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 ... 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-Ruvalcaba syndrome (BRRS; 153480). See 158350 for a discussion of these patients.
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 ... 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. - 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.
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 ... 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 (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.'
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 ... 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.
Proteus syndrome (PS) can be diagnosed based on clinical findings in individuals with classic signs. Molecular genetic testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis in individuals in whom the clinical findings are ambiguous or mild. ...
DiagnosisProteus syndrome (PS) can be diagnosed based on clinical findings in individuals with classic signs. Molecular genetic testing may be useful to confirm the diagnosis in these individuals and is used to establish the diagnosis in individuals in whom the clinical findings are ambiguous or mild. Clinical DiagnosisMajor findings are the following: Distorting, progressive overgrowth, a characteristic finding of PS is quite distinct from that of most overgrowth syndromes. The skeletal overgrowth of PS does not typically manifest until age six to 18 months and has had its onset as late as age 12 years (if the skeletal overgrowth is prenatal, it is unlikely to be PS). Whereas most other overgrowth syndromes have proportionate overgrowth (preservation of the general skeletal architecture), a key finding in PS is distortion of the skeletal architecture. This can be so severe that in isolation, a bone affected by PS can be unrecognizable in its shape. It is not uncommon for the overgrowth to accelerate rapidly in childhood, with leg length discrepancies of 20 cm being reported. Scoliotic curves of more than 90° are not uncommon. Any bone can be affected. Cerebriform connective tissue nevi (CCTN), present in most individuals with PS, is nearly pathognomonic. The CCTN is a specific type of the more common connective tissue nevus and is most commonly found (from most to least common location) on the plantar foot, hand, alae, ear, and lacrimal puncta, and on others less commonly. True CCTNs are firm and have a distinct pattern resembling the brain’s sulci (hence the term “cerebriform”). They should not be confused with prominent plantar or palmar wrinkling seen in other forms of overgrowth.Linear verrucous epidermal nevus (LVEN) is a streaky, pigmented, rough nevus that often follows the lines of Blaschko. They can be present anywhere on the body. Adipose dysregulation, most commonly manifest as “lipomatous” overgrowth, is frequently seen in persons with PS. Paradoxically in other areas of the body, the affected person can also have lipoatrophy. Note: Persons with PS do not have the typical, ovoid, encapsulated lipomas common in the elderly and so the term “lipoma” is technically incorrect, but in wide usage.Other findings include vascular malformations (most commonly capillary and lymphatic), overgrowth of other tissues (most commonly spleen, liver, thymus, gut), tumors (most commonly ovarian cystadenomas and meningiomas), bullous pulmonary degeneration, and facial dysmorphic features. The diagnosis is established in individuals with:All the following general criteria:Mosaic distribution of lesionsSporadic occurrenceProgressive course andSpecific criteria from categories A-C; either: One from category A or Two from category B orThree from category CCategories of Specific Criteria to Establish the Diagnosis of Proteus SyndromeCategory ACerebriform connective tissue nevus Note: Cerebriform connective tissue nevi are skin lesions characterized by deep grooves and gyrations as seen on the surface of the brain.Category BLinear epidermal nevusAsymmetric, disproportionate overgrowth (at least one of the following): Note: Asymmetric, disproportionate overgrowth should be carefully distinguished from asymmetric, proportionate, or ballooning overgrowth.Limbs Hyperostosis of the skullHyperostosis of the external auditory canalMegaspondylodysplasiaViscera: spleen/thymusSpecific tumors before second decadeBilateral ovarian cystadenomaParotid monomorphic adenomaCategory CDysregulated adipose tissue (either of the following):Lipomatous overgrowth Regional lipohypoplasiaVascular malformations (one of the following): Capillary malformationVenous malformationLymphatic malformationLung bullaeFacial phenotype (all of the following): DolichocephalyLong faceDown slanting palpebral fissures and/or minor ptosisDepressed nasal bridgeWide or anteverted naresOpen mouth at restOf note, substantial clinical diagnostic confusion regarding PS exists [Turner et al 2004]. It is now clear that PS is but one type, and in fact an uncommon type, of segmental overgrowth associated with cutaneous and subcutaneous manifestations such as linear nevi, fatty tissue overgrowth, and vascular malformations. See Differential Diagnosis.The disambiguation of these entities was challenging, but it is now widely accepted: the above clinical diagnostic criteria have proven to be very useful for segregating affected individuals into distinct categories for management and clinical research. More than 90% of those who meet the clinical criteria for Proteus syndrome have a somatic mosaic mutation in AKT1. Persons who do not meet these criteria do not have mutations in AKT1. That the clinical criteria have been so highly predictive of molecular testing is a robust validation of their predictive power and utility.Molecular Genetic TestingGene. AKT1 is the only gene in which mutations are known to cause Proteus syndrome. Table 1. Summary of Molecular Genetic Testing Used in Proteus SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAKT1Targeted mutation analysisc.49G>A (p.Glu17Lys)>90% (33/34) 2Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Somatic mosaicism for the c.49G>A AKT1 mutation is the only mutation identified to date in individuals with clinically confirmed PS [Lindhurst et al 2011].Interpretation of test resultsFor issues to consider in interpretation of sequence analysis results, click here.Detection of low-level mosaicism depends on test sensitivity and the tissue specimens chosen for analysis.Testing StrategyTo confirm/establish the diagnosis in a proband. Molecular genetic testing may be useful to confirm the diagnosis in individuals who meet clinical criteria and to establish the diagnosis in individuals in whom the clinical findings are ambiguous or mild. Because all AKT1 c.49G>A mutations reported to date are somatic and mosaic, more than one tissue may need to be studied. Reliable diagnosis generally requires DNA be analyzed from a biopsy of affected tissues, typically a punch biopsy of an affected area of skin. It is important to recognize that in only a minority of affected individuals (2/31 cases in a recent report [Lindhurst et al 2011] with the AKT1 c.49G>A mutation present in one or more tissues was the mutation also present in a sample of peripheral blood. Therefore, the absence of a mutation in a peripheral blood sample is a poor test to exclude the diagnosis. Prenatal diagnosis is not indicated as PS is not inherited. Genetically Related (Allelic) DisordersThe only other phenotypes associated with somatic mutations in ATK1 are tumors (primarily breast tumors) where a small minority of such tumors have the AKT1 p.Glu17Lys somatic mutation. It is hypothesized that a germline AKT1 p.Glu17Lys mutation would be lethal in early development [Happle 1986]. Animal data suggest that an embryo with a germline AKT1 p.Glu17Lys mutation would have early embryonic lethality, if such gametes are capable of leading to a fertilized embryo.
Proteus syndrome (PS) displays a wide range of severity. Most affected individuals have little or no manifestations at birth. The one exception is that a few (probably <5%) first manifest PS with hemimegencephaly, often associated with CNS migration defects and later intellectual disability. This manifestation is prenatal. In most other affected individuals, the congenital manifestations are so subtle as to be discounted or missed. These include subtle degrees of asymmetry or faint linear nevi. ...
Natural HistoryProteus syndrome (PS) displays a wide range of severity. Most affected individuals have little or no manifestations at birth. The one exception is that a few (probably <5%) first manifest PS with hemimegencephaly, often associated with CNS migration defects and later intellectual disability. This manifestation is prenatal. In most other affected individuals, the congenital manifestations are so subtle as to be discounted or missed. These include subtle degrees of asymmetry or faint linear nevi. Most typically, the first manifestations of the disorder occur between age six and 18 months with the onset of asymmetric overgrowth; it is most commonly of the feet or hands but may occur anywhere. The prognosis for an individual with PS is based on the location and degree of the overgrowth present in the individual and the presence or absence of significant complications such as bullous pulmonary disease, hemimegencephaly, and pulmonary embolism. The disorder is highly variable. Literature surveys are not useful for the purpose of establishing the prognosis because reported cases tend to show bias of ascertainment to more severe involvement and many of those reported to have “Proteus syndrome” do not meet clinical diagnostic criteria for the disorder. While it is difficult to calculate life expectancy, it is clear that there are many more children with PS than adults. With appropriate management, mildly affected individuals have an excellent prognosis. Overgrowth. The overgrowth in PS can be startling in its severity and rapidity of progression. Most segmental overgrowth disorders are congenital and proportional. That is, these other disorders manifest at birth with a limb, hand, or finger that is, for example, 30% larger than the contralateral body part, and this overgrown body part will continue to be approximately 30% larger than the contralateral body part at one year of age and three years of age. (See Differential Diagnosis for discussion of specific disorders.) In contrast, the overgrowth of PS is, for most parts of the skeleton (see above for exception re hemimegencephaly), absent at birth, possibly 15% larger at age one year, 30% larger at three years, and 100% larger at age six years (hypothetic examples). Once a clinician observes this phenomenon in a patient with bone fide PS, the distinction is evident. As well, plain radiographs clearly distinguish PS overgrowth from non-PS overgrowth. The bones affected by PS, especially the tubular bones of the limbs and the vertebral bodies and skull, develop distorting, bizarre, irregular calcified overgrowth that can render the bone unrecognizable with time. Such progressive and irregular bony changes are rare in non-PS overgrowth. The rapid and severe nature of the overgrowth poses a challenge to orthopedic management. Dermatologic findings. The CCTN lesion is rarely present in infancy, typically developing in childhood and progressing through adolescence. It rarely progresses in adulthood [Beachkofsky et al 2010]. The sulci of the CCTN lesions commonly get deep enough in late adolescence to pose challenges with cleanliness and malodor. The linear epidermal nevi and vascular malformations are most commonly recognized in the first months of life and are generally stable over time [Twede et al 2005]. Overgrowth of lipomatous tissue/lipoatrophy. It is common for individuals to manifest overgrowth of adipose tissue, most commonly in infancy. Overgrowth of adipose tissue can continue to appear in novel locations throughout childhood and into young adulthood. Similarly, many individuals with PS experience marked regional lipoatrophy, and many manifest both regional lipomatous overgrowth and lipoatrophy.Vascular malformations. Many individuals with PS have cutaneous capillary malformations and prominent venous patterning or varicosities; large and complex vascular malformations affect some individuals. Those with PS manifest skeletal and other overgrowth in areas where no vascular malformations are present (unlike other overgrowth conditions).Importantly, arteriovenous malformation (AVM) is uncommon in PS.
Proteus syndrome is known to be caused by only a single, mosaic mutation (p.Glu17Lys) in AKT1. Unpublished data suggest that the severity of the disorder is correlated with the cell type and degree of mosaicism of the mutation in the affected tissues. ...
Genotype-Phenotype CorrelationsProteus syndrome is known to be caused by only a single, mosaic mutation (p.Glu17Lys) in AKT1. Unpublished data suggest that the severity of the disorder is correlated with the cell type and degree of mosaicism of the mutation in the affected tissues.
As mentioned in Diagnosis and Clinical Description, significant diagnostic confusion regarding PS exists. Although the following disorders share some features with PS, both the natural history (i.e., almost always post-natal onset) and manifestations (e.g., disproportionate and progressive distorting skeletal overgrowth, CCTN) of PS are important distinctions that can aid in clinical diagnosis....
Differential DiagnosisAs mentioned in Diagnosis and Clinical Description, significant diagnostic confusion regarding PS exists. Although the following disorders share some features with PS, both the natural history (i.e., almost always post-natal onset) and manifestations (e.g., disproportionate and progressive distorting skeletal overgrowth, CCTN) of PS are important distinctions that can aid in clinical diagnosis.PTEN tumor hamartoma syndrome (PTHS) is a heterogeneous disorder that manifests asymmetric overgrowth, macrocephaly, cutaneous vascular malformations, and tumor susceptibility. The full spectrum of this interesting and distinctive disorder is not known but it can be readily distinguished from PS. A phenotypic subtype, described as type II segmental Cowden syndrome [Happle 2007] or SOLAMEN syndrome [Caux et al 2007] is the consequence of a germline mutation in PTEN with a somatic, mosaic second PTEN mutation that gives the phenotype its segmental attributes. PTHS includes growth abnormalities with linear nevi and vascular malformations that are clinically and molecularly distinct from those of PS. PTHS is inherited in an autosomal dominant manner; Proteus syndrome is not inherited. Thus, the genetic implications in the two disorders are quite distinct, providing further argument for a clear distinction between individuals affected with Proteus syndrome and those with the PTEN tumor hamartoma syndrome.CLOVE(S) syndrome. CLOVE is an acronym for congenital lipomatous overgrowth, vascular anomalies, and epidermal nevi. It was delineated in 2007, one of several now-distinct entities previously included in the heterogeneous designation of PS [Sapp et al 2007]. It manifests prenatal asymmetric overgrowth that is primarily proportionate in nature. Affected persons commonly have splayed feet and toes. The vascular malformations are most commonly combined lymphatico-venous anomalies with cutaneous blebbing and weeping. The lipomatous nature of the overgrowth is characterized by overgrowth of fat within normal fatty fascial planes and linear verrucous epidermal nevi. Some persons can have CNS abnormalities. Hemihyperplasia, either as an isolated finding or associated with one of a variety of other manifestations (for review, see Cohen et al [2002]) should be considered. One of the more specific types of hemihyperplasia is the hemihyperplasia with multiple lipomatosis syndrome [Biesecker et al 1998]. This congenital, primarily non-progressive form of hemihyperplasia is sometimes confused with Proteus syndrome. Klippel-Trenaunay syndrome is a disorder that manifests both overgrowth and vascular malformations. However, in this disorder the overgrowth is generally ipsilateral and overlapping with the vascular malformations, the typical vascular malformation is the lateral venous anomaly, and the skeletal overgrowth is entirely lacking in the distortion and progressivity seen in persons with Proteus syndrome [Cohen 2000]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Proteus syndrome, the following evaluations are recommended [Tosi et al 2011]:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Proteus syndrome, the following evaluations are recommended [Tosi et al 2011]:Detailed and comprehensive (general, spine, and hand) orthopedic evaluation Skeletal survey as a baseline study of the extent and severity of overgrowthCT imaging, possibly with three-dimensional reconstruction for patients with significant scoliosis. As the vertebral bodies are commonly progressively deformed, this study can be very helpful for surgical planning. Pulmonology consultation, pulmonary function testing, and high-resolution computed tomography of the chest for patients with signs or symptoms compatible with bullous pulmonary disease Other imaging techniques are highly useful and should be determined by manifestations on examination and by the medical history. Computed tomography, magnetic resonance imaging, and ultrasound have been extremely useful in the characterization of this disorder [Jamis-Dow et al 2004].Treatment of ManifestationsAs with any complex and multisystem disorder, patients with PS benefit from a coordinated and multidisciplinary clinical approach tailored to the individual’s specific needs and manifestations.Overgrowth is an ongoing issue for many patients with Proteus syndrome. The management is complex and highly dependent on the nature of the overgrowth, which can vary substantially among patients. For overgrowth of tubular bones, epiphysiostasis and epiphysiodesis should be the mainstays of management. One intervention that the authors have found to be detrimental to patients with Proteus syndrome is distraction osteotomy (so-called Ilizarov procedure) performed on the normal (shorter) limbs. Readers are referred to a recent review and conference report for more details on this complex issue [Tosi et al 2011]. The skeletal overgrowth of PS can result in significant biomechanical and functional compromise. Because of this, ongoing and comprehensive Rehabilitation Medicine care, including physical and occupational therapy, is important for many patients. In addition, many patients with PS develop substantial needs for custom-designed footwear or orthotics due to leg-length inequality or plantar CCTNs. Patients with PS who develop large plantar CCTNs should receive regular dermatologic care and attention to manage malodor (a potential complication of difficulty with cleanliness of the deepening of the sulci in late adolescence) and other concerns, such as pressure ulcerations. Large plantar CCTNs can also contribute to problems with shoe fit and often warrant pedorthic intervention as mentioned above.Management of the overgrowth of adipose tissue is challenging because the areas of adipose overgrowth are not encapsulated and discrete (in contrast to lipomas) and, therefore, can be difficult to resect and commonly regrow after surgical debulking. The authors generally recommend open surgical approaches over liposuction because the highly vascularized lipomatous overgrowth in some patients can result in hemorrhaging that is difficult to control and/or chronically weeping lymphatics.Deep vein thrombosis (DVT) and pulmonary embolism (PE). The most urgent and life-threatening complication of Proteus syndrome can be DVT and PE [Slavotinek et al 2000]. The rarity of this problem in the general pediatric population can result in a delay in diagnosis.The authors recommend emergent evaluation of patients who develop symptoms of DVT (e.g., palpable subcutaneous rope-like mass, swelling, erythema, pain, and distal venous congestion) or PE (e.g., shortness of breath, chest pain, and cough which may include hemoptysis). Because patients with PE can be asymptomatic, it is recommended that a patient with a DVT be evaluated for PE regardless of symptoms.Evaluation for DVTs. In the absence of cardiopulmonary compromise, consider the d-dimer assay and/or ultrasonographic evaluation. Evaluation of PE. High-resolution chest CT (so called spiral CT) with contrast is recommended. Ventilation-perfusion nuclear medicine scanning may be appropriate in some cases. Treatment of DVT and PE should follow recommended anticoagulation guidelines for these disorders. The authors recommend hematologic evaluation and consultation for consideration of anticoagulant prophylaxis for patients undergoing surgery or other procedures that may predispose to DVT/PE.Bullous pulmonary disease. Although uncommon, bullous pulmonary disease does affect some patients with Proteus syndrome, and, as with other disease manifestations, this can progress with startling rapidity. Pulmonary evaluation is recommended for these patients and resection of large bullous lesions may be indicated in some cases. Bullous disease in the context of scoliosis can pose significant and complex challenges for appropriate management.Psychosocial issues. In addition to functional compromise, the skeletal and connective tissue overgrowth of PS can result in disfigurement for some patients, a significant concern for many families [Turner et al 2007]. This condition is progressive and the degree of severity varies widely among patients, creating uncertainty for both clinicians and families. Coping with an ultra-rare and chronic condition like PS poses challenges for many patients and families, and genetic and psychosocial counseling is certainly warranted in most instances. Although PS is exceedingly rare, a robust support group infrastructure exists and many families find this very helpful (see Resources).SurveillanceIndividualized surveillance plans for the skeletal, pulmonary, soft-tissue, and other manifestations of PS should be developed according to patients’ specific needs.Because of the predisposition to a range of tumors (most of which are benign) patients should be monitored by their primary care provider with regular evaluations including a directed medical history and examination. Evaluation of Relatives at RiskBecause PS is not inherited, relatives are not at increased risk and do not require evaluation. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Proteus Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDAKT114q32.33RAC-alpha serine/threonine-protein kinaseAKT1 homepage - Mendelian genesAKT1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Proteus Syndrome (View All in OMIM) View in own window 164730V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOG 1; AKT1 176920PROTEUS SYNDROMEMolecular Genetic PathogenesisThe PI3KCA/AKT pathway includes a number of other genes that have been implicated in oncogenesis and/or overgrowth. This pathway is a key mediator of signal transduction from receptor tyrosine kinase growth-promoting and apoptosis-inhibiting factors. AKT2 mutations cause adipose dysregulation and hypoglycemia [Hussain et al 2011]. AKT3 mutations cause hemimegencephaly [Poduri et al 2012]. PTEN mutations (the best known) are known to cause both Cowden syndrome and segmental overgrowth phenotypes that overlap with, but are clinically distinct from, Proteus syndrome. PIK3CA mutations have been demonstrated in a number of clinically diverse overgrowth syndromes including CLOVE syndrome [Kurek et al 2012] and a phenotype termed fibroadipose overgrowth [Lindhurst et al 2012].Normal allelic variants. AKT1 extends over approximately 26 kb and includes 14 exons. The mRNA is approximately 3 kb, the reference cDNA is 3,008 bp (NM_005163.2), and the open reading frame is 1,443 bp. A number of putative normal allelic variants exist in AKT1 (see www.ncbi.nlm.nih.gov/snp). Most of the variants have been seen in multiple unrelated persons and are not believed to be associated with any phenotypic effects; however, they have not been rigorously analyzed for subtle effects. Pathologic allelic variants. Only the single c.49G>A (p.Glu17Lys) variant in AKT1 has been associated with Proteus syndrome. Of note, this variant has also been identified as being somatically mutated in a number of tumors (see COSMIC). A synonymous variant in AKT1 has been associated with schizophrenia [Tan et al 2008].Normal gene product. The gene encodes a protein of 480 amino acids (NP_005154.2). Abnormal gene product. It has been shown that the p.Glu17Lys mutation causes constitutive activation of the AKT1 kinase by means of pathologic localization to the plasma membrane and activation of the PI3KCA/AKT pathway [Carpten et al 2007].