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Proteus Syndrome

Proteus syndrome is a rare genetic disorder distinguished by an overgrowth of many different tissues in the body in a mosaic pattern. The skin, the musculoskeletal system, the central nervous system, and adipose tissues are affected the most, producing profound disfigurement and life-threatening complications. The diagnosis is made through a combination of clinical criteria and positive genetic studies for AKT1 gene mutations.


Presentation

Although Proteus syndrome is rarely encountered in clinical practice, several distinct signs are recognized in the affected population. Tissue overgrowth is, by far, the most important feature of this disorder and the skeletal system seems to be most severely affected [1] [2] [3] [4] [5] [6]. After an apparently normal birth, first signs usually appear in late infancy and early childhood (6-18 months of age), but a delayed presentation up to puberty has been encountered [1] [4]. Skeletal changes affect the limbs in most cases in an evidently disproportionate, asymmetric, and often severe and rapidly progressing fashion (leg length discrepancy of up to 20 centimeters has been reported) [1] [4]. The connective tissues and fat are also affected by this phenomenon, but atrophy of the adipose tissue can be simultaneously present in some patients [1] [2] [4]. Furthermore, studies have reported cases with overgrowth of different organs, including the thymus, the gastrointestinal tract, the spleen, and the liver [1] [4]. Vascular malformations involving, the arterial, venous, and/or lymphatic vessels are very frequent and predispose to life-threatening thromboembolic events [1] [2] [4]. Apart from tissue overgrowth, the formation of cutaneous lesions, such as linear verrucous epidermal nevi and cerebriform connective tissue nevi (CCTN) are hallmarks of Proteus syndrome [1] [2] [4] [5]. Other notable findings seen in Proteus syndrome are [1] [2] [3] [4]:

Splenectomy
  • The patients' bleeding tendency and hemostatic defects were completely corrected after they successfully underwent splenectomy.[ncbi.nlm.nih.gov]
Tonsillar Hypertrophy
  • We report the case of obstructive lingual tonsillar hypertrophy resulting in residual sleep disordered breathing after adenotonsillectomy in a child with PS, a previously unrecognized manifestation of the disease.[ncbi.nlm.nih.gov]
  • We report a rare case of Proteus syndrome which presented with dysphagia due to unilateral tonsillar hypertrophy.[ncbi.nlm.nih.gov]
  • Nuyen, Aria Jafari and Javan Nation, Refractory sleep-disordered breathing due to unilateral lingual tonsillar hypertrophy in a child with Proteus Syndrome, International Journal of Pediatric Otorhinolaryngology, 95, (114), (2017). M. Barreau and A.[doi.org]
Tonsillar Mass
  • We report such a rare case, which presented with a huge unilateral tonsillar mass causing dysphagia.[ncbi.nlm.nih.gov]
Exertional Dyspnea
  • This report documents a 25-year-old man with Proteus syndrome who presented with progressive exertional dyspnea and asymmetric overgrowth of his extremities. He underwent left pneumonectomy and his postoperative course was uneventful.[ncbi.nlm.nih.gov]
Rectal Bleeding
  • We describe a case of a 17-year-old girl with Proteus syndrome presented with symptomatic anaemia secondary to chronic rectal bleeding. Computed Tomography Angiogram of Abdomen and Pelvis confirmed the presence of rectal vascular malformations.[ncbi.nlm.nih.gov]
Flatulence
  • Vaginal flatulence can be awkward in the heat of the moment, but it's nothing to be ashamed of. The "Voice" host has been very open about his mental health and how he copes.[aolhealth.com]
Gingival Hypertrophy
  • The ENT manifestations of Proteus syndrome are high arched palate, gingival hypertrophy, malocclusion and overcrowding of teeth, hyperostosis of the external auditory meatus, and low nasal bridge.[ncbi.nlm.nih.gov]
Vaginal Bleeding
  • A 19-year-old girl with Proteus syndrome presented with vaginal bleeding. The histological examination revealed Müllerian papilloma of the uterine cervix and large bilateral ovarian cystadenomas.[ncbi.nlm.nih.gov]

Workup

Unfortunately, Proteus syndrome is severely debilitating during childhood and adolescence and up to 25% of patients are at risk of not surviving past the beginning of the third decade of life [6]. For this reason, an early diagnosis is essential. To recognize Proteus syndrome, it is first necessary to establish prerequisite criteria - a mosaic pattern of lesions, the absence of a familial component, and a rapidly progressive course of symptoms [1] [4] [5]. During the clinical assessment, use of diagnostic criteria that have been revised in the previous decade should be sufficient to solidify clinical suspicion [1] [4] [5].

The diagnosis is made when either Category A is fulfilled, when two signs from category B exist, or if three signs from category C are observed [1] [4] [6]. In addition to clinical findings, the revelation of specific mutations involving the AKT1 gene has allowed mutational analysis to be performed in this population [7]; thus genetic testing can be employed as a definitive diagnostic method [1] [3] [4].

Treatment

  • Dentists and physicians proposed an adjusted treatment plan. Maxillary disjunction was achieved with a combination of orthodontic treatment and surgical procedure.[ncbi.nlm.nih.gov]
  • Management and treatment Treatment requires a multidisciplinary approach. The interventions used to control overgrowth of tubular bones are epiphysiostasis, epiphysiodesis and amputation in extreme cases.[orpha.net]
  • While AKT signaling was suppressed with ARQ 092 treatment, cells retained their ability to respond to growth factor stimulation by increasing pAKT levels proportionally to untreated cells.[ncbi.nlm.nih.gov]
  • This article discusses the differential diagnosis of Proteus syndrome and the treatment methods used for macrodactyly along with the presentation of the case.[ncbi.nlm.nih.gov]
  • Endoscopic treatment with coblation effectively and safely treated the obstructive symptoms.[ncbi.nlm.nih.gov]

Prognosis

  • Prognosis of affected patients may be complicated by premature death, mostly due to pulmonary embolism and respiratory failure.[ncbi.nlm.nih.gov]
  • After the treatment long-term follow-up is needed as there is a chance of recurrence, but even then the prognosis is excellent. A 19-year-old girl with Proteus syndrome presented with vaginal bleeding.[ncbi.nlm.nih.gov]
  • Prognosis Prognosis varies depending on the severity of complications. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Further evaluation of a larger number of Proteus patients is needed in order to determine the frequency and prognosis of cardiac involvement. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.[ncbi.nlm.nih.gov]

Etiology

  • This disorder is thought to be caused by a somatic gene mutation, but the exact etiology is unknown. Commonly involved tissues include connective tissue, bone, skin and the central nervous system.[ncbi.nlm.nih.gov]
  • No intra-exonic mutations were identified, indicating that neither PTEN nor GPC3 are likely to have major roles in the etiology of Proteus syndrome in our series of patients.[ncbi.nlm.nih.gov]
  • The etiology is unknown to date. The aim of this article was to describe the clinical and radiographic periodontal findings and other oral manifestations in a patient with Proteus syndrome.[ncbi.nlm.nih.gov]
  • The etiology remains unclear. Limb deformities are common and often necessitate amputations. Only a few cases associated with spinal deformities have been described.[ncbi.nlm.nih.gov]
  • The etiology of these disorders will be studied using candidate gene analysis (primarily based on the PI3K/AKT pathway) and possibly exome and whole genome sequencing (done under protocol 10-HG-0065).[clinicaltrials.gov]

Epidemiology

  • Summary Epidemiology Approximately 120 cases of PS have been reported to date. The prevalence is estimated to be less than 1/1,000,000 live births. Clinical description Neonates usually appear normal at birth.[orpha.net]
  • Patients with PTEN mutation are now thought to have Proteus-like syndrome. [7, 8] Epidemiology Frequency Around 100 cases have been reported in the literature. [10] Race Proteus syndrome has no predilection for any particular race.[emedicine.com]
  • Epidemiology Frequency International Proteus syndrome is believed to be exceedingly rare, with less than 100 confirmed affected individuals reported worldwide. [5] This suggests that prevalence is less than 1 case per 1,000,000 live births.[emedicine.com]
Sex distribution
Age distribution

Pathophysiology

  • We conclude that the predisposition to thrombosis is likely to be multifaceted with risk factors including vascular malformations, immobility, surgery, additional prothrombotic factors, and possible pathophysiologic effects of the somatic AKT1 mutation[ncbi.nlm.nih.gov]
  • The cases that met the criteria were more often male, which has implications for hypotheses regarding the etiology and pathophysiology of PS.[ncbi.nlm.nih.gov]
  • ., Chief of the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute (NHGRI) who discovered the important role AKT plays in the pathophysiology of Proteus syndrome.[raredr.com]
  • Preserved castings of his soles show cerebriform cutaneous hyperplasia, a characteristic finding in persons with Proteus syndrome. [4] Pathophysiology Proteus syndrome is a rare, sporadic disease with patchy or mosaic manifestations. [5] In 2011, the[emedicine.com]

Prevention

  • Research Article Mutation analysis of the tumor suppressor PTEN and the glypican 3 ( GPC3 ) gene in patients diagnosed with Proteus syndrome Department of Human Genetics, McGill University, Montreal, Quebec, Canada Cancer Prevention Centre, Sir MB Davis‐Jewish[doi.org]
  • Management to prevent and monitor for blood clots is needed. Imaging. Imaging studies (x-rays) are often important to assess and monitor areas of overgrowth. No one type of imaging is best for everyone with Proteus syndrome.[texaschildrens.org]
  • Proteus syndrome treatment includes: detection of abnormalities at an early stage and using symptomatic and preventive treatment multiple orthopedic procedures to control the overgrowth surgery epiphysiodesis (removal or ablation of growth plates in bones[medigoo.com]
  • Doctors may also suggest surgically removing growth plates in the bone to prevent excessive growth. Proteus syndrome can cause numerous complications. Some can be life-threatening. Your child may develop large masses.[healthline.com]

References

Article

  1. Biesecker LG, Sapp JC. Proteus Syndrome. 2012 Aug 9. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  2. Cohen MM Jr. Proteus syndrome review: molecular, clinical, and pathologic features. Clin Genet. 2014 Feb;85(2):111-119.
  3. Alves C, Acosta AX, Toralles MBP. Proteus syndrome: Clinical diagnosis of a series of cases. Indian J Endocrinol Metab. 2013;17(6):1053-1056.
  4. Biesecker L. The challenges of Proteus syndrome: diagnosis and management. Eur J Hum Genet. 2006;14(11):1151-1157.
  5. Talari K, Subbanna PKA, Amalnath D, Suri SDK. Proteus syndrome: A rare case report. Indian J Hum Genet. 2012;18(3):356-358.
  6. Sapp JC, Hu L, Zhao J, et al. Quantifying survival in patients with Proteus syndrome. Genet Med. 2017 Jun 29.
  7. Lindhurst MJ, Sapp JC, Teer JK, et al. A Mosaic Activating Mutation in AKT1 Associated with the Proteus Syndrome. N Engl J Med. 2011;365(7):611-619.

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Last updated: 2019-06-28 12:04