#176920ICD+

PROTEUS SYNDROME

GIGANTISM, PARTIAL, OF HANDS AND FEET, NEVI, HEMIHYPERTROPHY, AND
MACROCEPHALY
Other entities represented in this entry:
ELATTOPROTEUS SYNDROME, INCLUDED
Phenotype-Gene Relationships
Location Phenotype Phenotype
MIM number
Pheno
map
key
Gene/Locus Gene/Locus
MIM number
14q32.33 Proteus syndrome, somatic 176920 3 AKT1 164730

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. Many features of Proteus syndrome overlap with other
overgrowth syndromes (Turner et al., 2004).

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 (158350) and Bannayan-Riley-
Ruvalcabasyndrome (BRRS; 153480). 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-Webersyndrome (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 (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 Proteussyndrome, 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 withProteus 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
withProteus 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 syndromemay 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 Proteussyndrome 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.

Differential Diagnosis

Bialer et al. (1988) discussed the differential diagnosis of the Proteus and Bannayan-
Zonanasyndromes. 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
forProteus 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
withProteus 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 Proteussyndrome 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