Proteus Syndrome

A number sign (#) is used with this entry because of evidence that Proteus syndrome is associated with mosaicism for a somatic activating mutation in the AKT1 gene (164730) on chromosome 14q32.3.

Description

Proteus syndrome is a highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Specific features include cerebriform connective tissue nevus, thin limbs, lipomas, and lung cysts. Some patients may have intellectual disability with dysmorphic facies. Deep venous thrombosis is common and constitutes a significant risk factor. Many features of Proteus syndrome overlap with other overgrowth syndromes (Turner et al., 2004; review by Cohen, 2014).

Cohen (2014) provided a detailed review of the clinical features, diagnosis, and management issues of Proteus syndrome.

Some authors (Zhou et al. (2000, 2001); Smith et al., 2002) have reported a 'Proteus-like' syndrome associated with germline and tissue-specific somatic mutations in the PTEN gene (601728), which is mutated in Cowden syndrome (CWS1); see 158350 for a discussion of these patients.

Clinical Features

Wiedemann et al. (1983) described a 'new' syndrome in 4 unrelated boys with the combination of partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies, and possible accelerated growth and visceral affections. The authors considered the disorder to fall into the category of congenital hamartomatous disorders and to be 'undoubtedly genetically determined,' perhaps as an autosomal dominant disorder. They named the syndrome for the Greek god Proteus, 'the polymorphous,' who could change his shape at will to avoid capture. Wiedemann et al. (1983) suggested that the patient reported by Temtamy and Rogers (1976) and probably also the patient of Graetz (1928) may have had this disorder. The disorder might be confused with the Klippel-Trenaunay-Weber syndrome (149000) and with Ollier disease (166000) and Maffucci syndrome (614569). Burgio and Wiedemann (1984) found that the skin changes are papillomatous epidermal nevi.

Costa et al. (1985) reported 2 cases; both had abdominal and pelvic lipomatosis. One, a 7-year-old boy, was noted at age 3 to have a conjunctival dermoid. Laparotomy at age 6 for acute abdominal pain showed right iliac fossa lipomatosis and twisted necrotic mesenteric fat as the presumed cause of pain. Some similarities to the Bannayan-Zonana syndrome (see 153480) and linear sebaceous nevus syndrome (163200) were noted. Costa et al. (1985) noted that mean paternal age at the time of birth of 10 of the patients was 30 (range 23 to 40), which is probably not significantly elevated.

Happle (1986) pointed out that the lesions follow the lines of Blaschko and suggested that the cause is a dominant lethal gene surviving by mosaicism. He suggested this mechanism also for Schimmelpenning-Feuerstein-Mims syndrome (163200) and the McCune-Albright syndrome (174800). (The hypothesis has been proved in the case of the latter condition.) Rescue of a lethal genotype by chimerism with normal embryos (Bennett, 1978) is an experimental model of this mode of inheritance.

Viljoen et al. (1987), Clark et al. (1987) and Malamitsi-Puchner et al. (1987) reported 6 cases, 11 cases, and 1 case, respectively. All emphasized lipomatosis as a feature. Malamitsi-Puchner et al. (1990) provided follow-up on the severely affected child originally reported by Malamitsi-Puchner et al. (1987). They found that striking overgrowth of tissues occurred after surgical operations. Furthermore, the patient, a 4.5-year-old child, developed testicular malignancy.

Viljoen et al. (1987) mentioned that surgical removal of lymphatic, fatty, or hemangiomatous elements is difficult and results in unsightly scars and keloids. Viljoen et al. (1988) described the skin manifestations of the Proteus syndrome in 6 patients. All had marked hypertrophy of the skin of the soles, which the authors believed to be a unique feature of this syndrome. Large epidermal nevi and linear macular lesions with areas of depigmentation and hyperpigmentation were seen in 3 patients. Light microscopy of affected skin from the soles demonstrated elongation of the cytoplasm of basal cells. Samlaska et al. (1989) reported a typical case and reviewed 34 reported cases, all sporadic.

Beluffi et al. (1990) reported a case with pelvic lipomatosis and demonstrated the use of CT scan for revealing pelvic lipomatosis. Hotamisligil and Ertogan (1990) described the case of a 9-month-old girl who, in addition to other features, had soft tissue masses in the paravertebral and gluteal areas with aggressive involvement of the spinal canal and a hyperpigmented epidermal nevus with hyperkeratosis on the left half of the body. There was macrodactyly of both feet and the left hand with syndactyly of the third and fourth left fingers. Nephrogenic diabetes insipidus was described in the Proteus syndrome for the first time.

Although Proteus syndrome is considered a sporadic congenital disorder, some reports have suggested familial transmission. Goodship et al. (1991) presented a possible case of father-son transmission of Proteus syndrome. The son had cranial hemihypertrophy, a lymphangioma, a lipoma, and epidermal nevi. The father had had a large lymphangioma resected from the right side of his face as a child. The possibility that the father was mosaic was raised. Kruger et al. (1993) observed mild Proteus syndrome in a boy whose mother had very mild manifestations. The mentally normal son had mild hypertrophy of the left side of the upper lip and cheek with impaired mimic expression in this region, hypertrophy of the left arm, partial gigantism of the left middle finger, and a large subcutaneous swelling in the upper left abdomen thought clinically and sonographically to be a lipoma. The mother had facial asymmetry with hypertrophy of the right lower cheek and impaired mimic expression in that region. Both the mother and the son had 'distinct venous marking' over the upper thorax.

Skovby et al. (1993) reported 2 patients who illustrated the 2 ways in which spinal compromise may develop in Proteus syndrome: vertebral anomalies or tumor infiltration. In one patient, spinal stenosis resulted from an angular kyphoscoliosis; in the other, cord compression resulted from infiltration of a paraspinal, intrathoracic angiolipoma.

Cohen (1993) reported 2 unusual cases that supported the concept of somatic mosaicism. In 1 patient, a huge connective tissue nevus covered the chest and abdomen, and hyperostoses of the calvaria were observed. In the other patient, linear verrucous epidermal nevi, epibulbar dermoids, and hyperostoses were found. No enlargement of the limbs or digits occurred, and the plantar surfaces of the feet were normal. Cohen (1993) also reviewed selective aspects of Proteus syndrome, including uncommon neoplasms, pulmonary and renal abnormalities, brain malformations, and types of abnormal growth in the craniofacial skeleton.

Smeets et al. (1994) reported a patient with regional manifestations of Proteus syndrome. Major findings included multiple hyperostoses of the calvaria, facial bones, and mandible. Additionally, the patient had a scleral tumor. The observations were interpreted as supporting the hypothesis of somatic mosaicism.

Gordon et al. (1995) observed 2 patients with Proteus syndrome who developed neoplasms. Patient 1 had a probable mesothelioma, although papillary carcinoma of the thyroid could not be completely ruled out; the patient, who died suddenly while sleeping at age 5 years, at autopsy had a papillary neoplasm, most likely of mesothelial origin, involving the inferior surface of the diaphragm and infiltrating into the musculature, within the omentum, in the pelvic area, within the scrotum, and within some of the mesenteric lymph nodes. Patient 2 had bilateral ovarian serous cystadenomas with nuclear atypia identified at 6 years and 3 months of age. A right ovarian oophorectomy was performed; invasion of the right fallopian tube was noted. A tabulation of uncommon neoplasms in Proteus syndrome was provided.

Lacombe and Battin (1996) described 2 unrelated children diagnosed at birth as having isolated macrodactyly (155500). Follow-up examination showed development of hemihypertrophy in both cases. Three dorsal angiomas were found in 1 child, a female, at the age of 4 years. The symptoms of both of these patients better fit the diagnostic criteria of Proteus syndrome.

Ceelen et al. (1997) described a man with Proteus syndrome who sustained a rupture of an enlarged spleen following a fall from a horse. Biesecker et al. (1998) described their experience with 18 patients with a referring diagnosis of Proteus syndrome. Splenic hyperplasia was found to be a manifestation. The spleen was enlarged in 2 of the 18 cases, and another patient with Proteus syndrome and asymptomatic splenomegaly was known to them. Enlargement of the thymus was also observed. Proteus syndrome was frequently confused with hemihyperplasia. Biesecker et al. (1998) described a distinct subtype of hemihyperplasia defined by static or mildly progressive hemihyperplasia and multiple lipomata.

De Becker et al. (2000) described ocular manifestations in a Proteus syndrome patient and reviewed ocular findings of published cases. Hodge et al. (2000) described a 10-year-old boy with Proteus syndrome who presented with a pericardial effusion and was found to have both hypogammaglobulinemia, with a specific deficiency in IgG and IgA accompanied by low levels of specific antibodies to pneumococcal and hemophilus type B polysaccharides, and global lymphopenia. No cause was found for this immune deficiency, leading the authors to suggest that it may represent a hitherto unrecognized feature of Proteus syndrome.

Gilbert-Barness et al. (2000) reported an unusual patient with Proteus syndrome in whom manifestations included multiple meningiomas, polymicrogyria, and periventricular heterotopias. Both eyes had epibulbar cystic lesions. The retina showed diffuse disorganization with nodular gliosis, retinal pigmentary abnormalities, chronic papilledema, and optic atrophy. Other abnormalities included progressive cranial, mandibular, maxillary, and auditory canal hyperostoses, epidermal nevi, and mental deficiency. The limbs were proportionate, and the hands and feet were normal.

Slavotinek et al. (2000) reported 3 patients with Proteus syndrome who died suddenly from pulmonary embolism. The first patient, who was diagnosed with Proteus syndrome at the age of 12 years, had varicose veins, portal vein thrombosis, right iliac vein occlusion, and recurrent pulmonary embolism. At age 25 years he died from pulmonary embolism. The second patient was a 9-year-old male who collapsed and died at home. Autopsy showed the cause of death to be pulmonary embolism associated with deep vein thrombosis. The third patient was a 17-year-old female undergoing inpatient treatment for sinusitis when she suddenly died. Autopsy showed a large pulmonary embolus with no identified deep vein thrombosis. Slavotinek et al. (2000) suggested that patients undergoing surgical procedures should be evaluated for coagulopathic potential and to determine whether antithrombotic prophylaxis is indicated.

Cohen (2001) reviewed at least 17 reported cases of premature death in Proteus syndrome and suggested that patients with this disorder and/or their families should make their health care providers aware of the risk of deep venous thrombosis and pulmonary embolism.

Biesecker (2001) reviewed Proteus syndrome in relation to a 5-year-old patient.

Mackay et al. (2002) reported a 12-year-old boy with Proteus syndrome who had presented with gross abdominal distention and severe intractable constipation. Axial T1-weighted MRI showed diffuse hyperintense signal tissue typical of fat surrounding and separating bowel loops. The lesion extended posteriorly on the left into the paraspinal musculature, displacing the psoas muscle anteriorly. At laparotomy a huge infiltrating lipomatous mass was found encasing the left colon, including the rectum.

Mohamedbhai et al. (2002) reported the case of a newborn male with Proteus syndrome whose mother had ingested misoprostol, an orally active prostaglandin, at 6 weeks' gestation in an attempt to abort the pregnancy.

See encephalocraniocutaneous lipomatosis (ECCL; 613001), which shares many features with Proteus syndrome.

Elattoproteus Syndrome

Happle (1999) suggested the designation elattoproteus syndrome for a disorder that he considered to be an inverse form of Proteus syndrome. He described a 7-year-old boy with partial lipohypoplasia and patchy dermal hypoplasia involving large areas of his body. These areas of deficient growth were similar to those described in many cases of Proteus syndrome. Paradoxically, however, he had only a few rather mild lesions of disproportionate overgrowth. The presence of a hyperostosis of the external auditory meatus was taken as a highly characteristic sign of Proteus syndrome (Cohen, 1993; Smeets et al., 1994). Happle (1999) proposed to explain this unusual phenotype in the following way: 'At the (so far unknown) gene locus responsible for Proteus syndrome, there may occur various allelic mutations giving rise to overgrowth of somatic tissues. Such mutations can be called Pleioproteus alleles, a term derived from the Greek word 'pleion,' meaning plus. Conversely, the same gene locus may harbor alleles responsible for deficient growth of somatic tissues. Such mutations can be called Elattoproteus alleles, after the Greek word 'elatton,' meaning minus. Patients affected with Proteus syndrome may show classic overgrowth or a mixture of Pleioproteus and Elattoproteus lesions or even an isolated elattoproteus phenotype that has so far not been described.'

Diagnosis

Biesecker et al. (1999) reviewed recommendations for diagnostic criteria, differential diagnosis, and guidelines for the evaluation of patients with Proteus syndrome that were developed at a workshop held at the National Institutes of Health in 1998. General criteria suggested as mandatory for the diagnosis were mosaic distribution of lesions, progressive course, and sporadic occurrence. Specific clinical manifestations also were suggested as necessary to meet diagnostic criteria. Connective tissue nevi, common manifestations in Proteus syndrome, were considered almost pathognomonic for the syndrome, although they are not present in all cases. Other combinations of manifestations (e.g., epidermal nevus, disproportionate overgrowth, specific tumors) were suggested to meet the diagnostic criteria.

Turner et al. (2004) reviewed 205 reported cases of Proteus syndrome. Only 97 (47.3%) were thought to meet the diagnostic criteria for Proteus syndrome; 80 cases (39%) clearly did not meet the criteria; and although 28 cases (13.7%) had features suggestive of Proteus syndrome, there were insufficient clinical data to make a diagnosis. Reported cases that met the Proteus syndrome criteria had a higher incidence of premature death and other complications (scoliosis, megaspondyly, central nervous system abnormalities, tumors, otolaryngologic complications, pulmonary cystic malformations, dental and ophthalmic complications) compared to those in the non-Proteus group. Cases that met the criteria were more often male, which has implications for hypotheses regarding the etiology and pathophysiology of Proteus syndrome. Turner et al. (2004) suggested revised diagnosis criteria for Proteus syndrome. Cerebriform connective tissue nevi (skin lesions characterized by deep grooves and gyrations as seen on the surface of the brain, which may be striking on the hands and feet) were considered characteristic. Specific tumors occurring before the second decade include ovarian cystadenoma and parotid monomorphic adenoma. Lung cysts were added as a criterion.

In a review, Cohen (2014) provided revised diagnostic criteria for Proteus syndrome, noting that the presence of cerebriform connective tissue nevus is a major diagnostic feature, although it is not found in all patients.

Differential Diagnosis

Bialer et al. (1988) discussed the differential diagnosis of the Proteus and Bannayan-Zonana syndromes. In their review of the literature, they found a history of consanguinity in 2 of 36 families with the Proteus syndrome. They stated that overlap among syndromes that include hamartomata as prominent features suggests that they may be etiologically or pathogenetically related, perhaps involving abnormal secretion of a growth factor or abnormal tissue or tissue response to a growth factor.

Inheritance

Brockmann et al. (2008) reported a pair of monozygotic 9-year-old male twins discordant for Proteus syndrome. The affected boy showed progressive postnatal overgrowth of his right leg and foot with asymmetric progressive overgrowth of single toes. There was a small cerebriform connective tissue nevus on his right fourth toe. The phenotype was mild but still fulfilled diagnostic criteria for Proteus syndrome. The findings supported the hypothesis that this condition is caused by a postzygotic mutation event resulting in mosaicism.

Molecular Genetics

Lindhurst et al. (2011) performed exome sequencing of 11 DNA samples from 6 patients with Proteus syndrome as well as 1 sample each from 5 unaffected parents and from 1 patient's unaffected identical twin sib, and identified an activating missense mutation in the AKT1 gene (E17K; 164730.0001) in 7 samples from 3 patients. The association was confirmed using a custom restriction-enzyme assay: overall, 26 (90%) of 29 patients with Proteus syndrome who were tested carried the mutation, as detected in 1 or more samples, with the fraction of mutant DNA in the positive specimens ranging from 1% to approximately 50%. Lindhurst et al. (2011) stated that there was no association between the proportion of mutant alleles and the overall clinical severity or specific manifestations of the phenotype; in addition, their data did not suggest a specific stage during development at which the mutation arose in these patients. Samples from 3 patients with typical Proteus syndrome were negative for the mutation; noting that only 2, 1, and 3 samples, respectively, were analyzed from these patients, who were clinically indistinguishable from mutation-positive patients, the authors stated that it was likely that these samples were negative by chance. Lindhurst et al. (2011) noted that their findings supported the mosaicism hypothesis that had been advanced earlier by Happle (1987), who suggested that sporadically occurring disorders with an irregular distribution of skin involvement, such as Proteus syndrome, might be the result of an autosomal dominant lethal gene that was compatible with survival only in the mosaic state.

Exclusion Studies

Barker et al. (2001) did not identify mutations in the PTEN gene in 8 unrelated patients with classic Proteus syndrome.

Thiffault et al. (2004) stated that the most plausible suggestion for the genetic basis of Proteus syndrome is the Happle somatic mosaic hypothesis (Happle, 1999), although no somatic mutations in candidate genes had been reported. Because germline mutations in the PTEN gene had been identified in patients diagnosed with Proteus syndrome, Thiffault et al. (2004) screened affected and unaffected tissue from 6 patients with Proteus syndrome by direct sequencing of genomic DNA for germline or somatic mutations in the PTEN or GPC3 (300037) genes. No intraexonic mutations were identified, indicating that neither PTEN nor GPC3 was likely to have a major role in the etiology of Proteus syndrome in this series of cases.

Nomenclature

Although Wiedemann et al. (1983) made this syndrome generally known, it had previously been delineated by Cohen and Hayden (1979). The assignment of a name with mnemonic value perhaps accounts for the greater success of Wiedemann than of Cohen in bringing the disorder to general attention. (Also, Cohen and Hayden's report was in a more obscure publication than Wiedemann's.) Cohen (1987, 1988, 1988) believed that Joseph Merrick (the Elephant Man), the famous patient of Sir Frederick Treves, had Proteus syndrome, not neurofibromatosis (162200) as often thought.