Nevoid basal cell carcinoma (Gorlin) syndrome
2004; Elsevier BV; Volume: 6; Issue: 6 Linguagem: Inglês
10.1097/01.gim.0000144188.15902.c4
ISSN1530-0366
Autores Tópico(s)Genetic and rare skin diseases.
ResumoWhen students ask me how I ever came to such a strange field as syndromes, I never hesitate to tell them my story of pure serendipity. It was a matter simply of hearing the right lecture at the right time. 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. I was transfixed, listening to her expand on what she called the "malignant" form of acanthosis nigricans. By that term, Helen meant the occurrence of hyperplastic skin on the neck, lips, tongue, flexural sites, inframammary areas, umbilicus, axillae, groin, palms, etc. of patients in association with "gastric adenocarcinoma." Skin lesions appeared dark and studded with acrochordon-like excrescences. The concept that there could be cutaneous and mucosal signs of internal malignancy was something I had never encountered before—I was captured. After the talk, I approached Helen and asked her what these associations were called. "Syndromes," she answered in her delightful Berliner accent. "'Syn' means 'together' and 'drome, drome, drome'—I forget. Why don't you look that up!" I found a medical dictionary and returned a minute or two later. "Run, run together," I offered. "You could do me a great favor and tell me about other syndromes that affect the face and mouth as I am a dentist." "Good Lord, a dentist, what are you doing in a course in dermatopathology?" I went on to explain how I was trying to expose myself to areas of learning that would help bolster my belief that oral pathology should be less dental pathology and more oral manifestations of systemic disease. As I said above, I was captured, raptured, and had a sort of religious experience—an apotheosis—this would be my field. In large part, it was chance that determined that I volunteered to help a friend who wished to go on vacation in 1958, two years after I came to Minnesota. I promised to sit in his Minneapolis dental office on Saturday mornings and take care of "emergencies." No real emergencies presented themselves—but I received a phone call from a woman who wanted me to "x-ray her jaws for those pesky cysts." After several minutes of inquiry, I determined that she had 20 to 30 cysts removed from both jaws dating from the age of 7 years. This unusual story greatly roused my curiosity because I could not imagine what type of cysts they might be. The patient told me that she was not much more than 39, that she had several cysts removed at the University of Minnesota School of Dentistry, and that her dentist in the "early days" had been Dr. Daniel Ziskin, oddly enough my mentor at Columbia University Dental School during my fellowship days. Following our phone conversation, I called my oral pathology laboratory and found that one of my graduate students, Dr. Nat Rowe, was working on his MS thesis that Saturday afternoon. After I told him the story, Nat repaired to the laboratory, found myriad slides of jaw cysts removed from my patient, examined them, and told me that they "looked boringly uniform." He added that the epithelium seemed to pull away from the underlying connective tissue. That description did not help me much at the time but he was correct, they were odontogenic keratocysts—a term not then used. I believe they were called primordial cysts in 1960. I arranged to see the patient the following Saturday morning. She was a middle-aged woman with macrocephaly, distinct kyphosis, and several small lesions scattered about her face that looked to me like basal cell carcinomas. She wore a prosthetic left eye due to "some congenital defect." As she predicted, there were several new jaw cysts present. I suggested a biopsy of one or more of these skin lesions, perhaps by my colleague, Dr. Robert Goltz, a rising star in our Department of Dermatology. After discussing the matter with her cousin, a well-known investigator from Chicago in mucopolysaccharide research, she consented. In the interim, puzzled by her disorder, I garnered records and radiographs from several hospitals where she had been treated for various problems over the years. I noted that she had calcification of the falx cerebri, several bifid and splayed ribs, and pelvic calcification. Searching the literature on combinations of jaw cysts, rib anomalies, and basal cell carcinomas, I came up almost empty handed. However, in a recently published AFIP fascicle on skin tumors, I found a picture of a woman who I suspected had the same disorder as my patient. She had a similarly affected child. This information, suggesting dominant inheritance, caused me to search the literature once more for inherited basal cell carcinomas. The yield wasn't much better. And my patient was unmarried and was not likely to change her status. She stated that no one in her family had stigmata of the syndrome. I suspect it was out of frustration that Dr. Jorge Yunis and I karyotyped my patient, not suspecting that we would find anything but were astonished to discover an "uncoiler chromosome 1," as it was then called, an unrelated polymorphism that on subsequent investigation ran through her family in an autosomal-dominant manner. Of note, it was not until a few years ago that I was informed that the sister of my proposita began to exhibit the first signs of the syndrome at age 55. This implied that one of their parents was affected—a confounding aspect of the story. After amassing as much data as we could and with further literature search back to 1880, Bob Goltz and I wrote "Multiple Nevoid Basal Cell Epitheliomata, Jaw Cysts, Bifid Rib-a Syndrome," which was published in New England Journal of Medicine 1960.1.Gorlin R.J. Goltz R. Multiple nevoid basal cell epitheliomata, jaw cysts, bifid rib-a syndrome.1:STN:280:DyaF3c3it1WrsQ%3D%3D13851319N Engl J Med. 1960; 262: 908-911Google Scholar If there was any effect from that article, it was mostly on me. The little ripples it caused were in the form of letters from various dermatologists who "had seen similar cases." It was in this way that I met Jim Howell, MD, of Dallas, Texas, who contributed greatly to our understanding of the disorder. Cases of the syndrome continued to accumulate and in 1963, 1965, 1970, 1971, 1972, and 1987, I published reviews of the disorder. In the 43 years since our first article, several patients with the syndrome stand out in my memory. One young fellow who worked in a pet store in St. Paul was bitten by a cobra. He was rushed to the city hospital on a motorbike that crashed into a truck on the way to the emergency ward and he suffered a fractured femur. While recovering from both afflictions, it was noted that he had several basal cell carcinomas scattered over his face and I was brought in on consultation. Another involved a phone call one January from a sheriff in Montana who wished to know whether having the disorder causes "mental aberrance," as he put it. It seems that a 16-year-old female had been told that because of bilateral ovarian fibromas (a not uncommon finding in the syndrome), she would be sterile. She became depressed and having imbibed much too much whiskey to drown her sorrow, took a header out the nearest window. Fortunately, the window was no more than six feet off the ground and she landed unhurt in a snowbank. The sheriff took her to the station to sober up. She, subsequently, claimed that he "manhandled" her. Hence, the sheriff's question. I told him that, in my experience, despite the ovarian fibromas, sterility is not a problem and that this good news should cheer her up considerably. In the 1980s, I had numerous requests for blood from my patients for DNA studies for gene localization of nevoid basal cell carcinoma syndrome. A rather substantial corpus of correspondence ensued between me and several investigators. In August 1991, a note was received from Dr. Allen Bale of Yale inviting me to a small get-together of people interested in "Gorlin syndrome." This was to take place at the 8th International Congress of Human Genetics in Washington, DC. In my naiveté, I thought that the sharing of positive information regarding the location of the gene or even sharing negative information might be possible, but that was not to be. Within a few months, gene mapping was accomplished simultaneously by Peter Farndon et al.2.Farndon P.A. Del Mastro R.G. Evans D.G.R. Location of gene for Gorlin syndrome.1:STN:280:DyaK387mslOitg%3D%3D1347096Lancet. 1992; 339: 581-582Google Scholar of Birmingham, André Reis et al.3.Reis A. Küster W. Linss G. Localisation of gene for the naevoid basal-cell carcinoma syndrome.1:STN:280:DyaK387mslOgtg%3D%3D1347116Lancet. 1992; 339: 617Google Scholar of Berlin, and Allen Bale et al.4.Bale A.E. Yu K.P. The hedgehog pathway and basal cell carcinomas.1:CAS:528:DC%2BD3MXjt1ajsbk%3D11257109Hum Mol Genet. 2001; 10: 757-762Google Scholar of New Haven. Allen also showed that the syndrome results from the uncovering of a tumor suppressor gene at this site, which explained not only the inordinate number of basal cell carcinomas but the cardiac fibromas, fetal rhabdomyomas, medulloblastomas, ovarian fibromas, lymphomesenteric cysts, and odontogenic keratocysts. The molecular aspects of the condition involving the Hedgehog pathway will be described later in this article. It is obvious that no work is done in a vacuum. Although this disorder has been named "Gorlin syndrome," perhaps because I've had such sustained interest in it, a veritable horde of investigators have contributed to its understanding. A few words regarding nomenclature—another name such as nevoid basal cell carcinoma syndrome is misleading because only about 50% of white patients, 20 years of age or older, exhibit significant numbers of skin cancers, and only a rare one becomes aggressive. In black patients, the skin cancers often are never present. The term basal cell nevus is not acceptable because the lesions are basal cell carcinomas from the beginning and the term nevus implies a hamartomatous condition. I am personally opposed to eponyms because they say nothing about the disorder, frequently give rise to argument regarding priority of discovery, and may be chauvinistic and unfair to those whose contributions to knowledge of the syndrome far exceed those of the individuals from whom the disorder gets its name. Perhaps the disorder should be named at the molecular level, but this has its obvious problems, and I do not have a solution to the problem. It is likely that the condition existed during Dynastic Egyptian times because a constellation of findings compatible with the syndrome has been reported in mummies from about 1000 BC.5.Satinoff M.I. Wells C. Multiple basal cell naevus syndrome in ancient Egypt.1:STN:280:DyaF1M3jsVWgsA%3D%3D48936291033957Med Hist. 1969; 13: 294-297Google Scholar Approximately 0.4% of all cases of basal cell carcinomas represent nevoid basal cell carcinoma syndrome.6.Maddox W.D. Winkelmann R.K. Harrison E.G. Multiple nevoid basal cell epitheliomas, jaw cysts and skeletal defects.JAMA. 1964; 188: 106-111Crossref Scopus (39) Google Scholar Rahbari and Mehregan7.Rahbari H. Mehregan A.H. Basal-cell nevus epithelioma [cancer in children and teenagers].1:STN:280:DyaL38%2FptlWjtw%3D%3D7053833Cancer. 1982; 49: 350-353Google Scholar noted that 2% of patients younger than 45 years of age with basal cell carcinomas have the syndrome. Evans et al.8.Evans D.G.R. Birth H.M. Orton C.I. Brain tumours and the occurrence of severe invasive basal cell carcinoma in first degree relatives with Gorlin syndrome.1:STN:280:DyaK387is1amtQ%3D%3D1772613Br J Neurosurg. 1991; 5: 643-646Google Scholar,9.Evans D.G.R. Farndon P.A. Burnell L.D. The incidence of Gorlin syndrome in 173 consecutive cases of medulloblastoma.1:STN:280:DyaK38%2FjtV2rsg%3D%3D19316251977448Br J Cancer. 1991; 64: 959-961Google Scholar suggested that the minimal prevalence was 1 per 57,000. An almost identical value was noted by Pratt and Jackson.10.Pratt M.D. Jackson R. Nevoid basal cell carcinoma syndrome.1:STN:280:DyaL2s3itlehuw%3D%3D3584581J Am Acad Dermatol. 1987; 16: 964-970Google Scholar The head appears large, i.e., > 60 cm in adults (See Fig 1, Fig 2, Fig 3, Fig 4, Fig 5, Fig 6, Fig 7). A relative macrocephaly (occipital frontal circumference greater than 95th centile for height) is found in 50%.11.Kimonis V.E. Goldstein A.M. Pastakia B. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome.1:STN:280:DyaK2s3ltFSkug%3D%3DAm J Med Genet. 1997; 69: 299-308Google Scholar However, hydrocephalus has been rarely present. Frontal bossing, noted in 25%, may cause the eyes to appear sunken. The question has often been raised as to swhether there is distinctive facies associated with the syndrome. That there is becomes evident if one attends parent support groups where up to 100 people are in attendance. One can often note the frontal bossing and pouting lower lip. Facial milia are scattered among the basal cell carcinomas in at least 50% to 60%. These are especially prominent around the eyes, eyelids, nose, malar region, and upper lip. Cleft lip and/or palate have been noted in 2–8%.12.Ruprecht A. Austermann K.H. Umstadt H. Cleft lip and palate, seldom seen features of the Gorlin-Goltz syndrome.1:STN:280:DyaL1M7ntFCrsQ%3D%3DDermatomaxillofac Radiol. 1987; 16: 99-103Google Scholar,13.Soekermann D. Fryns J.P. Caesar P. Increased head circumference and facial cleft as presenting signs of the nevoid basal cell carcinoma syndrome.Genet Couns. 1991; 2: 157-162PubMed Google ScholarFig 2Palmar pits with ingrained dirt.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3Numerous odontogenic keratocysts in both mandible and maxilla.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 4Calcification of Falx cerebri.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 5Many bifid ribs. (From patient specimens noted by Raoul Hennekam, Amsterdam.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 6a, multiple calcified lymphomesenteric cysts. b, Two lymphomesenteric cysts.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 7Fibroma of heart.View Large Image Figure ViewerDownload Hi-res image Download (PPT) About 10% to 25% have various ocular problems that include congenital cataract, microphthalmia, orbital cysts, coloboma of the iris, choroid and optic nerve, strabismus, and nystagmus.14.Gorlin R.J. Nevoid basal-cell carcinoma syndrome.1:STN:280:DyaL2s7ktlOhuw%3D%3D3547011Medicine. 1987; 66: 98-113Google Scholar, 15.Evans D.G.R. Ladusans E.J. Rimmer S. Complications of the naevoid basal cell carcinoma syndrome: Results of a population-based study.J Med Genet. 1993; 30: 462-464Crossref Scopus (422) Google Scholar, 16.Manners R.M. Morris R.J. Francis P.J. Microphthalmos in association with Gorlin's syndrome.1:STN:280:DyaK283ps1ahtg%3D%3D8703894505469Br J Ophthalmol. 1996; 80: 378Google Scholar Most striking are small very transient keratin-filled cysts (milia) found on the palpebral conjunctivae in about 40%. This observation is a personal one derived from a parental support group in Manchester, England. The author asked the assembled group if they ever had one or more of these transient cysts. This was repeated for an American support group for nevoid basal cell carcinoma syndrome. Because of the transient nature of these cysts, most noted that they were not significantly disturbed by their presence, but they had been to ophthalmologists who confirmed the presence of milia of the palpebral mucosa. The most pesky aspect of the syndrome are the inordinate number of basal cell carcinomas, which appear as early as two years of age. Rarely are they found below the waist. Perhaps the most common site for their initial appearance is the nape of the neck. There is a definite proclivity for proliferation of the cancers between puberty and 35 years of age.17.Shanley S. Ratcliffe J. Hockey A. Nevoid basal cell carcinoma syndrome: Review of 118 affected individuals.1:STN:280:DyaK2czhslOjtw%3D%3D8042673Am J Med Genet. 1994; 50: 282-290Google Scholar The median age of onset is about 25 years. However, I have seen one patient who did not have any basal cell carcinomas until she was 55 years of age. Only about 10% of individuals with the other classic stigmata have no evident basal cell carcinomas. There is definite relationship to sun exposure and skin pigmentation. Only about 40% of African-Americans with the syndrome manifest basal cell carcinomas and even then the number of lesions is usually small in contrast to many basal cell carcinomas evident in Caucasians.18.Goldstein A.M. Pastakia B. DiGiovanna J.J. 1994. Clinical findings in two African-American families with the nevoid basal cell carcinoma syndrome (NBCC).1:STN:280:DyaK2czhslOjtg%3D%3D8042672Am J Med Genet. 1994; 50: 272-281Google Scholar The cancers may vary from few to thousands and range in size from 1 to 10 mm in diameter. They are pearly to flesh-colored to pale brown. The sites most often involved are the face, back, and chest. Most show little growth. It is only after puberty that the basal cell cancers can become aggressive and invade locally. If a lesion increases in size or begins to bleed or crust, invasion is suggested. Radiation therapy causes proliferation in the basal cell carcinomas with invasion several years later; and rarely death results from extension to the brain. In only a few cases has there been any evidence of metastasis.19.Winkler P.A. Guyuron B. Multiple metastases from basal cell naevus syndrome.1:STN:280:DyaL1c%2FltFCqsQ%3D%3D3676586Br J Plast Surg. 1987; 40: 528-531Google Scholar,20.Berardi R.S. Korbe J. Melton J. Pulmonary metastasis in nevoid basal cell carcinoma syndrome.1:STN:280:DyaK3M3lvVSquw%3D%3D2045256Int Surg. 1991; 76: 64-66Google Scholar There are large numbers of cases in the dermatological literature relating unilateral or even quadrant involvement with basal cell carcinomas. We strongly suspect this represents somatic mutation.21.Camisa C. Rossana C. Little L. Naevoid basal-cell carcinoma syndrome with unilateral neoplasms and pits.1:STN:280:DyaL28%2FltFajtQ%3D%3D4063174Br J Dermatol. 1985; 113: 365-367Google Scholar The histopathology of nevoid basal cell carcinomas cannot be differentiated from that of ordinary sporadic basal cell carcinoma. The tumors are composed of nests and islands or sheets of large, deeply-stained nuclei with indistinct cell membranes. At the periphery of each lesion, the epithelial cells are well-polarized, suggestive of cutaneous basal cells. About 30% of NBCCS patients have two or more types of basal cell carcinoma patterns (morphea-like, solid, superficial, cystic, adenoid, fibroepithelial). Commonly (30–50%), one sees milia intermixed with the basal cell islands, and calcified foci may be noted not only within the tumor but in normal skin. Perhaps this reflects the "turning on" of the bone morphogenetic protein gene (see Discussion). Larger, often multiple, epidermal cysts arise on the limbs and trunk in about 35 to 50% of affected patients. As noted above, about 40% exhibit transitory multiple cysts on the palpebral conjunctiva. Palmar and, somewhat less often, plantar pits which measure about 1–2 mm in diameter are asymmetrically present in 65% to 80%.17.Shanley S. Ratcliffe J. Hockey A. Nevoid basal cell carcinoma syndrome: Review of 118 affected individuals.1:STN:280:DyaK2czhslOjtw%3D%3D8042673Am J Med Genet. 1994; 50: 282-290Google Scholar They are better visualized if the patient wets the hands in warm water for ten minutes before examination. Individuals whose occupations involve manual labor may have more obvious pits because of ingrained dirt or grease. The pits may be present in children, but a careful related study is lacking. Rarely, basal cell carcinomas have arisen in these pits. Patients with nevoid basal cell carcinoma syndrome are plagued with multiple cysts of the upper and lower jaws that may present as early as the seventh year of life. The youngest-known affected child was five years.22.Dowling P.A. Fleming P. Saunders I.D.F. Napier S.S. Odontogenic keratocysts in a 5-year-old: Initial manifestations of nevoid basal cell carcinoma syndrome.1:STN:280:DC%2BD3c7psVCrsw%3D%3D10730288Pediatr Dent. 2000; 22: 53-55Google Scholar The median age of appearance is about 15 years. This is at least 10 to 20 years earlier than in those with nonsyndrome keratocysts. The average number of cysts in nevoid basal cell carcinoma syndrome is 5 but has ranged from 1 to 30. Those in the mandible are three times as common as those that present in the maxilla. Evans et al.,15.Evans D.G.R. Ladusans E.J. Rimmer S. Complications of the naevoid basal cell carcinoma syndrome: Results of a population-based study.J Med Genet. 1993; 30: 462-464Crossref Scopus (422) Google Scholar in a population-based study, found odontogenic keratocysts in 90% of those over 40 years and in 80% in those over 20 years, with an overall frequency somewhat in excess of 65%. They peaked during the second and third decades but continued to appear throughout the life of the patient. There is no racial predilection. Although the cysts may be extremely large, and destroy large portions of the jaws, they rarely cause symptoms but markedly effect tooth displacement. Despite this, jaw fractures almost never occur. About one-half present with swelling, a quarter with mild pain, and 15% with unusual taste following rupture of a cyst. In the maxilla, the sinuses may be invaded, and in the mandible, the cysts may even extend to the coronoid process and may cross the midline. One of the most annoying aspects is the 60% recurrence following surgery. In part, this may be due to incomplete removal, i.e., from retention of epithelial islands and/or satellite microcysts, which occur with great frequency in the connective tissue capsule or from proliferation of the basal layer of the epithelium.23.Dominguez F.R. Keszler A. Comparative study of keratocysts associated and non-associated with nevoid basal cell carcinoma syndrome.1:STN:280:DyaL1c3ivF2rtA%3D%3D3131508J Oral Path. 1988; 17: 39-42Google Scholar There have been a few reports of ameloblastoma arising in odontogenic keratocysts.24.Schultz S.M. Twickler D.M. Wheeler D.E. Ameloblastoma with basal cell nevus (Gorlin syndrome: CT findings).1:STN:280:DyaL1c%2FgvVGnsQ%3D%3DJ Comput-Assist Tomog. 1987; 11: 901-904Google Scholar Less common, squamous cell carcinoma has arisen in a cyst wall.25.Hawegawa K. Amagasa T. Shioda S. Basal cell nevus syndrome with squamous cell carcinoma of the maxilla.J Oral Maxillofac Surg. 1989; 47: 629-633Abstract Full Text PDF PubMed Scopus (21) Google Scholar The odontogenic keratocysts microscopically present as being multilocular with parakeratinized (96%) or, rarely, orthokeratinized (4%) stratified squamous epithelium consisting of only a few rows of cells with a well-defined basal epithelial cell layer, palisaded nuclei but no rete ridges. Budding of the epithelium into the connective tissue with suprabasalar splitting has been noted in at least 50%. The cyst capsule is thin. Syndrome keratocysts tend to occur at a much earlier age than isolated keratocysts and apparently have a higher rate of postsurgical recurrence.26.Meara J.G. Shah S. Li K.K. The odontogenic keratocyst: A 20-year clinicopathologic review.1:STN:280:DyaK1c7jt1Chtg%3D%3D9473082Laryngoscope. 1998; 108: 280-283Google Scholar Most authors believe that odontogenic keratocysts arise from the dental lamina.14.Gorlin R.J. Nevoid basal-cell carcinoma syndrome.1:STN:280:DyaL2s7ktlOhuw%3D%3D3547011Medicine. 1987; 66: 98-113Google Scholar Mean height is increased (183 cm in males, 174 cm in females). About 15% of patients are extremely tall. The calvaria tends to be large with frontal and biparietal bossing, but this appears to be correlated with height. The mandibular coronoid processes are enlarged.27.Leonardi R. Caltabiano M. LoMuzio L. Bilateral hyperplasia of the mandibular coronoid processes in patients with nevoid basal cell carcinoma syndrome.12116218Am J Med Genet. 2002; 110: 400-403Google Scholar One of the most striking features of the disorder is the lamellar calcification of the falx, which is found in 55% to 95% of the population as opposed to perhaps 5% in the general population. One can also see calcification of the tentorium cerebelli in 20% to 40%, of the petroclinoid ligament in 20%, and of the diaphragma sellae in 60% to 80%.28.Ratcliffe J.F. Shanley S. Ferguson J. Chevenix-Trench G. The diagnostic implication of falcine calcification on plain skull radiographs of patients with basal cell naevus syndrome and the incidence of falcine calcification in their relatives and two control groups.1:STN:280:DyaK2Mzhs1enuw%3D%3D7795971Br J Radiol. 1995; 68: 361-368Google Scholar Radiologically, this appears as if the sella turcica is bridged, i.e., as if there were fusion of the anterior and posterior clinoid processes. Agenesis of the corpus callosum, with or without lipoma, has been noted as well as "empty sella syndrome."29.Takanashi J. Fujii K. Takano H. Empty sella syndrome in nevoid basal cell carcinoma syndrome.1:STN:280:DC%2BD3cvgvVekuw%3D%3D10838118Brain Dev. 2000; 22: 272-274Google Scholar Fused, splayed, or bifid ribs have been documented in 45% to 60%, and kyphosis with or without pectus deformity is noted in 40%. Spina bifida occulta of the cervical or thoracic vertebrae is found in 60%.30.Ratcliffe J.F. Shanley S. Chevenix-Trench G. The prevalence of cervical and thoracic congenital skeletal abnormalities in basal cell naevus syndrome: A review of cervical and chest radiographs in 80 patients with BCNS.1:STN:280:DyaK2MzltlKisQ%3D%3D7627481Br J Radiol. 1995; 68: 596-599Google Scholar However, in a series studied by Kimonis et al.,11.Kimonis V.E. Goldstein A.M. Pastakia B. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome.1:STN:280:DyaK2s3ltFSkug%3D%3DAm J Med Genet. 1997; 69: 299-308Google Scholar spina bifida occulta occurred in only 20%. Sprengel deformity has been observed in 10% to 40%. There has been a vast array of other skeletal anomalies. About 5% exhibit pre- or postaxial polydactyly of hand or feet, hallux valgus, or syndactyly of fingers 2 to 3. Small cystic bone lesions (flame-shaped lucencies) have been identified in phalanges, metapodial bones, carpal and tarsal bones, long bones, pelvis, and calvaria in 30%.31.Ly J.Q. Scintigraphic findings in Gorlin's syndrome.12607884Clin Nucl Med. 2002; 27: 913-914Google Scholar Calvarial involvement may give the erroneous impression that medulloblastoma has spread to bone.32.Hawkins J.C. Hoffman H.J. Becker L.E. Multiple nevoid basal cell carcinoma syndrome (Gorlin's syndrome): Possible confusion with metastatic medulloblastoma.758369J Neurosurg. 1979; 50: 100-102Google Scholar Histologically, the flame-like lesions consist of fibrous connective tissue, nerves, and blood vessels, i.e., they are hamartomas. Herzberg and Wiskemann33.Herzberg J.J. Wiskemann A. Die fünfte Phakomatose. Basalzellnaevus mit familiärer Belastung und Medulloblastom.1:STN:280:DyaF387ksF2isA%3D%3D13954184Dermatologica. 1963; 126: 106-123Google Scholar first pointed out the association of NBCCS with medulloblastoma in 1963. The tumor characteristically presents during the first two years of life as opposed to 7 to 8 years in the general population. The incidence of medulloblastoma was determined by Evans et al.15.Evans D.G.R. Ladusans E.J. Rimmer S. Complications of the naevoid basal cell carcinoma syndrome: Results of a population-based study.J Med Genet. 1993; 30: 462-464Crossref Scopus (422) Google Scholar to be 1% to 2% in 173 consecutive cases of the tumor. Conversely, a population study of NBCCS determined that 3% to 5% had medulloblastoma. There appears to be a 3M:1F sex predile
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