Gorlin Syndrome: A Comprehensive Evaluation of Skin Findings

Abstract

Objective:

Although Gorlin syndrome has rich skin findings, there is limited information about their subtypes, features specific to this genodermatosis, and relationships with each other.

Materials and Methods:

The demographic characteristics as well as cutaneous and extracutaneous findings of consecutive Gorlin syndrome patients diagnosed during 23 years were evaluated retrospectively. The relationship between palmoplantar pitting and basal cell carcinoma (BCC) in this localization and the relationship between odontogenic keratocysts (OKCs) and epidermoid cysts were investigated.

Results:

A total of 30 patients were diagnosed with Gorlin syndrome of whom 36.7% were children. BCC was the most common finding (90%) followed by OKCs (83.3%), skeletal system anomalies (76.7%), and palmoplantar pitting (76.7%). While classical BCC (63.3%) lesions were the predominant clinical subtype among all patients, acrochordon-like or small-sized papular BCCs were seen in 45.4% of pediatric patients. Three patients, 2 of whom were children, had BCC lesions in the palmoplantar region in association with palmoplantar pitting. Epidermoid cysts presenting clinically as solitary (n = 12) or a few nodules (n = 4) without punctum, located more commonly in acral areas (n = 10) were seen in 16 (53.3%) patients of whom 7 were children. Epidermoid cysts were seen in 60% of patients with OKCs, and the relationship between epidermoid cysts and OKCs was not statistically significant (P = .15). Extracutaneous tumors such as medulloblastoma (n = 3), cardiac fibroma (n = 1), and ameloblastoma (n = 1) were also recorded.

Conclusion:

The awareness of papular or acrochordon-like BCCs, palmoplantar BCCs, and acral epidermoid cysts without punctum may facilitate early diagnosis of Gorlin syndrome in children.

What is already known on this topic?

• The most common skin findings of the Gorlin syndrome are early-onset and/or multiple basal cell carcinoma (BCC) lesions and palmoplantar pitting. In addition, both findings were also stated among the major diagnostic criteria of the disease.

• Basal cell carcinomas may vary from a few to thousands with a wide range of appearances clinically with limited attention to acrochordon-like or small-sized papular BCCs and acral BCCs.

• Epidermoid cysts were reported with a frequency of 50% or greater in patients with Gorlin syndrome in various reports. Despite their high frequency, they are not considered a diagnostic criterion for Gorlin syndrome.

What this study adds on this topic?

• The awareness of small-sized papular or acrochordon-like BCCs, atypical located BCCs such as in palmoplantar area, and acral epidermoid cysts without blackhead-like punctum may facilitate early diagnosis of the disease, especially in childhood patients.

• When evaluated together with the frequency of epidermoid cysts in our study and their disease-specific clinical characteristics, it can be suggested that they may be among the diagnostic criteria of this genodermatosis in the future.

Introduction

Gorlin syndrome (OMIM #109400), also known as Gorlin–Goltz syndrome, nevoid basal cell carcinoma syndrome (NBCS), or basal cell nevus syndrome, is a rare autosomal dominant disease that causes various skin findings, and numerous system anomalies, with an increased tendency to some systemic malignancies. It is most commonly associated with a heterozygous germline mutation in PTCH1 and sometimes SUFU mutations, resulting in variations in clinical presentation.^1-3 The most common findings of the disease are basal cell carcinoma (BCC) lesions that occur at an early age and/or as multiple skin tumors, skeletal system anomalies, and odontogenic keratocysts (OKCs) observed in the jaw in addition to a broad scale of other systemic features.^1,4-9 Although many of the patients had one or more clinical signs suggestive of Gorlin syndrome beginning in early childhood, the diagnosis could not be established until adulthood. Cardiac fibroma, medulloblastoma, OKCs, BCC, and ovarian fibroma each appear in turn in patients with Gorlin syndrome from birth in addition to an increased risk of developmental delay and intellectual disability.^8-10 Although it is well known that the disease has rich skin findings, there is limited information about their subtypes, features specific to this syndrome, and relationships with each other or systemic features. In addition, it was previously suggested that differences in ethnicity and/or environmental factors may affect the incidence of BCC and other features in patients with Gorlin syndrome.^11,12 However, only a limited number of case reports from our country regarding Gorlin syndrome exist.^13-18 Our study aimed to review the clinical findings of Gorlin syndrome in a large series of Turkish patients of different ages mainly focusing on the skin findings to determine more specific characteristics of the disease which may be helpful in early diagnosis.

Materials and Methods

Patients and Diagnosis

Consecutive patients diagnosed with Gorlin syndrome in a tertiary dermatology center between 2001 and 2023 were evaluated retrospectively. The family history of the disease and clinical, radiological, and genetic findings of the patients were recorded, which are included in the current diagnostic criteria,¹ constituting a total of 6 major and 7 minor criteria (Table 1). The diagnosis of the disease was established based on (i) 1 major criterion and genetic confirmation, (ii) 2 major criteria, or (iii) 1 major criterion and 2 minor criteria.

Table 1.

Diagnostic Criteria of Gorlin (Basal Cell Nevus Syndrome) Syndrome¹

Major Criteria BCCs prior to age 20 years or multiple BCCs OKCs prior to age 20 years Palmar or plantar pitting Lameller calcification of the falx cerebri Medulloblastoma (desmoplastic variant) First-degree relative with BCNS

Minor Criteria Rib anomalies Macrocephaly Cleft lip/palate Ovarian/cardiac fibroma Lymhomesenteric cysts Ocular abnormalities Other specific skeletal malformations and radiological changes

BCCs, basal cell carcinomas; BCNS, basal cell nevus syndrome; OKCs, odontogenic keratocysts.

Data Collection

The demographic and phenotypic characteristics of the patients as well as cutaneous and extracutaneous findings were reviewed. At least one BCC lesion was histopathologically confirmed at the time of diagnosis and BCC lesions that occurred during follow-up were mostly diagnosed clinically in patients with Gorlin syndrome expressing this criterion. The total number (<10, 10-25, >25), predominant clinical subtype, and localization of BCC lesions were recorded during the follow-up period.

The epidermoid cysts and milia were mostly clinically diagnosed in these patients in addition to ultrasonographic findings in some of them. The number, localization, and clinical features of epidermoid cysts in addition to the age of patients at the time of epidermoid cyst occurrence were recorded.

The study was approved by the institutional Ethics Committee of İstanbul Faculty of Medicine and conducted in accordance with the Declaration of Helsinki (approval number/date: E-29624016-050.99-1738968/April 14, 2023). Written informed consent was obtained from the patients who agreed to take part in the study.

Statistical Analysis

Descriptive analysis was undertaken, and results were reported as the number, percentage, and/or mean. Fischer exact test was used to determine any associations between OKCs and epidermoid cysts in addition to palmoplantar pitting and BCCs in this localization. A significance level of P < .05 was considered as indicative of statistical significance. For all statistical analysis, the Statistical Package for the Social Sciences (SPSS), version 22.0 (IBM Corp., Armonk, NY, USA) software was used.

Results

Demographics

During the study period, a total of 30 (15 female, 15 male) patients were diagnosed with Gorlin syndrome with a mean follow-up duration of 60 ± 58.5 (2-215) months. Most patients were from different families (76.7%) and only 7 (23.3%) patients from 3 families were included in the study. The mean age of the patients at the time of diagnosis was 27.9 ± 14.9 (9-66) years, and 36.7% of the patients were diagnosed at the pediatric age (<18) (Table 2).

Table 2.

Main Cutaneous and Extracutaneous Features of Our Patients with Gorlin Syndrome

Patient Number/Sex/Age/Family History	Basal cell carcinoma			Odontogenic Keratocyst	Palmoplantar Pitting	Skeletal System Anomalies	Other Features	Major Criteria	Minor Criteria
	Number	Localization	Clinical Subtypes
1/F/32/−	10-25	Head, neck, trunk	Acrochordon-like papular	Present	Present	Kyphoscoliosis, macrocephaly	Ocular abnormalities (nystagmus), left radical nephrectomy due to hydronephrosis, milium	3	4
2*/M/19/+	<10	Head, neck	Pigmented	Present	Present	Kyphoscoliosis, pectus carinatum, macrocephaly	Milium	4	5
3*/M/12/+	None	None	None	Present	None	Pectus carinatum	Milium	2	1
4/M/33/+	>25	Head, lower extremity	Noduloulcerative, superficial, pigmented	None	Present	Macrocephaly	Milium	3	1
5*/M/51/+	<10	Head, trunk	Pigmented, superficial	Present	Present	Macrocephaly	Neurologic abnormalities (cerebral atrophy, enlargement of ventricles)	4	2
6/M/22/−	<10	Head, trunk	Noduloulcerative, superficial	None	None	Kyphoscoliosis	Neurologic abnormalities (cerebral atrophy, medulloblastoma), endocrinological abnormalities (hypogonadism, cryptorchidism)	2	1
7*/M/37/+	<10	Head, neck	Pigmented, superficial	Present	Present	None	None	4	–
8*/M/11/+	<10	Head	Acrochordon-like papular	Present	Present	Bifid costa	Ocular abnormalities (congenital amaurosis), milium	4	2
9*/F/13/−	<10	Head, trunk	Pigmented	Present	Present	Kyphoscoliosis, macrocephaly	Neurologic abnormalities (calcification of falx cerebri, hydrocephalus), milium, ovarian fibroma	4	3
10/F/37/−	<10	Head, neck	Noduloulcerative, pigmented	Present	Present		Milium	3	-
11/F/15/−	10-25	Neck, trunk, upper extremity	Acrochordon-like papular, superficial	Present	Present	Kyphoscoliosis, spina bifida occulta, bifid costa, polydactyly, macrocephaly	Ocular abnormalities (optic nerve coloboma), neurologic abnormalities (medulloblastoma), endocrinological abnormalities (hypogonadism), ovarian fibroma, kidney agenesis, cleft palate, lymhomesenteric cysts, milium	4	7
12*/M/17/−	10-25	Head, neck	Acrochordon-like papular, noduloulcerative	Present	Present		Ocular abnormalities (strabismus), milium	3	3
13*/F/41/−	<10	Head, trunk	Noduloulcerative	Present	Present	Macrocephaly	Milium	3	2
14/F/17/−	<10	Head, trunk	Noduloulcerative, superficial	Present	Present	Kyphoscoliosis, macrocephaly	Milium, ovarian cyst	3	3
15*/F/31/−	<10	Head	Noduloulcerative, superficial	Present	Present	Macrocephaly	Ocular abnormalities (congenital amaurosis), milium, ovarian cyst	3**	4
16/M/12/−	>25	Head, neck, trunk, upper extremity (palmar)	Acrochordon-like papular	Present	Present	Kyphoscoliosis, macrocephaly		3**	2
17*/F/34/−	<10	Head, neck, trunk	Noduloulcerative, superficial	Present	None	Kyphoscoliosis	Ocular abnormalities (congenital amaurosis), neurologic abnormalities (calcification of falx cerebri)	3	3
18/F/57/−	<10	Head, neck	Noduloulcerative	Present	None			2	1
19/M/30/−	>25	Head, neck, trunk	Superficial, noduloulcerative	Present	Present		Milium	3**	1
20*/M/17/+	10-25	Head, neck, trunk	Noduloulcerative, achrochordon-like papular	Present	None	Kyphoscoliosis, macrocephaly	Neurologic abnormalities (hydrocephalus), milium	3	3
21/F/49/+	<10	Head, neck	Noduloulcerative, acrochordon-like papular	None	Present	Kyphoscoliosis		3	1
22*/M/66/−	10-25	Head, neck, trunk	Noduloulcerative	Present	None		Ameloblastoma, milium	2	1
23*/M/35/−	>25	Head, neck, trunk	Noduloulcerative	Present	Present	Kyphoscoliosis, macrocephaly	Milium	3	3
24/F/21/−	>25	Head, neck, trunk, upper (palmar) and lower extremity	Acrochordon-like papular, noduloulcerative	None	Present	Kyphoscoliosis	Neurologic abnormalities (medulloblastoma), ovarian sex cord-stromal tumor, hypothyroidism	3	1
25*/F/9/−	10-25	Head, neck, lower extremity (plantar)	Noduloulcerative, acrochordon-like papular, superficial	None	Present	Rotoscoliosis, pectus excavatum, macrocephaly	Ocular abnormalities (glaucoma), milium	2**	3
26*/M/38/−	>25	Head, neck, trunk	Noduloulcerative, acrochordon-like papular, superficial	Present	Present			3**	1
27/F/19/−	10-25	Head, neck, trunk	Acrochordon-like papular	Present	Present	Macrocephaly	Milium	3	2
28/F/17/−	10-25	Head, neck	Acrochordon-like papular	Present	Present	Kyphoscoliosis, macrocephaly	Ocular abnormalities (nystagmus)	3	3
29/M/35/−	None	None	None	Present	None	Kyphoscoliosis		1**	1
30*/F/11/−	None	None	None	Present	Present	Macrocephaly	Cardiac fibroma	2	2

F, female; M, male.

*Patients with epidermoid cysts.

**Genetic confirmation was present.

Cutaneous Findings

Basal Cell Carcinoma

Although BCCs were the most common finding (n = 27), it was not recorded in 3 cases (10%) with an age of 11, 12, and 35 years in our series. Basal cell carcinoma lesions were located in the head and/or neck region in all patients (n = 27), followed by the trunk (n = 16) and extremities (n = 5) (Figure 1A-F). While the majority of the patients had multiple BCC lesions (8 patients: 10-25 BCC, 6 patients: >25 BCC), less than 10 BCC lesions were detected in 13 patients, 23.1% of whom were in the pediatric age group. While classical BCC lesions (noduloulcerative, superficial, and pigmented BCC) (Figure 1A-C) were seen as the predominant clinical subtype in the majority of patients (n = 19) clinically, 45.4% of pediatric patients and 15.7% of adult patients had BCC lesions mostly in the form of acrochordon-like or small-sized papular lesions (Figure 1D-F) (Table 2). Metastatic BCC was not recorded in any patients.

Figure 1.

Various clinical features of basal cell carcinomas in patients with Gorlin syndrome; (A) Two noduloulcerative type basal cell carcinomas in variable size with prominent telangiectasia on the surface of the upper one on the neck of an adult patient; (B) Multiple superficial type basal cell carcinomas on the forehead of an adult patient; (C) Pigmented type basal cell carcinomas in variable sizes on the eyelid and periocular region of a child patient; (D) Small-sized papular dermal nevus-like basal cell carcinomas on the forehead of a child patient; (E) Multiple small-sized papular dermal nevus-like basal cell carcinomas on the trunk of a child patient; (F) Acrochordon-like and small-sized papular basal cell carcinomas on the neck of a child patient.

Cutaneous Findings Other Than Basal Cell Carcinoma

Palmoplantar pitting was evident as shallow depressions in 76.7% (n = 23) of patients (Figure 2A). Three patients, 2 of whom were children, had BCC lesions in the palmoplantar region in association with palmoplantar pitting without a statistical significance (Figure 2B-C) (P > 0.05).

Figure 2.

(A) Multiple palmar pitting lesions appearing as shallow depressions on the palm of an adult patient; (B) A small-sized, pigmented papular basal cell carcinoma lesion on the center of the palm of a child patient associated with palmar pitting; (C) A small-sized papular basal cell carcinoma lesion on the palmar surface of the fourth finger of a child patient.

Epidermoid cysts were seen in 16 (53.3%) patients of whom 7 were <18 years of age at the time of occurrence of these lesions (Figure 3A-D). While most of the patients (n = 12) had only 1 cutaneous epidermoid cyst, some had 2 (n = 3) or 3 (n = 1) epidermoid cysts as skin-colored, smooth-surfaced, round papules, or nodules without a central blackhead-like punctum (Figure 3A-D). The lesions were most commonly seen on the acral localizations (n = 10) such as hand and foot (Figure 3B-D). In 1 adult patient in association with cutaneous epidermoid cysts, multiple, firm cysts were also seen protruding from the tarsus under the palpebral conjunctiva on eyelid eversion (Figure 3E) (Table 3). In addition, facial milia were found in 17 (56.7%) patients of whom 41.2% were children (Figure 3F). Epidermoid cysts were seen in 60% of patients with OKCs, and the relationship between epidermoid cysts and OKCs was not statistically significant (P = .15).

Figure 3.

Various clinical features of epidermoid cysts and milia in patients with Gorlin syndrome; (A) A bluish smooth-surfaced epidermoid cyst on the arm of a child; (B) A relatively bigger epidermoid cyst on the dorsum of the hand of an adult patient. Note that no punctum is seen; (C) A smooth-surfaced epidermoid cyst on the volar surface of the thumb of an adult patient; (D) An epidermoid cyst around the lateral malleolus of a young adult patient; (E) Multiple, small whitish cysts protruding from the tarsus under the palpebral conjunctiva on eyelid eversion of an adult patient; (F) Milium (on the right) on the eyelid and 3 small-sized, skin-coloured papular basal cell carcinomas on the periocular area of an adult patient.

Table 3.

Literature Review Regarding Cutaneous Epidermoid Cysts Seen in Patients with Gorlin Syndrome

Author/Year	Age/Gender	Localization	Number of Lesions
Zackheim et al/196644	17/F	Thumb, plantar	3
Nicolai/197940	16/F	Palms of both hands	Multiple
Leppard/198336	35/F	Upper arm, thigh	2
	61/M	Thumb	1
	32/M	Hands	4
	56/F	Trunk, limbs	19
	56/M	Lower back	2
	33/M	NA	1
Barr et al*/198642	39/F	Eyebrow	1
	28/M	Neck	3
Levine et al/198745	61/M	Palm, palpebral conjunctiva of the upper eyelids	Multiple
	41/F	Palm, palpebral conjunctiva of the upper eyelids	NA
Baselga et al*/199637	15/F	Fingers	2
Chiritescu et al/200122	8/F	Buttock	1
Hamel et al*/200347	38/M	Lower leg	1
Motegi et al*/200846	72/M	Trunk and extremities	25
Morice-Picard et al/200939	3/M	Hand, forearm, scalp	3
Tirado et al/201441	71/M	Hand	6
	38/F	Hand	1
	53/F	Hand, feet, trunk, face, extremities	10
	24/M	Hand, trunk, extremities	6
Matsudate et al*/201538	33/M	Upper eyelid, trunk, thigh	16
Goggins et al*/202143	6/F	Trunk	1
Present study/2023	11/M	Palm	1
	12/M	Trunk	1
	13/F	Foot, forearm	2
	17/M	Lower leg, palm	2
	17/M	Palm	1
	19/M	Trunk, foot, lower leg	3
	9/F	Plantar	1
	31/F	Upper thigh, upper eyelid (palpebral conjunctiva)	1 + mucosal
	34/F	Hand, plantar	2
	35/M	Palm	1
	37/M	Palm	1
	41/F	Trunk	1
	51/M	Upper eyelid	1
	66/M	Axillary region	1
	38/M	Trunk	1
	11/F	Palm	1

F, female; M, male; NA, non-available

*Cutaneous cysts were stated as keratocyst.

Extracutaneous Findings

Phenotypic features such as occipitofrontal width and hypertelorism were evident in the vast majority of patients (76.7%) followed by OKCs (n = 25) and macrocephaly and/or other skeletal system anomalies (n = 23). A minority of patients also had extracutaneous tumors such as cardiac fibroma (n = 1), ovarian fibroma (n = 1), medulloblastoma (n = 3), and ameloblastoma (n = 1). In addition, unilateral congenital amaurosis was present in 3 patients.

Discussion

Basal cell carcinoma is the most frequent skin cancer in the fair-skinned adult population over 50 years of age. It can show local invasion but has a very low risk of systemic metastasis, only in advanced cases. Although BCC mostly occurs sporadically, it may infrequently occur as a component of Gorlin syndrome. In this case, it can appear from an earlier age and present as multiple lesions.^1,10,19 Approximately 1/200 of all BCC patients have Gorlin syndrome, while this rate reaches 20% in those who develop BCC before the age of 20. We diagnosed 30 Gorlin syndrome patients in 23 years in a tertiary center. The incidence of Gorlin syndrome is estimated to be approximately between 1/31 000 and 1/256 000 without a sex predilection, as in our series.^{1,4,6,7,9,11,12,20} Given the extreme variation in the expression of Gorlin syndrome resulting in a challenge for clinicians in the diagnosis of genodermatosis, different diagnostic criteria have been used over the years.^1,5,7

As implied by its synonym, the most recognized feature associated with Gorlin syndrome is BCC, which may vary from a few to thousands with a wide range of appearances clinically.^7,21 Although Gorlin syndrome patients may have BCC at any location, most tumors are located in sun-exposed areas. In our series, the head and/or neck (90%) region was the most common localization of BCCs in line with previous reports.^1,4-9 This is also similar to the most common location of sporadic BCC, implying that sun exposure plays a role in the development of these tumors.^19,22 Remarkably, trunk (53.3%) localization of BCCs is also common in our patients with Gorlin syndrome. In addition, in a large study evaluating perianal and genital BCCs, 5 perianal and 28 genital BCCs were found in 2 patients with Gorlin syndrome, which was not recorded in our series.²³ It is recommended that sun-protected areas should also be included in the dermatological examination of patients with Gorlin syndrome.^7,21,24

The palmar and plantar pitting appear as shallow depressions which are found mainly on the palms (Figure 2A) and soles, but they can also be present on the fingers and toes’ sides, web spaces, and dorsum.⁷ Palmoplantar pitting, among Gorlin syndrome’s major diagnostic criteria, was found in 76.7% of our patients. Histopathological analysis of the acral pitting demonstrates hypokeratosis, basal cell hyperplasia and palisading basal keratinocytes.¹⁰ It has since been suggested that basaloid cell nests, histologically similar to BCCs, reside within palmoplantar pitting but remain a different entity. However, in a few reports, the presence of BCCs in the palms and soles, along with the presence of palmoplantar pitting, was suggested as an idea that pitting may indeed represent an early BCC.^4,18,25-28 Similarly, palmoplantar region involvement of BCCs was found remarkable in 3 of our patients of whom 2 were children along with the presence of palmoplantar pitting in all of them (Figure 2B-C). However, palmoplantar BCC was not recorded in other patients with palmoplantar pitting (n = 20) in our series.

Although BCC accompanies the majority of patients with Gorlin syndrome, sometimes no BCC may be present, as 2 pediatric and 1 adult patients (10%) in our series. In a large series of 202 patients with Gorlin syndrome, 67 had not a BCC of whom 30 (44.8%) were <20 years of age.²⁹ Similarly, in a large series of 118 Gorlin syndrome patients, 15% of those over 20 years and only 5% of those over 40 years had not yet developed a BCC, and the age at which BCCs were diagnosed was less than 20 years in 47% of the cases.⁶ Basal cell carcinomas usually develop in adolescence in Gorlin syndrome but may appear as early as the first year of life, with a median age of onset of 20 years.^7,10 In a series of 61 patients with Gorlin syndrome, 54% of the pediatric group had already experienced at least one BCC, and this percentage was higher when compared to prior reports.²¹ In that study, the median age of the syndrome diagnosis was 11 years and the median age of the first BCC was 16 years.²¹ Interestingly, the mean age of BCC onset was reported as 37.4 years in a study reported from Japan, representing a much older age.¹¹

In our study, while noduloulcerative, superficial, and pigmented types of BCC (Figure 1A-C) were found frequently, the absence of morpheic-type BCC lesions was found remarkable. In addition to classical subtypes, BCCs may also appear as soft pedunculated lesions in Gorlin syndrome that can be mistaken for acrochordons.^16,30,31 The “skin tags” of Gorlin syndrome were described by Nomland in 1932 and they represent the “nevi” of this syndrome.^4,22,32 In addition, “more than 10 basal cell naevi” was stated as a diagnostic criterion for Gorlin syndrome described by Evans et al in 1993.⁵ Whereas these lesions were found anywhere on the body, they were frequently seen in areas of friction in a similar way to true acrochordons, sometimes also admixed with these benign tumors.^24,31 Although the “nevoid” lesions imply the disease’s name, only a limited number of case reports are available, and the ratio of BCCs presenting with these features has not been evaluated previously.^{16,21,22,24,30,31} Basal cell carcinoma lesions in the form of acrochordon (skin-tag) or dermal nevus-like, reflecting the early nevoid phase of Gorlin syndrome were frequently encountered in our series especially in the childhood period (45.4% in children and 15.7% in adults) (Figure 1D-F). Histopathological examination should be performed on acrochordon-like lesions in children because they may be the presenting sign of Gorlin syndrome.²²

In a series of 61 patients with Gorlin syndrome, 3 children had over 100 BCCs.²¹ In addition, patients who are survivors of medulloblastoma treated with therapeutic radiation have a high risk of developing a large number of BCCs in the radiation field, which was also noted in 2 of our child patients.^4,7,17,21,33 While the majority of our patients had numerous BCC lesions (8 patients: 10-25 BCC, 6 patients: >25 BCC), less than 10 BCC lesions were detected in 13 patients, 23.1% of whom were in the pediatric age group.

Odontogenic keratocysts of the jaw are present in 44%-92% of the patients with Gorlin syndrome, which is almost always seen in Gorlin syndrome patients with PTCH1 mutation.¹ Odontogenic keratocysts start to develop around the age of 8 years and tend to decrease after the age of 30 years.¹ In our series, OKCs were present in 83.3% of patients as the second most common feature of whom 36% were children. Odontogenic keratocysts of the jaw are benign and initially asymptomatic, but the typically slow progression may result in major tooth dislocation and even fractures of the jaw.¹

Epidermoid cysts, the most common type of cutaneous cysts with an epidermis-like lining, present usually on the face, neck, periauricular area, and upper trunk as solitary or multiple lesions. A small central blackhead-like punctum on the surface is a typical clinical feature of them. Most lesions are sporadic occurring in adults.^34,35 Epidermoid cysts have also been reported in various series of Gorlin syndrome with a frequency of 50% or greater and in a few case reports (Table 3).^{4,5,10,22,36-47} Despite these high rates, they are not considered a diagnostic criterion for Gorlin syndrome.^1,5 However, in most series distribution patterns and the clinical appearance of epidermoid cysts or the age of these patients have not been emphasized.^{4,6,7,11,12,20,22} On the contrary, in some series, epidermoid cysts were not stated in any patients which may be underrecognized. While epidermoid cysts were also seen in 53.3% of our patients (Figures 3A-D), nearly half (43.7%) of them were of pediatric age, in line with some previous reports (Table 3).^22,36-47 Although in ancient reports, epidermoid cysts in Gorlin syndrome were suggested to be more commonly located around the limbs or trunk,^36,40 in the first international colloquium on NBCS, it was stated that dermatologic examination should include epidermoid cysts, especially at the web space of the first and second fingers.⁸ In another study evaluating 23 cutaneous cysts in Gorlin syndrome, 52.2% of them were localized on the hands and feet.⁴¹ Similarly, in our patients lesions were most commonly (62.5%) localized on hands or feet (Figure 3B-D), which is not a common localization for sporadic epidermoid cysts (Table 3). In addition, some authors have mentioned that acral localization of epidermoid cysts is a typical feature of Gorlin syndrome.^37,40 Most of our patients with Gorlin syndrome had solitary epidermoid cysts (75%), in line with previous reports.^22,37,39,40 In a minority of patients with Gorlin syndrome, epidermoid cysts may be multiple up to 25 lesions in 1 patient previously reported.⁴⁶ Clinically, a visible central blackhead-like punctum which is common in sporadic epidermoid cysts was not present in any epidermoid cysts of our patients with Gorlin syndrome. This finding has been emphasized only in 2 patients previously, to the best of our knowledge.^37,42

Milia are common small epidermoid cysts that may be found intermixed with papular BCCs on the face in patients with Gorlin syndrome (Figure 3F). They have been noted in approximately 30%-50% of the patients with Gorlin syndrome in various studies, in a similar way to our study (56.7%).^1,4,6,10 Previously, it has been suggested that the periorbital and perinasal area must be examined for milia in patients with Gorlin syndrome.⁸

In some previous reports, cutaneous cysts in Gorlin syndrome were stated as keratocysts due to the similar histopathological appearance of OKCs, supporting the possibility that they could be another cutaneous marker for this genodermatosis.^{37,38,42,43,46,47} In another study investigating 23 epidermoid cysts in Gorlin syndrome, no differences were recorded between lesions in palmoplantar and other anatomic locations regarding histologic and immunohistochemical characteristics.⁴¹ Remarkably, epidermoid cysts were also recorded on the palpebral conjunctiva of upper eyelid in one of our adult patients, which has rarely been reported previously.^1,45,48-50 Intratarsal eyelid cysts have been suggested to appear similar to sporadic intratarsal keratinous cysts and closely resembled OKCs of the jaw histopathologically.⁴⁹ Our investigation of cutaneous epidermoid cysts and OKCs did not reveal a statistically significant association.

Apart from rich skin findings, children with Gorlin syndrome may have an increased risk of developmental delay and intellectual disability.¹ Approximately, 3%-5% of all patients with Gorlin syndrome develop a cardiac fibroma which typically presents in infancy and was present only in one child patient in our series.¹ Medulloblastoma, reported in only 1%-4% of patients with Gorlin syndrome, is mainly of the desmoplastic subtype which was present in our 3 child patients (10%). Medulloblastomas usually develop in the first 3 years of life, earlier than sporadic medulloblastomas, which is almost always seen in Gorlin patients with SUFU mutation.^1,4,7,11,33

The main limitations of our study were its retrospective nature to be conducted in a single center and the small number which depends on the rarity of the disease.

Early diagnosis and close monitoring are essential for Gorlin syndrome patients because of the broad range of symptoms and the development of several types of tumors. Therefore, apart from other systemic features presenting in children, the awareness of small-sized papular or acrochordon-like BCCs, atypical located BCCs such as palmoplantar area and acral epidermoid cysts may facilitate early diagnosis in childhood patients. When evaluated together with the frequency of epidermoid cysts in our study and their disease-specific clinical characteristics, it can be suggested that they may be among the diagnostic criteria of the disease in the future.

Funding Statement

This study received no funding. This study was presented as an oral presentation in “Ord. Prof. Dr. Hulusi Behçet 12. Dermatoloji Bahar Sempozyumu, April 27-30, 2023, Dalaman”.