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Acrochordons as a presenting sign of nevoid basal cell carcinoma syndrome
Acrochordons as a presenting sign of nevoid basal cell carcinoma syndrome Elvira Chiritescu, MD, and Mary E. Maloney, MD Hershey, Pennsylvania Background: Nevoid basal cell carcinoma syndrome (NBCCS) is a genodermatosis with autosomal dominant inheritance. In identified kindreds the diagnosis is relatively easy, but for the patients without family history of this syndrome a high clinical suspicion is necessary for diagnosis. Objective: Acrochordons are distinctly uncommon in childhood. Our purpose was to evaluate skin tags that develop at an early age. Methods: This is a retrospective series evaluation of 7 children who presented with pedunculated papules (acrochordon-like growths). A full history was then correlated with biopsy results in each patient. Results: Clinically, lesions consisted of flesh-colored and pigmented pedunculated papules. Histopathologic examination of these papules showed basal cell carcinomas in each biopsy specimen. Conclusion: We consider that “skin tag”–like basal cell carcinomas in childhood may represent a marker for NBCCS. Early diagnosis of this syndrome and early sun protection of the affected children could help decrease the number of lifetime tumors. Biopsy should be performed on acrochordons in children because they may be the presenting sign of NBCCS. Because these tags may precede other stigmata of the NBCCS, recognition may facilitate early diagnosis and allow early treatment and sun protection. (J Am Acad Dermatol 2001;44:789-94.)
N
evoid basal cell carcinoma syndrome (NBCCS) is a genodermatosis with autosomal dominant inheritance.1 Its clinical findings include multiple basal cell carcinomas (BCCs), jaw cysts, pitting of the hands and feet, skeletal abnormalities, ectopic calcifications, and other less common abnormalities.2 Recent work has shown a defect of the PTCH gene.3-5 Although patients may have BCC at any location, most tumors are located on sun-exposed areas, especially the head and neck.6 This mimics the most common location of sporadic BCC, implying that sun exposure plays a role in the development of these tumors7 and that sun protection could help decrease the number of lifetime tumors. Early diagnosis of this syndrome would identify these children as at risk, allowing early sun protection. From the Division of Dermatology, The Pennsylvania State University, College of Medicine, The Milton S. Hershey Medical Center. Reprints not available from authors. Correspondence: Mary E. Maloney, MD, Dermatology Division, University of Massachusetts Medical School, Worcester, MA 01655. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/1/112399 doi:10.1067/mjd.2001.112399
Many of the classic features, such as BCC, calcified falx cerebri, and palmar pits, may not develop until the later teens or early twenties.2,8-10 Any early sign of this syndrome would help identify patients at risk. Skin tags are benign epithelial tumors most commonly seen in adults in areas of friction (neck, axillae, inframammary). They are distinctly uncommon in childhood. We describe the development of pedunculated papules in 7 children with a clinical appearance of skin tags that when removed showed BCC. On further investigation all had NBCCS. We consider that this finding may represent a marker for NBCCS.
CASE REPORTS Case 1 An 11-year-old white girl was referred to the Dermatology Clinic for an increasing number of skin tags that had been appearing over the past 4 to 5 years. They were asymptomatic, but the family was concerned because they were so numerous. No evaluation for a genetic disease had previously been undertaken. Her medical history was significant for congenital hydrocephalus, mandibular jaw cysts, borderline mental retardation, and a learning disability. Physical examination showed numerous fleshcolored and pigmented pedunculated papules, on 789
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Fig 1. Patient 1. Characteristic phenotype and one “skin tag”–like growth in the right infraorbital area.
Fig 3. Patient 1. BCC, follicular type. (Hematoxylin-eosin stain; original magnification ×100.)
Fig 2. Patient 1. “Skin tag”–like growths on the neck and upper back.
the upper chest and back, neck, axillae and left infraorbital area (Figs 1 and 2). She had several palmoplantar pits that were 0.5 to 1 mm in diameter. Her clinical phenotype was striking; she had macrocephaly, frontal bossing, divergent strabismus, broad nasal root, ocular hypertelorism, epicanthal folds, abnormal teeth insertion, and mild prognatism. In addition, she had narrow and slanting outline of the shoulder girdle. Findings of chest, cardiac, and abdominal examinations were unremarkable. Biopsy specimens of several pedunculated papules showed follicular BCC (Fig 3). The patient was scheduled for laser surgery and she had most of the lesions removed. Her primary care physician was advised about the need of further work-up for the patient and to have the other members of the family screened for NBCCS. Her mother has history of a BCC on the nose surgically treated
when she was 42 years old and a jaw cyst when she was very young. The patient has 2 maternal aunts who appear unaffected and a maternal uncle with jaw cysts. The patient’s mother remembers that her mother has had “some jaw cyst problem,” and she died of liver cirrhosis. Case 2 The 8-year-old sister of the patient described in case 1 had several “skin tags” around the neck, palmar pits, and facial characteristics similar to her sister’s features. Case 3 An 8-year-old white girl was referred to the Dermatology Clinic for evaluation of hundreds of skin tags and nevi all over the body (Fig 4). When she was 2 years of age, her pediatrician reported “fine papules in the diaper area”; during the next 6 months “nevi” developed all over her body and continued to increase in number during the next few years. During infancy she had chalazions of both eyes, and an epidermal inclusion cyst was noticed on her left buttock. An umbilical hernia was detected
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Fig 4. Patient 3. Flesh-colored and pigmented pedunculated growths around the neck.
Fig 5. Patient 3. Photomicrograph of biopsy specimen shows BCC, keratotic type. (Hematoxylin-eosin stain; original magnification ×100.)
when she was 9 months old. Her family history was unremarkable. Physical examination showed hundreds of tiny, often pedunculated tan-brown papules all over the body. She had a café au lait macule on the left arm and palmoplantar pits. Her head circumference was greater than the 98th percentile for age. She had epicanthal folds and her inner and outer canthal distances were 3.2 cm (approximately 75th percentile) and 8.7 cm (approximately 90th percentile), respectively. Findings of chest and cardiac examinations were unremarkable. Ultrasound examination of the abdomen did not reveal any abnormality. Radiographic survey of the facial bones, skull, and cervical spine was unremarkable. Panorex radiography of the mandible did not show any cystic lesions. Biopsy specimens of several pedunculated papules revealed pigmented, keratotic, and cystic BCCs (Fig 5). The patient was diagnosed as having NBCCS. The BCCs were treated with carbon dioxide laser and at 3-year follow-up there were only a few small tumors on the skin.
mentation on the periorbital areas, right temple, neck, axillae, left flank, and back. He had hypertelorism and malposition of teeth. There was no palmoplantar pitting. Findings of chest, cardiac, abdominal, genitourinary, and neurologic examinations were unremarkable. A computed tomographic (CT) scan of the head showed a cavum septum pellucidum, and an electroencephalogram had mildly abnormal findings because of background slowing. A skin biopsy specimen of a pedunculated papule on the back showed nodular BCC. Carbon dioxide laser ablation was done for all BCCs.
Case 4 A 14-year-old white boy was referred to the Dermatology Clinic for evaluation of multiple nevi. Some of them had been treated with liquid nitrogen. His medical history was significant for mental retardation, attention deficit disorder, behavioral disorder, and episodes of psychosis. He had surgical correction of strabismus. He was born with 6 toes. His family history was unremarkable. Physical examination showed multiple pedunculated papules, with variable degrees of hyperpig-
Case 5 A 6-year-old white boy, with a family history of NBCCS (father), was referred to the Dermatology Clinic for screening for NBCCS. A few skin tags had been noticed in the past 3 years. His medical history was significant for macrocephaly, hypertelorism, cleft palate, and an extra digit on the left foot. He had developmental delay. A mandible series did not show any odontogenic cysts or other abnormalities. A CT scan of the head showed prominence of the ventricular system and no abnormal calcification. Physical examination showed few slightly brown, pedunculated papules on the back, left axilla, and left ankle. He also had palmar pits. Skin biopsy specimens of all “skin tag”–like growths showed follicular BCC. Case 6 A 5-year-old girl had several asymptomatic growths on the right side of her upper trunk that had been apparent for approximately 3 years. She was born with pulmonary valve stenosis and a large head. A CT scan was done to rule out hydrocephalus
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Table I. Nevoid basal cell carcinoma syndrome: Features and diagnostic criteria8,10,15 Major features
Minor features
Multiple BCCs Palmar and plantar pitting Odontogenic keratocysts Calcification of the falx cerebri
Diagnostic criteria
Developmental and skeletal abnormalities (frontal bossing, macrocephaly, strabismus, cleft palate, bifid ribs, ectopic calcifications) Tumors (medulloblastoma, ovarian fibroma) Mental retardation
At least two major features, or One major feature and an affected firstdegree relative, or Two minor features and an affected firstdegree relative, or Multiple BCCs in childhood
Table II. Summary of findings Age (y) at Patient Age onset of No. (y) skin tags
Histopathologic findings of skin tag
1
11
6
BCC, follicular
2 3
8 8
8 2
4
14
13
5
6
3
BCC, follicular
6
5
2
BCC, follicular
7
5
4
BCC, nodular
BCC, pigmented, keratotic, cystic BCC, nodular
Medical hx/family hx
Congenital hydrocephalus, jaw cysts, strabismus, mental retardation NBCCS in first-degree relative Chalazions, umbilical hernia, epidermal inclusion cyst Mental retardation, behavioral disorder, strabismus, 6 toes Cleft palate, 6 toes, father with NBCCS Pulmonary valve stenosis
Clinical findings
Palmoplantar pits, macrocephaly, frontal bossing, broad nasal root, hypertelorism Palmoplantar pits Palmoplantar pits, macrocephaly Hypertelorism, malposition of teeth Palmar pits, hypertelorism, macrocephaly Macrocephaly, frontal bossing, hypertelorism, broad nasal root Palmoplantar pits, broad forehead, wide nasal root
Years of delay in diagnosis of NBCCS after onset of skin tags
5
Unknown 6 1 3 3 1
hx, History.
and did not reveal any abnormality. Panorex radiography of the mandible did not revealed any jaw cysts. As far as her parents know, there is no family history of similar problems. Physical examination showed numerous pedunculated papules on the face, trunk, axillae, and popliteal areas. There was no palmoplantar pitting. She had macrocephaly, frontal bossing, broad nasal root, hypertelorism, and mild prognatism. A skin biopsy specimen of a papule was consistent with follicular BCC. At the screening of her parents and 3 siblings (7year-old, 21⁄2-year-old, and 5-month-old sisters), there were no findings consistent with NBCCS. Case 7 A 5-year-old white girl had skin growths that were noticed 1 year before presentation to the Dermatology Clinic. Her medical and family histories were not significant. Radiography of the jaw has not been done.
Physical examination showed “skin tag”–like lesions on the neck, trunk, arms and legs, palmoplantar pits, broad forehead, wide nasal root, and low frontal hairline. The skin biopsy specimen of one papule showed nodular BCC.
DISCUSSION NBBCS is an autosomal dominant disorder, with high penetrance (~97%) but markedly variable expression,11 mapped to chromosome 9q22.3-31.1 The responsible gene, the PTCH gene, is a tumor suppressor, and the patients with genetic alteration in this gene have a predisposition not only for multiple BCCs but also for the development of primitive neuroectodermal tumors of the central nervous system3 and other types of tumors. Some cases appear as spontaneous mutations.8 NBCCS may be recognized under different names such as basal cell nevus syndrome, BCC syndrome, multiple basal cell nevi, Gorlin’s syndrome, and Gorlin-Goltz syndrome.12
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The major features of this syndrome occur in more than 75% of reported cases and are listed in Table I.8,13 The minor features of NBCCS are multiple and include developmental and skeletal abnormalities13,14 and frequently have a characteristic phenotype (Table I). Diagnostic criteria implies at least two major features, one major feature and an affected first-degree relative, two minor features and an affected first-degree relative,8,10,15 or multiple BCCs in childhood (Table I). A high index of suspicion is necessary and characteristic facies, together with enlarged calvaria, may lead the clinician to search for NBCCS very early in life, even in the absence of a family history of this syndrome.14 When cysts of the jaws develop, they usually occur after 7 years of age and peak during the second or third decades, when the rate of development of new cysts tends to decrease.2,14,16 Often the cysts are asymptomatic and they are detected on a routine dental examination.14 Other patients with cysts may present with jaw swelling, pain, abnormal taste sensation, or a discharge in the mouth.8 Palmar or plantar pits (or both) may be seen in patients as young as 5 years, but generally develop during the second decade of life and later.2,6,14 The pits may be made more obvious by soaking the hands in water for 15 minutes.8 Calcification of the falx cerebri has been found in 35% of patients older than 14 years9 and peaks during the second to fourth decades.10 In the cases presented, the “skin tags” were present as early as 2 and 3 years of age and therefore could have allowed a very early diagnosis (Table II). The “skin tags” of NBCCS were described by Nomland17 and represent the “nevi” of this syndrome. On biopsy they showed “dark staining basal cells” resulting in the use of the term “nevus of basal cell.”2 These findings suggest that “skin tags” in a child may be a sign leading to early diagnosis and deserve biopsy. Although some of our patients did have some signs of NBCCS, the biopsy findings of the skin tags clearly established the diagnosis before calcification of the falx cerebri or invasive BCC developed. Therefore sun protection and close follow-up should be started at a young age to hopefully prevent future invasive BCC. We thank the participating families and their physicians. We also thank Klaus F. Helm, MD, for his help in photographic work and James B. Howell, MD, for reprints regarding NBCCS. REFERENCES 1. Unden AB, Stahle-Backdahl M, Holmberg E, Larsson C, Toftgard R. The mapping of the locus for nevoid basal cell carcinoma syndrome on chromosome 9q. Acta Derm Venereol 1997;77: 4-9.
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2. Howell JB, Anderson DE. “The basal-cell nevus” by Howell and Caro, January 1959. Commentary: the nevoid basal cell carcinoma syndrome. Arch Dermatol 1982;118:813-26. 3. Wolter M, Reifenberger J, Sommer C, Ruzicka T, Reifenberger G. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinoma of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 1997;57:2581-5. 4. Hahn H, Wicking C, Zaphiropoulos PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996;85:841-51. 5. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272:1668-71. 6. Howell JB. Nevoid basal cell carcinoma syndrome: profile of genetic and environmental factors in oncogenesis. J Am Acad Dermatol 1984;11:98-104. 7. Goldstein AM, Bale SJ, Peck GL, DiGiovanna JJ. Sun exposure and basal cell carcinomas in the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol 1993;29:34-41. 8. Shanley S, Ratcliffe J, Hockey A, Haan E, Oley C, Ravine D, et al. Nevoid basal cell carcinoma syndrome: review of 118 affected individuals. Am J Med Genet 1994;50:282-90. 9. Howell JB, Anderson DE, McClendon JL. Multiple cutaneous cancers in children: the nevoid basal cell carcinoma syndrome. J Pediatr 1996;69:97-103. 10. Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kaas R, DiGiovanna JJ, et al. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 1997; 69:299-308. 11. Anderson DE, Taylor WB, Falls HF, Davidson RT. The nevoid basal cell carcinoma syndrome. Am J Hum Genet 1967;19:12-22. 12. Howell JB. The roots of the naevoid basal cell carcinoma syndrome. Clin Exp Dermatol 1980;5:339-48. 13. Evans DGR, 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;30:460-4. 14. Gorlin RJ. Nevoid basal-cell carcinoma syndrome. Medicine 1987;66:98-109. 15. Chenevix-Trench G, Wicking C, Berkman J, Sharpe H, Hockey A, Hann E, et al. Further localization of the gene for nevoid basal cell carcinoma syndrome (NBCCS) in 15 Australasian families: linkage and loss of heterozygosity. Am J Hum Genet 1993;53: 760-7. 16. Howell JB, Anderson DE. The nevoid basal cell carcinoma syndrome. In: Andrade R, editor. Cancer of the skin. Philadelphia: WB Saunders; 1976. p. 883-98. 17. Nomland R. Multiple basal cell epitheliomas originating from congenital pigmented basal cell nevi. Arch Dermatol Syphilol 1932;25:1002-8. 18. Binkley GW, Johnson HH Jr. Epithelioma adenoides cysticum, basal cell nevi, agenesis of the corpus callosum and dental cysts: a clinical and autopsy study. Arch Dermatol Syphilol 1951;63:73-82. 19. Gorlin RJ, Sedano HL. The multiple nevoid basal cell carcinoma syndrome revisited. Birth Def 1971;7:140-8. 20. Hashimoto K, Howell JB, Yamanishi Y, Holubar K, Bernhard R Jr. Electron microscopic studies of palmar and plantar pits of nevoid basal cell epithelioma. J Invest Dermatol 1972;59:38093. 21. Howell JB, Freeman RG. Structure and significance of the pits with their tumors in the nevoid basal cell carcinoma syndrome. J Am Acad Dermatol 1980;2:224-38.
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22. Dawber RPB, Ryan TJ. Basal cell naevus syndrome and malignant meningioma. Br J Dermatol 1980;103(Suppl 18):42. 23. Satoh M, Fukazawa H, Yagawa K, Endo H, Suzuki A. Two cases of nevoid basal cell carcinoma syndrome. Acta Pathol Jpn 1977; 27:713-27. 24. Bansal MP, Sengupta SR, Krishnan EC. Basal cell naevus syndrome. Indian J Cancer 1975;12:214-8. 25. Kedem A, Even-Paz Z, Freund M. Basal cell nevus syndrome associated with malignant melanoma of the iris. Dermatologica 1970;140:99-106. 26. Beddis IR, Mott MG, Bullimore J. Nasopharyngeal rhabdomyosarcoma and Gorlin’s nevoid basal cell carcinoma syndrome. Med Pediatr Oncol 1983;11:178-9.
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27. Howell JB, Caro MR.The basal-cell nevus: its relationship to multiple cutaneous cancers and associated anomalies of development. Arch Dermatol 1959;79:67-80. 28. Howell JB, Mehregan AH. Story of the pits. Arch Dermatol 1970; 102:583-5. 29. Howell JB, Mehregan AH. Pursuit of the pits in the nevoid basal cell carcinoma syndrome. Arch Dermatol 1970;102:586-97. 30. Howell JB, Anderson DE. The nevoid basal cell carcinoma syndrome. Arch Dermatol 1982;118:813-25.
N
evoid basal cell carcinoma syndrome (NBCCS) is a genodermatosis with autosomal dominant inheritance.1 Its clinical findings include multiple basal cell carcinomas (BCCs), jaw cysts, pitting of the hands and feet, skeletal abnormalities, ectopic calcifications, and other less common abnormalities.2 Recent work has shown a defect of the PTCH gene.3-5 Although patients may have BCC at any location, most tumors are located on sun-exposed areas, especially the head and neck.6 This mimics the most common location of sporadic BCC, implying that sun exposure plays a role in the development of these tumors7 and that sun protection could help decrease the number of lifetime tumors. Early diagnosis of this syndrome would identify these children as at risk, allowing early sun protection. From the Division of Dermatology, The Pennsylvania State University, College of Medicine, The Milton S. Hershey Medical Center. Reprints not available from authors. Correspondence: Mary E. Maloney, MD, Dermatology Division, University of Massachusetts Medical School, Worcester, MA 01655. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/1/112399 doi:10.1067/mjd.2001.112399
Many of the classic features, such as BCC, calcified falx cerebri, and palmar pits, may not develop until the later teens or early twenties.2,8-10 Any early sign of this syndrome would help identify patients at risk. Skin tags are benign epithelial tumors most commonly seen in adults in areas of friction (neck, axillae, inframammary). They are distinctly uncommon in childhood. We describe the development of pedunculated papules in 7 children with a clinical appearance of skin tags that when removed showed BCC. On further investigation all had NBCCS. We consider that this finding may represent a marker for NBCCS.
CASE REPORTS Case 1 An 11-year-old white girl was referred to the Dermatology Clinic for an increasing number of skin tags that had been appearing over the past 4 to 5 years. They were asymptomatic, but the family was concerned because they were so numerous. No evaluation for a genetic disease had previously been undertaken. Her medical history was significant for congenital hydrocephalus, mandibular jaw cysts, borderline mental retardation, and a learning disability. Physical examination showed numerous fleshcolored and pigmented pedunculated papules, on 789
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Fig 1. Patient 1. Characteristic phenotype and one “skin tag”–like growth in the right infraorbital area.
Fig 3. Patient 1. BCC, follicular type. (Hematoxylin-eosin stain; original magnification ×100.)
Fig 2. Patient 1. “Skin tag”–like growths on the neck and upper back.
the upper chest and back, neck, axillae and left infraorbital area (Figs 1 and 2). She had several palmoplantar pits that were 0.5 to 1 mm in diameter. Her clinical phenotype was striking; she had macrocephaly, frontal bossing, divergent strabismus, broad nasal root, ocular hypertelorism, epicanthal folds, abnormal teeth insertion, and mild prognatism. In addition, she had narrow and slanting outline of the shoulder girdle. Findings of chest, cardiac, and abdominal examinations were unremarkable. Biopsy specimens of several pedunculated papules showed follicular BCC (Fig 3). The patient was scheduled for laser surgery and she had most of the lesions removed. Her primary care physician was advised about the need of further work-up for the patient and to have the other members of the family screened for NBCCS. Her mother has history of a BCC on the nose surgically treated
when she was 42 years old and a jaw cyst when she was very young. The patient has 2 maternal aunts who appear unaffected and a maternal uncle with jaw cysts. The patient’s mother remembers that her mother has had “some jaw cyst problem,” and she died of liver cirrhosis. Case 2 The 8-year-old sister of the patient described in case 1 had several “skin tags” around the neck, palmar pits, and facial characteristics similar to her sister’s features. Case 3 An 8-year-old white girl was referred to the Dermatology Clinic for evaluation of hundreds of skin tags and nevi all over the body (Fig 4). When she was 2 years of age, her pediatrician reported “fine papules in the diaper area”; during the next 6 months “nevi” developed all over her body and continued to increase in number during the next few years. During infancy she had chalazions of both eyes, and an epidermal inclusion cyst was noticed on her left buttock. An umbilical hernia was detected
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Fig 4. Patient 3. Flesh-colored and pigmented pedunculated growths around the neck.
Fig 5. Patient 3. Photomicrograph of biopsy specimen shows BCC, keratotic type. (Hematoxylin-eosin stain; original magnification ×100.)
when she was 9 months old. Her family history was unremarkable. Physical examination showed hundreds of tiny, often pedunculated tan-brown papules all over the body. She had a café au lait macule on the left arm and palmoplantar pits. Her head circumference was greater than the 98th percentile for age. She had epicanthal folds and her inner and outer canthal distances were 3.2 cm (approximately 75th percentile) and 8.7 cm (approximately 90th percentile), respectively. Findings of chest and cardiac examinations were unremarkable. Ultrasound examination of the abdomen did not reveal any abnormality. Radiographic survey of the facial bones, skull, and cervical spine was unremarkable. Panorex radiography of the mandible did not show any cystic lesions. Biopsy specimens of several pedunculated papules revealed pigmented, keratotic, and cystic BCCs (Fig 5). The patient was diagnosed as having NBCCS. The BCCs were treated with carbon dioxide laser and at 3-year follow-up there were only a few small tumors on the skin.
mentation on the periorbital areas, right temple, neck, axillae, left flank, and back. He had hypertelorism and malposition of teeth. There was no palmoplantar pitting. Findings of chest, cardiac, abdominal, genitourinary, and neurologic examinations were unremarkable. A computed tomographic (CT) scan of the head showed a cavum septum pellucidum, and an electroencephalogram had mildly abnormal findings because of background slowing. A skin biopsy specimen of a pedunculated papule on the back showed nodular BCC. Carbon dioxide laser ablation was done for all BCCs.
Case 4 A 14-year-old white boy was referred to the Dermatology Clinic for evaluation of multiple nevi. Some of them had been treated with liquid nitrogen. His medical history was significant for mental retardation, attention deficit disorder, behavioral disorder, and episodes of psychosis. He had surgical correction of strabismus. He was born with 6 toes. His family history was unremarkable. Physical examination showed multiple pedunculated papules, with variable degrees of hyperpig-
Case 5 A 6-year-old white boy, with a family history of NBCCS (father), was referred to the Dermatology Clinic for screening for NBCCS. A few skin tags had been noticed in the past 3 years. His medical history was significant for macrocephaly, hypertelorism, cleft palate, and an extra digit on the left foot. He had developmental delay. A mandible series did not show any odontogenic cysts or other abnormalities. A CT scan of the head showed prominence of the ventricular system and no abnormal calcification. Physical examination showed few slightly brown, pedunculated papules on the back, left axilla, and left ankle. He also had palmar pits. Skin biopsy specimens of all “skin tag”–like growths showed follicular BCC. Case 6 A 5-year-old girl had several asymptomatic growths on the right side of her upper trunk that had been apparent for approximately 3 years. She was born with pulmonary valve stenosis and a large head. A CT scan was done to rule out hydrocephalus
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Table I. Nevoid basal cell carcinoma syndrome: Features and diagnostic criteria8,10,15 Major features
Minor features
Multiple BCCs Palmar and plantar pitting Odontogenic keratocysts Calcification of the falx cerebri
Diagnostic criteria
Developmental and skeletal abnormalities (frontal bossing, macrocephaly, strabismus, cleft palate, bifid ribs, ectopic calcifications) Tumors (medulloblastoma, ovarian fibroma) Mental retardation
At least two major features, or One major feature and an affected firstdegree relative, or Two minor features and an affected firstdegree relative, or Multiple BCCs in childhood
Table II. Summary of findings Age (y) at Patient Age onset of No. (y) skin tags
Histopathologic findings of skin tag
1
11
6
BCC, follicular
2 3
8 8
8 2
4
14
13
5
6
3
BCC, follicular
6
5
2
BCC, follicular
7
5
4
BCC, nodular
BCC, pigmented, keratotic, cystic BCC, nodular
Medical hx/family hx
Congenital hydrocephalus, jaw cysts, strabismus, mental retardation NBCCS in first-degree relative Chalazions, umbilical hernia, epidermal inclusion cyst Mental retardation, behavioral disorder, strabismus, 6 toes Cleft palate, 6 toes, father with NBCCS Pulmonary valve stenosis
Clinical findings
Palmoplantar pits, macrocephaly, frontal bossing, broad nasal root, hypertelorism Palmoplantar pits Palmoplantar pits, macrocephaly Hypertelorism, malposition of teeth Palmar pits, hypertelorism, macrocephaly Macrocephaly, frontal bossing, hypertelorism, broad nasal root Palmoplantar pits, broad forehead, wide nasal root
Years of delay in diagnosis of NBCCS after onset of skin tags
5
Unknown 6 1 3 3 1
hx, History.
and did not reveal any abnormality. Panorex radiography of the mandible did not revealed any jaw cysts. As far as her parents know, there is no family history of similar problems. Physical examination showed numerous pedunculated papules on the face, trunk, axillae, and popliteal areas. There was no palmoplantar pitting. She had macrocephaly, frontal bossing, broad nasal root, hypertelorism, and mild prognatism. A skin biopsy specimen of a papule was consistent with follicular BCC. At the screening of her parents and 3 siblings (7year-old, 21⁄2-year-old, and 5-month-old sisters), there were no findings consistent with NBCCS. Case 7 A 5-year-old white girl had skin growths that were noticed 1 year before presentation to the Dermatology Clinic. Her medical and family histories were not significant. Radiography of the jaw has not been done.
Physical examination showed “skin tag”–like lesions on the neck, trunk, arms and legs, palmoplantar pits, broad forehead, wide nasal root, and low frontal hairline. The skin biopsy specimen of one papule showed nodular BCC.
DISCUSSION NBBCS is an autosomal dominant disorder, with high penetrance (~97%) but markedly variable expression,11 mapped to chromosome 9q22.3-31.1 The responsible gene, the PTCH gene, is a tumor suppressor, and the patients with genetic alteration in this gene have a predisposition not only for multiple BCCs but also for the development of primitive neuroectodermal tumors of the central nervous system3 and other types of tumors. Some cases appear as spontaneous mutations.8 NBCCS may be recognized under different names such as basal cell nevus syndrome, BCC syndrome, multiple basal cell nevi, Gorlin’s syndrome, and Gorlin-Goltz syndrome.12
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The major features of this syndrome occur in more than 75% of reported cases and are listed in Table I.8,13 The minor features of NBCCS are multiple and include developmental and skeletal abnormalities13,14 and frequently have a characteristic phenotype (Table I). Diagnostic criteria implies at least two major features, one major feature and an affected first-degree relative, two minor features and an affected first-degree relative,8,10,15 or multiple BCCs in childhood (Table I). A high index of suspicion is necessary and characteristic facies, together with enlarged calvaria, may lead the clinician to search for NBCCS very early in life, even in the absence of a family history of this syndrome.14 When cysts of the jaws develop, they usually occur after 7 years of age and peak during the second or third decades, when the rate of development of new cysts tends to decrease.2,14,16 Often the cysts are asymptomatic and they are detected on a routine dental examination.14 Other patients with cysts may present with jaw swelling, pain, abnormal taste sensation, or a discharge in the mouth.8 Palmar or plantar pits (or both) may be seen in patients as young as 5 years, but generally develop during the second decade of life and later.2,6,14 The pits may be made more obvious by soaking the hands in water for 15 minutes.8 Calcification of the falx cerebri has been found in 35% of patients older than 14 years9 and peaks during the second to fourth decades.10 In the cases presented, the “skin tags” were present as early as 2 and 3 years of age and therefore could have allowed a very early diagnosis (Table II). The “skin tags” of NBCCS were described by Nomland17 and represent the “nevi” of this syndrome. On biopsy they showed “dark staining basal cells” resulting in the use of the term “nevus of basal cell.”2 These findings suggest that “skin tags” in a child may be a sign leading to early diagnosis and deserve biopsy. Although some of our patients did have some signs of NBCCS, the biopsy findings of the skin tags clearly established the diagnosis before calcification of the falx cerebri or invasive BCC developed. Therefore sun protection and close follow-up should be started at a young age to hopefully prevent future invasive BCC. We thank the participating families and their physicians. We also thank Klaus F. Helm, MD, for his help in photographic work and James B. Howell, MD, for reprints regarding NBCCS. REFERENCES 1. Unden AB, Stahle-Backdahl M, Holmberg E, Larsson C, Toftgard R. The mapping of the locus for nevoid basal cell carcinoma syndrome on chromosome 9q. Acta Derm Venereol 1997;77: 4-9.
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