A guideline for the clinical management of basal cell naevus syndrome (Gorlin–Goltz syndrome)*

The guideline is presented as a detailed review with highlighted recommendations for practical use in the clinic by dermatologists and other healthcare professionals, including general practitioners, clinical geneticists, paediatricians, ophthalmologists, craniomaxillofacial surgeons, neurologists, cardiologists and psychologists. The guideline does not cover therapeutic recommendations for (nondermatological) symptoms, as the guideline mainly focuses on screening and follow-up of symptoms. Therapeutic recommendations for basal cell carcinomas (BCCs) in general have been published in international BCC guidelines.1, 2 The guideline was developed at the Maastricht University Medical Centre (MUMC+), the Dutch BCNS expert centre accredited by the Dutch Ministry of Health, Welfare and Sport.3 The guideline development group (GDG) consisted of two dermatologists, a clinical geneticist, a molecular geneticist, an ophthalmologist, a paediatrician, a gynaecologist, a craniomaxillofacial surgeon and a paediatric neurologist, all of whom worked at the MUMC+. Two residents in dermatology were also part of the GDG and acted as project managers. Furthermore, three patient/carer representatives commented on drafts of the guideline. The GDG developed clinical questions relevant for the management of patients with BCNS, all of which related to the diagnosis and surveillance of symptoms. During the development of the guideline, the GDG met twice face-to-face, and if input from the complete GDG was requested to resolve disagreements, it was solicited via email. This guideline was developed using the Appraisal of Guidelines Research and Evaluation II and Grading of Recommendations Assessment, Development and Evaluation (GRADE) instruments.4 A systematic literature search of the PubMed and Embase databases was conducted to identify key articles in English using the search terms ‘basal cell nevus syndrome’ and ‘Gorlin syndrome’ from January 2011 to January 2021. A total of 2747 articles were found. All titles were screened and case reports on general features, image quizzes, and unrelated articles were excluded (n = 1112). The reference lists of all relevant articles were scanned for additional suitable articles (n = 13). The titles and abstracts of the remaining 1648 articles were screened and 1576 articles were excluded as they did not provide the highest level of evidence available or information pertinent to the scope of the guideline. In the final analysis, 72 articles were included (Table S1; see Supporting Information). The level of evidence was graded according to the GRADE system (high, moderate, low, very low) by two authors (B.J.A.V. and B.C.). Recommendations were based on evidence drawn from the systematic review of the literature and discussed with the GDG during the consensus meetings. For each recommendation, benefits, risks and side-effects were systematically considered. Expert opinion of the GDG was used to generate recommendations if documented evidence-based data were not available. This guideline was set up by a multidisciplinary team of physicians, which was restricted to a Dutch care centre. Diagnostic strategies and involved medical (sub)specialists may vary according to the healthcare system and local conditions. BCNS is a very rare disorder and the literature on specific symptoms is scarce. Randomized controlled trials are lacking and for most recommendations only indirect evidence was available. GRADE strength of recommendations (GSoR) are therefore often based on low or very low GRADE evidence certainty (GEC) levels. Results of future studies may require changes to some of the recommendations. These guidelines will be re-evaluated after 5 years to determine whether a (modular) update will be necessary. BCNS (OMIM #109400), also known as Gorlin–Goltz syndrome, is a rare autosomal dominant disorder with an estimated prevalence varying from 1 : 31 000 to 1 : 256 000.5, 6 The most common genetic cause of BCNS is a heterozygous germline mutation in the patched-1 (PTCH1) gene.7 This gene encodes the transmembrane glycoprotein PTCH1, a tumour suppressor of the Hedgehog (Hh) signalling pathway.8 In addition to its important role in embryonic development, the Hh signalling pathway is involved in cell proliferation and differentiation. During the inactive state, PTCH1 has an inhibitory effect on smoothened (SMO), and downstream signalling is inhibited. Further downstream, the suppressor of fused (SUFU) also inhibits the pathway by directly binding to glioma-associated (GLI) transcription factors and preventing translocation to the nucleus. Mutations in PTCH1 could relieve its inhibitory effect on SMO and subsequently SUFU is activated. This results in translocation of GLI transcription factors to the cell nucleus and upregulation of the Hh signalling pathway. Mutations in other genes of the Hh signalling pathway, either as germline mutation or postzygotic mosaicism, have been described but are less common.9-12 The most common features of BCNS are BCCs and odontogenic keratocysts (OKCs) of the jaw, but a broad scale of other characteristic features has been described.13 Owing to the low prevalence and broad variety of symptoms, the management and follow-up of patients with BCNS is often challenging. In 2011, Bree et al. proposed a management protocol for the surveillance of patients with BCNS. However, at that time, genetic analysis played a less important role and the differences between patients with heterozygous mutations in PTCH1 and SUFU were not yet evident.14 Here, we provide an up-to-date, multidisciplinary, practical, guideline for the clinical management of patients with BCNS (or suspicion of BCNS). Diagnostic criteria for BCNS were first proposed by Evans et al. in 1993, modified by Kimonis et al. in 1997 and revised by Bree et al. in 2011.14-16 According to the most recent publication,14 the diagnosis of BCNS can be established based on: (i) one major criterion and genetic confirmation; (ii) two major criteria or (iii) one major criterion and two minor criteria (Table 1). In patients with suspected BCNS, it is important to obtain a complete medical (family) history during the first consultation and perform a physical examination to search for dysmorphic features, skeletal abnormalities and skin abnormalities. Possible features are listed in Table 2. All recommendations are listed in Table 3. Table 4 provides a clear surveillance checklist for each age category. Mutation analysis including prenatal testing Radiological examination for diagnostic criteria without therapeutic consequences should be avoided as much as possible. (GEC, very low; GSoR, strong) If possible, we recommend performing genetic testing in all patients with suspected BCNS. (GEC, very low; GSoR, strong) We recommend a stepwise approach that first includes genetic testing of the PTCH1 gene. If no mutation is found, but the clinical suspicion is high, we advise testing for mutations in SUFU. If again no variant is found in the presence of a high clinical suspicion, DNA from at least two different BCCs can be isolated and genetically tested for PTCH1 and SMO using sensitive next-generation sequencing technologies to examine the possibility of postzygotic mosaicism. If a variation is found, the relevance of the mutation and its consequences for the protein function should be verified. (GEC, very low; GSoR, weak) There is insufficient evidence for genetic testing of PTCH2. (GEC, low; GSoR, strong) The most common cutaneous manifestation in patients with BCNS is multiple BCCs, both nonpigmented and pigmented, involving all histological subtypes and occurring on both sun-exposed and nonsun-exposed parts of the body.31 Some patients with BCNS will develop > 100 BCCs during their lifetime. The first BCC can develop during early childhood.31 Sunscreen use must be discussed frequently, as it can prevent the development of BCCs in patients with BCNS.32, 33 Other frequently found skin abnormalities (palmoplantar pits, basaloid follicular hamartomas, facial milia and epidermoid cysts) are benign and do not need treatment, but may be helpful in establishing the diagnosis.34-36 Adequate sun-protective measures are very important and should be discussed during every visit. (GEC, very low; GSoR, strong) Total body inspection, including nonsun-exposed sites, is recommended annually until the development of the first BCC. From that moment on, the follow-up frequency should be intensified to up to every 3–6 months, depending on the number and frequency of new BCCs. (GEC, very low; GSoR, strong) Treatment of BCCs should be carried out according to international guidelines. (GEC, evidence varies per treatment and is summarized in these guidelines1, 2; GSoR, strong) Radiotherapy is relatively contraindicated. (GEC, very low; GSoR, strong) Treatment with oral HPIs can be considered for the treatment of multiple BCCs. (GEC: moderate, GSoR: strong) It is preferable that surveillance for specific symptoms and diseases is performed by the most experienced specialist and depends on the expertise of available (sub)specialists. Physicians should be aware of the possible increased risk of developmental delay and monitor the development of children with BCNS. (GEC, very low; GSoR, strong) Bone deformities are often described as a feature of BCNS and qualify as a minor criterion (Table 2).14, 35 Macrocephaly, frontal bossing, (kypho)scoliosis, Sprengel deformity, pectus deformity, short fourth metacarpal, polydactyly and syndactyly can be observed on direct physical examination. Physicians should identify bone deformities via physical examination at diagnosis to make early intervention possible when needed. (GEC. very low; GSoR, strong) All children with BCNS, suspicion of BCNS or children at risk should be screened with a cardiac ultrasound. If cardiac symptoms occur in a patient with BCNS, a cardiac ultrasound should be repeated to exclude a late-onset cardiac tumour. (GEC, very low; GSoR, weak) In children with a PTCH1 mutation, MRI should be considered when clinical symptoms or abnormal psychomotor development are present. However, routine MRI is not indicated. (GEC, low; GSoR, weak) In cases where there is a clinical diagnosis without genetic testing or in children with an SUFU mutation, a baseline MRI is recommended and should be repeated every 4 months until the age of 3 years and twice per year until the age of 5 years. (GEC, low; GSoR, weak) When BCNS is diagnosed in adulthood, a baseline brain MRI is not necessary. (GEC, low; GSoR, strong) In patients with BCNS, suspicion of BCNS or patients at risk, a baseline ophthalmological examination, including an ocular pressure measurement if possible, is recommended. (GEC, low; GSoR, strong) From the age of 8 years, only patients with a heterozygous PTCH1 mutation should be screened for OKCs every 2 years using an OPG/MRI. (GEC, very low; GSoR, weak) After the first OKC, follow-up with an OPG/MRI is recommended annually. (GEC, very low; GSoR, weak) After the age of 22 years, follow-up can be continued by the dentist and additional OPGs/MRIs can be performed in cases where there is pain or unexplained positional change of the teeth. (GEC, very low; GSoR, weak) Gynaecological ultrasound examination and surveillance in nonsymptomatic patients is not strictly advised. In cases of abdominal complaints such as pain or menstrual irregularities, female patients should undergo gynaecological ultrasound examination to investigate the presence of an ovarian fibroma. (GEC, very low; GSoR, weak) Physicians should screen for (lympho)mesenteric cysts using ultrasound examination in patients with BCNS who report unexplained abdominal pain. (GEC, very low; GSoR, strong) Psychological evaluation for support and counselling after the diagnosis is recommended for all patients (and their families). During follow-up, physicians should pay attention to psychological distress and address the possibility of a psychological consultation. (GEC, very low; GSoR, strong) To provide optimal care for patients with BCNS we advocate a multidisciplinary approach. (GEC, very low; GSoR, strong) As these guidelines demonstrate, there is a need for high-quality evidence to refine screening indications for different symptoms. Genotype–phenotype studies revealed that the occurrence of medulloblastomas is higher in patients with a SUFU heterozygous mutation, whereas OKCs do not occur in patients with this genotype. As BCNS is a rare disease, international collaboration between expert centres is important in order to be able to merge data on genetically substantiated cohorts. Furthermore, there should be more awareness of patients without a genetic mutation, as this lack of mutation can either be attributed to genetic mosaicism or an unknown genetic cause. In some patients, there will be a desire for treatment of multiple BCCs with oral HPIs. However, the associated adverse events make oral HPIs unsuitable for lifelong use. Topical HPIs have been developed, but results of an international placebo-controlled trial are required in order to be able to make claims about the efficacy and safety of this new medication. We are very grateful to the patients’ representatives and the patient carer representatives for their input into this guideline. Furthermore, we are very grateful to L. Gijezen, S.M. Koudijs, and T. van Gorp for their contribution to this guideline. Babette J.A. Verkouteren: Conceptualization (equal); Investigation (lead); Methodology (equal); Writing-original draft (lead); Writing-review Investigation (lead); Methodology (equal); Writing-original draft (lead); Writing-review Writing-original draft (supporting); Writing-review Writing-original draft (supporting); Writing-review Writing-original draft (supporting); Writing-review Writing-original draft (supporting); Writing-review Writing-original draft (supporting); Writing-review Writing-original draft (supporting); Writing-review Writing-original draft (supporting); Writing-review Supervision (supporting); Writing-original draft (supporting); Writing-review Investigation (equal); Methodology (equal); Supervision (lead); Writing-original draft (supporting); Writing-review & editing (supporting). Table S1 Summary of findings. Table S2 Overview of all papers discussing oral hedgehog pathway inhibitor monotherapy for multiple basal cell carcinomas in patients with basal cell naevus syndrome. Table S3 Efficacy of oral hedgehog pathway inhibitors in the treatment of multiple basal cell carcinomas in patients with basal cell naevus syndrome. Table S4 Side-effects of oral hedgehog pathway inhibitors in the treatment of multiple basal cell carcinomas in patients with basal cell naevus syndrome. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.