2001-02-16-10 Proteus syndrome © Sleurs www.thefetus.net/
Submitted by Elke Sleurs, MD*&, Luc De Catte, MD*
*Vrije Universiteit Brussel and &Women’s Health Alliance, Nashville TN
Definition: a disorder which consist of skeletal, hamartomatous and other mesodermal malformations, characterized by asymmetrical focal overgrowth, subcutaneous tumors, hemihypertrophy. The manifestations are highly variable and features may be present at birth but become more apparent with time1.
Etymology: from the Greek god PrwteuV (=Proteus, the polymorphous, thus the word “protean”). Proteus was considered either the son of Poseidon (the god of the sea), or his assistant. He was the guardian of the seals. Proteus knew the past, present, and future. Of course many would come to ask him about it, and he did not like to prophesize so he would hide. In order to hear him the visitor had to sneak on him during the nap he took with his seals on the island K?rpathos in the south-east Aegean sea. When caught he would metamorphose into all sorts of monsters and wild beasts. If the visitor was not discouraged, he would return to his normal appearance and tell the answer.
Prevalence: rare2; diagnosis is usually made later in life, only a few cases of in utero diagnosis of Proteus syndrome are reported1,2,3.
Etiology: Unknown, possible somatic mosaicisme4.
Recurrence risk: sporadic4
Sonographic findings: limbs enlargement with large, cystic spaces in the soft tissue; overgrowth (may involve the whole body or may be localized in a limb or even a digit), focal lymphangiomata or hemangiomata; macrocephaly5.
A 20-year-old primigravida was referred at the ultrasound department at 34 weeks of gestational age for an unspecified fetal mass. Her past surgical and obstetrical histories were uneventful. Before and during pregnancy the patient had been using soft drugs (Marijuana).
The sonogram demonstrated multiple subcutaneous cystic structures of shoulders and thorax; abnormal position of the arms; dilatation of the jugular vein and an asymmetrical heart (right ventricle > left ventricle).
There are 3 video clips of the shoulder (1.1 MB) and the chest (0.9 MB) which demonstrate the findings better then the images below. There is also a combined clip that is more complete (but adds no further findings) and is 5.8 MB
The first set of images are the shoulder of the baby (the other side presents similar findings)
The normal brain of the baby (the image was not obtained to demonstrate the brain, thus the oblique cut, but there is no brain alterations of size or morpholgy).
The chest of the baby:
The patient underwent a caesarean section at 36 weeks of gestation. She delivered a boy of 3310 grams and 46 centimeters. The baby suffered from extensive congenital lymphangioma of the thorax and upper limbs.
The newborn underwent 3 surgical resections and left the neonatal unit after 6 weeks. The baby was readmitted 3 weeks later for a fourth surgical resection of a lymphangioma at the right shoulder. The intervention was uneventful. But he developed a fistula at the scar from a previous excision in the left axilla with a quick recurrence of the lymph – hemangiomas, necessitating another surgical intervention. Due to infiltration into the larynx the tumor could only be resected partially. The first day after surgery the baby developed a septicemia and died of septic shock.
Autopsy demonstrated the presence of multiple, extended lymphangiomas and hemangiomas of the limbs, the thorax, the neck, the mediastinum and the pleura. There was also macrodactyly. The autopsy revealed a bilateral bronchopneumonia with septic embolisms and signs of shock in several organs.
Diagnostic criteria: Recommendations for diagnostic criteria were developed by the participants of a workshop held in March 1998 at the National Institute of Health6. The criteria were differentiated between “general criteria” and “specific criteria”. General criteria (mandatory) are:
- mosaic distribution of lesions,
- progressive course and
- sporadic occurrence.
Connective tissue nevi are a major specific criterion. There presence is almost pathognomonic for Proteus syndrome but is not mandatory. Epidermal nevi found in Proteus syndrome are soft, flat and non-organoid.
The table below lists the “specific criteria”. In order to make the diagnosis of Proteus syndrome, the patient must have all 3 general criteria + a specific number of “specific criteria”. This is either one of category one, 2 of category 2 or 3 of category 3 in the table below.
Connective tissue nevus (F)
1. Epidermal nevus (F)
2. Disproportional overgrowth (one or more) of:
- Limbs: arms, legs, hands, feet, digits (F)
- Skull (F)
- External auditory meatus (R)
- Vertebrae: megaspondylodysplasia (F)
- Viscera: spleen, thymus (R)
3. Specific tumors before end of second decade (either one)
- Ovarian cystadenomas (R)
- Parotid monomorphic adenoma (R)
Any 2 of these criteria
1. Abnormal adipose tissue (either one)
- Lipomas (F)
- Regional absence of fat (F)
2. Vascular malformations (one or more)
- Capillary malformation (F)
- Venous malformation (F)
- Lymphatic malformation (F)
3. Facial phenotype (R)
- Long face
- Minor downslanting of palpebral fissures and/or minor ptosis
- Low nasal bridge
- Wide or anteverted nares
- Open mouth at rest
Any 3 of these criteria
F = frequent; R = rare
Adapted from Biesecker et al. Am J Med Gen 1999;84:398-95.
Associated anomalies are:
- ocular manifestations: most commonly strabismus and epibulbar tumors, cystic lesions but also nystagmus, retinal pigmentary abnormalities, chronic papill edema, and optic atrophy7,8,9
- (moderate) mental deficiency (20%); renal involvement with deteriorating renal function has been described10 as there is also a case report of a 9-month-old girl with Proteus syndrome and nephrogenic diabetes insipidus11.
Two disorders most commonly confused with Proteus syndrome are Klippel - Trenaunay - Weber syndrome and hemihyperplasia syndrome6. Post-natal evaluation is essential in order to distinguish these conditions despite prenatal diagnosis:
Klippel-Trenaunay-Weber syndrome: association of large cutaneous hemangiomata with hypertrophy of the related bones and soft tissues, due to capillary malformations, atypical varicosities, and venous malformations, resulting in gigantism of the affected limb or part of the body (localized masses); most commonly found on the legs, buttocks and lower trunk; probably due to a single gene defect4,12,13
Hemihyperplasia syndrome: characterized by multiple lipomas. Cutaneous capillary malformation may occur, but there is no progressive overgrowth6
Parkes-Weber syndrome: vascular malformations involving upper and lower limbs characterized by a capillary blush, warmth and underlying arteriovenous shunt6
Amniotic band syndrome: localized cranial, body wall or limb defects due to an amniotic disruption complex.
Lymphangiomata: abnormalities of the lymphatic vessels characterized by cysts within soft tissues usually in the nuchal region
Mafucci syndrome: characterized by multiple enchondromata and venous vascular malformations, which can occur anywhere but most commonly in the hands; long bone involvement is common and leads to progressive skeletal deformity and pathological fractures; chondrosarcomata occur in 30% of the cases4,14.
Neurofibromatosis: characterized particularly by café-au-lait spots and fibromatous tumors of the skin; the disease is caused by mutations in the NF1 gene, 20% of cases are new mutations; inheritance is autosomal dominant4
Bannayan-Riley syndrome: characterized by macrocephaly, lipomas, capillary malformations, polyposis of the colon and rectum, pigmented macules of the penis, and Hashimoto thyroiditis; inheritance is by autosomal dominant transmission6,15.
Prognosis and Management:
The prognosis of Proteus syndrome is variable depending of the degree of organ involvement. Local malformations may require multiple surgical procedures, occasionally amputation of the extremities may be necessary.
Sudden death caused by pulmonary embolism was reported for the first time by Eberhard16 in 1994, and recently by Slavonitek17 in 3 other cases of patients with Proteus syndrome. In every case the cause of death was confirmed at autopsy. The authors concluded that pulmonary embolism is a serious complication of Proteus syndrome and recommended vigilance concerning the signs and symptoms of thrombosis in individuals with Proteus syndrome, including children. Patients with Proteus syndrome with signs or symptoms of deep venous thrombosis demand for an aggressive and urgent evaluation and treatment.
Proteus patients can also develop compromise of the spinal cord. This can be the result of either infiltration of the spine by the tumor or narrowing of the canal from vertebral hypertrophy (angular kyphoscoliosis)19,20.
1: Sigaudy S, Fredouille C, Gambaelli D, Potier A, Cassin D, Piquet C, Philip N. Prenatal ultrasonographic findings in Proteus syndrome. Prenat Diagn 1998;18(10):1091-4
2: Tissot H, Maugey B, Serville F, Verge F, Vergnes P, Dallay D. Prenatal diagnosis of abdomino-pelvic cystic lymphangioma as part of Proteus syndrome J Gynecol Obstet Biol Reprod 1991;20(3):335-40
3: Richards DS, Williams CA, Cruz AC, Hendrickson JE. Prenatal sonographic findings in a fetus with Proteus syndrome. J Utrasound Med 1991;10(1):47-50
4: OMIM database 176920, 149000, 166000, 162200
5: Benacerraf B. Ultrasound of fetal syndromes. Churchill Livingstone, 1998
6: Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL, Cohen MM Jr. Proteus syndrome: diagnostic criteria, differential diagnosis, and patient evaluation. Am J Med Genet 1999;84:389-395
7: De Becker I, Gajda DJ, Gilbert-Barness E, Cohen MM Jr. Ocular manifestations in Proteus syndrome. Am J Med Genet 2000;92(5):350-2
8: Gilbert-Barness E, Cohen MM Jr, Opitz JM. Multiple meningiomas, craniafacial hyperostosis and retinal abnormalities in Proteus syndrome. Am J Med Genet 2000;93(3):234-40
9: Burke JP, Bowell R, O’Doherty N. Proteus syndrome: ocular complications. J Pediatr Ophtalmol Strabismus 1988;25(2):99-102
10: Sato T, Ota M, Miyazaki S. Proteus syndrome with renal involvement. Acta Paediatr Jpn 1995;37(1):81-3
11: Hotamisligil GS, Ertogan F. The Proteus syndrome: association with nephrogenic diabetes insipidus. Clin Genet 1990;38(2):139-44
12: Jeanty P, Silva SR. Klippel-Trenaunay-Weber syndrome. www.thefetus.net/
13: Escobar CAM. Klippel-Trenaunay-Weber syndrome. www.thefetus.net/
14: Kaplan RP, Wang JT, Amron DM, Kaplan L. Maffucci’s syndrome: two cases reports with a literature
review. J Am Acad Dermatol 1993;29:894-9
15: Gujrati M, Thomas C, Zelby A, Jensen E, Lee JM. Bannayan-Zonana syndrome: a rare autosomal dominant syndrome with multiple lipomas and hemangioms: a case report and review of literature. Surg Neurol 1998;50(2):164-8
16: Eberhard DA. Two-year-old boy with Proteus syndrome and fatal pulmonary thromboembolism. Pedriatr Pathol 1994;14(5):771-9
17: Slavotinek AM, Vacha SJ, Peters KF, Biesecker LG. Sudden death caused by pulmonary thromboembolism in Proteus syndrome. Clin Genet 2000;58:386-9
18: Gordon PL, Wilroy RS, Lasater OE, Cohen MM Jr. Neoplasms in Proteus syndrome. Am J Med Genet 1995;57(1):74-8
19: Skovby F, Graham JM, Sonn-Holm S, Cohen MM Jr. Compromise of the spinal canal in Proteus syndrome. Am J Med Genet 1993;47(5):656-9
20: Ring D, Snyder B. Spinal canal compromise in Proteus syndrome: case report and review of the literature. Am J Orthop 1997;26(4):275-8