Proteus syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Synonyms and keywords:PS

Overview

Proteus syndrome is an exceedingly rare disorder which falls under the category of hamartomatous disorder. Proteus syndrome is a very complex disorder which involves multiple organ systems in the body. In The United States of America in order to say a condition is a rare disease it should affect fewer than 200,000 people. Rare diseases also called as orphan diseases. Orphan Drug Act was passed on 1983 by congress for the rare diseases. Today an average of 25-30 million americans have been reported with rare diseases. The number of people with individual rare disease may be less but overall the number of people with rare diseases are large in number.

Historical Perspective

Discovery

• Proteus syndrome was first discovered by Frederick Treves, a British surgeon, in 1884.
• Frederick Treves showed the proteus syndrome on Joseph Merrick, who used to be called as the famous Elephant Man, to the Pathological Society of London.

Classification

• Proteus syndrome is one of the syndromes which falls under PTEN hamartoma tumor syndromes (PHTS). PHTS are due to germline mutations in PTEN gene.
• PTEN hamartoma tumor syndromes (PHTS) which include the following:
  • Proteus syndrome
  • Cowden syndrome
  • Bannayan-Riley-Ruvalcaba syndrome
  • Lhermitte-Duclos disease
  • Autism spectrum disorders
  • https://selly.gg/@brandon122

Pathophysiology

• Genes involved in the pathogenesis of proteus syndrome include: Mutations in the AKT1 and PTEN gene leads to oncogenesis
• Phosphatase and tensin homolog (PTEN) gene plays an important role in the following:
  • Phosphoinositide-3-kinase (PI3K)-AKT pathway and
  • Rapamycin (mTOR) signaling pathways
• PTEN track backs to 10q23 which encodes and plays a significant role in the following:
  • Effects G1 cell cycle arrest and apoptosis
  • Cellular proliferation and
  • Migration
  • Apoptosis

Causes

• The most common cause of proteus syndrome is a mutation which has mosaic variant in a gene called AKT1 and phosphatase and tensin homolog (PTEN) mutations in some patients.

Differentiating Proteus syndrome from other Diseases

Proteus syndrome must be differentiated from the following rare disorders:

• Encephalocraniocutaneous lipomatosis
• Hemihyperplasia lipomatosis syndrome
• Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) syndrome
• Klippel-Trenaunay-Weber syndrome
• Ollier disease
• Macrodactyly
• Maffucci syndrome
• Neurofibromatosis type 1
• Bannayan-Riley-Ruvalcaba syndrome
• Cowden syndrome
• Lhermitte-Duclos disease

Epidemiology and Demographics

Incidence

• The incidence of proteus syndrome is approximately 1 per 1,000,000-1:10,000,000 individuals worldwide.
• There are few than 100 cases of proteus syndrome have been reported worldwide.

Race

• There is no racial predilection to proteus syndrome.

Gender

• Males are more commonly affected by proteus syndrome than females.

Risk Factors

• There are no established risk factors for proteus syndrome.

Screening

• There is insufficient evidence to recommend routine screening for proteus syndrome.

Natural History, Complications, and Prognosis

Natural History

• The symptoms of proteus syndrome usually develop in the first decade of life, most commonly begin in toddler period, and start with symptoms such as segmental or patchy overgrowth which effects skeleton, skin, adipose, and central nervous system(CNS).

Complications

• Common complications of proteus syndrome include:
  • Hemihyperplasia
  • Bullous pulmonary disease
  • Hemimegalencephaly due to AKT3 pathogenic variants
  • Scoliosis
  • Macrocephaly
  • Deep vein thrombosis (DVT)
  • Pulmonary embolism (PE)
  • Strabismus
  • Learning disabilities or mental retardation

Prognosis

• Prognosis is generally excellent in mildly affected children with proteus syndrome.
• Depending on the location of the gene and the degree of the overgrowth at the time of diagnosis, the prognosis may vary.
• Survival rate of patients with proteus syndrome is approximately ranges from nine months to 29 years based on the severity of the condition.

Diagnosis

Diagnostic study of choice

• Punch biopsy of an affected area of skin and identification of AKT1 gene at chromosome 14q32.33, gene testing is the gold standard test for the diagnosis of proteus syndrome.
• On AKT1 gene testing methods used to find the mutation are targeted analysis, sequence analysis, deletion/duplication analysis, other non-sequencing-based tests, exome sequencing and genome sequencing.

Diagnostic criteria of Proteus syndrome includes the following:

• According to the National Institutes of Health in 1998, diagnosis of the proteus syndrome requires the following:
  • Positive all general characteristics and one feature of category A or two features of category of B or three features of category C

General criteria (All are Required)	Specific criteria Category A	Specific criteria Category B	Specific criteria Category C (All the three are reuired)
Mosaic pattern of lesions	Cerebriform connective tissue nevus is mandatory	Epidermal nevus	Lipomas or lack of adipose tissue in the affected area
Sporadic occurrence(not inherited)		Asymmetric or disproportionate overgrowth of one or more of the following: limbs, digits, cranium, vertebrae, spleen external auditory meatus, and or thymus Specific tumors with onset before the second decade: Bilateral ovarian cystadenomas or parotid monomorphic adenoma	Vascular malformations(1 of 4 is required): Capillary Malformation or Venous Malformation or Lymphatic malformation or Lung bullae
Following a progressive course			Facial features: Dolichocephaly Elongated face Down - slanting palpebrae or ptosis Depressed nasal bridge Narrow or wide nostrils(anteverted nares) Open mouth position while at rest

History

• Patients with proteus syndrome may have a positive history of:
  • Mosaic distribution of lesions
  • Rapidly progressive, asymmetric postnatal overgrowth of tissues
  • Positive history of vascular malformations
  • Cystic lung abnormalities
  • Deep vein thrombosis (DVT)
  • Pulmonary emphysema

Common Symptoms

• Asymmetrical limb overgrowth
• Bullous pulmonary degeneration
• Shortness of breath
• Chest pain
• Cough
• Hemoptysis
• Palpable subcutaneous rope-like mass
• Swelling
• Erythema
• Signs of obstruction or compression

Physical Examination

Skin

• Cerebriform nevi: One of the hallmark of the proteus syndrome
• Port wine stain

Back

• Scoliosis
• lipoma

HEENT

• Macroglossia
• Ear enlargement with hyperpigmentation
• Retrognathia

Extremities

Proteus syndrome- Note the generalized overgrowth, upper and lower limb length discrepancy, localized limb distortion of the left knee (A), postural flexion deformity of the left knee (B), and mild dorsal scoliotic deformity (C). Case courtesy by Tamer Ahmed EL-Sobky Et Al

X-ray in Proteus Syndrome- Asymmetric and disproportionate overgrowth of right hand fingers with macrodactyly. Case courtesy -Suresh Kumar Angurana Et Al

• Asymmetrical limb overgrowth: The limb overgrowth is very characteristic and pathognomonic for the patients with proteus syndrome
• Macrodactyly with splayin
• Proximal muscle wasting
• Syndactyly
• Micromelia

Laboratory Findings

• Peripheral blood testing is usually normal for patients with proteus syndrome.
• Platelet studies are reserved for the patients who are positive for vascular malformations or petechiae.
• PT, APTT, BT are done in patients who are at high risk for deep vein thrombosis (DVT) or pulmonary embolism (PE).

Electrocardiogram

• There are no ECG findings associated with proteus syndrome.

X-Ray Findings

• An x-ray may be helpful in the diagnosis of proteus syndrome. Findings on an x-ray suggestive of proteus syndrome include:
  • Scoliosis or kyphosis
  • Macrodactyly(Large digits)
  • Periarticular bony overgrowth
  • Soft tissue overgrowth in tibiocalcaneal joint
  • Hyperostotic lesion over vertex on skull

Ultrasound

• Ultrasound may be helpful in the diagnosis of proteus syndrome. Findings on an ultrasound suggestive of proteus syndrome include:
  • Venous ultrasound in lower extremities helps in diagnosing deep vein thrombosis which might lead to pulmonary embolism.
  • Identification of fat necrosis.

CT-Scan Findings

• CT scan may be helpful in the diagnosis of proteus syndrome. Findings on CT scan suggestive of proteus syndrome include:
  • Intracranial anatomy(cerebral cortex overgrowth)
  • Evaluating bony overgrowth of the cranium
  • Evaluating facial structures
  • Pulmonary cystic malformations
  • Extent of cystic lung involvement
  • Pulmonary embolism
  • Hemihypertrophy

  • 

    Ct scan shows, Hemihypertrophy of the right chest, and a soft-tissue mass under the right crus. Case courtesy by Nishant Mukesh Gandhi Et Al

MRI Findings

• MRI may be helpful in the diagnosis of proteus syndrome. Findings on MRI suggestive of proteus syndrome include:
  • Plantar cerebriform hyperplasia of the soles and the palms
  • Scoliosis(MRI is required to confirm the diagnosis)
  • 3D reconstruction without exposing to radiation
  • MRI helps in surgical intervention regarding scoliosis

Treatment

Medical Therapy

• The majority of cases of proteus syndrome require orthopedic management and it is challenging

Surgery

• Surgery is the mainstay of treatment for proteus syndrome patients.

Epiphysiostasis and Epiphysiodesis

• Epiphysiostasis is a form of surgery which helps in reduces projected limb length which is a form of temporary growth arrest
• Epiphysiostasis is done in children with proteus syndrome who are many years away from puberty
• Epiphysiostasis is only considered and done in overgrowth limb not the normal limb which is short
• Epiphysiodesis is usally considered when the patient enters into teens.
• The advantage of doing epiphysiostasis and epiphysiodesis the patients can be ambulatory after the surgery very fast and it reduces the risk of formation of thrombosis.

Amputation

• Even though amputation looks like and extreme step taken into consideration but amputation has it advantages like
  • Amputation and replacing the body part with prosthesis improve the quality of life of the patients with proteus syndrome
  • Amputation reduces the progressive and chronic pain of the patients with proteus syndrome
  • Amputation and replacing the body part with prosthesis reduces psychological distress

Patellectomy

• In patients with proteus syndrome knee flexion contracture which is a hallmark sign of patelle overgrowth, Patellectomy should be considered.
• Patellectomy should be considered in a very young child
• One of the complication of patellectomy is more chance of heterotopic bone formation

Case Studies

Case #1