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Proteus Syndrome is a congenital disorder causing asymmetric ecto-/meso-/endodermal tissue overgrowth.
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The estimated incidence is less than 1/1,000,000 live births.
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The genetic background is a somatic mosaicisms implicating the PI3K-AKT-mTOR pathways activation.
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Proteus Syndrome overlaps with other genetic syndromes: Neurofibromatosis, PTEN hamartoma tumour syndrome, etc.
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To date, 205 cases responding to the NIH criteria have been published worldwide.
1. Clinical background
We present the clinical history of a 20-year-old woman who developed calvarial hyperostosis and hemihyperplasia-induced scoliosis since her infancy. By the age of 7 she was found to have ipselateral ocular hamartoma and otomastoid cholesteatoma; and at the age of 10 she became symptomatic for hydrocephalus secondary to non-tumoural choroid plexus cysts, requiring endoscopic exploration and insertion of a ventriculo-peritoneal shunt. The successful management of her hydrocephalus unfortunately aggravated the progression of her calvarial hyperostosis, leading to a deterioration of her already impaired visual acuity due to a persistently raised intracranial pressure, as noted during a 48-h trial of ICP (intracranial pressure) monitoring. After discussion in the craniofacial MDT, a fronto-orbital advancement was performed. This intervention stabilized the intracranial pressure, improved the visual disturbances and was accompanied by satisfactory cosmetic results. Despite a degree of mild mental retardation, the patient never suffered epilepsy, developed normally and attended mainstream school. She had yearly follow ups with neurosurgery, neurology, psychology, ENT and orthopaedic surgeons till her transition to adult care Fig. 1.
Fig. 1A, B, C: MRI scan (T1/T2-W Axial, and T1-W Sagittal views) showing the dolicocephaly conformation with calvarial hyperostosis (triangles), the left ptosis with retinal detachment and several homolateral intracranial lesions, including intraventricular cysts (arrow), sylvian meningioma (dashed arrows) and otomastoid cholesteatoma (asterisk). Despite the absence of hydrocephalus due to a properly functioning left parietal ventriculo-peritoneal shunt, note the degree of cerebellar tonsils’ herniation beyond the Chamberlain line (dashed line on Sagittal view).
This MRI Head shows the remarkable features of Proteus syndrome (PS) where the calvarial hyperostosis tend to be more accentuated on one side of the skull, with a rich pattern of diverse unilateral intracranial lesions including intraventricular cysts, sylvian and parietal meningiomas and otomastoid cholesteatoma. PS is a rare sporadic, congenital and progressive disorder characterized by overgrowth of ecto-, meso-, and endodermal tissue. The clinical traits of this syndrome are the results of disproportionate growth of hamartomatous tissues including skin, brain, connective tissue and bone. This extremely rare disease is manifested by hemihyperplasia, lipomatosis, hamartomas, exostoses, scoliosis and it carries distinctive craniofacial and skull changes.
PS is a congenital disorder with somatic mosaicisms implicating the PI3K-AKT-mTOR pathways activation. Its characteristic ecto-/meso-/endodermal tissue overgrowth tends to be progressive and asymmetric, thus reminiscent of the Greek God Proteus’ metamorphic ability [
]. To date, 205 cases responding to the NIH criteria (see Table 1) have been published worldwide: this figure is in keeping with an estimated incidence of less than 1/1,000,000 live births [
]. Clinicians should be mindful of the clinical overlap between PS and other more common genetic syndromes that should be considered in the differential diagnosis: Neurofibromatosis, PTEN hamartoma tumour syndrome (a.k.a. Cowden syndrome or Proteus-like syndrome), Klippel-Trenaunay-Weber syndrome, etc. All the above mentioned conditions may in fact present with bilateral, rather than unilateral, tissue overgrowth, and may lead to macrocephaly, complex craniosynostosis and multiple intracranial tumours [
Facial phenotype characterized by: long face, dolicocephaly, down slanted palpebral fissures, wide and anteverted nostrils, open mouth at rest
A conclusive diagnosis of Proteus Syndrome requires all General Criteria plus some Specific Criteria (i.e.: 1 from Category A, or 2 from Category B, or 3 from Category C).
This said, the other options provided in the question regarding the most likely diagnosis could have been easily ruled out for the following reasons:
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Tuberous Sclerosis is a multisystem genetic disease that causes intracranial, as well as extracranial (kidneys, heart, liver, eyes, skin), benign tumours. It is not associated with calvarial hyperostosis and about 50% of patients present with various degrees of learning difficulties [
Crouzon syndrome and Saethre-Chotzen syndrome are both well known syndromic craniosynostosis with a specific genetic pattern. Crouzon patients often show proptosis and sensorineural hearing loss; approximately 30% of them develop hydrocephalus, but intracranial tumours are not typical of this syndrome. Patients with Saethre-Chotzen syndrome present with facial asymmetry but their spinal abnormalities are usually due to fusion of vertebral bodies rather than scoliotic deformities [
In this case, the evidence of Type I Chiari malformation confirms the persistent, mild and asymptomatic degree of raised intracranial pressure; this aspect has been widely described, and its incidence seems to range between 1% and 5% depending on the type of craniosynostosis and the various surgical procedures adopted to correct them [
]. Of note, the patient’s meningiomatosis is under neuroradiological surveillance and radiosurgical treatment has been offered since it could prevent the otherwise progressive tumoural growth [
Mr. Ganau and Dr. Paris: Study concept and design, Aquisition of data, Analysis and Interpretation; Mr. Uff: Study Supervision, Critical revision of the manuscript.
Conflicts of interest/disclosures
The authors declare that they have no financial or other conflicts of interest in relation to this publication. Informed consent was obtained prior to submission from the patient and her next of kin.
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