygen species. Reactive oxygen species induce oxidative damage to DNA and prevent its repair.^1,11 This finding supports the results of the study on the effectiveness of strict sun protection for genetically susceptible populations.^12,13

Table 1.

The role of several key genes (PTCH1, PTCH2, SMO, and SUFU) in the pathogenesis of NBCCS.

Gene	Function and role	Role in the pathogenesis of NBCCS
PTCH1	Encodes Patched1 protein, a negative regulator in the Hedgehog signaling pathway.	Mutations in PTCH1 lead to reduced inhibition of Smoothened, resulting in excessive activation of the Hedgehog pathway.
	Suppresses the activity of Smoothened to control the pathway’s activity.	Excessive activation of the Hedgehog pathway may contribute to the development of basal cell carcinoma.
PTCH2	Encodes Patched2 protein, similar to PTCH1, also a negative regulator in the Hedgehog pathway.	PTCH2 functions similarly to PTCH1, and mutations in PTCH2 can also lead to abnormal activation of the Hedgehog pathway.
	Controls the pathway’s activity by inhibiting Smoothened.	Although PTCH2 mutations are less common, they have unique implications in basal cell carcinoma.
SMO	Encodes Smoothened protein, a positive regulator in the Hedgehog pathway.	Under normal conditions, Smoothened is inhibited by PTCH proteins, maintaining the Hedgehog pathway in the off state.
	Activation of the Hedgehog pathway is associated with the activation of Smoothened.	Mutations in PTCH reduce inhibition on Smoothened, leading to abnormal activation of the Hedgehog pathway.
	Participates in regulating cell proliferation and growth by activating Gli transcription factors.	Excessive activation of the Hedgehog pathway may contribute to the development of basal cell carcinoma.
SUFU	Encodes Suppressor of Fused protein, a negative regulator in the Hedgehog pathway.	Negatively regulates the activity of the Hedgehog pathway by inhibiting the transcriptional activity of Gli proteins.
	Sequesters Gli proteins in the cytoplasm, preventing their nuclear entry.	Mutations in SUFU may lead to abnormal activation of the Hedgehog pathway, increasing the risk of cancer.
	Regulates Hedgehog pathway transduction to maintain its activity at appropriate levels.	Malfunction of SUFU may result in inappropriate activation of the Hedgehog pathway, contributing to the pathogenesis of basal cell carcinoma.

NBCCS: nevoid basal cell carcinoma syndrome.

The current diagnostic criteria for NBCCS require either two main criteria or one main criterion plus two secondary criteria. ¹⁴ The main criteria include the following: (a) BCC before the age of 20 years; (b) excessive BCC inconsistent with sun exposure and skin type (such as multiple BCCs in non-sun exposure sites) (more than 5); (c) odontogenic keratocyst of the jaw diagnosed before the age of 20 years; (d) palm or plantar depression; (e) cerebral falx calcification; (f) medulloblastoma; and (g) first-degree relatives of patients with NBCCS. The secondary criteria include the following: (a) rib abnormalities; (b) other specific skeletal malformations and radiological changes (i.e. spinal abnormalities, kyphosis, fourth metacarpal shortening, and post-axial polydactyly); (c) big head; (d) cleft lip and palate; (e) ovarian and cardia inflammation; (f) lymphomesenteric cyst; and (g) eye diseases (strabismus, orbital hypertelorism, congenital cataract, glaucoma, and ocular tissue defect). It remains controversial whether medulloblastoma should be included in the main diagnostic criteria. ¹⁴ Furthermore, other genetic syndromes, such as Muir–Torre syndrome, ¹⁵ Bazex syndrome, and Rombo syndrome, should be excluded. ¹⁶ The present patient fulfilled the following major criteria: (a) multiple BCCs; (b) palm punctate depression; and (c) multiple calcifications in the cerebral falx and tentorium of the cerebellum on cranial CT. The following minor criteria were also met: (a) vertebral anomaly (T2 cleft); (b) cleft palate; and (c) orbital hypertelorism. The identification of a somatic PTCH1 mutation in lesional tissue further supported the diagnosis. Therefore, the diagnosis of NBCCS was established based on sufficient clinical and molecular evidence.

The choice of treatment options for BCC is mainly based on various factors such as the size, location, and histological type of the lesion. ¹⁷ Treatment methods include surgical resection, Mohs microsurgery, liquid nitrogen freezing, topical 5-fluorouracil, imiquimod, and photodynamic therapy. Following the in-depth study of the molecular mechanism underlying its pathogenesis, vismodegib and sonidegib, oral drugs against Smo receptors, have been approved for the treatment of BCC,^18–20 thereby representing new breakthroughs in the management of NBCCS. However, the therapeutic effect and safety of the drugs require further evaluation and research. GS is an autosomal dominant genetic disorder associated with the PTCH1 tumor suppressor gene that dysregulates the Shh pathway. Current studies recommend incorporating hedgehog inhibitors (HHIs) such as vismodegib and sonidegib into the therapeutic armamentarium for GS-associated BCCs. These SMO-targeting oral agents have demonstrated clinical efficacy in laBCCs or metastatic BCCs, as supported by recent evidence specifically in the GS setting. ²¹ For young patients with recurrent, malignant, high-risk condition, drugs, laser, freezing, photodynamic, and other treatment methods are often used in combination to preserve normal tissue and prevent disfigurement. ²²

Furthermore, NBCCS affects multiple organ systems beyond the skin. Studies have shown that odontogenic keratocysts occur in the majority of patients and may precede BCCs. ²³ Less frequently, medulloblastoma and cardiac fibroma may also occur.^24,25 Given this broad spectrum of manifestations, regular multidisciplinary surveillance is recommended for all confirmed patients with NBCCS.

In this report, the patient was a young female with a long-standing history of multiple facial lesions with ulcers. We adopted surgical resection combined with carbon dioxide laser therapy, which resulted in favorable outcomes and improvement in the patient’s quality of life. In addition, daily attention should be paid to sun protection and reducing exposure to radioactive substances, and regular follow-up is necessary.

In summary, NBCCS is a familial genetic disorder characterized primarily by a predisposition to BCCs, accompanied by various skeletal or soft tissue developmental abnormalities. Its pathogenesis remains incompletely understood. Genetics and genomics remain major focuses of NBCCS research. This condition involves multiple organ systems and requires multidisciplinary comprehensive management. CT and magnetic resonance imaging (MRI) are recommended to regularly determine the progression of lesions. Overall, early diagnosis and multidisciplinary comprehensive treatment are essential to prevent recurrence and improve the survival rate of patients. The reporting of this study conforms to Case Report (CARE) guidelines. ²⁶

Conclusion

We report a case of a 31-year-old female patient with multifocal facial masses, diagnosed with NBCCS based on clinical presentation, imaging findings, and genetic testing. To the best of our knowledge, this report presents the first description of a novel PTCH1 somatic nonsense variant (c.3080G>A, p.Trp1027Ter), thereby expanding the known mutational spectrum of NBCCS. The early onset of multiple BCCs in this young patient underscores the importance of regular dermatoscopic surveillance from childhood for early detection in individuals with NBCCS.