Proteus syndrome is a very rare mosaic condition characterized by progressive and asymmetric overgrowth of tissues due to a somatic activating mutation of the akt1 gene. Clinical manifestations include distinct cutaneous features, like cerebriform connective tissue nevi, epidermal nevi, vascular malformations, and adipose abnormalities. Other unusual features include bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and deep vein thrombosis, resulting in premature death. Prognosis of affected patients may be complicated by premature death, mostly due to pulmonary embolism and respiratory failure.
Key words: proteus syndrome (ps); disproportionate overgrowth; hemihyperplasia; asymmetry; hyperostoses; cerebriform connective tissue nevus.
Proteus syndrome (ps) is part of overgrowth syndromes and it is due to a mosaic, activating akt1 mutation (c.49g>a, p.glu17lys)1. PS is a rare complex disorder with multisystem involvement and great clinical variability, first described in 19792. In 1983, rudolf wiedemann, a german pediatrician, named it proteus syndrome after a greek sea-god, who could change his shape at will assuming many forms to escape capture. This name was given to represent the variable clinical manifestations seen in the first patients identified with this syndrome and the morphological changes of its presentation and evolution3, 4. It is an extremely rare syndrome with an estimated prevalence of approximately 1:1.000.000, being more common among males at a ratio of 1:9:13, 4. This disease is characterized by a mosaic distribution, sporadic occurrence, and progressive course. Clinical features may be present at birth but typically develop over time, starting between 1 and 18 months of age. The postnatal, progressive, and asymmetrical overgrowth occurs in a mosaic pattern. Bone, connective tissue, fat, central nervous system, eye, spleen, thymus, and colon are commonly involved tissues5. The complications of ps include hyperostosis, cerebriform connective tissue progressive, skeletal deformities, benign and malignant tumors, capillary vascular malformations and deep venous thrombosis with pulmonary embolism. The syndrome has an incidence of less than 1 per 1, 000.000 live births and is estimated that 120 individuals with ps are currently alive worldwide6, 4.
Newborns with proteus syndrome have few or no signs of the condition, and overgrowth becomes apparent between 6 and 18 months of life, getting more severe with age
Cerebriform connective tissue nevus: the cerebriform connective tissue nevus found in some patients is not obligatory. They occur most frequently on the plantar surfaces of the feet (fig. 1), but may also occur on the hands, abdomen, and nose. They are characterized by highly collagenized connective tissue. Epidermal nevi and other skin lesions: In Proteus syndrome, such nevi are evident in early life and may occur on the neck (Fig. 2), trunk, or extremities. Histopathological findings consist of acanthosis and hyperkeratosis. Patchy areas of dermal hypoplasia and hypopigmentation have also been observed 8.
Fig.1 New England J Med 2011; 365:611-619
Fig.2 From Cohen and Hayden
Dysregulated adipose tissue
Overgrowth of adipose tissue is common in infancy but it 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.
Bullous lung abnormalities have been discussed by several authors. It is known also pulmonary venous dilatation 4, 9.
Disproportionate asymmetric overgrowth and skeletal abnormalities (table 2)
Overgrowth in proteus syndrome is disproportionate, asymmetric, distorting, and relentless11. Skeletal abnormalities include kyphoscoliosis abnormal vertebral bodies (asymmetrical vertebral body overgrowth), segmentation defects, focal calvarial thickening, limb overgrowth, premature degenerative changes, macrodactyly and sometimes nondevelopment of peripheral bones11, 3. In proteus syndrome, the long bones are overgrown with abnormally thin cortices and deficiency of the overlying soft tissue 12. (fig.3)
- Hyperostosis of the skull
- Hyperplasia of osteoid with variable calcification, producing abnormal bony edges
- Abnormally calcified connective tissue
- Invasion of joint spaces, eventually resulting in immobility of the affected joints
- Abnormal bone that may be difficult to recognize radiologically
- Overgrowth of long bones often with abnormally thin cortices and frequently with deficiency of overlying soft tissue
Tab. 2. Skeletal abnormalities (Adapted from Jamis-Dow et al. and Turner et al.)
Fig.3 Asymmetric overgrowth of legs with thin cortices and deficiency of the overlying soft tissue. From Cohen.
Only lipomas are common. Other reported neoplasms include monomorphic adenoma of the parotid gland; cystadenomas of the ovary; testicular tumors; meningiomas and mesothelioma 13.
The facial phenotype is present in only a minority of patients and may be associated with cognitive deficits and, in some cases, seizures and brain malformations. Manifestations include dolichocephaly, long face, minor downslanting palpebral fissures and/or minor ptosis, low nasal bridge, wide or anteverted nares, and an open mouth at rest3, 8. (fig.4)
Fig.4 Evolution of facial abnormalities in a patient with Proteus syndrome. Left: Age 1 month. Center: Age 5 months. Right: Age 5½ years. Note connective tissue nevus on left side of nose. From Cohen
Vascular malformations can be profound and include vascular ectasia, haemangiomata, lymphangiomata and varicosities14. The vascular ectasia may be progressive (figures 9–14). Deep-vein thrombosis leading to pulmonary embolism is the commonest cause of death in this group of patients, possibly related to venous stasis in grossly ectatic vessels 15.
Cerebral arteriovenous malformations, abnormal grey–white matter differentiation and hydrocephalus are commonly seen. Schizencephaly, spinal lipomatosis and perineural cysts have also been described 16. (fig.5, 6)
Fig. 5, 6. (5) Asymmetry of the cerebral hemispheres and lateral ventricles with abnormal grey–white matter differentiation (arrow) and areas of macrogyria in the left cerebral hemisphere. MRI image, axial T2, repetition time 5700 ms, echo time 98 ms. M J Kaduthodil et al. (6) Asymmetrical calvarial thickening (vertical arrow) and arteriovenous malformation (horizontal arrow). MRI image, axial T2, repetition time 5700 ms, echo time 98 ms. M J Kaduthodil et al.
Diagnosis and differential diagnosis
The diagnostic criteria for proteus syndrome are shown in table 117. To meet diagnostic criteria, the patient must meet the single criterion from category a, two criteria from category b, or all three criteria from category c3. Biesecker’s group demonstrated that a mosaic activating akt1 mutation, c.49g>a, p.glu17lys was the cause of proteus syndrome. They examined 29 patients, all of whom met the clinical diagnostic criteria (table 1). Of these, 26 had the akt1 mutation. In the remaining three patients the mutation has not been identified. Lindhurst et al. Suggest that the clinical criteria for proteus syndrome alone may be sufficient for the diagnosis (table 1) without identifying the mutation, except in early cases when the clinical findings are not definitive1. 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. The differential diagnosis of ps must be made with other hamartomatous disorders such as klippel-trenaunay-weber (ktws; asymmetry in one limb and hemangioma), maffucci disease (enchondromatosis and hemangioma)18, ollier's disease (enchondromatosis), neurofibromatosis type i (macrocephaly, café-au-lait spots, subcutaneous neurofibromas), bannayan-zonana syndrome (macrocephaly, craniofacial abnormalities), hemihyperplasia and multiple lipomatosis syndrome (hhml) and other disorders that present with hemihyperplasia19. In ps, the abnormal growth is asymmetric, distorting, relentless, and occurred at a faster rate compared to the rest of the body. Furthermore, ps is associated with irregular and disorganized bone, including hyperostoses, hyperproliferation of osteoid with variable calcification, calcified connective tissue, and elongation of long bones with abnormal thinning. In contrast, non-proteus cases displayed overgrowth that is asymmetric but grew at a rate similar to the growth found in unaffected areas of the body. Also, the overgrowth in non-proteus cases is associated with normal or enlarged bones together with ballooning of the overlying soft tissues20. The two conditions which must be primarily distinguished from the proteus syndrome are klippel–trenaunay–weber syndrome (ktws) and neurofibromatosis type 1. In ktws, the changes of soft tissue growth and hypertrophy are present at birth and are usually severe. The key distinction between the two conditions is presence of bone involvement and progressive hypertrophy in ps, which is absent in ktws11. Neurofibromatosis is usually distinguished from ps by the presence of the clinical triad of pigmented skin nodules (cafe´-au-lait spots), lisch nodules and axillary freckling15. The proteus syndrome must also be differentiated from cloves syndrome. Cloves is composed of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies. While some of these abnormalities may develop over time, a significant number of them may be present at birth21. It is caused by activating mutations in pik3ca22.
Evaluations following initial diagnosis
To 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 overgrowth
• Ct 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
As with any complex and multisystem disorder, patients with ps benefit from a coordinated and multidisciplinary clinical approach. 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. The approaches are diverse and include various orthopedic procedures to delay or halt linear bone growth; correction of skeletal deformities such as scoliosis22, 8. For overgrowth of tubular bones, epiphysiostasis and epiphysiodesis should be the mainstays of management. 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. 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.
Any organ or tissue can be affected and, thus, the secondary complications are highly variable.
Surveillance: monitoring should be tailored to individual patients’ presentations; routine monitoring for evidence of tumor development is by medical history and physical examination; periodic imaging is not indicated 22.
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