two-year-old boy with proteus syndrome and fatal pulmonary thromboembolism
TRANSCRIPT
TWO-YEAR-OLD BOY WITH PROTEUS SYNDROME AND FATAL PULMONARY THROMBOEMBOLISM
David A. Eberhard, MD, PhD Health Sciences Center, Charlottesville, Virginia, USA
Department of Pathology, University of Virginia
A 2-year-old boy with a relatively mild form of Proteus syndrome (PS) died suddenly during a previously uncomplicated postsurgical convalescence. Autopsy demonstrated massive acute pulmo naly embolism, which has not been previously reported in PS. In addition, clinically occult mesodermal hamartomata, predominantly hernolymphangiomata, were found to be widespread in the pelvoabdominal viscera, including spleen, appendix, kidnqrs, adrenal gland, liver, and retro- peritoneal so) tissues. Such lesions may well be common in PS patients but may not be detected by conventional radiographic imaging techniques unless t h q are fairly large.
Keywords P r o h s syndrome, nngiodysplastic syndrome, anpoma, pulmonaly embolism, pathol- ogy, autopsy
The Proteus syndrome (PS) , defined by Wiedemann et al. in 1983 [ 1 1, is a rare sporadic hamartomatous dysplasia with a wide range of phenotypic expression. PS is characterized by the progressive development in infancy and childhood of skeletal and soft tissue overgrowth resulting in regional hyper- trophy or gigantism and hamartomatous masses composed of fatty, fibrous, and vascular (i.e., mixed mesodermal) elements. The involved areas may be localized or extensive, including skin, soft tissues, and bone of extremities, head, and trunk. Major clinical features include hemihypertrophy, macro- dactyly, subcutaneous masses, plantar or palmar masses (often with a rugated cerebriform or “moccasin skin” appearance), macrocephaly or exostoses of the skull, epidermal nevi, and scoliosis. The differential diagnoses include enchondromatoses (Maffucci’s syndrome and Ollier’s dyschondroplasia) , neurofibromatosis, Bannayan syndrome, and Klippel-Trenaunay syndrome. Distinction of localized forms of PS from the latter may be difficult, but prominent tumorous masses, marked plantar or palmar thickening with rugae, macrocephaly, and exostoses are not typical of Klippel-Trenaunay
Received 21January 1994; accepted 10 March 1994. The author thanks Dr. K. Teja for helpful discussions. Address correspondence to David A. Eberhard, Department of Pathology, Box 214, Univcrsity of
Virginia Health Sciences Center, Charlottesville, Virginia 22908.
Pediatric Pathology, 14:771-779, I994 Copyright 0 I994 Taylor &Francis 0277-0938/94 $10.00 + .00 771
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112 D. A. EBERHARD
syndrome. Detailed summaries of clinical findings in PS and its differentia- tion from related syndromes have been presented [ 2-71.
Deep intra-axial lesions have been demonstrated by imaging techniques in several cases [e.g., 1,5, 61, but the incidence and extent ofvisceral organ involvement are unclear because few of the recognized cases have come to autopsy. Serious primary anomalies incompatible with life at least through adolescence are exceptional in PS; however, some patients have died pre- maturely from complications of their condition. Three deaths due to pulmo- nary disease resulting from thoracic cage deformities have been reported [2, 7,8], and brain abscess [7], postsurgical laryngospasm [7], congenital heart disease [9], and severe seizure disorder [ 101 have accounted for death in one patient each. Herein is described a 2-year-old Caucasian boy with a relatively mild form of PS who died suddenly during a previously uncomplicated postsurgical convalescence. Autopsy demonstrated massive pulmonary em- bolism and revealed clinically unsuspected mesodermal hamartomata involv- ing several internal organs.
CLINICAL HISTORY
In infancy, the patient developed progressive asymmetric bilateral hyper- trophy and macrodactyly of the lower extremities with the left side more severely affected, angiomatous subcutaneous masses and skin lesions involv- ing the lower extremities and face, and macrocephaly. Parents were non- consanguineous, and gestational history was unremarkable with no known maternal illness or exposures. No other known relatives were affected. Bio- metric parameters at age 8 months were weight 8.3 kg (30th percentile), height (crown-heel) 70 cm (35th percentile), and head circumference 46 cm (75th percentile); at age 15 months, weight 10.1 kg (25th percentile), height 79 cm (45th percentile), and head circumference 49 cm (80th percentile). Proteus syndrome was diagnosed by our Divisions of Medical Genetics and Plastic and Maxillofacial Surgery. The clinical findings have been summa- rized elsewhere (patient 8 ofVaughn et al. [4]).
A series of debulking and reconstructive procedures were performed, including resection of large lymphangiomata involving left thigh, lower leg, and foot, foreshortening and metatarsal reconstruction of the left foot, and excision of a bleeding lymphangioma from the left upper eyelid (age 8 months); further resection of left lower extremity lymphangiomata (age 9 % ) months) ; partial resection of lymphangiomata involving the left lower extremity from hip to foot, excision of cystic lymphatic tumors involving the right great toe and pretibial region, and electrodessication of cutaneous lymphangioma on the left lower leg (age 15 months) ; excision of right plantar lipomatosis, amputation of all macrodactylic toes except for the right great
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toe, partial excision of left lower extremity hemolymphangiomata, and exci- sion of a lymphangioma from the left cheek (age 20 months). He was last admitted at age 22 months with a diagnosis of lymphangiomatosis involving both lower extremities, with recurrent bleeding and secondary chronic anemia. Debulking of the left foot and right thigh was performed without complication. The postoperative course was uneventful, and he was dis- charged 4 days after surgery. While leaving the hospital, he suffered sudden cardiopulmonaryarrest and could not be resuscitated. Permission for autopsy excluded examination of the brain.
The surgical pathology specimens all contained cutaneous or subcutane- ous lymphangiomata or hemolymphangiomata intimately admixed, in vari- able proportions, with abundant proliferations of mature fibrous and adipose tissue.
AUTOPSY FINDINGS
External Examination
The lower extremities (Figure 1) displayed asymmetric hypertrophy, left greater than right, and extensive subcutaneous lymphangiomata. Cutaneous hemolymphangiomata, resembling “port wine” hemangiomata but darker in color [4], were present on the lateral aspects of both lower extremities. Macrodactyly of the one remaining digit resulted from bone and soft tissue hypertrophy rather than tumorous growths. The plantar aspects were mark- edly thickened and slightly rugated. A modest decrease in overall soft tissue mass was appreciated in the trunk and upper extremities. Scoliosis was not apparent. Facial features were unremarkable.
Visceral Examination
The cause of death was massive acute pulmonary embolism, with multiple thromboemboli occluding both left and right main pulmonary arteries and first-order branches. Otherwise, the lungs appeared normal. The source of the thromboemboli was probably the pelvis or lower extremities. Multiple large venous thrombi were found in the bladder serosa. Thrombi were not present in the pelvic segments of the iliac veins; more distal portions were not examined. No thrombi were found in the heart, which was structurally normal.
The vasculature of the pelvic floor was diffusely ectatic and congested. Small (up to 2-3 cm) cystic lymphangiomata and cavernous hemolymph- angiomata were scattered throughout the soft tissues of the pelvis and
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774 D. A. EBERHARD
Figure 1. Lower extremities at autopsy. (A) Left side; (B) right side.
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retroperitoneum, extending superiorly nearly to the diaphragm. Within the scrota1 sac, a hemorrhagic cyst ( 1 cm) associated with a thrombosed, necrotic vein was located external to the tunica albuginea of the right testicle. Micro- scopic lymphangiomata occupied the soft tissues around the cyst.
Gross abnormalities of the visceral organs were noted in the spleen and appendix. The spleen (weight 100 g) displayed striking hemolymph- angiomatosis with numerous cysts that contained blood, amber fluid, or colloid (Figure 2A). Other lymphoid organs-thymus and lymph nodes- were without abnormality. Attached to the appendix was a large thin-walled cyst containing serous fluid (Figure 2B). Microscopic examination revealed serosal and intramuscular lymphangioma and infiltration of the muscularis and submucosa by adipocytes (Figure 2C).
Histologic examination revealed microscopic angiomatosis of other or- gans that were normal in size and gross appearance. Both kidneys contained cavernous hemolymphangiomata within the connective tissue of the renal pelves, with extension of abnormal vessels into the parenchyma (Figure 2D). The medulla of one adrenal gland contained a small cavernous hemangioma. A random section of liver demonstrated small groups of simple vessels in periportal areas. Additional findings included an adrenal rest of the left testis and increased bone marrow cellularity consistent with the history of second- ary chronic anemia.
DISCUSSION
Pulmonary thromboembolism is an unusual postsurgical complication in pediatric patients, but the presence of large congenital vascular lesions may increase the risk of developing thromboemboli. Phlebitis and thrombosis occur rather commonly in congenital angiodysplasias such as Klippel-Tren- aunay syndrome [ 11, 121, and fatal pulmonary embolism has been reported in two patients with the syndrome [13, 141. Fatal pulmonary embolism has also occurred in an infant with a large congenital hemangioma of the knee [ 151. In Proteus syndrome, one patient suffered probable thrombophlebitis involving a thigh tumor [6], but pulmonary thromboembolism has not been reported until now.
The present case represented a form of PS that was fairly localized on clinical examination, with the typical growth abnormalities, cutaneous le- sions, and soft tissue tumors limited to the lower extremities and head. However, autopsy revealed widespread angiomatosis of pelvic, retroperito- neal, and intra-abdominal tissues. The gross lesions appeared as small cysts and vascular malformations but did not form sizable masses except for a rather large simple para-appendiceal cyst. The fibrovascular proliferations extended into the parenchyma of several organs including spleen, appendix,
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Figure 2. Visceral hamartomata. (A) Cross section of spleen demonstrates numerous hemangiomata and cystic lymphangiomata. (B) Appendix with parata-appendiceal cyst.
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AUTOPSY FINDINGS IN PROTEUS SYNDROME 777
Figure 2. Visceral hamartoma ( Conlznued). ( C ) Cross section of appendix demonstrates serosal lyniph- angioma (I2) and submucosal aggregates of adipocytes (arrowheads). Original magnification, ~ 6 0 . (D) Cavernous hemangioma (CH) involving renal pelvis and adjacent kidney parenchyma ( K ) . Original magnification, ~ 6 0 , reproduced at 77%.
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kidneys, adrenal gland, and liver; the appendix contained an infiltrative adipose component as well. Visceral abnormalities were noted as a possible major feature of PS by Wiedemann et al. [ 13, but intra-axial lesions demon- strated in most subsequent radiologic studies have been limited to the soft tissues without clear evidence of organ involvement. Only three unlimited autopsy examinations of PS patients have been previously described. One patient died of bronchopneumonia and was found to have cerebral poly- microgyria and heterotopias, submucosal vascular malformations in the colon, rectum, and urinary bladder, a renal cavernous hemangioma, and a cystiform lung lesion [ 71. Another patient died after suffering restrictive lung disease and pneumonitis [8] ; autopsy revealed multiple cavernous hem- angiomas in subcutaneous tissues, stomach, spleen, and spermatic cord, and a mixed mesenchymal-bronchial hamartoma of the lung. The third patient died at age 4% years of pneumonia and ventilatory failure secondary to massive rib overgrowth, but the only stated autopsy finding was inequality in the sizes of the two histologically normal kidneys [ 23. Thus, three of four reported full autopsies (including the present case) revealed mesenchymal hamartomata, particularly angiomata, in multiple organs. Similar lesions have been described in patients subjected to surgical exploration because of hemorrhage, torsion, or possible malignancy, including bladder angioma and colorectal angiomatosis [ 5 ] , mesenteric lipomatosis [8], spermatic cord lymphangioma [6], and serous ovarian cysts [ 5 ] . It seems likely that visceral hamartomata in PS are common but may be often asymptomatic and may not be detected by routine body computed tomography and magnetic resonance imaging unless fairly large masses are present.
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