Dermatology Online Journal

Gorlin syndrome or basal cell nevus syndrome (BCNS): A case report
K N Shivaswamy MBBS MD DNB, T K Sumathy MD MNAMS, A L Shyamprasad MD, C Ranganathan MD DD
Dermatology Online Journal 16 (9): 6

M S Ramaiah Medical Teaching Hospital

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Abstract

Gorlin syndrome, also known as Basal Cell Nevus Syndrome (BCNS), is a rare autosomal dominant disorder with complete penetrance and variable expressivity. This syndrome is characterized by developmental anomalies, such as odentogenic keratocysts of the mandible and postnatal tumors, especially multiple basal cell carcinomas (BCCs). The prevalence of this syndrome is variously estimated to be 1 in 60,000 to 1 in 120,000 persons. Mutation in a tumor suppressor, the PTCH1 gene residing on long arm of Ch 9, is responsible for the development of many postnatal tumors. Patients with Gorlin syndrome show multiple abnormalities, none of which is unique to this condition. Our case had almost all the features of this rare syndrome.

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Introduction

Gorlin syndrome, also known as Basal Cell Nevus Syndrome (BCNS), is an uncommon autosomal dominant disorder with complete penetrance and variable expressivity. This syndrome is characterized by developmental anomalies such as odentogenic keratocysts of the mandible and postnatal tumors, especially multiple basal cell carcinomas (BCCs) [1, 2]. Patients with Gorlin syndrome show multiple abnormalities, none of which is unique to this condition [3, 4]. Here we present a case of Gorlin syndrome in a 28-year-old female, manifesting with almost all the features of the syndrome.

Case report

Figure 1	Figure 2

Figure 3

A 28-year-old female patient presented to us with multiple asymptomatic pigmented lesions over her face, chest, and thigh, all of which had been present for 10 years. These lesions were initially small and gradually progressed to the present size. The patient had also noticed an increase in the number in the recent past. On enquiry, the patient complained of numerous pits over her palms and soles that she attributed to her routine household work. Fifteen years ago she was operated on for jaw swelling the nature of which was not known. There was no history of bleeding from the lesions, seizures, loss of appetite, nor loss of weight. Also, there was no history suggestive of pain in the abdomen or menstrual irregularities. None of the family members had similar complaints.

Figure 4	Figure 5

Figure 6	Figure 7

Figure 8

On examination, multiple discrete, darkly pigmented, smooth- to rough-surfaced papules, and plaques of varying sizes were noted over the face (Figure 1), abdomen, thigh, and groin (Figure 2). A solitary hyperpigmented plaque resembling seborrheic keratosis was noted over the sternum (Figure 3). Numerous tiny pits were evident over her palms and soles (Figure 4 and 5). Other noticeable findings were hypertelorism and a horizontal scar over the right side of the mandible. Hair shaft examination was normal. With these clinical findings a probable diagnosis of Gorlin syndrome or basal cell nevus syndrome was made and further investigations were carried out.

Histopathological examination of a representative specimen from one of the pigmented papules showed tumor nests consisting of basiloid cells having cellular and nuclear atypia and arranged in a palisading fashion, dispersed throughout the dermis (Figures 6 and 7). These histological findings were consistent with basal cell carcinoma. Plain X-ray of the skull showed a linear calcification of falx cerebri (Figure 8). Anteroposterior view of the chest radiograph showed splaying of 1st and 4th ribs along with hemivertebra of T1 with partial fusion of C6-C7 and T1-T2. Plain CT scan of the mandible showed a lytic lesion involving both rami of the mandible (Figures 9 and 10). However, CT scan of the brain and ultrasound scan of the abdomen did not reveal any abnormality. These investigative findings were consistent with our clinical diagnosis of Gorlin syndrome.

Figure 9	Figure 10

Discussion

Gorlin syndrome, also known as Basal Cell Nevus Syndrome (BCNS), is a rare autosomal dominant disorder with complete penetrance and variable expressivity. This syndrome is characterized by developmental anomalies such as odontogenic keratocysts of the mandible and postnatal tumors, especially multiple basal cell carcinomas (BCCs). The prevalence of this syndrome is variously estimated to be 1 in 60,000 to 1 in 120,000 persons. [1, 2] The exact mechanism by which these patients are prone to develop multiple BCCs is not yet clear. However, mutation in a tumor suppressor gene, PTCH1, residing on the long arm of Ch 9, is responsible for the development of many postnatal tumors [3]. PTCH1 plays a central role in the hedgehog signaling pathway that is essential for the development of normal body and limb patterning in metazoan organisms [4]. PTCH1 protein inhibits the hedgehog signaling pathway by inhibiting the function of central G protein-coupled receptor, smoothened (SMO). Mutations of SMO protein have been identified in approximately 10 percent of BCCs, and these mutations appear to render SMO protein resistant to PTCH1 inhibition [5]. Patients with Gorlin syndrome show multiple abnormalities caused by such mutations, none of which is unique to this condition [1].

The characteristic findings in this condition are multiple BCCs, palmar and plantar pits, jaw cysts, bony abnormalities, and medulloblastoma. Jaw cysts are usually the earliest features and are the most common stigma of the syndrome. The mandible is more often involved than the maxilla, as seen in our case. Usually these cysts are asymptomatic; however, they may cause dental pain and swelling when they erode the bone. Histologically these cysts are odontogenic keratocysts [6, 7]. Basal cell carcinomas also appear early in life and are numerous. Together with jaw cysts they aid in early diagnosis. Basal cell carcinomas seen in this condition cannot be distinguished from those that arise sporadically or familially. However, the appearance of numerous BCCs at an early age and over sites not exposed to sunlight differentiates it from the rest. Palmar and plantar pits represent an aborted or immature attempt to form BCC. They are visibly more pronounced when hands and feet are immersed in warm water for a few minutes [1, 8, 9].

Other skin manifestations include facial milia, which can be numerous, and meibomian cysts in the eyelids. Sebaceous cysts and dermoid cysts are also common. Skin tags (especially around the neck) often have the histological appearance of BCCs but do not act aggressively. Cardiac and ovarian fibromas do occur in about 2 percent to 20 percent of the cases. Cardiac fibromas are usually present at birth or soon after. They can be asymptomatic or can cause arrhythmia or obstruction of cardiac flow. Ovarian fibromas are usually an incidental finding on ultrasound examination or at Caesarian section. They may cause torsion of the ovary but are not thought to affect fertility. They can become large and calcified, but malignant transformation is uncommon. Rhabdomyomas may occur at other sites as well as in the heart [10].

Kimonis et al. [11] have devised criteria for the diagnosis of Gorlin syndrome, which include at least 2 major or 1 major and 2 minor criteria.

Major criteria

1. More than 2 BCCs or 1 BCC in a person younger than the age of 20
2. Odontogenic keratocysts before age 15
3. Three or more palmar and/or plantar pits
4. Ectopic calcification or early (<20years) calcification of the falx cerebri
5. Fused, bifid, or markedly splayed ribs
6. First degree relative with BCNS
7. PTC gene mutation in normal tissue

Minor criteria

1. Macrocephaly determined after adjustment for height
2. Congenital malformations
   1. Frontal bossing
   2. Coarse face
   3. Moderate to severe hypertelorism
   4. Cleft lip/cleft palate
3. Skeletal abnormalities
   1. Sprengel deformity
   2. Marked pectus deformity
   3. Marked syndactyly of digits
4. Radiological abnormalities:
   1. Bridging of sella turcica
   2. Lucencies of hands and feet
   3. Bifid and splayed ribs
   4. Hemivertebra
   5. Fusion of vertebral bodies
5. Ovarian fibroma
6. Medulloblastoma

Gorlin syndrome has to be differentiated from other conditions with multiple basal cell carcinomas. These include Bazex syndrome and Rombo syndrome. Hair shaft abnormalities along with atrophoderma are common in the former and trichoepethelioma in the later, which are not features of Gorlin syndrome. Multiple hereditary infundibulocystic basal cell carcinoma and generalized basilar follicular hamartoma should be included in the differential diagnosis. Both will demonstrate histological variants of BCCs and are characterized by palmar pits and milia. Patients with long-term arsenic ingestion may develop multiple BCCs. Dyschromia and lack of other phenotypic abnormalities differentiate this from Gorlin syndrome [1].

The most important aspect in the management of Gorlin syndrome is frequent examination, counseling about sun protection, and early treatment of small tumors by surgical or nonsurgical methods. Nonsurgical modes of therapy include 5-fluorouracil, imiquimod [12], oral retinoids, and photodynamic therapy [13]. Cyclopamine, an agent that antagonizes the hedgehog signaling pathway, is being investigated as a treatment for BCC, medulloblastoma, and rhabdomyosarcoma. X-ray irradiation can be employed in those who are not candidates for surgery [1].

Life expectancy in patients with Gorlin syndrome does not significantly differ from the rest of the population. The major problem is with the cosmetic effect of the treatment of multiple BCCs and to a lesser extent with dental cysts.

Here, then, is the approach to adult patients with known or suspected Gorlin syndrome: baseline MRI of brain (if not done at age 8), dermatological examination every 4 months, digital panorex of the jaw twice a year until cyst-free for 2 years, and yearly and prenatal or preconception counseling, along with PTCH gene sequence analysis to look for mutations [1, 14].

PTCH analysis is now offered as a comprehensive test, including sequence analysis and deletion or duplication testing. Using genomic DNA obtained from of the submitted specimen (blood in EDTA), bi-directional sequence analysis of exons 1-23 and determination of the splice sites of the PTCH gene is performed. Simultaneously, targeted array comparative genomic hybridization (CGH) analysis with exon-level resolution is performed to evaluate for a deletion or duplication of one or more exons of this gene. Approximately 60 percent of patients with a diagnosis of Gorlin syndrome are expected to have a mutation in the PTCH gene identifiable by sequencing [14].

Conclusion

Our case was unusual in that she presented with nearly all of the clinical findings of BCNS.

References

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