ArticlePDF Available

Iatrogenic Vitamin D Deficiency in a Patient with Gorlin Syndrome: The Conundrum of Photoprotection

Authors:

Abstract and Figures

Acute and chronic UV exposure is an important risk factor leading to photocarcinogenesis, photoimmuno-suppression and photoaging (1, 2). Patients with Gorlin syndrome (GS) harbour a hereditary predisposition to develop basal cell carcinomas (BCC) and are, therefore, advised that effective sun protection is essential and can help reduce skin cancer risk (1-4). On the other hand, adherence to strict sun-protection habits can result in vitamin D deficiency, which has been demonstrated in many patients with GS (2, 3). Vitamin D deficiency is associated with an increased risk of osteomalacia, bone fractures, autoimmune diseases, cancer and cardiovascular disease (1).
Content may be subject to copyright.
Acta Derm Venereol 94
SHORT COMMUNICATION
Acta Derm Venereol 2014; 94: 459–460
© 2014 The Authors. doi: 10.2340/00015555-1714
Journal Compilation © 2014 Acta Dermato-Venereologica. ISSN 0001-5555
Acute and chronic UV exposure is an important risk
factor leading to photocarcinogenesis, photoimmuno-
suppression and photoaging (1, 2). Patients with Gorlin
syndrome (GS) harbour a hereditary predisposition to
develop basal cell carcinomas (BCC) and are, therefore,
advised that effective sun protection is essential and can
help reduce skin cancer risk (1–4). On the other hand,
adherence to strict sun-protection habits can result in
vitamin D deciency, which has been demonstrated in
many patients with GS (2, 3). Vitamin D deciency is
associated with an increased risk of osteomalacia, bone
fractures, autoimmune diseases, cancer and cardiovas-
cular disease (1).
CASE REPORT
Here, we report a 54-year-old man with GS who was
admitted to our hospital for surgical treatment of multiple
BCC (Fig. 1). Characteristic features of GS were present
in the form of multiple BCC since youth, palmoplantar
pits, an odontogenic cyst, calcication of the falx cerebri,
and positive family history (5). DNA analysis by
m
ulti-
plex
l
igation-dependent
p
robe
a
mplication revealed a
novel heterozygous deletion of exons 11 and 12 within
the PTCH1 gene, leading to a frame shift and premature
termination codon. Moreover, the patient’s medical his-
tory revealed that within the past decades, multiple bone
fractures had occurred after minimal trauma, suggesting
a bone calcication disorder. The patient reported of his
strict photoprotection habits by daily textile and cosmetic
sun protection measures as well as trying to avoid sun
exposure. Laboratory work-up including parameters of
bone turnover and metabolism showed serum 25(OH)D
levels of < 4 ng/ml, far below the normal range (30–70
ng/ml), elevated alkaline phosphatase and low serum
phosphate concentrations. Serum calcium, parathyroid
hormone and vitamin A, E and K concentrations were
within normal ranges. Dual-energy X-ray absorptiometry
(DEXA) was consistent with severe osteoporosis ac-
cording to the WHO classication, with a mean T-score
of –3.6 measured from the hip (Fig. 2). Based on these
observations, we concluded that the patient suffered from
a disorder of bone mineralisation caused by vitamin D
deciency. Substitution therapy was initiated with a
single dose of intramuscularly administered vitamin
D3 derivative (cholecalciferol 100,000 IU) followed by
long-term daily oral substitution of 2,000 IU of vitamin
D3. The 25(OH)D level was within the normal range 3
months after initiation of therapy.
Vitamin D deciency has been described in GS pa-
tients and is thought to be related to strict sun protection
habits (1–3). The time of vitamin D measurement in
our patient was spring (April), where probands usually
have higher vitamin D levels than during winter (2), but
they were still below the detection limit of the labora-
tory test. Normal serum levels of the other lipophilic
vitamins (vitamins A, E, K) argue against an intestinal
malabsorption disorder or an imbalanced overall nu-
tritional vitamin supply in our patient. There were no
signs of renal or hepatic insufciency which could have
inuenced vitamin D metabolism (6).
DISCUSSION
Vitamin D deciency is well-known in GS patients (3),
but no data have so far been available regarding the
clinical relevance (2). Our patient experienced multiple
bone fractures due to insufcient bone mineralisation
and had a high need for vitamin D substitution.
The present case shows that strict photoprotec-
tion habits of GS patients are a double-edged sword.
Iatrogenic Vitamin D Deciency in a Patient with Gorlin Syndrome: The Conundrum of
Photoprotection
Sabrina Gentzsch1, Johannes S. Kern1, Stefan Loeckermann1, Eva Geissler1, Jochen Seufert2, Carsten Bernard3, Juergen
Kohlhase3, Leena Bruckner-Tuderman1 and Frank Meiss1
1Department of Dermatology, University Freiburg – Medical Center, Hauptstrasse 7, DE-79104 Freiburg, 2Division of Endocrinology and Diabetology, Depart-
ment of Internal Medicine II, University Hospital Freiburg, and 3Center for Human Genetics, Freiburg, Germany. E-mail: frank.meiss@uniklinik-freiburg.de
Accepted Jun 26, 2013; Epub ahead of print Nov 6, 2013
Fig. 1. The patient presented with multiple basal cell carcinomas on the
head, a typical feature for Gorlin syndrome.
460 Short communication
Therefore, we strongly support the plea for analysis
of vitamin D levels in GS patients (3). Moreover, a
thorough screening for clinical features heralding a
vitamin D deciency is recommended. Interestingly, in
vitamin D receptor decient mice (serving as model of
vitamin D deciency), BCC development was shown
after UV exposure and was attributed to overactivation
of the hedgehog signalling pathway, which is also the
pathophysiological basis for BCC development in GS
patients (7, 8). Hence, iatrogenic vitamin D deciency
of GS patients could even represent an environmental
factor enhancing BCC development in these individuals.
ACKNOWLEDGEMENT
We thank Prof Dr. Rudolf Happle for his critical and helpful
revision of the manuscript.
The authors declare no conflicts of interest.
REFERENCES
1. Reichrath J. Sunlight, skin cancer and vitamin D: What are
the conclusions of recent ndings that protection against
solar ultraviolet (UV) radiation causes 25-hydroxyvitamin
D deciency in solid organ-transplant recipients, xeroderma
pigmentosum, and other risk groups? J Steroid Biochem
Mol Biol 2007; 103: 664–667.
2. Tang JY, Wu A, Linos E, Parimi N, Lee W, Aszterbaum M,
et al. High prevalence of vitamin D deciency in patients
with basal cell nevus syndrome. Arch Dermatol 2010; 146:
1105–1110.
3. Querings K, Reichrath J. A plea for the analysis of vitamin-D
levels in patients under photoprotection, including patients
with xeroderma pigmentosum (XP) and basal cell nevus
syndrome (BCNS).
Cancer Causes Control
2004; 15: 219.
4. Goldstein AM, Bale SJ, Peck GL, DiGiovanna JJ. Sun ex-
posure and basal cell carcinomas in the nevoid basal cell
carcinoma syndrome. J Am Acad Dermatol 1993; 29: 34–41.
5. Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker
N, Farndon PA. Complications of the naevoid basal cell
carcinoma syndrome: results of a population based study.
J Med Genet 1993; 30: 460–464.
6. Tsiaras WG, Weinstock MA. Factors inuencing vitamin D
status. Acta Derm Venereol 2011; 91: 115–124.
7. Teichert AE, Elalieh H, Elias PM, Welsh J, Bikle DD.
Overexpression of the hedgehog signaling is associated
with epidermal tumor formation in vitamin D receptor-null
mice. J Invest Dermatol 2011; 131: 2289–2297.
8. Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome.
Genet Med 2004; 6: 530–539.
Fig. 2. (a) Dual-energy X-ray-absorptiometry (DEXA)
of the left hip. (b) T-score of –2.6 (black square) for the
neck of the femoral bone (bone mineral density: BMD).
(c) Results of DEXA showing BMD, T-score, Z-score and
percentage compared to indicated reference population
(young adults, age match) at different regions of the left
hip and mean values.
Acta Derm Venereol 94
Book
Full-text available
D Vitamini Kimyasal Yapısı ve Metabolizması Hülya Cenk D Vitamini Ve Genetik Aydın Rüstemoğlu D Vitamininin Normal Serum Düzeyleri, D Vitamin Düzeylerini Etkileyen Faktörler Ve D Vitamini Yetmezliği Sabiye Akbulut Serum D Vitamininin Ölçümü Andaç Uzdoğan, Çiğdem Yücel D Vitamini Biyoyararlanımı ve Doğal Beslenme Kaynakları Atilla Çifci, Halil İbrahim Yakut Sistemik D Vitamini Tedavi Ajanları, Biyoyararlanımı ve Tedavi Yönetimi Işıl Deniz Oğuz Topikal D Vitamini Tedavisi, Tedavi Yönetimi ve Kullanıldığı Hastalıklar Dursun Türkmen Deride D Vitamini Sentezi Mekanizmaları Abdullah Demirbaş, Ömer Faruk Elmas Güneşten Koruyucu Kullanımı ve D Vitamini Nursel Dilek, Yunus Saral D Vitamininin Deri Yapısı ve Fizyolojisine Etkisi Pelin Hızlı Deri Yaşlanması ve D Vitamini Ülker Gül Psoriasis ve D Vitamini Ülker Gül Psöriatik Artrit ve D Vitamini Mehmet Uçar Atopik Dermatit ve D Vitamini Ayşegül Ertuğrul, İlknur Bostancı Mast Hücresi ve Kutanöz Mastositozda D Vitamini Selçuk Doğan, Tülin Çataklı, İlknur Bostancı Ürtiker ve D Vitamini Kemal Özyurt Kaşıntı ve D Vitamini Kübra Yüce Atamulu Likenoid Dermatozlar ve D Vitamini Nihal Altunışık Vitiligo ve D Vitamini Ayşe Akbaş Melasma ve D Vitamini İbrahim Etem Arıca Rozase ve D Vitamini Nalan Saraç Akne ve D Vitamini Selma Korkmaz Hidradenitis Süpürativa ve D Vitamini Yılmaz Ulaş Seboreik Dermatit ve D Vitamini Dilek Başaran Otoimmün Büllöz Hastalıklar ve D Vitamini Sezgi Sarıkaya Solak Bağ Doku Hastalıkları ve D Vitamini Kevser Gök Behçet Hastalığı ve D Vitamini Şule Ketenci Ertaş, Ragıp Ertaş İdiyopatik Fotodermatozlar ve D Vitamini Bülent Nuri Kalaycı İktiyozis ve D Vitamini Tubanur Çetinarslan Epidermolizis Bülloza ve Vitamin D Eda Haşal Kseroderma Pigmentozum, Epidermodisplasia Verrusiformis ve D Vitamini Derya Yayla Nevüsler ve D Vitamini Serpil Şener, Suat Sezer Aktinik Keratoz ve Seboreik Keratozda D Vitamini Mahmut Sami Metin Deri Maliniteleri ve D Vitamini Sevda Önder Vaskülitler ve Vitamin D Havva Hilal Ayvaz Venöz Trombozis ve D Vitamini Cahit Yavuz Yara İyileşmesi ve D Vitamini Bülent Nuri Kalaycı Diyabetik Ayak Ülseri ve D Vitamini Gözde Ulutaş Demirbaş, Abdullah Demirbaş Granülomatöz Hastalıklar ve D Vitamini Selma Bakar Dertlioğlu Deri Enfeksiyonları ve Vitamin D Atıl Avcı Oral Mukoza Hastalıkları ve D Vitamini Ali İhsan Güleç Tırnak Sağlığı ve Hastalıklarında D Vitamini Hülya Cenk Alopesiler ve D Vitamini Munise Daye Hirsutizm ve D Vitamini Efşan Gürbüz Yontar Sistemik Kortikosteroid Kullanımında D Vitamini Desteği Selma Korkmaz Fototerapi ve D Vitamini Tuğba Özkök Akbulut Covıd-19 Ve Vitamin D Sibel Altunışık Toplu D Vitamini Tedavisinin Yan Etkileri ve D Vitamini Tedavisi Sürecinde Dikkat Edilecek Hususlar Dursun Türkmen, Nihal Altunışık D Vitamini Ve İlaç İlaç Etkileşimleri Şule Gökşin D Vitamini İntoksikasyonu Bedriye Müge SÖNMEZ
Chapter
Full-text available
Basal cell nevoid carcinoma syndrome (BCNCS) is a rare autosomal dominant genetic syndrome that is predisposed to cancer. It is characterized by the presence of multiple basal cell carcinomas (BCCs) on the skin, as well as numerous maxillary odontogenic keratocyst (QTOs), palmoplantar punctate depressions (pits), skeletal abnormalities, and other developmental defects. The genetic basis of this syndrome lies in causal mutations in the PTCH1 gene, a tumor suppressor gene located on chromosome 9. The present study aimed to review recent literature concerning SCNBC, addressing aspects such as clinical manifestations, diagnostic criteria, genetic etiology, and molecular tests used. A total of 88 articles were included, most of which were clinical cases. Among the clinical manifestations, QTOs were the most frequently mentioned major diagnostic criteria, followed by calcification of the cerebral sickle. Ocular anomalies, on the other hand, were the alterations belonging to the most prevalent minor criteria. A total of 18 clinical cases underwent molecular testing for mutations in the PTCH1 gene. The most used methods were genetic sequencing and the mutations frequently found were frameshift and nonsense mutation, which occurred in exons 2, 3, 6, 8, 11, 12, 18, and 21. Despite the existence of several mutations in the PTCH1 gene that are attributable to the etiology of SCNBC, the performance of diagnostic molecular tests were not performed in many of the studies analyzed, and even those that did not identify a correlation with the patient's phenotype or prognosis, and these are indicated only in some particular cases.
Article
Full-text available
Background Global concern about vitamin D deficiency has fueled debates on photoprotection and the importance of solar exposure to meet vitamin D requirements. Methods An international panel of thirteen experts in endocrinology, dermatology, photobiology, epidemiology and biological anthropology reviewed the literature prior to a one‐day meeting in June 2017, during which the evidence was discussed. Methods of assessment and determining factors of vitamin D status, and public health perspectives were examined and consequences of sun exposure and the effects of photoprotection were assessed. Results A serum level of ≥ 50 nmol/L 25(OH)D is a target for all individuals. Broad‐spectrum sunscreens, that prevent erythema, are unlikely to compromise vitamin D status in healthy populations. Vitamin D screening should be restricted to those at risk of hypovitaminosis, such as patients with photosensitivity disorders, who require rigorous photoprotection. Screening and supplementation are advised for this group. Conclusions Sunscreen use for daily and recreational photoprotection does not compromise vitamin D synthesis, even when applied under optimal conditions. This article is protected by copyright. All rights reserved.
Article
Basal cell nevus syndrome is an autosomal dominant disorder that stems from mutations in multiple genes, namely Patched 1 gene. The classic triad of symptoms consists of basal cell carcinomas (BCCs), keratocysts, and cerebral calcifications, although there are many other systemic manifestations. Because of the broad range of symptoms, in addition to the development of several types of tumors, early diagnosis and close monitoring is essential to preserve quality of life. Targeting treatment is often difficult because of tumor prevalence. Newer inhibitors of Hedgehog signaling pathway and proteins involved in proliferative growth have shown therapeutic promise. In addition, preventive medications are being devised. We propose a method for determining appropriate treatment for cutaneous tumors. This article is protected by copyright. All rights reserved.
Article
Full-text available
The vitamin D receptor (VDR) ligand, 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), reduces proliferation and enhances differentiation, and thus has been investigated for a role in preventing or treating cancer. Mice deficient for the VDR display a hyperproliferative response in the hair follicle and epidermis and decreased epidermal differentiation. Unlike their wild-type littermates, when treated with 7,12 dimethylbenzanthracene (DMBA) or UVB, they develop skin tumors, including some characteristic of overexpression of the hedgehog (Hh) pathway. Both the epidermis and utricles of the VDR-null animals overexpress elements of the Hh pathway (sonic hedgehog (Shh) 2.02-fold, patched1 1.58-fold, smoothened 3.54-fold, glioma-associated oncogene homolog (Gli)1 1.17-fold, and Gli2 1.66-fold). This overexpression occurs at an age (11 weeks) at which epidermal hyperproliferation is most visible and is spatially controlled in the epidermis. DMBA- or UVB-induced tumors in the VDR-null mice also overexpress elements of this pathway. Moreover, 1,25(OH)(2)D(3) downregulates the expression of some members of the Hh pathway in an epidermal explants culture system, suggesting a direct regulation by 1,25(OH)(2)D(3). Our results suggest that increased expression of Shh in the keratinocytes of the VDR-null animal activates the Hh pathway, predisposing the skin to the development of both malignant and benign epidermal neoplasms.
Article
Full-text available
The steroid hormone vitamin D is required for normal calcium and phosphorus metabolism and is thus an important contributor to musculoskeletal health. Recent data have linked low vitamin D levels to a wide range of diseases, including cancer, cardiovascular disease, autoimmune disease and infection. Adequate levels of vitamin D are maintained through its cutaneous photosynthesis and oral ingestion. By some estimates, one billion people worldwide have vitamin D deficiency or insufficiency. A number of factors influence the photosynthesis and bioavailability of vitamin D and contribute to risk of impaired vitamin D status. These factors include variation in sun exposure due to latitude, season, time of day, atmospheric components, clothing, sunscreen use and skin pigmentation, as well as age, obesity and the incidence of several chronic illnesses. This review will focus on factors that influence vitamin D status and contribute to the prevalence of low vitamin D levels.
Article
Full-text available
There are many potential complications which have been reported in association with the naevoid basal cell carcinoma syndrome. We have been able to show the relative frequencies of these problems in a population based study of 84 cases in the north west of England. The major complications of basal cell carcinomas and jaw cysts occur in over 90% of patients by 40 years of age, but may both occur before 10 years of age. Less well described complications are ovarian calcification or fibroma (24%), medulloblastoma (5%), cardiac fibroma (3%), cleft palate (5%), and ophthalmic abnormalities such as squint or cataract (26%). This study more clearly defines the possible complications of the syndrome and gives clearer guidelines for counselling and screening affected and at risk persons.
Article
To evaluate vitamin D status in patients with basal cell nevus syndrome (BCNS) who practice photoprotection because of their genetic predisposition to skin cancer and to determine risk factors for deficiency. Retrospective cohort study. Academic medical centers. Forty-one ambulatory patients with BCNS who participated in a 2-year chemoprevention clinical trial. Population-based controls (n = 360) were selected and matched by age, sex, Fitzpatrick skin type, and season/geography. Levels of 25-hydroxyvitamin D (25[OH]D) and vitamin D deficiency (defined as a 25[OH]D level of ≤20 ng/mL). Twenty-three patients with BCNS (56%) were vitamin D deficient. Patients with BCNS had mean 25(OH)D levels below those of the general population (-3 ng/mL; P = .02) and were 3 times more likely to be vitamin D deficient (56% vs 18%; P < .001). Levels of 25(OH)D were lower in patients who were overweight (-3.0 ng/mL; P = .04) and who had blood collected in the winter compared with the summer (-7.1 ng/mL; P < .001). Conclusion: Patients with BCNS may be at increased risk for vitamin D deficiency, depending on their adherence to photoprotection practices.
Article
Nevoid basal cell carcinoma syndrome (NBCC) is an autosomal dominant multisystem disorder. Persons with the NBCC gene have varied susceptibility to basal cell carcinoma (BCC) development. We examined the anatomic site-specific distribution of BCCs and the relation between sun exposure and numbers of BCCs in NBCC cases. A questionnaire asking about lifetime sun exposure, sun behavior habits, and number of BCCs was sent to 16 families with NBCC evaluated between 1985 and 1991. The results were compared with previously published data for the general population. In the general population, 88% of all BCCs in women and 86% in men occurred on the face, head, neck, and arms versus 59% in women with NBCC and 65% in men with NBCC. Of BCCs in the general population 9% and 12% occurred on the trunk versus 38% and 32% of BCCs in NBCC cases, in women and men, respectively. We did not observe a strong relation between numbers of BCCs and history of lifetime sun exposure. The anatomic-site distribution of BCCs suggests that frequent sun exposure may not be essential for the development of BCCs in patients with NBCC. However, the observation that there are more tumors on sun-exposed areas suggests that exposure to the sun promotes the development of BCCs in patients with NBCC.
Article
Sir, UV exposition is the main reason for the development of skin cancer. Sun protection is of particular importance in patients that are deficient in repair of UVinduced DNA-damage, including patients with genodermatoses XP and BCNS. However, 90% of all requisite vitamin-D has to be formed in the skin through the action of the sun – a serious problem, for a connection between vitamin-D deficiency and a variety of adverse consequences including various types of cancer [1] (e.g. colon-, prostate- and breast cancer), autoimmune diseases including type 1 diabetes [2] as well as an increased risk for hypertension and cardiovascular disease [3] has now been clearly indicated in a large number of epidemiologic and laboratory studies. What is the explanation for these findings? Recent investigations have now revealed that 1a,25(OH)2D3 is not exclusively produced in the kidney. It has been shown that many other tissues as prostate, colon, skin,
Article
As I recall, Columbia Presbyterian Medical Center was not a hot bed of liberalism during the 1940s. Helen Ollendorf Curth was a famous and highly qualified dermatologist. She had come to New York City to escape the Holocaust. At that time, she had no appointment to Columbia’s Dermatology Department. In Berlin, she and Professor A. Buschke had described many disorders, including a syndrome of connective tissue nevi and bones that looked as if candle wax were dripped on them (Buschke-Ollendorf syndrome). An invitation came for Helen to give a lecture at Columbia on Helen’s favorite disease, acanthosis nigricans. Although we now know that acanthosis nigricans represents a nonspecific keratinocyte proliferation secondary to inter alias, a deficiency of insulin-binding receptors, in the late 1940s, we were only in the clinically descriptive stage. Based upon her experience, Helen divided acanthosis nigricans into an autosomal dominant “benign” form, a pseudoacanthosis nigricans seen in rather obese brunettes, a nongenetic so-called malignant acanthosis nigricans, and a miscellaneous group that included various associated endocrinopathies and a Crouzon-like disorder that we now know as Crouzonodermoskeletal dysplasia.
Article
A connection between vitamin D deficiency and severe health problems including various types of cancer has been demonstrated. We have shown that patients that have to protect themselves against solar UV radiation for medical reasons, including patients with xeroderma pigmentosum (XP), basal cell nevus syndrome (BCNS), lupus erythematodes (LE) or transplant recipients, are at risk to develop vitamin D deficiency. We conclude that 25-hydroxyvitamin D serum levels as a measure of vitamin D status have to be analyzed in patients that have to protect themselves against solar UV radiation for medical reasons. Suboptimal vitamin D status has to be substituted (e.g. via oral treatment) to protect against serious vitamin D deficiency-related health problems without increasing the risk to develop solar UV-induced skin cancer. Our finding that protection against solar UV radiation causes vitamin D deficiency underlines the need for re-defining dermatological recommendations for solar UV protection in skin cancer prevention programs.