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Craniofacial hyperostoses in Proteus syndrome – a case report
ARTICLE IN PRESS Journal of Cranio-Maxillofacial Surgery (2004) 32, 391–394 r 2004 European Association for Cranio-Maxillofacial Surgery doi:10.1016/j.jcms.2004.06.007, available online at http://www.sciencedirect.com
Case Report Craniofacial hyperostoses in Proteus syndrome – a case report Nicolai ADOLPHS1, Sigrid TINSCHERT2, Ju¨rgen BIER1, Martin KLEIN1 1
Department for Oral and Maxillofacial Surgery, Surgical Robotics and Navigation (Head: Prof. Dr. mult. h.c. Ju¨rgen Bier); 2Institute for Medical Genetics (Head: Prof. Dr. Stefan Mundlos), University Hospital Charite´, Campus Virchow-Klinikum, Medizinische Fakulta¨t der Humboldt-Universita¨t zu Berlin, Germany
SUMMARY. Objective: Description of a patient with a rare syndrome leading to the partial overgrowth of craniofacial bones. Case report: In a 17-year-old female patient with severe hyperostoses of the craniofacial bones asymmetric overgrowth of the right upper and left lower limbs, linear hyperpigmentation of the right arm and a history of regional lipomatosis were found. These manifestations were suggestive of Proteus syndrome. The management of the craniofacial involvement is described and a literature overview presented. Conclusion: Proteus syndrome is a rare overgrowth syndrome probably related to a somatic mutation that involves craniofacial structures in about 30% of patients. Early diagnosis is required for adequate interdisciplinary treatment. r 2004 European Association for Cranio-Maxillofacial Surgery
Keywords: Partial gigantism; Proteus syndrome; Craniofacial hyperostoses
patient evaluation (Biesecker et al., 1999). In 2002 about 80 patients that met these strict criteria were recorded (Lublin et al., 2002).
INTRODUCTION Proteus syndrome is a rare and highly polymorphic condition characterized by disproportionate and localized overgrowth of various tissues and cell lineages. Characteristic features include partial gigantism of limbs, hyperostoses of craniofacial bones, lipomatosis, epidermal naevi, connective tissue hyperplasia, and vascular malformations. The features demonstrate a mosaic pattern. This syndrome occurs sporadically and has a progressive course. The syndrome was first described in 1979 on two patients with features of a ‘newly recognized hamartomatous syndrome’ not belonging to neurofibromatosis or Klippel–Trenaunay syndrome (Cohen and Hayden, 1979). Independently, Wiedemann et al. (1983) had described four patients in 1983 and named the syndrome after the ancient greek god of the sea, Proteus (the polymorphous) who was able to change his appearance at will. The aetiology of the Proteus syndrome is still unclear. It was hypothesized that a somatic mutation in mosaic form, lethal in the non-mosaic state, would cause the variable phenotypes and the sporadic occurrence (Happle, 1987). The association of Proteus syndrome with germ-line mutations in the PTEN suppressor gene as reported by Zhoue et al. (2001) and Smith et al. (2002) could not be confirmed by others (Barker et al., 2001; Biesecker et al., 2001). In 1998, the First National Conference on Proteus Syndrome in Bethesda, Maryland tried to define diagnostic criteria, differential diagnosis and rules for
CASE REPORT The female patient was born in 1985 after unremarkable pregnancy. Her parents are non-consanguinous and of German descent. A niece of the mother had an operative procedure due to non-syndromic craniosynostosis. Furthermore, no genetic disorders were known in the extended family. Not only after the age of three years was an asymmetry of her body noted. The most severely affected regions were her right craniofacial skeleton and her right lower extremity. Initially, enlargement of these regions was discrete but it increased markedly during the preadolescent period and adolescence. Later there was less progression. At the age of 9 years, otopexy was performed, during which a biopsy of the skull was taken. Histological findings showed normal bony tissue. At the age of 15 years, the patient had liposuction of her right hip. Since that time there has been a relapse of fatty tissue overgrowth. Her right ovary is known to have a cystic lesion, which is being closely monitored since ovarian cysts often occur bilaterally in patients with Proteus syndrome (Kousseff, 1986; Bouzas et al., 1993; Gordon et al., 1995, Gilbert-Barness et al., 2000) and bilateral involvement is suggestive of cystadenocarcinomas. 391
ARTICLE IN PRESS 392 Journal of Cranio-Maxillofacial Surgery
On examination at age 17 the patients height was 177 cm. There was a difference of 7 cm in length between the right and the left legs. The difference between the circumferences of right and left thigh was 9 cm, and was 3 cm between the circumferences of the right and left calves. Her right shoes have to be one size larger. A pigmented epidermal naevus was present on her right arm. The craniofacial skeleton showed severe signs of partial bony hyperplasia. The enlargement of the bony structures was predominantely situated on the right side (Fig. 1). Massive hyperostotic formations were found along the full length of the parietal suture reaching as far as the right mastoid region. Frontal, temporal and parietal bones of the right side as well as the greater wing of the right sphenoid, right zygoma, right maxilla and right mandible were enlarged in comparison with the structures on the left side. Severe hyperostotic lesions were present in regions of sutures and fontanels. Such lesions were situated near the anterior and posterior fontanels, left coronary suture, metopic suture, right lambdoid suture as well as occipital protuberance. As a consequence of this enlargement, there was a shift of the bony midline to the left, and the bipupillary line sloped up slightly to the right. The occlusal plane was tilted down to the right due to enlargement of the right zygoma and local hyperostosis of the alveolar crest of the right maxilla. The patient had Fig. 2 – 17 year old girl; preoperative stereolithography model of the skull.
a compensated Angel’s class I occlusion following orthodontic treatment. The atlas bone showed enlargement of the right arch. Conventional radiographs of the skull taken at the age of 6, already showed changes in the regions described above. However, remarkable progression occurred later. She requested surgery to reduce the visible bossing of her frontal region and to the shape her skull. A routine preoperative work-up was performed. In addition to conventional CT-scans, 3-D-reconstructions were also performed and a stereolithograph model was fabricated for pre-operative planning (Fig. 2). Corrective osteotomies were performed on hyperostotic lesions of the right frontal bone and the right orbit using a bicoronal approach without complications. Histological investigation of the bony material removed showed hyperplastic bone with regular structure. As a second procedure, corrective osteotomy of the right zygoma was discussed with the patient but has not yet been performed. The patient is currently content with the result. She is followed up regularly and shows no signs of recurrence (Fig. 3).
DISCUSSION Fig. 1 – 17 year old girl; preoperative photography demonstrating ‘frontal bossing’ and right zygomatic hyperplasia.
The diagnosis of Proteus syndrome in this patient is in accordence with the rather strict criteria of
ARTICLE IN PRESS Craniofacial hyperostoses 393
increases with age. Therefore, early corrective procedures help to improve normal development and improve quality of life (Vaughn et al., 1993; GilbertBarness et al., 2000). Simple corrective procedures might be performed in early life. Major osteotomies for the correction of dysgnathia should be performed after completion of skeletal growth and might be repeated in order to stabilize the symmetrical appearance of the craniofacial skeleton (Pinto et al., 1998; Becktor et al., 2002).
CONCLUSIONS Proteus syndrome is characterized by disproportionate overgrowth, epidermal naevi and lipomatosis. In 30% of the patients, hyperostoses of the craniofacial skeleton are present. Adequate treatment of this rare syndrome requires early diagnosis and an interdisciplinary approach. References
Fig. 3 – 17 year old girl; postoperative photography after surgical removal of frontal hyperostoses (6 months postop.).
Biesecker et al. (1999). Our patient showed disproportionate overgrowth (right upper and lower limbs, and skull) epidermal naevus, and lipomatosis. Craniofacial hyperostosis is seen in patients with Proteus syndrome in about 30% of cases (Stricker et al., 1992). However, only a few reports have been found in the literature with a comparably severe manifestation (Vaughn et al., 1993; Tattelbaum and Dufresne, 1995; Pinto et al., 1998; Gilbert-Barness et al., 2000; Becktor et al., 2002). The time of onset of hyperostosis is known to be variable but most of the manifestations occur during the first year of life (Tattelbaum and Dufresne, 1995). The tissue overgrowth in Proteus syndrome is progressive in nature. In the patient reported here, the overgrowth appeared to stabilize after adolescence (Cohen, 1993; Becktor et al., 2002). There is no specific treatment for Proteus syndrome, the therapy should be symptomatic and interdisciplinary. (Biesecker, 2001). Lesions of the genital glands may require more aggressive treatment due to the high incidence of neoplasia (Lublin et al., 2002). In the craniofacial area, reduction procedures of soft and hard tissues are mainly indicated due to the typical overgrowth. As this syndrome is progressive in character, the craniofacial distortion typically
Barker K, Martinez A, Wang R, Bevan S, Murday V, Shipley J, Houlston R, Harper J: PTEN mutations are uncommon in Proteus syndrome. J Med Genet 38: 480–481, 2001 Becktor KB, Becktor JP, Karnes PS, Keller EE: Craniofacial and dental manifestations of Proteus syndrome: a case report. Cleft Palate Craniofac J 39: 233–245, 2002 Biesecker LG: The multifaceted challenges of Proteus syndrome. J Am Med Assoc 285: 2240–2243, 2001 Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham Jr, JM, Viljoen DL, Cohen Jr, MM: Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84: 389–395, 1999 Bouzas EA, Krasnewich D, Koutroumanidis M, Papadimitriou A, Marini JC, Kaiser-Kupfer MI: Ophthalmologic examination in the diagnosis of Proteus syndrome. Ophthalmology 100: 334–338, 1993 Cohen Jr, MM: Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Am J Med Genet 47: 645–652, 1993 Cohen Jr, MM, Hayden PW: A newly recognized hamartomatous syndrome. Birth Defects Orig Artic Ser 15: 291–296, 1979 Gilbert-Barness E, Cohen Jr, MM, Opitz JM: Multiple meningiomas, craniofacial hyperostosis and retinal abnormalities in Proteus syndrome. Am J Med Genet 93: 234–240, 2000 Gordon PL, Wilroy RS, Lasater OE, Cohen Jr, MM: Neoplasms in Proteus syndrome. Am J Med Genet 57: 74–78, 1995 Happle R: Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol 16: 899–906, 1987 Kousseff BG: Pleiotropy versus heterogeneity in Proteus syndrome. Pediatrics 78: 544–546, 1986 Lublin M, Schwartzentruber DJ, Lukish J, Chester C, Biesecker LG, Newman KD: Principles for the surgical management of patients with Proteus syndrome and patients with overgrowth not meeting Proteus criteria. J Pediatr Surg 37: 1013–1020, 2002 Pinto PX, Beale V, Paterson AW: Proteus syndrome. A case report of a hamartomatous syndrome with severe mandibular hemihypertrophy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85: 82–85, 1998 Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ: Germline mutation of the tumour suppressor PTEN in Proteus syndrome. J Med Genet 39: 937–940, 2002
ARTICLE IN PRESS 394 Journal of Cranio-Maxillofacial Surgery Stricker S: Musculoskeletal manifestations of Proteus syndrome: report of two cases with literature review. J Pediatr Orthop 12: 667–674, 1992 Tattelbaum AG, Dufresne CR: Proteus syndrome: A newly recognised hamartomatous syndrome with significant craniofacial dysmorphology. J Craniofac Surg 6: 151–160, 1995 Vaughn RY, Selinger AD, Howell CG, Parish RA, Edgerton MT: Proteus syndrome: diagnosis and surgical management. J Pediatr Surg 28: 5–10, 1993 Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E: The Proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 140: 5–12, 1983 Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM: Eng C. Association of germline mutation in the
PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 358: 210–211, 2001 Dr. med. Dr. med. dent. Nicolai ADOLPHS Department for Oral and Maxillofacial Surgery Surgical Robotics and Navigation University Hospital Charite´ Campus Virchow-Klinikum Augustenburger Platz 1 D-13353 Berlin Germany Tel.: +4930-450555022 Fax: +4930-450555901. E-mail: [email protected] Paper received 28 July 2003 Accepted 24 June 2004
Case Report Craniofacial hyperostoses in Proteus syndrome – a case report Nicolai ADOLPHS1, Sigrid TINSCHERT2, Ju¨rgen BIER1, Martin KLEIN1 1
Department for Oral and Maxillofacial Surgery, Surgical Robotics and Navigation (Head: Prof. Dr. mult. h.c. Ju¨rgen Bier); 2Institute for Medical Genetics (Head: Prof. Dr. Stefan Mundlos), University Hospital Charite´, Campus Virchow-Klinikum, Medizinische Fakulta¨t der Humboldt-Universita¨t zu Berlin, Germany
SUMMARY. Objective: Description of a patient with a rare syndrome leading to the partial overgrowth of craniofacial bones. Case report: In a 17-year-old female patient with severe hyperostoses of the craniofacial bones asymmetric overgrowth of the right upper and left lower limbs, linear hyperpigmentation of the right arm and a history of regional lipomatosis were found. These manifestations were suggestive of Proteus syndrome. The management of the craniofacial involvement is described and a literature overview presented. Conclusion: Proteus syndrome is a rare overgrowth syndrome probably related to a somatic mutation that involves craniofacial structures in about 30% of patients. Early diagnosis is required for adequate interdisciplinary treatment. r 2004 European Association for Cranio-Maxillofacial Surgery
Keywords: Partial gigantism; Proteus syndrome; Craniofacial hyperostoses
patient evaluation (Biesecker et al., 1999). In 2002 about 80 patients that met these strict criteria were recorded (Lublin et al., 2002).
INTRODUCTION Proteus syndrome is a rare and highly polymorphic condition characterized by disproportionate and localized overgrowth of various tissues and cell lineages. Characteristic features include partial gigantism of limbs, hyperostoses of craniofacial bones, lipomatosis, epidermal naevi, connective tissue hyperplasia, and vascular malformations. The features demonstrate a mosaic pattern. This syndrome occurs sporadically and has a progressive course. The syndrome was first described in 1979 on two patients with features of a ‘newly recognized hamartomatous syndrome’ not belonging to neurofibromatosis or Klippel–Trenaunay syndrome (Cohen and Hayden, 1979). Independently, Wiedemann et al. (1983) had described four patients in 1983 and named the syndrome after the ancient greek god of the sea, Proteus (the polymorphous) who was able to change his appearance at will. The aetiology of the Proteus syndrome is still unclear. It was hypothesized that a somatic mutation in mosaic form, lethal in the non-mosaic state, would cause the variable phenotypes and the sporadic occurrence (Happle, 1987). The association of Proteus syndrome with germ-line mutations in the PTEN suppressor gene as reported by Zhoue et al. (2001) and Smith et al. (2002) could not be confirmed by others (Barker et al., 2001; Biesecker et al., 2001). In 1998, the First National Conference on Proteus Syndrome in Bethesda, Maryland tried to define diagnostic criteria, differential diagnosis and rules for
CASE REPORT The female patient was born in 1985 after unremarkable pregnancy. Her parents are non-consanguinous and of German descent. A niece of the mother had an operative procedure due to non-syndromic craniosynostosis. Furthermore, no genetic disorders were known in the extended family. Not only after the age of three years was an asymmetry of her body noted. The most severely affected regions were her right craniofacial skeleton and her right lower extremity. Initially, enlargement of these regions was discrete but it increased markedly during the preadolescent period and adolescence. Later there was less progression. At the age of 9 years, otopexy was performed, during which a biopsy of the skull was taken. Histological findings showed normal bony tissue. At the age of 15 years, the patient had liposuction of her right hip. Since that time there has been a relapse of fatty tissue overgrowth. Her right ovary is known to have a cystic lesion, which is being closely monitored since ovarian cysts often occur bilaterally in patients with Proteus syndrome (Kousseff, 1986; Bouzas et al., 1993; Gordon et al., 1995, Gilbert-Barness et al., 2000) and bilateral involvement is suggestive of cystadenocarcinomas. 391
ARTICLE IN PRESS 392 Journal of Cranio-Maxillofacial Surgery
On examination at age 17 the patients height was 177 cm. There was a difference of 7 cm in length between the right and the left legs. The difference between the circumferences of right and left thigh was 9 cm, and was 3 cm between the circumferences of the right and left calves. Her right shoes have to be one size larger. A pigmented epidermal naevus was present on her right arm. The craniofacial skeleton showed severe signs of partial bony hyperplasia. The enlargement of the bony structures was predominantely situated on the right side (Fig. 1). Massive hyperostotic formations were found along the full length of the parietal suture reaching as far as the right mastoid region. Frontal, temporal and parietal bones of the right side as well as the greater wing of the right sphenoid, right zygoma, right maxilla and right mandible were enlarged in comparison with the structures on the left side. Severe hyperostotic lesions were present in regions of sutures and fontanels. Such lesions were situated near the anterior and posterior fontanels, left coronary suture, metopic suture, right lambdoid suture as well as occipital protuberance. As a consequence of this enlargement, there was a shift of the bony midline to the left, and the bipupillary line sloped up slightly to the right. The occlusal plane was tilted down to the right due to enlargement of the right zygoma and local hyperostosis of the alveolar crest of the right maxilla. The patient had Fig. 2 – 17 year old girl; preoperative stereolithography model of the skull.
a compensated Angel’s class I occlusion following orthodontic treatment. The atlas bone showed enlargement of the right arch. Conventional radiographs of the skull taken at the age of 6, already showed changes in the regions described above. However, remarkable progression occurred later. She requested surgery to reduce the visible bossing of her frontal region and to the shape her skull. A routine preoperative work-up was performed. In addition to conventional CT-scans, 3-D-reconstructions were also performed and a stereolithograph model was fabricated for pre-operative planning (Fig. 2). Corrective osteotomies were performed on hyperostotic lesions of the right frontal bone and the right orbit using a bicoronal approach without complications. Histological investigation of the bony material removed showed hyperplastic bone with regular structure. As a second procedure, corrective osteotomy of the right zygoma was discussed with the patient but has not yet been performed. The patient is currently content with the result. She is followed up regularly and shows no signs of recurrence (Fig. 3).
DISCUSSION Fig. 1 – 17 year old girl; preoperative photography demonstrating ‘frontal bossing’ and right zygomatic hyperplasia.
The diagnosis of Proteus syndrome in this patient is in accordence with the rather strict criteria of
ARTICLE IN PRESS Craniofacial hyperostoses 393
increases with age. Therefore, early corrective procedures help to improve normal development and improve quality of life (Vaughn et al., 1993; GilbertBarness et al., 2000). Simple corrective procedures might be performed in early life. Major osteotomies for the correction of dysgnathia should be performed after completion of skeletal growth and might be repeated in order to stabilize the symmetrical appearance of the craniofacial skeleton (Pinto et al., 1998; Becktor et al., 2002).
CONCLUSIONS Proteus syndrome is characterized by disproportionate overgrowth, epidermal naevi and lipomatosis. In 30% of the patients, hyperostoses of the craniofacial skeleton are present. Adequate treatment of this rare syndrome requires early diagnosis and an interdisciplinary approach. References
Fig. 3 – 17 year old girl; postoperative photography after surgical removal of frontal hyperostoses (6 months postop.).
Biesecker et al. (1999). Our patient showed disproportionate overgrowth (right upper and lower limbs, and skull) epidermal naevus, and lipomatosis. Craniofacial hyperostosis is seen in patients with Proteus syndrome in about 30% of cases (Stricker et al., 1992). However, only a few reports have been found in the literature with a comparably severe manifestation (Vaughn et al., 1993; Tattelbaum and Dufresne, 1995; Pinto et al., 1998; Gilbert-Barness et al., 2000; Becktor et al., 2002). The time of onset of hyperostosis is known to be variable but most of the manifestations occur during the first year of life (Tattelbaum and Dufresne, 1995). The tissue overgrowth in Proteus syndrome is progressive in nature. In the patient reported here, the overgrowth appeared to stabilize after adolescence (Cohen, 1993; Becktor et al., 2002). There is no specific treatment for Proteus syndrome, the therapy should be symptomatic and interdisciplinary. (Biesecker, 2001). Lesions of the genital glands may require more aggressive treatment due to the high incidence of neoplasia (Lublin et al., 2002). In the craniofacial area, reduction procedures of soft and hard tissues are mainly indicated due to the typical overgrowth. As this syndrome is progressive in character, the craniofacial distortion typically
Barker K, Martinez A, Wang R, Bevan S, Murday V, Shipley J, Houlston R, Harper J: PTEN mutations are uncommon in Proteus syndrome. J Med Genet 38: 480–481, 2001 Becktor KB, Becktor JP, Karnes PS, Keller EE: Craniofacial and dental manifestations of Proteus syndrome: a case report. Cleft Palate Craniofac J 39: 233–245, 2002 Biesecker LG: The multifaceted challenges of Proteus syndrome. J Am Med Assoc 285: 2240–2243, 2001 Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham Jr, JM, Viljoen DL, Cohen Jr, MM: Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 84: 389–395, 1999 Bouzas EA, Krasnewich D, Koutroumanidis M, Papadimitriou A, Marini JC, Kaiser-Kupfer MI: Ophthalmologic examination in the diagnosis of Proteus syndrome. Ophthalmology 100: 334–338, 1993 Cohen Jr, MM: Proteus syndrome: clinical evidence for somatic mosaicism and selective review. Am J Med Genet 47: 645–652, 1993 Cohen Jr, MM, Hayden PW: A newly recognized hamartomatous syndrome. Birth Defects Orig Artic Ser 15: 291–296, 1979 Gilbert-Barness E, Cohen Jr, MM, Opitz JM: Multiple meningiomas, craniofacial hyperostosis and retinal abnormalities in Proteus syndrome. Am J Med Genet 93: 234–240, 2000 Gordon PL, Wilroy RS, Lasater OE, Cohen Jr, MM: Neoplasms in Proteus syndrome. Am J Med Genet 57: 74–78, 1995 Happle R: Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin. J Am Acad Dermatol 16: 899–906, 1987 Kousseff BG: Pleiotropy versus heterogeneity in Proteus syndrome. Pediatrics 78: 544–546, 1986 Lublin M, Schwartzentruber DJ, Lukish J, Chester C, Biesecker LG, Newman KD: Principles for the surgical management of patients with Proteus syndrome and patients with overgrowth not meeting Proteus criteria. J Pediatr Surg 37: 1013–1020, 2002 Pinto PX, Beale V, Paterson AW: Proteus syndrome. A case report of a hamartomatous syndrome with severe mandibular hemihypertrophy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 85: 82–85, 1998 Smith JM, Kirk EP, Theodosopoulos G, Marshall GM, Walker J, Rogers M, Field M, Brereton JJ, Marsh DJ: Germline mutation of the tumour suppressor PTEN in Proteus syndrome. J Med Genet 39: 937–940, 2002
ARTICLE IN PRESS 394 Journal of Cranio-Maxillofacial Surgery Stricker S: Musculoskeletal manifestations of Proteus syndrome: report of two cases with literature review. J Pediatr Orthop 12: 667–674, 1992 Tattelbaum AG, Dufresne CR: Proteus syndrome: A newly recognised hamartomatous syndrome with significant craniofacial dysmorphology. J Craniofac Surg 6: 151–160, 1995 Vaughn RY, Selinger AD, Howell CG, Parish RA, Edgerton MT: Proteus syndrome: diagnosis and surgical management. J Pediatr Surg 28: 5–10, 1993 Wiedemann HR, Burgio GR, Aldenhoff P, Kunze J, Kaufmann HJ, Schirg E: The Proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 140: 5–12, 1983 Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM: Eng C. Association of germline mutation in the
PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 358: 210–211, 2001 Dr. med. Dr. med. dent. Nicolai ADOLPHS Department for Oral and Maxillofacial Surgery Surgical Robotics and Navigation University Hospital Charite´ Campus Virchow-Klinikum Augustenburger Platz 1 D-13353 Berlin Germany Tel.: +4930-450555022 Fax: +4930-450555901. E-mail: [email protected] Paper received 28 July 2003 Accepted 24 June 2004