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Gorlin Syndrome

Basal Cell Nevus Syndrome


Presentation

Several researches have reported the prevalence of the multiple signs and symptoms presented in Gorlin syndrome [4] [5] [6] [7] [8]. Certain features like palmar or plantar pits, skull deformities and other radiological results occur in childhood. These can be useful in making an early diagnosis [9] [10]. A single patient may not present with all of the signs and symptoms, but a combination of some of them.

Basal cell carcinoma, a type of skin cancer is the most common presentation of Gorlin syndrome. They may appear as spots on the skin or as small growths or nodules which differ in number, from few to numerous. Variations in their size are seen from 1mm to 10mm or more. The basal cell carcinoma can encroach upon the local tissue causing related symptoms. Areas which are exposed to the sun are mainly affected, though the sun protected areas may also present with the cancer.

The age group which usually presents with basal cell carcinoma is from puberty to 35 years. Kimonis et al found that 50% of white individuals had their first BCC by age 21.5 years and 90% had it by age 35 years [8].

Keratocystic odontogenic tumors or odontogenic keratocytes or jaw cysts, are lumps or swellings in the jaw bone, especially the mandible. They develop in the first decade of life and their highest occurrences are in the second decade and often seen as recurring growths. They may rapidly grow in size causing pain, fractures of the maxilla and mandible and may also affect dental growth. It can lead to disfigurement of the face.

Patients may develop small pits on the palms (palmar pits) and on the soles of the feet (plantar pits). Some patients also develop multiple skin tags.

Patients with Gorlin suffer from Medulloblastoma i.e. malignant tumours of the cerebellum, mainly in childhood from birth to about 3 years of age. Patients may experience headaches which get better as the day passes, along with vomiting and imbalance. These tumours can spread to other parts of the nervous system. The occurrence ratio with respect to gender is 3:1 (male: female).
Approximately 90% patients suffer from calcification or hardening of some parts of the central nervous system by the second decade of life. Falx cerebri which consists of the dura mater is commonly affected.

Skeletal deformities and abnormalities which occur in patients with Gorlin syndrome include rib defects or dislocations, scoliosis, spina bifida, polydactyly , syndactyly (webbed fingers or toes) and Sprengel deformity (raised or underdeveloped scapula). Chest abnormalities are also seen in patients for example- a sunken chest or a protruded chest (pectus carinatum or excavatum respectively). As an after effect of spina bifida, some may suffer from hydrocephalus.

Patients may suffer from macrocephaly, frontal bossing, Hypertelorism (wide spaced eyes), facial milia (small white lumps on the skin below the eyes or over the forehead), cleft palate, cleft lip, microphthalmia, cataracts, nystagmus (rapid involuntary eye movement) or coloboma (partial absence of tissue from the iris or retina) etc. Strabismus i.e. crossed eyes may also be seen [11].

Bilateral calcified benign fibromas of the ovary are found in women, while men may have cryptorchidism or gynecomastia with decrease in body hair growth.

Cardiac fibromas develop in very few patients and especially in children. These may not present with any symptoms or may lead to arrhythmias or circulation obstruction.

Kiminois et al proposed major and minor criteria to diagnose the disease. These criteria also help in deciding the laboratory investigations that may be needed for the same. 2 major or 1 major and 2 minor criteria if present than the disease can be diagnosed as Gorlin syndrome.

  • Major criteria include basal cell carcinoma, odontogenic keratocytes, palmar or plantar pits and abnormal calcification of the parts of CNS and first degree relative. 
  • Minor criteria include skeletal, spinal, head, face, eye abnormalities, ovarian fibromas and medulloblastoma.
Shivering
  • […] lesions may reoccur after the end of the therapy [ 4, 5 ] Interferon – in the experimental stage; injected directly into the neoplastic lesions 3 times a week for the period of 3 weeks; the method needs to be confirmed; side effects include: fever, shivering[pubmedcentral.nih.gov]
Proportionate Short Stature
  • Abstract Meier-Gorlin syndrome (MGS) is a rare autosomal recessive primordial dwarfism disorder, characterized by microtia, patellar applasia/hypoplasia, and a proportionate short stature.[ncbi.nlm.nih.gov]
Piebaldism
  • Crouzon syndrome, Jackson–Weiss syndrome ) FGFR3 ( Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome ) INSR ( Donohue syndrome Rabson–Mendenhall syndrome ) NTRK1 ( Congenital insensitivity to pain with anhidrosis ) KIT ( KIT Piebaldism[en.wikipedia.org]
Pigmented Tumor
  • Both women had pigmented tumors that were histologically nonaggressive. The cancers did not recur after curettage or excision.[ncbi.nlm.nih.gov]
Hypertelorism
  • Because of macrocrania, hypertelorism and epidermal punctiform lesions in the palm of the hand, Gorlin syndrome was clinically suspected and molecularly confirmed by finding a deletion of 22 base pairs in the PTCH1 gene.[ncbi.nlm.nih.gov]
  • Physical findings include "coarse face" in 54%, relative macrocephaly in 50%, hypertelorism in 42%, frontal bossing in 27%, pectus deformity in 13%, and Sprengel deformity in 11%.[ncbi.nlm.nih.gov]
  • […] carcinoma younger than 45 years and 19 years of age, respectively, are estimated to have the syndrome. multiple basal cell carcinomas, often at puberty and in adolescence craniofacial anomalies odontogenic keratocysts, often multiple frontal bossing hypertelorism[radiopaedia.org]
  • Hypertelorism (line), prognathism (head arrow), milia (asterisks) and severe palmar pits (arrows) FIGURE 5 Radiological findings.[scielo.br]
Frontal Bossing
  • Physical findings include "coarse face" in 54%, relative macrocephaly in 50%, hypertelorism in 42%, frontal bossing in 27%, pectus deformity in 13%, and Sprengel deformity in 11%.[ncbi.nlm.nih.gov]
  • bossing hypertelorism : 5% macrocephaly calcified falx cerebri calcified tentorium and petroclinoid ligaments cleft lip ocular defects including: coloboma of the iris microphthalmia bridging of the sella turcica high arched palate agenesis of the corpus[radiopaedia.org]
  • It is characterized by multiple basal cell carcinomas, palmoplantar pits, jaw cysts, and bony deformities like kyphoscoliosis and frontal bossing.[e-ijd.org]
  • SIGN Frontal Bossing in 54% Flat Nose Hypertelorism in 42% Multiple jaw cyst(OKC) in 74% - Until 20 years old Multiple pits in palm and sole in 87% - in second decade of life Macrocephali in 50% Vertebra and ribs anomalis(bifurcation of ribs and[slideshare.net]
Testicular Swelling
  • He presented with left testicular swelling and underwent a radical orchiectomy on suspicion of a malignant paratesticular tumor. The tumor arose from the testis exophytically and was diagnosed as a thecoma histopathologically.[ncbi.nlm.nih.gov]

Workup

Special imaging procedures are used to diagnose Gorlin syndrome. These can be MRI-Magnetic Resonance Imaging, USG-Ultrasound of the abdomen, X-ray of the skull, of the skeletal system, the jaw and teeth [10] [12]. MRI can accurately report brain calcifications. Ovarian fibromas can be detected on USG. X-rays of the different parts of the body can help to find any abnormalities in the skeletal system. Dental radiographs can help in early detection of odontogenic keratocysts which can affect the jaw.

Echocardiogram is necessary in cases to detect cardiac fibromas if suspected.

Molecular genetic testing can detect gene mutations thus helping in early diagnosis of Gorlin syndrome.

Biopsy of the skin lesions helps in detecting skin cancers related to Gorlin syndrome. The biopsy of the odontogenic keratocysts reveals a specific pathological keratinizing epithelial lining.

Hypercholesterolemia
  • CVID2 ) TNFRSF6 ( Autoimmune lymphoproliferative syndrome 1A ) Lipid receptor LRP : LRP2 ( Donnai–Barrow syndrome ) LRP4 ( Cenani–Lenz syndactylism ) LRP5 ( Worth syndrome, Familial exudative vitreoretinopathy 4, Osteopetrosis 1 ) LDLR ( LDLR Familial hypercholesterolemia[en.wikipedia.org]

Treatment

Topical chemotherapy agents like imiquimod [13] and 5-fluorouracil are used to apply over the affected areas. These are usually used in combination with other therapies [14].
Photodynamic therapy includes application of topical agents that are activated by exposure to a specific light which causes tumour destruction [15] [16].

In a study in 2012, a drug called Vismodegib showed 70% decrease in new tumours and reduction in size of old ones. But other studies show recurrence of tumours after stopping treatment [17] [18] and treatment related bad side-effects [19].

Most tumours may require surgical excision. Early detection and early treatment of tumours helps to prevent them from becoming invasive. Numerous tumours occur in patients with Gorlin syndrome. Hence, invasive surgical procedures are chosen for larger tumours while the small ones are first treated with topical therapies. Direct surgery involves excision of the tumours and then suturing the skin over that area.

Moh’s micrographic surgery is used to heal tumours of Gorlin syndrome which fail to improve after other treatments.
For single or small lesions, one may use cryotherapy which includes applying a freezing agent over the lesion to destroy the tissues and cells.

Another therapy used is electrodessication and curettage. In this, the lesion is scraped off and the remaining tissue is treated with heat using an electrosurgical needle.

All cases of Gorlin syndrome require long-term monitoring of the disease. Regular consultations with dermatologists, dentists and dental surgeons, cardiologists, ophthalmologists, neurologists, gynaecologists etc must be done.

Prognosis

Skin cancer and other tumours that develop in Gorlin syndrome are responsible for the mortality and morbidity of the patients. Medulloblastoma can lead to premature death. Complications can arise due to treatment methods like radiation therapy which can cause multiple basal cell carcinoma. For better prognosis treat skin lesions with chemoprevention. Vitamin A can help in stopping the growth of new skin cancer.

Etiology

Gorlin syndrome is caused by mutations in PTCH gene (allele 1) located on the long arm (q) of chromosome 9 (9q22.3-q31). It is commonly an inherited disorder but may occur due to spontaneous new mutations in the gene (35-50% cases).

Ultra-violet (UV) light exposure is known to cause Basal Cell Carcinomas. Hence, parts exposed to sun are more likely to be affected with the cancer. Genetic researches about UV-related mutations in basal cell carcinoma report that causes other than UV-B may cause alterations to the gene [1]. Basal cell carcinomas have been reported to develop in patients treated with radiation therapy for medulloblastoma. Areas previously exposed to radiation show rapid growth of this cancer.

Epidemiology

The estimated prevalence of Gorlin syndrome is reported as 1 per 56,000 – 1, 64,000 population. The exact incidence may in fact be higher because many cases with mild symptoms go undetected. Gorlin syndrome is seen in all races and male to female ratio is almost equal (1:1.3).

Basal cell carcinoma (skin cancer) with Gorlin syndrome is seen more in the white population as compared to the black population. One survey estimating incidence in an African cohort found that only 20% people with Gorlin syndrome had basal cell carcinoma [2]. Another Japanese study also reported a lower rate of Basal Cell Carcinoma compared with whites [3].

Sex distribution
Age distribution

Pathophysiology

Gorlin syndrome is an autosomal dominant disorder. A single copy of the dominant mutated gene when inherited from a single parent can produce symptoms and signs of the disorder. This disorder presents with complete penetrance i.e. all those who inherit the mutated gene are affected with Gorlin syndrome and have variable expressivity i.e. patients present with wide variety of signs and symptoms.

Prevention

Since it's a genetically transmitted disorder, there is no prevention available for Gorlin's syndrome.

Patient Information

Gorlin syndrome also called as Nevoid basal cell carcinoma is a genetic disorder which presents in the form of multi-organ abnormalities and a tendency to develop certain forms of cancer especially skin cancers. Its causes include genetic changes, either new or familial. It is an autosomal dominant disorder which means that only a single copy of the abnormal gene inherited form any one parent is enough to cause the disease. This indicates that all the people who inherit the dominant abnormal gene will develop the symptoms.

Also, patients suffering from Gorlin syndrome show extensively variable signs and symptoms. These include mainly Basal cell carcinoma i.e. lesion of skin cancer, keratocystic odontogenic tumors, small pits on the palms and soles, medulloblastomas i.e. malignant tumours of the cerebellum or calcification or hardening of some parts of the central nervous system. It may also involve skeletal deformities and abnormalities like curved spine, additional or webbed fingers or toes, raised or underdeveloped scapula or sunken or protruded chest, larger head circumference or a bulging forehead. Various eye related signs include wide spaced eyes, cataracts, rapid involuntary movements of the eyes, partial absence of tissue from the iris or retina or crossed eyes may also be seen. One may also develop different fibromas like ovarian, cardiac etc. 

Investigations to detect the disorder include MRI scanning, X-rays of the entire skeletal system, Ultrasonography of the abdomen and dental radiographs. Molecular genetic testing facilitates early detection of the mutations of the genes. Biopsy of the lesions helps confirm skin cancers.

Treatment involves topical chemotherapy agents like imiquimod and 5-fluorouracil, photodynamic therapy, surgical excision of the tumours, cryotherapy, electrodessication and curettage etc. Patients suffer from many tumours at different areas. Most of the large tumours need surgical excision leaving behind scars which may even need skin grafting. Hence, non-surgical treatments are chosen for smaller tumours.

It is essential for patients with Gorlin syndrome to continue regular follow ups with specific consultants for long term monitoring of the signs and symptoms.

References

Article

  1. Goldstein AM, Bale SJ, Peck GL, et al. Sun exposure and basal cell carcinomas in the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol. Jul 1993;29(1):34-41. 
  2. Titinchi F, Nortje CJ, Parker ME, et al. Nevoid basal cell carcinoma syndrome: a 40-year study in the South African population. J Oral Pathol Med. Feb 2013;42(2):162-5.
  3. Endo M, Fujii K, Sugita K, et al. Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma. Am J Med Genet A. Feb 2012;158A(2):351-7.
  4. Evans DG, Farndon PA, Burnell LD, et al. The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma. Br J Cancer. Nov 1991;64(5):959-61. 
  5. Evans DG, Ladusans EJ, Rimmer S, et al. Complications of the naevoid basal cell carcinoma syndrome: results of a population based study. J Med Genet. Jun 1993;30(6):460-4. 
  6. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine (Baltimore). Mar 1987;66(2):98-113. 
  7. Shanley S, Ratcliffe J, Hockey A, , et al. Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet. Apr 15 1994;50(3):282-90. 
  8. Kimonis VE, Goldstein AM, Pastakia B, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet. Mar 31 1997;69(3):299-308. 
  9. Kimonis VE, Singh KE, Zhong R, et al. Clinical and radiological features in young individuals with nevoid basal cell carcinoma syndrome. Genet Med. Jan 2013;15(1):79-83. 
  10. Veenstra-Knol HE, Scheewe JH, van der Vlist GJ, et al. Early recognition of basal cell naevus syndrome. Eur J Pediatr. Mar 2005;164(3):126-30. 
  11. Lo Muzio L. Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis. Nov 25 2008;3:32.
  12. Kimonis VE, Mehta SG, Digiovanna JJ, et al. Radiological features in 82 patients with nevoid basal cell carcinoma (NBCC or Gorlin) syndrome. Genet Med. Nov-Dec 2004;6(6):495-502.
  13. Ferreres JR, Macaya A, Jucglà A, et al . Hundreds of basal cell carcinomas in a Gorlin-Goltz syndrome patient cured with imiquimod 5% cream. J Eur Acad Dermatol Venereol. Aug 2006;20(7):877-8. 
  14. Wolfe CM, Green WH, Cognetta AB Jr, et al. A possible chemopreventive role for photodynamic therapy in Gorlin syndrome: a report of basal cell carcinoma reduction and review of literature. Australas J Dermatol. Feb 2013;54(1):64-8. 
  15. Itkin A, Gilchrest BA. delta-Aminolevulinic acid and blue light photodynamic therapy for treatment of multiple basal cell carcinomas in two patients with nevoid basal cell carcinoma syndrome. Dermatol Surg. Jul 2004;30(7):1054-61. 
  16. Oseroff AR, Shieh S, Frawley NP, , et al. Treatment of diffuse basal cell carcinomas and basaloid follicular hamartomas in nevoid basal cell carcinoma syndrome by wide-area 5-aminolevulinic acid photodynamic therapy. Arch Dermatol. Jan 2005;141(1):60-7. 
  17. Tang JY, Mackay-Wiggan JM, Aszterbaum M, et al. Inhibiting the hedgehog pathway in patients with the basal-cell nevus syndrome. N Engl J Med. Jun 7 2012;366(23):2180-8. 
  18. Wolfe CM, Green WH, Cognetta AB Jr, et al. Basal cell carcinoma rebound after cessation of vismodegib in a nevoid basal cell carcinoma syndrome patient. Dermatol Surg. Nov 2012;38(11):1863-6. 
  19. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. Jun 7 2012;366(23):2171-9.

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Last updated: 2019-07-11 21:48