Proteus Syndrome

A rare congenital hamartomatous disorder characterized by multiple, diverse, somatic manifestations: partial bilateral gigantism of hands and feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly with cranial hyperostoses.

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Elattoproteus Syndrome; Wiedemann Syndrome; Partial Gigantism of Hands and Feet Syndrome; Nevi Hemihypertrophy Macrocephaly Syndrome; Encephalocraniocutaneous Lipomatosis Syndrome; Hamartomas Disorder, Multifarious Mesodermal Malformation, Plurifocal Overgrowth.

It is named after the Greek god Proteus, “the polymorphous,” who could change his shape at will to avoid capture. Proteus lived on the Island of Pharos, close to the mouth of the Nile or in the caves of the island of Karpatos, between Crete and Rhodos. It was described by Hans-Rudolf Wiedemann, a German pediatrician, in 1983. Joseph Merrick, known as the “elephant man” is now, in retrospect, believed to have been affected by Proteus syndrome.

Internationally, it is estimated that approximately 200 individuals are affected with this medical condition. The prevalence is believed to be less than 1 per 1,000,000 live births. There is no predilection for any race and sex. All cases are sporadic. At least, some of the abnormalities are present at birth, or they appear within the first year of life. This medical condition usually progresses until puberty.

Postulated to be genetic although cases are mainly sporadic. Few cases with autosomal inheritance reported. The cause may be a dominant lethal gene, with survival by somatic mosaicism.

May involve abnormal secretion of a growth factor or abnormal tissue or tissue response to a growth factor.

The diagnostic criteria of Proteus syndrome include regional generalized tissue hyperplasia (such as digital gigantism, macrocephaly, hemihypertrophy), skin lesions (e.g., hypoor hyperpigmented, thickened skin creases), and mesodermal hamartomas (such as lipoma, lymphangioma, hemangioma, exostosis, or fibroma). There is unique marked hypertrophy of the skin of the soles—“moccasin sole”—with light microscopic findings of elongation of the cytoplasm of basal cells. Histologic examination of subcutaneous masses has identified a variety of lipomatous, hamartomatous, and angiomatous tumors.

The disease appears soon after birth and progresses at a variable rate leading to gross deformity in later childhood. Some patients are born with large, complex, mixed vascular malformations. Overgrowth, usually digital, is noted during infancy. In childhood, patients may also develop linear epidermal nevi. The skeletal system is mainly affected with hemihypertrophy, macrodactyly, scoliosis, and exostoses over the skull. Intelligence is usually normal. Spinal compromise may develop in Proteus syndrome from vertebral anomalies (e.g., angular kyphoscoliosis) or tumor infiltration. There may be associated pulmonary involvement (rapidly progressive diffuse cystic emphysematous pulmonary disease that is potentially fatal, secondary chronic restrictive pulmonary disease from scoliosis). Pulmonary hypertension is often a feature of this syndrome. Anomalies of the cervical spine (vertebral enlargement, hemivertebrae, dysplastic vertebrae, dystrophic intervertebral diseases) are common and may predispose to airway obstruction. The prognosis is unknown. Surgical removal of lymphatic, fatty, or hemangiomatous elements is difficult and results in unsightly scars and keloids. A predisposition to tumors exists, especially cystadenomas of the ovary and mesothelioma. Thrombosis is a frequent complication and more frequent in males.

Scoliosis is common, as is cystic emphysematous pulmonary disease and restrictive pulmonary disease. Their presence requires a detailed respiratory assessment, including pulmonary function tests. A difficult tracheal intubation may be anticipated in patients with cervical spine anomalies and prominent carious teeth. An antisialagogue should be given if a fiberoptic scope-assisted intubation is to be attempted. Patients on anticonvulsant therapy should have the appropriate drug levels checked and the seizure control optimized prior to surgery. Investigations: full blood count, serum electrolytes, anticonvulsant level, chest radiograph, arterial blood gas, lung function test, cervical spine radiograph.

Preparation for a difficult direct laryngoscopy and tracheal intubation should be done. The presence of severe spinal deformities may make positioning difficult and predispose the patient to pressure sores. A regional anesthetic technique may also be difficult in the presence of spinal deformity. Intermittent positive-pressure ventilation should be used with care in patients with cystic lung changes. These patients are at risk for deep venous thrombosis, pulmonary embolism, and pulmonary hypertension.

The presence of cystic changes in the lungs contraindicates the use of nitrous oxide.

Klippel-Trenaunay Syndrome: A vascular malformation involving the lower or upper limbs, but usually, only one limb is affected. The vascular (i.e., capillary, lymphatic, and venous) malformations always exist in combination. Unilateral overgrowth is present at birth. This medical entity is considered more severe than the vascular malformations reported in the Proteus syndrome. However, Klippel-Trenaunay syndrome lacks subcutaneous tumors, palmar and/or plantar cerebriform hyperplasia, and cranial exostoses, which usually are found in Proteus syndrome.

Parkes-Weber Syndrome: A vascular malformation involving the upper and lower limbs. It is characterized by a diffuse capillary blushing, warmth, and underlying arteriovenous shunts.

Maffucci Syndrome: Characterized by hemangiomas and enchondromas.

Neurofibromatosis Generalisata: Characterized by the presence of café-au-lait macules, axillary freckling, Lisch nodules, and neurofibromas, rather than epidermal nevi and hamartomas.

Bannayan-Zonana Syndrome: Characterized by macrocephaly, lipomas, capillary malformations, and polyposis of the colon and rectum. It does not cause asymmetric growth, cranial exostoses, epidermal nevi, palmar, or plantar changes.

Hemihyperplasia Lipomatosis Syndrome: Lacks the progressive overgrowth seen in patients with Proteus syndrome.

Encephalocraniocutaneous Lipomatosis: It is considered to be a circumscribed form of Proteus syndrome. However, it is believed by most authors that both conditions are different. This disease is a congenital hamartomatous disorder characterized by partial gigantism (hands and feet, macrodactyly), hemihypertrophy, macrocephaly, scoliosis, exostoses, and nevi.

Cowden Syndrome: A rare syndrome characterized by multiple hamartomas (small flesh-colored bumps on the skin involving a hair follicle and small wart-like growths) and a risk of breast, thyroid, and uterine neoplasias.

Riley-Smith Syndrome: A rare syndrome very similar to the Bannayan-Zonana syndrome characterized by macrocephaly, pseudopapillema, hemangiomata, and multiples lipomas. Subcutaneous hemangioma may be present at birth or appear later in childhood.