ANTICANCER RESEARCH 27: 1783-1788 (2007)

Diagnosis and Treatment of Patients with Nevoid Basal Cell Carcinoma Syndrome [Gorlin-Goltz Syndrome (GGS)]

REINHARD E. FRIEDRICH

Maxillofacial Surgery (Nordwestdeutsche Kieferklinik), Eppendorf University Hospital, University of Hamburg, Hamburg, Germany

Abstract. Background: The nevoid basal cell carcinoma petrosellar ligament (2/9) and carotid siphon (1/9). Cerebral cysts syndrome (NBCC) is a rare and autosomal dominant inherited occurred in one third of these patients (3/9). One patient disease with well-defined characteristics, summarized by Gorlin underwent surgery for a medulloblastoma during childhood. In and Goltz in 1960. In the head and neck region, cerebral this series of CCT of 9 patients, no cortical atrophy was found. calcifications, basal cell carcinoma (BCC) and multiple Conclusion: The NBCC is a well-known syndrome with a variety keratocysts of the jaws are the predominant findings. The aim of of findings inside and outside the head and neck region. this study was to determine the diagnostic findings and the therapy Interdisciplinary cooperation is mandatory in the diagnosis and for patients with NBCC. Patients and Methods: The medical files follow-up control of patients with NBCC. of 17 patients with NBCC, treated in a single institution (females: 9, males: 8) were evaluated. Thirteen patients were also physically The nevoid basal cell carcinoma (NBCC) syndrome is a rare investigated, including X-ray diagnosis. Results: The age at the and autosomal dominant inherited disease with well-defined time of first surgical treatment related to the syndrome was 3 to characteristics (1-6), summarized by Gorlin and Goltz in 1960 57 years (mean: 21.3 years). A family history for NBCC was (synonym: Gorlin-Goltz syndrome (GGS) (7-10)). In the evident for 4 patients. The number of patients with characteristic head and neck region, multiple basal cell carcinomas (BCC) head and neck findings in the spectrum of NBCC varied: basal and multiple keratocysts of the jaws are the predominant cell carcinoma (n=15), keratocysts of the jaws (n=13), cerebral findings (11-15). In the face, the periorbital region, nose and calcification visible on plain radiographs (n=15), palmar pits upper lip often give rise to BCC (16). Further, cerebral (n=9). Facial dysmorphism (hypertelorism) was evident in 4, and calcifications in typical locations, visible on radiographs, are skeletal anomalies outside the skull occurred in 10 patients. The diagnostic for NBCC syndrome (7, 9, 17-19). The syndrome is medical histories revealed a cleft lip and palate in 2, and characterized by the development of BCC in regions usually unilateral kidney agenesis in further 2 patients, emphasizing the not exposed to the sunlight, like the axillary and inguinal variability of the syndrome. Treatment was exclusively surgical in region, elbow, or knee. According to Gorlin (7) the BCC all but 2 patients. One of these 2 patients underwent external usually develop between puberty and the 35th year of life, irradiation for a BCC of the frontotemporal region. Nine years much earlier than in patients with BCC without a later a frontal BCC had to be treated. The other developed several syndromatic/genetic background. Further findings in NBCC other BCC inside and outside the irradiation field. Up to 50 BCC syndrome are palmar and plantar pits, skeletal anomalies (e.g. per patient had to be resected. The number of keratocysts of all bifid ribs, hypo- or aplasia of ribs, scoliosis, shortening of patients was 66, with a predeliction for the mandibular angle in metacarpalia, cyst-like of long bones), calcification of 44%. On cranial computed tomograms (CCT, n=9) a number the cerebral falx, and endocrine disorders (10). It was stated of calcifications became evident: falx (8/9), tentorium (9/9), that the facial appearance of patients with NBCC syndrome might be pathognomonic and that macrocephalus might be a further finding (4, 18). Therapy for BCC and cysts is surgical. The aim of this study was to evaluate the surgical therapy for Correspondence to: Prof. Dr. R.E. Friedrich, Maxillofacial Surgery, and the findings associated with NBCC syndrome. Eppendorf University Hospital, University of Hamburg, Martinist. 52, D-20246 Hamburg, Germany. Tel: +49 404 28033259, Fax: +49 Patients and Methods 404 28038120, e-mail: [email protected] The medical files of 17 patients with NBCC syndrome, treated at a Key Words: Nevoid basal cell carcinoma syndrome, basal cell single institution (females: 9, males: 8) were evaluated. Thirteen carcinoma, Gorlin-Goltz syndrome, keratocysts, basal cell nevus patients were re-evaluated 1 to 10 years following initial therapy. syndrome, kidney aplasia, cleft lip and palate. One patient was deceased, one could not be investigated due to age-

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Table I. Synopsis of clinical and radiological findings with NBCC (GGS) in 17 patients.

No. Gender Age at Age at Family BCC Keratocyst Calcification Palmar Facial Skeletal Further investigation first history of dura pits dysmorphism anomalies findings (years) surgical therapy for NBCC (years)

1 m 64 42 – + – + – – + Bridging of sella turcica 2 f 31 12 – – + + + + + Cleft lip, alveolus and palate; bone cyst 3 m 66 52 – + + + + – + , bridging of sella turcica, strabism 4 m 42 17 – + + + – – – 5 m 31 25 – + + + – – – 6 m 63 32 + + + + + – + Bone cysts, chalazion, kidney cyst 7 m 27 16 – + + + + – + Bridging of sella turcica 8 f 40 14 – + + + + + + 9 m 3 3 + + – 0 – – + Agenesis of one kidney, syndactyle, myofibromatosis, congenital hydrocephalus 10 f † 0 0 + – + 0 0 0 Sebaceous nevus 11 m 64 40 + + + + – – – 12 f 63 10 – + + + + – + Congenital strabism, amaurosis, calcified follicular cyst, malignant 13 f 19 9 + (+) + + – 0 – Café-au-lait spots 14 f 19 10 + (+) + – – 0 – Nevus cell nevi 15 f 51 7 – + + + + + – (legs) 16 f 84 57 – + (+) + + 0 + Osteoporosis, ovarectomy, 17 f 8 1 – + – + + + + Bilateral cleft lip, alveolus and palate, nystagmus, unilateral kidney agenesis, medulloblastoma, mental retardation

+=positive finding; –=missing data; ( )=inconclusive finding; 0=not determined; f=female; m=male. Patient 9 is the son of patient 8. Patient 14 is the daughter of patient 4. associated immobility, and two were lost at follow-up. The clinical Discussion investigation included: counting of visible alterations (BCC, dyskeratosis), evaluation of facial dysmorphism, a panoramic view of the jaws (all patients), and computed tomograms of the skull (9 This report describes the high number of associated findings patients). in NBCC syndrome, in addition to the diagnostic triad of BCC, keratocysts and cerebral calcifications. BCC were Results diagnosed in 14 patients. A further 2 patients, young of age, had café-au-lait spots or nevi, leaving 1 patient without Palmoplantar pits were present in 56%. In one case an cutaneous findings. This percentage of BCC in NBCC epidermoid cyst of the foot was excised (6). Keratocysts were syndrome is in accordance with earlier reports (11, 16). diagnosed in 13 patients. The ratio of keratocysts arising in Predominant localisations of BCC were the face, breast, the mandible or maxilla was 3:2. The number of recurrences back and extremities, or axillary and inguinal region, even per patient and the disease-free intervals (months to years) the outer acusticus meatus (9). Keratocysts were diagnostic varied considerably. Skeletal anomalies were diagnosed in for NBCC syndrome in many patients, emphasizing the 59% and clefts of the lip and palate were apparent in 2 need for continuous medical and dental education to (11.7%). Two patients had severe findings of the kidneys. investigate patients with multiple keratocysts for other Keratocysts were the initial finding in 9 patients. The results findings indicative of the syndrome. As two patients were are summarized in Tables I-III. young of age, the number of 13 patients (76.4%) with

1784 Friedrich: Nevoid Basal Cell Carcinoma (NBCC) Syndrome

Table II. CCT findings in 9 patients (symbols: see legend to Table I).

No. Gender Age Falx Tentorium Further Enlarged Cerebral Cortical Macro- Remarks calcification calcification calcifications ventricles cyst atrophy encephaly

1 m 64 + + Ligamentum + (adequate Septum – – petrosellare, for age) pellucidum bilateral 2 f 31 + + Ligamentum – – – – petrosellare, bilateral 3 m 66 + + Carotid syphon, – – – – bilateral 442++–– – –– 5 m 31 + + – – Arachnoidea – – 6m63+ + – – – – – 7m27+ + – – – – – 8m63+ + – – – – – 9 f 8 – + – – Septum – 0 History of pellucidum medulloblastoma

Table III. Localization and frequency of 66 jaw cysts in patients with nevoid basal cell carcinoma (NBCC) syndrome.

Mandible Maxilla

Molar and angle region 29 (44%) Molar and sinus region 13 (20%) Ramus 5 (7%) Meadian and paramedian region 6 (9%) Meadian and paramedian region 13 (20%)

Total 40 (60%) Total 26 (40%)

histologically proven keratocysts might increase over time. Two patients had kidney aplasia. Reports on aplastic Schlien et al. (13) reported that about 50% of patients kidneys in NBCC are very rare (3 reports: 27-29). Other develop keratocysts before the onset of puberty. The kidney alterations were reported in NBCC patients: predominance of mandibular keratocysts in females was also calcifications or deformities (24, 28) or cysts (12, 30). Two stressed in other reports (3:1 (7)). patients of this series had a cyst or stones of the kidneys. Skeletal anomalies should be expected in more than 50% Cerebral calcifications were reported as present in (9, 14). Our findings are in that range. Malformations of the more than 90% (11, 12, 16). Calcification of the falx is rib were proposed as an early diagnostic finding for children observed regularly in the normal population, in particular with NBCC syndrome (20), but seem to be less frequent in in elder individuals, but with a different pattern compared larger studies (4). However, skeletal findings other than to NBCC patients (7). In addition to this pathognomonic keratocysts are frequently observed in NBCC syndrome (4). falx calcification, computed tomograms also revealed a We were not able to substantiate earlier judgements that high number of tentorial calcifications (12, 31), the latter the physiognomy of NBCC patients appears to be being an even more constant CT finding. Cerebral cysts pathognomonic (4, 7, 19). A bright nasal root and/or seem to contribute to the panel of findings in NBCC hypertelorism was found in only 4 patients. Indeed, these syndrome (32, 33). The head circumference of our findings contribute to a characteristic individual aspect, but patients was in the normal range. Others reported on do not constitute interrelationships. enlarged head circumference associated with NBCC Some reports deal with the association of NBCC syndrome syndrome (34) and severe cerebral complications and clefts of the lip, alveolus and palate (12, 15, 21-26). Van associated with this entity (24). Dijk and Neering (26) reported that about 4% of NBCC The cerebral malformations or tumors we found were less patients develop a cleft lip and palate (CLP). This estimate frequent than those previously reported (4, 21, 35). Neither was confirmed by recent studies (5% (8), 2.8% (4)). In this cortical atrophy nor enlarged ventricles (1,18, 36) were small series the incidence of CLP is much higher (11.7%). present in our series. On the other hand, medulloblastoma

1785 ANTICANCER RESEARCH 27: 1783-1788 (2007)

Figure 1. Palmar pits in a patient with nevoid basal cell carcinoma syndrome.

(one case) was repeatedly reported in NBCC syndrome, in particular in young patients (4, 12, 17, 24, 37).

Conclusion

The nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome) is an autosomal dominant inherited disease. Several findings other than the diagnostic triad of keratocysts, multiple basal cell carcinoma and cerebral calcifications might occur in these patients and cause severe complications. Interdisciplinary management is mandatory for NBCC patients. Continuous medical and in particular dental education should focus on the differential diagnosis of jaw keratocysts frequently being the first findings in young patients with NBCC syndrome (13).

References

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