American Journal of M e d i c a l Genetics 35:283-285 (1990)
Brief Clinical Report Proteus Syndrome: Course of a Severe Case Ariadne Malamitsi-Puchner, Dimitris Dimitriadis, Christos Bartsocas, and H.-R. Wiedemann Department of Neonatology, General Hospital “Alexandra” (A.M.-P.), Orthopedic Department, “Penteli” Children’s Hospital (D.D.), First Pediatric Departnzent, “P. and A. Kyriakou” Children’s Hospital (C.B.), Athens, Greece; Pediatric Uniwrsity Clinic of Kiel, Kiel. Federal Republic of Germany CH.-R.W.I
We report on the course of a 4l/z-year-old boy with Proteus syndrome who was first described 3 years ago. Details are given on the phenotypic changes, the complications of corrective surgery o n tissue overgrowth, and the development of a mesothelioma of the tunica vaginalis of the testis.
KEY WORDS: gigantism, hemihypertrophy, growth factors, mesothelioma INTRODUCTION The Proteus syndrome is a disorder of unknown cause characterized by hemihypertrophy, gigantism and deformities of hands and feet, hyperostoses, subcutaneous hamartomatous tumours, and skin lesions such as hyperpigmented streaks. Hemihypertrophy, as well as finger deformities, often lead to orthopedic surgery. We report on the complications of tissue overgrowth following surgery, as well as on the development of a malignancy of the testis in a child of @/a years with a severe form of the syndrome, described earlier. CLINICAL REPORT After our previous report [Malamitsi-Puchner et al., 19871the patient, M.T., demonstrated an extreme development of the hyperostoses on the skull, hemihypertrophy of the right side, clinodactyly of fingers and toes, and lipolymphangiomas on the trunk and the right thigh (Fig. 1).At the age of 3 years his right tonsil was removed as it occluded his airway. At the same age his right leg exceeded his left by 7.5 cm. The valgus femoral necks created hip subluxation on both sides, although more advanced on the right leg. The 3 middle fingers of both hands were gigantic and presented deviation (ulnar of the second and radial of the third and fourth) associated with considerable stiffness at the interphalangeal joints. The right knee had a valgus deformity and there was onset of mild scoliosis. At age 39 months the boy underwent a subtrochanteric osteotomy Received for publication July 3, 1989; revision received August 2, 1989. Address reprint requests t o Ariadne Malamitsi-Fuchner, Department of Neonatology, General Hospital “Alexandra,” K.Lourou-Street 1, Athens, Greece.
0 1990 Wiley-Liss, Inc.
of the right femur. An osseous piece of 3 cm was removed from the femoral shaft and a varus angulation of 35”was performed. The texture of the bone at the intertrochanteric region was extremely soft making the fixation of the proximal fragment tenuous. However, histological examination of the bone specimen and of the surrounding soft tissues showed no detectible abnormalities. The patient showed little progress in leg function after the operation with the aid of physiotherapy. Six months later his right tibia had a growth spurt demonstrating, in the scanogram, a length difference of 6 cm compared to the left tibia. It is worth mentioning that the preoperative difference was 3.5 cm. The shortened femur overgrew again by 1.5 cm, so that the total length difference was again 7.5 cm as before the operation. Radiographs of the right knee joint showed an increase of thejoint space of about 1.75 cm compared to the opposite side being 0.5 cm. There was also a spotty deposition of calcium in the hypertrophic right knee joint. At age 4 years his left leg was shorter with femur and tibia length corresponding to that of a 2-year-old according to the Anderson tables. The skull demonstrated an overgrowth of the right half with enlargement of the frontal bone anterior to the frontal sinus. The right temporal bone as well as the left parietal bone are also involved with many extuberances. The right external ear canal became completely closed by bone overgrowth. The gigantic fingers have grown even more, and despite diligent and careful splinting by the parents, clinodactyly progresses further. Lipolymphangiomas increased in size and number under the left nipple: in both axillae, on the right lateral abdominal area and on the right thigh. The left testicle presented a tumorous hypertrophy, firm on palpation, accompanied by a hydrocele. Acute pain and consideration of a possible malignancy led the 51-month-old child to surgery. The left testicle was removed as well as 2 intraabdominal cysts containing approximately 100 ml odorless greenish fluid. The histological examination showed a highly differentiated papillary mesothelioma of the tunica vaginalis of the testis (Fig. 2-4). The testis showed atrophy and disorganization of the tubuli due to marked fibrosis. The a-fetoprotein level was not elevated. M.T.’smental maturation is advancing slowly, but his ambulation is still very limited. Attempts are made at mobility through a specially designed “bouncer.” He is attending a special school with satisfactory results.
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Fig. 2. Normal testicular tissue on the left and mesothelioma on the right. H + E. x 120.
Fig. 1. Patient M. T., 4% years old. Asymmetry of the skull, hyperostosis of the right ear canal, gigantic fingers and clinodactyly, soft tissue tumors, hypertrophy of the right and atrophy of the left leg, gigantic toes on right foot.
DISCUSSION The progressive changes of our patient’s clinical findings signifies the presence of a severe form of the Proteus syndrome. We would like to concentrate Our comments on 2 areas: a) the overgrowth of tissues after a surgical operation and b) the development of a malignancy. Viljoen et al. [19871 mentioned that surgical removal of lymphatic, fatty, or hemangiomatous elements involving deeper structures, is difficult and results in formation of unsightly scars and keloids. Azouz et al. [19871 reported recurrence of genu valgum deformity after surgery in 2 children. Our patient demonstrated extreme deformities and limb and tissue overgrowth after surgery. One can speculate that localized growth factors such as epidermal or nervous growth factors, are excessively triggered by surgical interventions. It is worth mentioning that the histology of the resected bone in the cases of Azouz et al. [19871 as well as in our case, was normal. We wish also to note that the opposite limb is “atrophic” as compared to normal development. Although the syndrome is characterized as a hamartoneoplastic disorder and authors refer to the possibility of malignant development [Tibbles and Cohen, 1986; ViIjoen et a1-9 19871 our patient Seems to be the first in the literature with a confirmed malignancy. The ap-
Fig, 3. Papillary and tubular morphology of the neoplasm. H
+ E.
x 120.
Fig. 4. Papillaryprocessofthetumorwithpsammomabodies. H ~120.
+ E.
Proteus Syndrome pearance of the neoplasm (mesothelioma) a t such a n early age could be due to the very early and severe manifestations of the syndrome. There is actually no symptom known in the F’roteus syndrome which was not present in our patient. Prognosis is poor as the development of another malignancy cannot be excluded. Finally, we should report a n observation that growth spurt, generalized as well a s localized (fingers, leg and thigh bones, etc), occurred during spring and a t a lesser rate in the fall.
285
REFERENCES Arrow EM, Costa T, Fitch N (1987): Radiologic findings in the Proteus syndrome. Pediatr Radio1 17:481-485. Malamitsi-Puchner A, Kitsiou S, Bartsocas CS (1987): Brief clinical report: Severe Proteus syndrome in an 18-month-oldboy. Am J Med Genet 27:119-125. Tibbles JAR, Cohen MM, Jr (1986): The Proteus syndrome: The Elephant Man diagnosed. Br Med J 293583-685. Viljoen DL, Nelson MM, de Jong G, Beighton P (1987): Proteus syndrome in South Africa: Natural history and clinical manifestations in six individuals. Am J Med Genet 27:87-97.
Brief Clinical Report Proteus Syndrome: Course of a Severe Case Ariadne Malamitsi-Puchner, Dimitris Dimitriadis, Christos Bartsocas, and H.-R. Wiedemann Department of Neonatology, General Hospital “Alexandra” (A.M.-P.), Orthopedic Department, “Penteli” Children’s Hospital (D.D.), First Pediatric Departnzent, “P. and A. Kyriakou” Children’s Hospital (C.B.), Athens, Greece; Pediatric Uniwrsity Clinic of Kiel, Kiel. Federal Republic of Germany CH.-R.W.I
We report on the course of a 4l/z-year-old boy with Proteus syndrome who was first described 3 years ago. Details are given on the phenotypic changes, the complications of corrective surgery o n tissue overgrowth, and the development of a mesothelioma of the tunica vaginalis of the testis.
KEY WORDS: gigantism, hemihypertrophy, growth factors, mesothelioma INTRODUCTION The Proteus syndrome is a disorder of unknown cause characterized by hemihypertrophy, gigantism and deformities of hands and feet, hyperostoses, subcutaneous hamartomatous tumours, and skin lesions such as hyperpigmented streaks. Hemihypertrophy, as well as finger deformities, often lead to orthopedic surgery. We report on the complications of tissue overgrowth following surgery, as well as on the development of a malignancy of the testis in a child of @/a years with a severe form of the syndrome, described earlier. CLINICAL REPORT After our previous report [Malamitsi-Puchner et al., 19871the patient, M.T., demonstrated an extreme development of the hyperostoses on the skull, hemihypertrophy of the right side, clinodactyly of fingers and toes, and lipolymphangiomas on the trunk and the right thigh (Fig. 1).At the age of 3 years his right tonsil was removed as it occluded his airway. At the same age his right leg exceeded his left by 7.5 cm. The valgus femoral necks created hip subluxation on both sides, although more advanced on the right leg. The 3 middle fingers of both hands were gigantic and presented deviation (ulnar of the second and radial of the third and fourth) associated with considerable stiffness at the interphalangeal joints. The right knee had a valgus deformity and there was onset of mild scoliosis. At age 39 months the boy underwent a subtrochanteric osteotomy Received for publication July 3, 1989; revision received August 2, 1989. Address reprint requests t o Ariadne Malamitsi-Fuchner, Department of Neonatology, General Hospital “Alexandra,” K.Lourou-Street 1, Athens, Greece.
0 1990 Wiley-Liss, Inc.
of the right femur. An osseous piece of 3 cm was removed from the femoral shaft and a varus angulation of 35”was performed. The texture of the bone at the intertrochanteric region was extremely soft making the fixation of the proximal fragment tenuous. However, histological examination of the bone specimen and of the surrounding soft tissues showed no detectible abnormalities. The patient showed little progress in leg function after the operation with the aid of physiotherapy. Six months later his right tibia had a growth spurt demonstrating, in the scanogram, a length difference of 6 cm compared to the left tibia. It is worth mentioning that the preoperative difference was 3.5 cm. The shortened femur overgrew again by 1.5 cm, so that the total length difference was again 7.5 cm as before the operation. Radiographs of the right knee joint showed an increase of thejoint space of about 1.75 cm compared to the opposite side being 0.5 cm. There was also a spotty deposition of calcium in the hypertrophic right knee joint. At age 4 years his left leg was shorter with femur and tibia length corresponding to that of a 2-year-old according to the Anderson tables. The skull demonstrated an overgrowth of the right half with enlargement of the frontal bone anterior to the frontal sinus. The right temporal bone as well as the left parietal bone are also involved with many extuberances. The right external ear canal became completely closed by bone overgrowth. The gigantic fingers have grown even more, and despite diligent and careful splinting by the parents, clinodactyly progresses further. Lipolymphangiomas increased in size and number under the left nipple: in both axillae, on the right lateral abdominal area and on the right thigh. The left testicle presented a tumorous hypertrophy, firm on palpation, accompanied by a hydrocele. Acute pain and consideration of a possible malignancy led the 51-month-old child to surgery. The left testicle was removed as well as 2 intraabdominal cysts containing approximately 100 ml odorless greenish fluid. The histological examination showed a highly differentiated papillary mesothelioma of the tunica vaginalis of the testis (Fig. 2-4). The testis showed atrophy and disorganization of the tubuli due to marked fibrosis. The a-fetoprotein level was not elevated. M.T.’smental maturation is advancing slowly, but his ambulation is still very limited. Attempts are made at mobility through a specially designed “bouncer.” He is attending a special school with satisfactory results.
284
Malamitsi-Puchner e t al.
Fig. 2. Normal testicular tissue on the left and mesothelioma on the right. H + E. x 120.
Fig. 1. Patient M. T., 4% years old. Asymmetry of the skull, hyperostosis of the right ear canal, gigantic fingers and clinodactyly, soft tissue tumors, hypertrophy of the right and atrophy of the left leg, gigantic toes on right foot.
DISCUSSION The progressive changes of our patient’s clinical findings signifies the presence of a severe form of the Proteus syndrome. We would like to concentrate Our comments on 2 areas: a) the overgrowth of tissues after a surgical operation and b) the development of a malignancy. Viljoen et al. [19871 mentioned that surgical removal of lymphatic, fatty, or hemangiomatous elements involving deeper structures, is difficult and results in formation of unsightly scars and keloids. Azouz et al. [19871 reported recurrence of genu valgum deformity after surgery in 2 children. Our patient demonstrated extreme deformities and limb and tissue overgrowth after surgery. One can speculate that localized growth factors such as epidermal or nervous growth factors, are excessively triggered by surgical interventions. It is worth mentioning that the histology of the resected bone in the cases of Azouz et al. [19871 as well as in our case, was normal. We wish also to note that the opposite limb is “atrophic” as compared to normal development. Although the syndrome is characterized as a hamartoneoplastic disorder and authors refer to the possibility of malignant development [Tibbles and Cohen, 1986; ViIjoen et a1-9 19871 our patient Seems to be the first in the literature with a confirmed malignancy. The ap-
Fig, 3. Papillary and tubular morphology of the neoplasm. H
+ E.
x 120.
Fig. 4. Papillaryprocessofthetumorwithpsammomabodies. H ~120.
+ E.
Proteus Syndrome pearance of the neoplasm (mesothelioma) a t such a n early age could be due to the very early and severe manifestations of the syndrome. There is actually no symptom known in the F’roteus syndrome which was not present in our patient. Prognosis is poor as the development of another malignancy cannot be excluded. Finally, we should report a n observation that growth spurt, generalized as well a s localized (fingers, leg and thigh bones, etc), occurred during spring and a t a lesser rate in the fall.
285
REFERENCES Arrow EM, Costa T, Fitch N (1987): Radiologic findings in the Proteus syndrome. Pediatr Radio1 17:481-485. Malamitsi-Puchner A, Kitsiou S, Bartsocas CS (1987): Brief clinical report: Severe Proteus syndrome in an 18-month-oldboy. Am J Med Genet 27:119-125. Tibbles JAR, Cohen MM, Jr (1986): The Proteus syndrome: The Elephant Man diagnosed. Br Med J 293583-685. Viljoen DL, Nelson MM, de Jong G, Beighton P (1987): Proteus syndrome in South Africa: Natural history and clinical manifestations in six individuals. Am J Med Genet 27:87-97.
