Use of SEM/EDX methods for the analysis of ambient particulate matter adhering to the skin surface.

BACKGROUND: The skin is exposed to numerous particulate and gaseous air pollutants. The ones that need particular attention are the particles that adhere to the skin surface, which can later cause direct skin damage. This study aimed to characterize air pollution (AP) particles adhered to the human skin by using scanning electron microscopy (SEM) combined with X-ray dispersive energy spectrometry (EDX). METHODS: Tape stripping was performed from six healthy volunteers exposed to urban AP to collect stratum corneum samples from the cheeks and forehead. The samples were analysed using SEM equipped with EDX system with a silicon drift detector at an accelerating voltage of 20 keV. After the preliminary examination, the particles were located and counted using 1000× magnification. Each particle was analysed, increasing magnification up to 5000× for precise dimension measurement and elemental composition analysis. At least 100 fields or a surface of approximately 1 mm2 were examined. RESULTS: Particles adhered to the skin were identified in all samples, with a particle load ranging from 729 to 4525. The average area and perimeter of all particles identified were 302 ± 260 µm2 and 51 ± 23 µm subsequently, while the equivalent circular diameter was, on average, 14 ± 6 µm. The particles were classified into ten groups based on morphology and elemental composition. Chlorides were the most numerous particle group (21.9%), followed by carbonaceous organic particles (20.3%), silicates (18%), carbonates (16.4%), metal-rich particles (14%), and a minor number of bioaerosols, quartz-like, and fly ash particles. CONCLUSION: The SEM-EDX analysis provides evidence of the contamination of exposed skin to various airborne PM of natural or anthropogenic origin. This method may provide new insights into the link between exposure to AP and AP-induced skin damage.

Which medical disciplines diagnose and treat melanoma in Europe in 2019? A survey of experts from melanoma centres in 27 European countries.

BACKGROUND AND OBJECTIVES: The incidence of melanoma is increasing. This places significant burden on societies to provide efficient cancer care. The European Cancer Organisation recently published the essential requirements for quality melanoma care. The present study is aimed for the first time to roughly estimate the extent to which these requirements have been met in Europe. MATERIALS AND METHODS: A web-based survey of experts from melanoma centres in 27 European countries was conducted from 1 February to 1 August 2019. Data on diagnostic techniques, surgical and medical treatment, organization of cancer care and education were collected and correlated with national health and economic indicators and mortality-to-incidence ratio (MIR) as a surrogate for survival. Univariate linear regression analysis was performed to evaluate the correlations. SPSS software was used. Statistical significance was set at P < 0.05. RESULTS: The MIR was lower in countries with a high health expenditure per capita and with a higher numbers of general practitioners (GPs) and surgeons (SURG) per million inhabitants. In these countries, GPs and dermatologists (DER) were involved in melanoma detection; high percentage of DER used dermatoscopy and were involved in the follow-up of all melanoma stages; both medical oncologists (ONC) and dermato-oncologists administered systemic treatments; and patients had better access to sentinel lymph node biopsy and were treated within multidisciplinary tumour boards. CONCLUSION: Based on these first estimates, the greater involvement of GPs in melanoma detection; the greater involvement of highly trained DER in dermatoscopy, dermatosurgery, follow-up and the systemic treatment of melanoma; and the provision of ongoing dermato-oncology training for pathologists, SURG, DER and ONC are necessary to provide an optimal melanoma care pathway. A comprehensive analysis of the melanoma care pathway based on clinical melanoma registries will be needed to more accurately evaluate these first insights.

Identification of the sulfotransferase iso-enzyme primarily responsible for the bio-activation of topical minoxidil.

Pattern hair loss (i.e., androgenetic alopecia) is a common condition afflicting approximately fifty percent of men and women by the age of fifty. Currently, topical minoxidil is the only US FDA approved drug for the treatment of pattern hair loss in men and women.

The effect of topical minoxidil treatment on follicular sulfotransferase enzymatic activity.

Minoxidil is the only US FDA-approved topical drug for the treatment of female and male pattern hair loss. Previously, it was demonstrated that topical minoxidil is metabolized to its active metabolite, minoxidil sulfate, by sulfotransferase enzymes located in the outer root sheath of hair follicles. The expression of sulfotransferase in the scalp varies greatly between individuals, and this difference in expression explains the varied response to minoxidil treatment. Previously, we have demonstrated the clinical utility of detecting sulfotransferase in plucked hair follicles to predict minoxidil response in pattern hair loss patients. Typically, exogenous exposure to substrates affects the expression of the enzymatic system responsible for their metabolism. For example, Phase I metabolizing enzymes, such as the cytochrome P450 family of enzymes, are known to be up-regulated in the presence of xenobiotic substrates. However, it is not known if Phase II metabolizing enzymes, such as the sulfotransferase family of enzymes, are similarly affected by the presence of substrates. In this study, we recruited 120 subjects and analyzed their sulfotransferase enzymatic activity before and after treatment with topical minoxidil. Adjusting the results for biologic (within subject) variability, we discovered that the sulfotransferase enzymatic system expression is stable over the course of minoxidil treatment. To the best of our knowledge, this is the first study to demonstrate the stability of sulfotransferase, a Phase II metabolizing enzyme, over the course of minoxidil treatment.

Low-dose daily aspirin reduces topical minoxidil efficacy in androgenetic alopecia patients.

Topical minoxidil is the only US FDA approved OTC drug for the treatment of androgenetic alopecia (AGA). Minoxidil is a pro-drug converted into its active form, minoxidil sulfate, by the sulfotransferase enzymes in the outer root sheath of hair follicles. Previously, we demonstrated that sulfotransferase activity in hair follicles predicts response to topical minoxidil in the treatment of AGA. In the human liver, sulfotransferase activity is significantly inhibited by salicylic acid. Low-dose OTC aspirin (75-81 mg), a derivative of salicylic acid, is used by millions of people daily for the prevention of coronary heart disease and cancer. It is not known whether oral aspirin inhibits sulfotransferase activity in hair follicles, potentially affecting minoxidil response in AGA patients. In the present study, we determined the follicular sulfotransferase enzymatic activity following 14 days of oral aspirin administration. In our cohort of 24 subjects, 50% were initially predicted to be responders to minoxidil. However, following 14 days of aspirin administration, only 27% of the subjects were predicted to respond to topical minoxidil. To the best of our knowledge, this is the first study to report the effect of low-dose daily aspirin use on the efficacy of topical minoxidil.

Potential risk of developing herpes simplex encephalitis in patients treated with sildenafil following primary exposure to genital herpes.

Herpes simplex encephalitis (HSE) is associated with significant mortality and morbidity. As a consequence of HSE, up to 75% of infected individuals die or experience irreversible neurological damage. While the pathogenesis of the disease is unknown, it is traditionally hypothesized that the viral infection occurs by neuronal transmission directly from peripheral sites. Non-neuronal modes of infection have generally been overlooked as the brain is protected by the blood-brain-barrier (BBB). The BBB poses an effective barrier to pathogens as well as to drugs such as chemotherapies. In the pursuit to deliver chemotherapeutic agents to the brain, several studies demonstrated that phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may increase the permeability of the BBB enabling successful delivery of chemotherapeutic agents to the brain. In this communication, we report a case of HSE infection in a 62-year-old man, which we suspect was facilitated by the use of sildenafil during a primary genital herpes simple virus (HSV) infection. Due to large number of patients treated with PDE5 inhibitors for erectile dysfunction and the high incidence of genital HSV infection in the general population, a larger study should examine the potential risk of developing HSE in patients treated with PDE5 inhibitors.

Mechanism of action of minoxidil in the treatment of androgenetic alopecia is likely mediated by mitochondrial adenosine triphosphate synthase-induced stem cell differentiation.

Topical minoxidil is the only topical drug approved by the US Food and Drug Administration (FDA) for the treatment of androgenetic alopecia. However, the exact mechanism by which minoxidil stimulates anagen phase and promotes hair growth is not fully understood. In the late telegen phase of the hair follicle growth cycle, stem cells located in the bulge region differentiate and re-enter anagen phase, a period of growth lasting 2-6 years. In androgenetic alopecia, the anagen phase is shortened and a progressive miniaturization of hair follicles occurs, eventually leading to hair loss. Several studies have demonstrated that minoxidil increases the amount of intracellular Ca2+, which has been shown to up-regulate the enzyme adenosine triphosphate (ATP) synthase. A recent study demonstrated that ATP synthase, independent of its role in ATP synthesis, promotes stem cell differentiation. As such, we propose that minoxidil induced Ca2+ influx can increase stem cell differentiation and may be a key factor in the mechanism by which minoxidil facilitates hair growth. Based on our theory, we provide a roadmap for the development of a new class of drugs for the treatment of androgenetic alopecia.

Social selection favours offspring prone to the development of androgenetic alopecia.

In recent years, dermatologists have observed an increase in the incidence of male androgenetic alopecia (AGA). In a survey of 41 dermatologists, 88% reported an increase in incidence of AGA in men younger than 30 years. This phenomenon has no apparent explanation. However, due to the strong genetic inheritance component of AGA, a social or environmental factor which favours the inheritance of genes that increase the risk of developing AGA is suspected. To date, the strongest predictor of AGA in men has been the length of the CAG repeat located in the androgen receptor gene (AR gene) on the X chromosome. The same genetic variant in women is associated with ovulation at a later age, higher antral follicle count, and lower risk for premature ovarian failure. This led us to theorize that, due to social pressure to conceive later in life, women carriers of the short CAG repeat in the AR gene would have a selective advantage to conceive later in life and would thus favour male offspring exhibiting AGA.

Doppler laser imaging predicts response to topical minoxidil in the treatment of female pattern hair loss.

Topical minoxidil is the only drug approved by the US FDA for the treatment of female pattern hair loss. Unfortunately, following 16 weeks of daily application, less than 40% of patients regrow hair. Several studies have demonstrated that sulfotransferase enzyme activity in plucked hair follicles predicts topical minoxidil response in female pattern hair loss patients. However, due to patients’ discomfort with the procedure, and the time required to perform the enzymatic assay it would be ideal to develop a rapid, non-invasive test for sulfotransferase enzyme activity. Minoxidil is a pro-drug converted to its active form, minoxidil sulfate, by sulfotransferase enzymes in the outer root sheath of hair. Minoxidil sulfate is the active form required for both the promotion of hair regrowth and the vasodilatory effects of minoxidil. We thus hypothesized that laser Doppler velocimetry measurement of scalp blood perfusion subsequent to the application of topical minoxidil would correlate with sulfotransferase enzyme activity in plucked hair follicles. In this study, plucked hair follicles from female pattern hair loss patients were analyzed for sulfotransferase enzyme activity. Additionally, laser Doppler velocimetry was used to measure the change in scalp perfusion at 15, 30, 45, and 60 minutes, after the application of minoxidil. In agreement with our hypothesis, we discovered a correlation (r=1.0) between the change in scalp perfusion within 60 minutes after topical minoxidil application and sulfotransferase enzyme activity in plucked hairs. To our knowledge, this is the first study demonstrating the feasibility of using laser Doppler imaging as a rapid, non-invasive diagnostic test to predict topical minoxidil response in the treatment of female pattern hair loss.

The significance of structured parental educational intervention on childhood atopic dermatitis: a randomized controlled trial.

BACKGROUND: Parental education is important in managing childhood chronic diseases. OBJECTIVES: The aim of the study was to evaluate the effects of a short-term structured educational programme for parents of children with moderate to severe atopic dermatitis ( AD), aged 3 months to 7 years, on the clinical course of AD, parental stress, anxiety and the quality of family life. METHODS: One hundred thirty-four parents with AD children were recruited in a randomized controlled clinical trial at the Outpatient Unit of Pediatric Dermatology, Children's Hospital in Zagreb. The primary outcome was change in the severity of eczema measured using SCORing AD (SCORAD) and Patient Oriented (PO) SCORAD index, changes of symptom scores for pruritus and sleep disturbance. Secondary outcomes included change in stress level according to the Perceived Stress Scale (PSS); change in anxiety level according to State Trait Anxiety Inventory (STAI) and change in the quality of family life according to the Croatian version of the Family Dermatology Life Quality Index (FDLQI). RESULTS: Participants in the intervention group had a significantly lower SCORAD (P = 0.000), PO SCORAD (P = 0.000) index, pruritus (P = 0.000), sleep disturbance (P = 0.001), level of perceived stress (P = 0.024) and anxiety as a state (P = 0.42) than those in the control group at the second visit. After the educational programme, participants in the intervention group had a significantly lower impact of AD on the total quality of family life (P = 0.006). We found a statistically significant difference between the two groups with respect to additional education received between the visits. The control group had acquired significantly more additional education (P = 0.007). There was no significant difference between groups in the amount of corticosteroid used. CONCLUSION: Our structured educational programme had a positive effect on AD severity, quality of family life, parental stress and anxiety.

[PSYCHODERMATOLOGY].

Psychodermatologic disorders are conditions involving an interaction between the mind and the skin. Correlation between psychiatric and dermatological disorders is a highly complex relation considering etiology, diagnostic procedures and treatment. There are three major groups of psychodermatological disorders: psychosomatic (psychophysiologic) disorders, primary psychiatric disorders and secondary psychiatric disorders. Psychosomatic disorders are dermatological diseases which can be exacerbated or worsened by emotional stress, but are not caused directly by stress. Emotional stress can exacerbate many chronic dermatoses like urticaria, eczema, psoriasis, acne, seborrheic dermatitis, atopic dermatitis, alopecia areata, psychogenic purpura, rosacea, atypical pain syndromes and hyperhidrosis. The treatment of patients with the resistant chronic dermatosis can be difficult when stress is not recognized as a provoking factor. Primary psychiatric disorders are psychiatric conditions which induce development of various skin changes, e.g trichotillomania, factitial dermatitis, neurotic excoriations, delusions of parasitosis and dysmorphophobia. They include psychiatric disorders with anxiety, compulsive- opsessive and depressive symptoms and pathologic delusional ideas or hallucinations regarding the skin. Secondary psychiatric disorders appear as a result of a certain disfiguring skin disease that induces psychologic suffering such as loss of self-confidence, anxiety and social phobia. This category includes diseases like psoriasis, chronic eczema, various ichthyosiform syndromes, rhinophyma, multiple neurofibromas, severe acne, and other cosmetically disfiguring cutaneous lesions. The therapeutic approach of psychodermatological disorders should be multidisciplinary including primary care physicians, dermatologist, psychiatrist and psychologist. It is very important to educate dermatologists in the diagnostic procedures and therapy of psychiatric disorders which sometimes coexist with the skin disease. Majority of psychodermatological disorders can be treated with cognitive-bihevioral psychotherapy, psychotherapeutic stress-and-anxiety-management techniques and psychotropic drugs. Psychopharmacologic treatment includes anxiolytics, antidepressants, antipsychotics and mood stabilizer.

Sun behaviour patterns and perception of illness among melanoma patients.

BACKGROUND: Melanoma is one of the most aggressive skin tumours for which the major risk factor is ultraviolet radiation. Sun protection is extremely important, especially for melanoma patients who, once diagnosed with melanoma, have 500 times greater chance of developing another melanoma than the general population. OBJECTIVE: In this study, we examined the perception of melanoma and attitudes towards sun protection among melanoma patients and compared their results with the patients suffering from other dermatological disorders. METHODS: In total, 240 participants were included in the study: 120 patients suffering from melanoma and 120 participants in the control group. The Sun Behaviour Patterns Questionnaire and the Brief Illness Perceptions Questionnaire were used in this study to assess sun behaviours and perception of melanoma. RESULTS: Melanoma patients have negative attitude towards sunbathing: 57% avoid sunbathing and 27% spend time in the sun only during swimming, otherwise seeking shade, whereas participants in the control group have more positive attitude towards sunbathing. Results indicate very short time of using sunscreen protection during the year and very small number of people using adequate SPF value, in both melanoma and control group. CONCLUSION: Participants in control group perceive melanoma as a more serious illness than patients who think that melanoma has mild symptoms, is easy to cure and control, has moderate consequences and lasts relatively long. Both melanoma patients and participants in the control group show relatively good sun behaviour patterns and slightly negative attitudes towards sun protection.

Surgical and histologic pitfalls in the management of lentigo maligna melanoma.

Lentigo maligna melanoma (LMM) is a malignancy with increasing incidence, accounting for about 4% to 15% of all melanomas. Lentigo maligna (LM) is LMM in situ, usually presenting an irregular tan colored or brownish pigmented macular lesion persisting for years on chronically sun-exposed skin. Left untreated, LM may evolve into invasive form of LMM. Histologic evaluation of LM/LMM can be difficult due to widespread atypical melanocytes that are present in the area chronically sun damaged skin. It has been shown that chronically sun-damaged non-lesional skin can display some atypical features even in the absence of a melanocytic neoplasm. It is important for dermatopathologists to be aware of these findings so that such features are interpreted appropriately when making a histological assessment that may ultimately influence therapy and outcome. LMM is characterized by significant subclinical lesion extension which makes the treatment another challenge. Nowadays, a variety of therapeutic options are available in the treatment of LMM. Surgery remains the mainstay of LMM therapy, however the treatment of LM remains controversial subject in the literature. Non-surgical treatment modalities for LM include: destructive procedures such radiotherapy, cryotherapy, curettage, laser, electro-destruction and immunotherapy with the topical application of 5% imiquimod cream. These treatment options should be considered for a subset of patients with LM, especially in elderly patients with extensive or unresectable disease in difficult areas on the face or, as a second-line therapy if surgery is contraindicated. Surgical options include simple excision and margin-control techniques such as staged excision and Mohs micrographic surgery.In this article, authors are reviewing the latest diagnostic and therapeutic advances in the management of LMM.

Prognostic value of galectin-3 in primary cutaneous melanoma.

BACKGROUND: Galectin-3, one of the ß-galactoside-binding lectins, has been suggested as a marker of disease progression in melanoma patients because of its overexpression observed in recent studies. However, prognostic value of galectin-3 in primary cutaneous melanoma (PCM) has not been clearly defined. OBJECTIVES: The aim of the study was to analyse whether the intensity of galectin-3 expression can predict survival in patients with PMC. METHODS: Galectin-3 expression was evaluated using immunohistochemistry in 104 PCM samples, including 71 (68.2%) superficial spreading (SSM) and 33 (31.8%) nodular melanomas (NM). RESULTS: Significant difference of galectin-3 expression between SSM and NM was determined (P < 0.001). Increased galectin-3 expression was positively correlated with tumour thickness (P < 0.001), Clark (P < 0.001) and Breslow (P < 0.001) stage, mitotic rate (P < 0.001), presence of tumour ulceration (P < 0.001), lymphatic invasion (P = 0.018), positive sentinel lymph node (P < 0.022) and distant metastases (P < 0.001). Kaplan-Meier analysis showed an association between increased galectin-3 expression and reduced recurrence-free survival (RFS) (P = 0.001) and reduced disease-specific survival (DSS) (P = 0.015). In Cox proportional hazards regression analysis, significant predictors of reduced RFS were positive sentinel lymph node (P = 0.025) and lymphovascular invasion (P = 0.021), whereas predictors of DSS were tumour thickness (P = 0.012), lymphovascular invasion (P = 0.047), Clark stage (P = 0.029) and location of tumour on upper extremities (P = 0.024). CONCLUSIONS: Our results support the potential role of galectin-3 in PCM development, progression and metastasis. Moreover, galectin-3 could serve as an additional prognostic marker that might help in further stratifying the risk of disease progression and metastasis in patients with PMC.

The Euromelanoma skin cancer prevention campaign in Europe: characteristics and results of 2009 and 2010.

BACKGROUND: Euromelanoma is a skin cancer education and prevention campaign that started in 1999 in Belgium as 'Melanoma day'. Since 2000, it is active in a large and growing number of European countries under the name Euromelanoma. OBJECTIVE: To evaluate results of Euromelanoma in 2009 and 2010 in 20 countries, describing characteristics of screenees, rates of clinically suspicious lesions for skin cancer and detection rates of melanomas. METHODS: Euromelanoma questionnaires were used by 20 countries providing their data in a standardized database (Belgium, Croatia, Cyprus, Czech Republic, FYRO Macedonia, Germany, Greece, Hungary, Italy, Lithuania, Luxembourg, Malta, Moldavia, Portugal, Serbia, Slovenia, Spain, Sweden, Switzerland and Ukraine). RESULTS: In total, 59,858 subjects were screened in 20 countries. Most screenees were female (64%), median ages were 43 (female) and 46 (male) and 33% had phototype I or II. The suspicion rates ranged from 1.1% to 19.4% for melanoma (average 2.8%), from 0.0% to 10.7% for basal cell carcinoma (average 3.1%) and from 0.0% to 1.8% for squamous cell carcinoma (average 0.4%). The overall positive predictive value of countries where (estimation of) positive predictive value could be determined was 13.0%, melanoma detection rates varied from 0.1% to 1.9%. Dermoscopy was used in 78% of examinations with clinically suspected melanoma; full body skin examination was performed in 72% of the screenees. CONCLUSION: Although the population screened during Euromelanoma was relatively young, high rates of clinically suspected melanoma were found. The efficacy of Euromelanoma could be improved by targeting high-risk populations and by better use of dermoscopy and full body skin examination.

Technique and survival after laparoscopically assisted right hemicolectomy.

BACKGROUND: The role of laparoscopic colon resection in the management of colon cancer is still controversial. In this article, the surgical strategy and techniques are described, with further consideration of the oncologically relevant aspects. METHODS: Between March 1993 and July 2003, we performed laparoscopic right hemicolectomy in 56 patients with right colon carcinoma. Average age was 74.5 years (range, 17-92). We performed a standardized surgical procedure that included mobilization from the vascularized mesenteric bridges with a window technique, transection of the ileocolic lymphovascular pedicle, and lateral and proximal mobilization of the ileocecum, ascending colon, right flexure, and proximale transversum. After enlargement of one of the trocar incisions the exteriorized colon was resected and an extracorporeal anastomosis was performed in the standard manner. RESULTS: There were no conversions to open. The mean operating time was 119 +/- 38 min, the mean length of resected colon was 27.8 +/- 4.48 cm, and the average width of the clear margins was 6.8 +/- 5.3 cm. One patient died. Lymph nodes were positive in 21 patients. The 5-year survival rate in the 48 patients who were operated on with curative intent was 75%. We have had two local recurrences. The overall 5-year mortality-free fraction was 63%. Cox multivariate analysis showed that the mortality-prognostic factors were tumor stage and length of resected colon, whereas Kaplan-Meier analysis showed that the mortality-prognostic factors were positive lymph nodes and tumor stage. CONCLUSIONS: Our results show that laparoscopic right hemicolectomy for colon cancer can be performed safely. Complications and recurrence rates are comparable to those for left-sided laparoscopic and open procedures. Therefore, we recommend this procedure as the method of choice. Laparoscopically treated patients with stage II and stage III disease have almost the same cumulative rate of survival.

Increased incidence of colorectal cancer in the split-dalmatia county: epidemiological study.

AIM: To investigate the incidence of colorectal cancer in the Split-Dalmatia County in the 1981-1998 period, and compare it with the incidence in the Republic of Croatia. METHODS: The data were obtained using case records and registries of all hospitals and Public Health Institute in the County and the Croatian Cancer Registry. Age-standardized incidence per 100,000 was calculated from the number of patients with colorectal cancer and the number of inhabitants. RESULTS: There were 2,454 new cases of colorectal cancer (1,383 men and 1,071 women) in the Split-Dalmatia County in 1981-1998. Colon cancer was diagnosed in 55% of the cases. Age-standardized incidence rates for colorectal carcinoma per 100,000 population were 11.4 (men 14.8, women 9.0) in 1981, and 63.5 (men 93.1, women 42.5) in 1998. The total incidence increased from 16.1 (colon cancer 7.9, rectal cancer 8.2) in 1981-1985 period to 52.8 (colon cancer 30.5, rectal cancer 22.3) in 1994-1998 period, or approximately 3.3 times. The colorectal cancer incidence rate in the Split-Dalmatia County increased from 16.2 in 1985 to 46.4 in 1995, and in whole Croatia from 32.4 in 1985 to 37.8 in 1995. CONCLUSION: There was a great increase in the reported incidence of colorectal cancer in the Split-Dalmatia County in the 1981-1998 period. The relative increase of incidence in the colorectal cancer was much greater in the Split-Dalmatia County than in Croatia as a whole. These changes call for preventive and screening measures for colorectal carcinoma.

Variable expression of Gorlin syndrome may reflect complexity of the signalling pathway.

Nevoid Basal Cell Carcinoma Syndrome (NBCCS) or Gorlin syndrome is an autosomal dominant disorder characterized by cancer predisposition and multiple developmental defects. Syndrome related disorders have been attributed to alterations of PTCH gene, which plays an important role in Shh signalling pathway. Unresolved complexities of the pathway impede understanding of mechanisms through which PTCH alterations lead to variable phenotype expression in Gorlin syndrome patients, while the role of chromosomal instability is not yet clear. To increase our understanding of NBCCS, every manifestation of the syndrome and associated genetic damage should be seriously considered. Therefore, several atypical NBCCS cases are presented in this paper.