Novel de Novo Mutation in Woman with Clinical Gorlin Syndrome: a Case Study
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Gorlin syndrome (nevoid basal cell carcinoma syndrome) is a rare disorder hallmarked by multiple basal cell skin cancers. While most cases involve inheritance from affected parents, up to 40% of mutations leading to the disease arise from de novo mutations in the individual. In this case study, a woman with a clinical diagnosis of Gorlin Syndrome undergoes genetic testing to identify a possible causative mutation for which her children could be tested for carrier status.
KeywordsGorlin syndrome Nevoid basal cell carcinoma syndrome Genetic mutations Variant classification
Nevoid Basal Cell Carcinoma Syndrome (NBCCS) is a rare disease affecting an estimated 1 in 40,000  to 1 in 57,000–164,000 . Germline PTCH1 gene mutations cause NBCCS and are inherited in an autosomal dominant fashion. However, 20–40% may be de novo cases with clinical disease but no affected parent . Variable levels of disease expression can be common despite high penetrance, making diagnoses of the syndrome, even within families, difficult to reach .
The product of the PTCH1 gene is thought to be a tumor suppressor, functioning as a receptor to where Sonic Hedgehog (SHH) binding takes place in a cell membrane and thus represses transcription of signaling proteins, Smoothened (Smo), in the transforming growth factors . In most cases of basal cell carcinomas, anomalous activation of the Hedgehog pathway is associated with tumor growth and survival .
The major criteria for diagnosis would include the following: (1) BCC prior to 20 years old or excessive numbers of BCCs out of proportion to prior sun exposure and skin type; (2) odontogenic keratocyst of the jaw prior to 20 years of age; (3) palmar or plantar pitting; (4) lamellar calcification of the falx cerebri; (5) medulloblastoma, typically desmoplastic; (6) first degree relative with BCNS. The minor criteria would then include (1) rib anomalies; (2) other specific skeletal malformations and radiologic changes (i.e., vertebral anomalies, kyphoscoliosis, short fourth metacarpals, postaxial polydactyly); (3) macrocephaly; (4) cleft/lip palate; (5) ovarian/cardiac fibroma; (6) lymphomesenteric cysts; (7) ocular abnormalities (i.e., strabismus, hypertelorism, congenital cataracts, glaucoma, coloboma). 
The patient is a 44-year-old Caucasian woman born in the USA and currently residing in England with her husband and children. The patient granted written consent for the case report via electronic correspondence, and interviews took place over several occasions in person and via email. The patient recalled that in childhood, she had 10 original teeth removed by an oral surgeon as the adult teeth were erupting without normal loss of first teeth. She was diagnosed with mild scoliosis around age 12. At approximately age 17 while having her braces removed, imaging revealed multiple cysts in her jaw that were determined to be keratocysts on pathology. Her left mandible was very thin and required bone grafting to prevent fracture. At age 19, she had an ovarian cyst that ruptured, requiring hospitalization. She has had multiple additional ovarian cysts seen on gynecologic imaging since, but all have resolved spontaneously. By age 20, she had a basal cell carcinoma (BCC) removed from the right side of her nose. In her mid-twenties, she had more basal cell lesions erupt. The patient reported at that time she was given the diagnosis of nevoid basal cell carcinoma syndrome (NBCCS), commonly referred to as Gorlin syndrome, after a dermatologist noted the presence of palmar pits. She found herself having skin checks and biopsies every 6 months as well as 3 to 4 Moh’s resections to remove the multiple BCCs that were arising in various places all over her body. She now has two children for which she has concern of inheriting her disease; identifying a known causative mutation for the syndrome would provide a way to assess for the presence of the condition in the children.
In addition to the physical resection of the basal cell carcinomas, the patient undertook other treatments and preventative measures. Prior to moving overseas, the patient was enrolled in a clinical trial through Columbia University Medical Center in which 60 participants who met clinical criteria for NBCCS received celecoxib or placebo twice daily for up to 2 years or if there were unacceptable toxicities reported. She left the trial early because of her relocation overseas, and was never informed of whether she had been in the control or experimental arm of the study. She has used imiquimod in the past, but now is using topical fluorouracil, citing better efficacy. She has had conversations with her providers about using an oral hedgehog pathway inhibitor, vismodegib, the mechanism of action of which is binding to Smo and preventing Hh pathway reactivation. However, because of a large side-effect profile, the patient has declined its use for the time being.
Upon moving to England, she had been referred to Great Ormond Hospital in London. Her physician had her tested for both PTCH1, the most common gene of disease-causing mutations in NBCCS, and for SUFU, another tumor suppressor gene involved in cell proliferation, for which no known pathogenic mutations were found. However, she had a variant of uncertain significance (VUS) in PTCH1: c.1706C > A. Because there was no data about this variant in databases and population studies, it was recommended that her parents back in the USA be tested. As her parents did not display signs of NBCCS, finding this variant in either one would determine that it likely was not related to the disease. However, if both were negative, this would indicate a de novo mutation and increase the confidence that this variant was responsible for the symptoms seen in the patient.
A difficulty encountered when considering the testing of the family is that none of the commercial labs in the USA recognized this particular variant as having any significance. Again, there were no notations of this variant in the literature or in databases that amassed genetic data. The author contacted four of the commercial labs about this variant, and one agreed to look for it in the analysis as a VUS. Because this was a novel variant, it was recommended to have the patient herself provide a sample to the lab for which to provide positive control when testing the parents. A full 84 gene panel was run using Next-Generation Sequencing, revealing only the known mutation in PTCH1. Her parents’ tests did not identify this variant. As such, the lab considered this a de novo mutation, and reclassified the variant to “likely pathogenic.”
While the children could be monitored for clinical symptoms of the disease such as palmar pitting, other hallmarks such as bifurcated ribs would require exposure to radiation, which is not recommended in those who may carry these mutations as the associated ionizing DNA damage can actually potentiate the formation of the carcinomas. Therefore, a genetic marker would be the best and most absolute confirmation of the disease.
The London physician following this family left the option to test the children up to their mother. At their current ages, 3 and 6, there are no recommendations for prevention in medical management other than avoiding ionizing radiation (whether medical or solar) unless the disease is identified in the child. However, because of the multiple surgeries and subsequent disfiguring scars the patient has received, the patient is hoping to prevent her children from undergoing the experience by initiating earlier screening and interventions. According to the consensus statement of 2011, pediatric surveillance in known NBCCS includes MRI to screen for medulloblastoma until age 8, baseline cardiac ultrasound and pelvic ultrasound at menarche in females for fibroma detection, annual skin check that moves to every 6 months if a BCC is discovered, digital panorama of the jaw annually until age 21 to monitor for keratocyst development, baseline spine films for scoliosis surveillance, and routine assessment of developmental milestones . The patient ultimately opted to defer testing in the children because of the possibility of future genetic discrimination, such as the ability to take out personal life insurance policies, if they are diagnosed with a genetic disorder at such young ages. She will continue to work with her physician in London to monitor the children for clinical signs of the disease.
Compliance with Ethical Standards
The author confirms that there was no funding provided for the undertaking of this case report. There are no known conflicts of interest to declare. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. As this is a summary of historical data within records that do not provide identification of the patient presented, ethical approval by organizational committee was not required. The patient represented in this case study is aware of the intent to utilize this information for dissemination to the medical community, and granted consent through written electronic correspondence.