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Proteus syndrome
Proteus syndrome A case report of a hamartomatous syndrome with severe mandibular hemihypertrophy Pascal X. Pinto, MDS, FDS, a Victoria Beale, FDS, a and Anthony W. Paterson, FDS, FRCS, b London, United Kingdom ROYAL LONDON HOSPITAL Proteus syndrome is a rare congenital hamartomatous malformation that is characterized by a wide range of deformities, including craniofacial deformities. Skin and skeletal developmental malformations are common and may assume tremendous proportions. The syndrome is often mistaken for other, more commonly recognized conditions, including neurofibromatosis. The softtissue masses in Proteus syndrome are not nerve tumors but are usually hamartomatous proliferations. The case report describes its varied manifestations, which include significant craniofacial dysmorphism, and discusses the differential diagnosis and management. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:82-5)
Proteus syndrome (PS) is a complex hamartomatous syndrome. Its features are partial gigantism and asymmetry of the limbs, plantar hyperplasia, hemangiomas, lipomas, lymphangiomas, varicosities, verrucous epidermal nevi, macrocephaly, cranial hyperostosis, and long bone overgrowth. W i e d e m a n n et al. 1 first proposed the term Proteus syndrome, which is a reference to the ancient Greek god Proteus the Polymorphous, and they called the condition to the attention of pediatricians. Although evidence of the syndrome has been cited in the medical literature since 1907, recognition has been difficult because of the variability of the syndrome's manifestations and because of its rarity. Joseph Merrick, famous as the "Elephant Man," is now known to have had PS and not neurofibromatosis. 2,3 We present a case with multiple skeletal and skin abnormalities that included a craniofacial deformity originally labelled plexiform neurofibromatosis. Unlike those in previously reported cases, 2,4,5 the soft tissue lesions in this case were not lipomatous but collagenous hamartomas.
CASE REPORT A 42-year-old woman appeared for treatment with a history of multiple skin and skeletal abnormalities that had begun during infancy and were thought to be due to neurofibromatosis. She had been born of unrelated parents with no history of congenital disorders. Previous surgeries included a hysterectomy that had shown multiple sessile, intramural, and subserosal polyps; the removal of an exostosis and cholesteatoma from the right external auditory meatus; the excision of extensive hamartomatous lesions from the feet; aSenior House Officer, Department of Oral and Maxillofacial Surgery, Carlisle Hospitals NHS Trust. bConsultant, Department of Oral and Maxillofacial Surgery, Carlisle Hospitals NHS Trust. Received for publication Aug. 10, 1996; returned for revision Nov. 7, 1996; accepted for publication Aug. 27, 1997. Copyright © 1998 by Mosby, Inc. 1079-2104/98/$5.00 + 0 7/14/85780 82
and a right tibial osteotomy, Upper thoracic laminectomies had been performed for spinal canal stenosis and for an upper thoracic myelopathy secondary to spinal deformity. Examination of the head and neck revealed a marked facial asymmetry (Fig. 1, A) There was significant right hemimandibular hyperplasia resulting in prognathism, deviation of the chin point to the left side, and a markedly increased right lower facial height. The right oral commisure was lower than the left. The maxilla showed a slight compensatory asymmetry that resulted in an occlusal cant of about 10 degrees to the horizontal. There was a mild open bite in the fight buccal segment. Intraoral examination showed an osteoma of the left mandibular alveolus. The lower dental midline deviated to the left. Radiographs revealed severe right condylax hyperplasia with a large increase in the vertical height of the ramus and body of the mandible on that side (Fig. 2). The posterior facial height was nearly 4 cm greater on the right than on the left. The radiograph indicated that the facial asymmetry was entirely due to hemimandibular hypertrophy with no soft-tissue, neural, or dental involvement. Skeletal deformities included macrodactyly of several fingers (Fig. 1, B), marked dorsal scoliosis to the right, and a bony swelling over the occiput. There was a faint hemangiomatous lesion on the right trunk. There were no neurofibromata, cafe-au-lait spots, or axillary freckles. Skin lesions showed plaque-like patches of thickened, fissured skin over the soles of the feet (Fig. 1, C) and the dorsum of the hands. Microscopic examination of these cerebriform hyperplastic lesions revealed no irregular masses or tumors within nerves, but a proliferation of dense fibrous connective tissue was observed in the subcutaneous region. The appearance was suggestive of a collagenous hamartoma similar to connective tissue nevi. There was no evidence of neurofibroma in the sections (Fig. 3).
DISCUSSION PS has been characterized as an overgrowth syndrome because o f the fact that hyperplasias, hamartomas, and neoplasias are features of the disorder. The clinical manifestations are extensive and involve significant craniofacial d y s m o r p h i s m . 6 There have been
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 85, Number 1
Pinto, Beale, and Paterson 83
Fig. 1. Features of PS in 46-year-old female patient. A, Severe right mandibular hemihypertrophy and deviation of lower face. B, Macrodactyly of right third finger and left index finger. C, Plaque-like patches of thickened, fissured skin over soles of feet.
approximately 70 patients diagnosed with the disorder and recorded in the medical literature. There has been no family history in most cases, and the syndrome is thought to be due to the action of a dominant lethal gene surviving by mosaicism. 7,8 Diagnosis of the condition has been complicated by the presence of dysplasia involving all three germ layers. To simplify recognition, Vaughn et al. 4 have suggested that the two essential features of the syndrome are regional gigantism and lymphangiomatous hamartomas. However, a review of the literature, including those presented by Vaughn et al.,
Fig. 2. Orthopantomograph shows mandibular hemihypertrophy of right side and contrasts it with the normal left side. The grotesque hyperplasia of the mandible does not allow it to fall within the focal trough of the orthopantogram.
84 Pinto, Beale, and Paterson
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
January 1998
Fig. 3. Photomicrographs show proliferation of dense fibrous connective tissue similar to connective tissue nevi in the subcutaneous region. This is covered by epidermis showing hyperkeratosis and a prominent grannular layer, but no appendages. A, Hematoxylin-eosin, original magnification xl00. B, Comparative photomicrograph; hematoxylin-eosin, original magnification x30.
has shown that lymphangiomatous hamartomas need not be present in all cases. In a summary of 37 cases, Tattlebaum and Dufresne 6 concluded that the individual clinical features of hemihypertrophy, macrodactyly, subcutaneous tumors, plantar or palmar masses, exostoses, epidermal nevi, and scoliosis were noted in more than one half of patients with PS. Plantar or (less commonly) palmar cerebriform hyperplasia is highly characteristic of PS; some authors 9 feel that it is pathognomic. In about one third of the cases reported, facial anomalies occurred; these included malformed ears, high-arched palates, malocclusions, mandibular prognathism, and depressed nasal bridges. The skull in about one half of the cases displayed macrocephaly or frontal bossing. Exostoses may be found involving the cranium, nasal bones, external auditory meatus, and alveolar ridges) ° Enamel hypoplasia and gingival hyperplasia have been reported. 5,11 The craniofacial appearance becomes more bizarre with age, 4 as was the case with the patient we treated. Two different modes of abnormal bone growth were responsible for the craniofacial malformations: focal overgrowth of membrane bones, which produced the exostoses; and overgrowth of condylar cartilage, which resulted in severe dentofacial deformity.9 Differentiating PS from other congenital hamartomas is difficult. As described in the case report,, the patient had earlier been thought to have plexiform neurofibromatosis. The presence of hemihypertrophy and soft-tissue tumors suggested an initial diagnosis of neurofibromatosis. The biopsies of the lesions were consistent with collagenous hamartomas--an unusual finding, because these subcutaneous tumors are ordinarily composed primarily of lipomatous tissue. 11 Although
expressivity is variable, the presence of multiple cafeau-lait macules, axillary freckling, Lisch nodules, neurofibromas, and a family history of the condition help to distinguish neurofibromatosis from PS. 4 BannayanZona syndrome has some of the features of PS, but it lacks many of the distinctive skeletal changes. Endochondromatosis (Ollier's disease and Maffucci's syndrome) may mimic PS clinically, but the former is marked by endochondromas and retardation of long bone growth. 4,5 Klippel-Trenauney-Weber syndrome, epidermal nevus syndrome, and linear sebaceous nevus syndrome are less easily distinguishable from PS and are thought to represent a phenotypic continuum. These syndromes have several overlapping phenotypic features and may have a common pathogenic process. In the literature, few deaths have been attributed to PS, but the long-term prognosis for an individual with the condition is still uncertain. Onset is variable, but most of the manifestations occur during the first year of life. As the affected child ages, the abnormalities tend to progress, and multiple early surgical procedures are required to minimize the secondary deformity. Psychological counseling and a multidiscipilinary team approach are necessary, with the older patient collaborating in the surgical management. With PS, the importance of early diagnosis must be emphasized. Only when this unusual syndrome is diagnosed early can subsequent manifestations be recognized readily and treatment begun promptly. Because the condition is polymorphous and its expression is variable, important single observations may either go unpublished or be ascribed to other conditions. The authors thank Dr. S. Mallett, Consultant Dermatologist at Peterborough District Hospital, and Janis Corrigan, Senior,
Pinto, Beale, and Paterson 85
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Volume 85, Number 1 Medical Photographer at Carslisle Hospitals NHS Trust, for their help in preparing this article.
REFERENCES 1. Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. The Proteus syndrome. Eur J Pediatr 1983;140:512. 2. Burgio GR, Weidemann HR. Further and new details on the Proteus syndrome. Eur J Pediatr 1984;143:71-3. 3. Tibbles JAR, Cohen MM Jr. Proteus syndrome: the elephant man diagnosed. Br Med J 1986;293:683-5. 4. Vaughn RY, Selinger AD, Howell CG, Parrish RA, Edgerton MT. Proteus Syndrome: diagnosis and surgical management. J Pediatr Surg 1993;28:5-10. 5. Barmakian JT, Posner MA, Silver L, Lehman W, Vine DT. Proteus syndrome. J Hand Surg [Am] 1992;17:32-4. 6. Tattlebaum G, Dufresne CR. Proteus syndrome: a newly recognized hamartomatous syndrome with significant craniofacial dysmorphology. J Craniomaxillofac Surg 1995;6:151-60.
7. Lacombe D, Taieb A, Vergnes R Sarlangue J, Chateil JF, Bucco R et al. Proteus Syndrome in 7 patients: clinical and genetic considerations. Genet Couns 1991;2:93-101. 8. Viljoen DL, Saxe N, Temple-Camp C. Cutaneous manifestations of the Proteus syndrome. Pediatr Dermatol 1988;5:14-21. 9. Kreiborg S, Cohen MM Jr, Skowby E Craniofacial characteristics of Proteus syndrome: two modes of abnormal growth. Proceedings of the Finnish Dental Society 1991 ;87:183-8. L0. Mason C, Roberts G. Unusual distribution of enamel hypoplasia in an 11-year-old child with Proteus syndrome. International Journal of Paediatric Dentistry 1995;5:103-7. 11. Arendorf TM, Hanslo B. Proteus syndrome: association with gingival hyperplasia. J Oral Pathol Med 1995;24:383-4.
Reprint requests: R X. Pinto, MDS, FDS Department of Oral and Maxillofacial Surgery Royal London Hospital Whitechapel, London E1 1BB UK
Proteus syndrome (PS) is a complex hamartomatous syndrome. Its features are partial gigantism and asymmetry of the limbs, plantar hyperplasia, hemangiomas, lipomas, lymphangiomas, varicosities, verrucous epidermal nevi, macrocephaly, cranial hyperostosis, and long bone overgrowth. W i e d e m a n n et al. 1 first proposed the term Proteus syndrome, which is a reference to the ancient Greek god Proteus the Polymorphous, and they called the condition to the attention of pediatricians. Although evidence of the syndrome has been cited in the medical literature since 1907, recognition has been difficult because of the variability of the syndrome's manifestations and because of its rarity. Joseph Merrick, famous as the "Elephant Man," is now known to have had PS and not neurofibromatosis. 2,3 We present a case with multiple skeletal and skin abnormalities that included a craniofacial deformity originally labelled plexiform neurofibromatosis. Unlike those in previously reported cases, 2,4,5 the soft tissue lesions in this case were not lipomatous but collagenous hamartomas.
CASE REPORT A 42-year-old woman appeared for treatment with a history of multiple skin and skeletal abnormalities that had begun during infancy and were thought to be due to neurofibromatosis. She had been born of unrelated parents with no history of congenital disorders. Previous surgeries included a hysterectomy that had shown multiple sessile, intramural, and subserosal polyps; the removal of an exostosis and cholesteatoma from the right external auditory meatus; the excision of extensive hamartomatous lesions from the feet; aSenior House Officer, Department of Oral and Maxillofacial Surgery, Carlisle Hospitals NHS Trust. bConsultant, Department of Oral and Maxillofacial Surgery, Carlisle Hospitals NHS Trust. Received for publication Aug. 10, 1996; returned for revision Nov. 7, 1996; accepted for publication Aug. 27, 1997. Copyright © 1998 by Mosby, Inc. 1079-2104/98/$5.00 + 0 7/14/85780 82
and a right tibial osteotomy, Upper thoracic laminectomies had been performed for spinal canal stenosis and for an upper thoracic myelopathy secondary to spinal deformity. Examination of the head and neck revealed a marked facial asymmetry (Fig. 1, A) There was significant right hemimandibular hyperplasia resulting in prognathism, deviation of the chin point to the left side, and a markedly increased right lower facial height. The right oral commisure was lower than the left. The maxilla showed a slight compensatory asymmetry that resulted in an occlusal cant of about 10 degrees to the horizontal. There was a mild open bite in the fight buccal segment. Intraoral examination showed an osteoma of the left mandibular alveolus. The lower dental midline deviated to the left. Radiographs revealed severe right condylax hyperplasia with a large increase in the vertical height of the ramus and body of the mandible on that side (Fig. 2). The posterior facial height was nearly 4 cm greater on the right than on the left. The radiograph indicated that the facial asymmetry was entirely due to hemimandibular hypertrophy with no soft-tissue, neural, or dental involvement. Skeletal deformities included macrodactyly of several fingers (Fig. 1, B), marked dorsal scoliosis to the right, and a bony swelling over the occiput. There was a faint hemangiomatous lesion on the right trunk. There were no neurofibromata, cafe-au-lait spots, or axillary freckles. Skin lesions showed plaque-like patches of thickened, fissured skin over the soles of the feet (Fig. 1, C) and the dorsum of the hands. Microscopic examination of these cerebriform hyperplastic lesions revealed no irregular masses or tumors within nerves, but a proliferation of dense fibrous connective tissue was observed in the subcutaneous region. The appearance was suggestive of a collagenous hamartoma similar to connective tissue nevi. There was no evidence of neurofibroma in the sections (Fig. 3).
DISCUSSION PS has been characterized as an overgrowth syndrome because o f the fact that hyperplasias, hamartomas, and neoplasias are features of the disorder. The clinical manifestations are extensive and involve significant craniofacial d y s m o r p h i s m . 6 There have been
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY Volume 85, Number 1
Pinto, Beale, and Paterson 83
Fig. 1. Features of PS in 46-year-old female patient. A, Severe right mandibular hemihypertrophy and deviation of lower face. B, Macrodactyly of right third finger and left index finger. C, Plaque-like patches of thickened, fissured skin over soles of feet.
approximately 70 patients diagnosed with the disorder and recorded in the medical literature. There has been no family history in most cases, and the syndrome is thought to be due to the action of a dominant lethal gene surviving by mosaicism. 7,8 Diagnosis of the condition has been complicated by the presence of dysplasia involving all three germ layers. To simplify recognition, Vaughn et al. 4 have suggested that the two essential features of the syndrome are regional gigantism and lymphangiomatous hamartomas. However, a review of the literature, including those presented by Vaughn et al.,
Fig. 2. Orthopantomograph shows mandibular hemihypertrophy of right side and contrasts it with the normal left side. The grotesque hyperplasia of the mandible does not allow it to fall within the focal trough of the orthopantogram.
84 Pinto, Beale, and Paterson
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
January 1998
Fig. 3. Photomicrographs show proliferation of dense fibrous connective tissue similar to connective tissue nevi in the subcutaneous region. This is covered by epidermis showing hyperkeratosis and a prominent grannular layer, but no appendages. A, Hematoxylin-eosin, original magnification xl00. B, Comparative photomicrograph; hematoxylin-eosin, original magnification x30.
has shown that lymphangiomatous hamartomas need not be present in all cases. In a summary of 37 cases, Tattlebaum and Dufresne 6 concluded that the individual clinical features of hemihypertrophy, macrodactyly, subcutaneous tumors, plantar or palmar masses, exostoses, epidermal nevi, and scoliosis were noted in more than one half of patients with PS. Plantar or (less commonly) palmar cerebriform hyperplasia is highly characteristic of PS; some authors 9 feel that it is pathognomic. In about one third of the cases reported, facial anomalies occurred; these included malformed ears, high-arched palates, malocclusions, mandibular prognathism, and depressed nasal bridges. The skull in about one half of the cases displayed macrocephaly or frontal bossing. Exostoses may be found involving the cranium, nasal bones, external auditory meatus, and alveolar ridges) ° Enamel hypoplasia and gingival hyperplasia have been reported. 5,11 The craniofacial appearance becomes more bizarre with age, 4 as was the case with the patient we treated. Two different modes of abnormal bone growth were responsible for the craniofacial malformations: focal overgrowth of membrane bones, which produced the exostoses; and overgrowth of condylar cartilage, which resulted in severe dentofacial deformity.9 Differentiating PS from other congenital hamartomas is difficult. As described in the case report,, the patient had earlier been thought to have plexiform neurofibromatosis. The presence of hemihypertrophy and soft-tissue tumors suggested an initial diagnosis of neurofibromatosis. The biopsies of the lesions were consistent with collagenous hamartomas--an unusual finding, because these subcutaneous tumors are ordinarily composed primarily of lipomatous tissue. 11 Although
expressivity is variable, the presence of multiple cafeau-lait macules, axillary freckling, Lisch nodules, neurofibromas, and a family history of the condition help to distinguish neurofibromatosis from PS. 4 BannayanZona syndrome has some of the features of PS, but it lacks many of the distinctive skeletal changes. Endochondromatosis (Ollier's disease and Maffucci's syndrome) may mimic PS clinically, but the former is marked by endochondromas and retardation of long bone growth. 4,5 Klippel-Trenauney-Weber syndrome, epidermal nevus syndrome, and linear sebaceous nevus syndrome are less easily distinguishable from PS and are thought to represent a phenotypic continuum. These syndromes have several overlapping phenotypic features and may have a common pathogenic process. In the literature, few deaths have been attributed to PS, but the long-term prognosis for an individual with the condition is still uncertain. Onset is variable, but most of the manifestations occur during the first year of life. As the affected child ages, the abnormalities tend to progress, and multiple early surgical procedures are required to minimize the secondary deformity. Psychological counseling and a multidiscipilinary team approach are necessary, with the older patient collaborating in the surgical management. With PS, the importance of early diagnosis must be emphasized. Only when this unusual syndrome is diagnosed early can subsequent manifestations be recognized readily and treatment begun promptly. Because the condition is polymorphous and its expression is variable, important single observations may either go unpublished or be ascribed to other conditions. The authors thank Dr. S. Mallett, Consultant Dermatologist at Peterborough District Hospital, and Janis Corrigan, Senior,
Pinto, Beale, and Paterson 85
ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY
Volume 85, Number 1 Medical Photographer at Carslisle Hospitals NHS Trust, for their help in preparing this article.
REFERENCES 1. Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E. The Proteus syndrome. Eur J Pediatr 1983;140:512. 2. Burgio GR, Weidemann HR. Further and new details on the Proteus syndrome. Eur J Pediatr 1984;143:71-3. 3. Tibbles JAR, Cohen MM Jr. Proteus syndrome: the elephant man diagnosed. Br Med J 1986;293:683-5. 4. Vaughn RY, Selinger AD, Howell CG, Parrish RA, Edgerton MT. Proteus Syndrome: diagnosis and surgical management. J Pediatr Surg 1993;28:5-10. 5. Barmakian JT, Posner MA, Silver L, Lehman W, Vine DT. Proteus syndrome. J Hand Surg [Am] 1992;17:32-4. 6. Tattlebaum G, Dufresne CR. Proteus syndrome: a newly recognized hamartomatous syndrome with significant craniofacial dysmorphology. J Craniomaxillofac Surg 1995;6:151-60.
7. Lacombe D, Taieb A, Vergnes R Sarlangue J, Chateil JF, Bucco R et al. Proteus Syndrome in 7 patients: clinical and genetic considerations. Genet Couns 1991;2:93-101. 8. Viljoen DL, Saxe N, Temple-Camp C. Cutaneous manifestations of the Proteus syndrome. Pediatr Dermatol 1988;5:14-21. 9. Kreiborg S, Cohen MM Jr, Skowby E Craniofacial characteristics of Proteus syndrome: two modes of abnormal growth. Proceedings of the Finnish Dental Society 1991 ;87:183-8. L0. Mason C, Roberts G. Unusual distribution of enamel hypoplasia in an 11-year-old child with Proteus syndrome. International Journal of Paediatric Dentistry 1995;5:103-7. 11. Arendorf TM, Hanslo B. Proteus syndrome: association with gingival hyperplasia. J Oral Pathol Med 1995;24:383-4.
Reprint requests: R X. Pinto, MDS, FDS Department of Oral and Maxillofacial Surgery Royal London Hospital Whitechapel, London E1 1BB UK