Parry Romberg syndrome G51.8

The syndrome is named after the two first describers, the British general practitioner Caleb Hillier Parry (1825) and the German neurologist Moritz Heinrich Romberg (1846).

Parry-Romberg syndrome (PRS), also known as hemiatrophia faciei progressiva or progressive hemifacial atrophy, was first described by C. Parry and M. Romberg and is an idiopathic, gradually progressive, asymmetric, craniofacial atrophy resulting from idiopathic atrophy (of the skin), subcutis, muscles, and bony and cartilaginous structures. It manifests in the first two decades in morphologically normal born individuals. Usually, one or more dermatomes in the area of the trigeminal nerve are affected. There is often early ophthalmologic and neurologic involvement or cardiac manifestation (Shah SS et al 2022).

W:m=1:3. The incidence of PRS is reported to be 0.3 to 2.5 cases/ 100,000 population/year.

Theory of "trophoneurosis": The earliest conception was a dysfunction of the trophic fibers of the trigeminal and other peripheral nerves - the complaints of chronic facial pain and trigeminal neuralgia support this theory. Confocal microscopy shows a reduction in corneal nerve endings supplied by the ophthalmic portion of the trigeminal nerve, supporting this theory (Bucher F et al 2015).

Immune-mediated process: A widely accepted theory is that PRS is an autoimmune disease (Duymaz A et al. 2009). It is also discussed that Parry-Romberg syndrome is a variant of circumscritic scleroderma. The combination of hemiatrophia facialis with circumscritic scleroderma of the morphea or even linear type is detectable and is found in 30% of cases (see below). Co-occurrence with other autoimmune diseases has also been documented (systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, vitiligo, and thyroid disease (Garcia-de la Torre I et al. 1995; Gonul M et al. 2005)).

Neurovasculitis theory: Histopathology of cerebral lesions shows lymphocytic vasculitis resembling Rasmussen encephalitis. Interstitial neurovasculitis involving the great vessels explains the aneurysms and other cerebrovascular malformations that occasionally occur in PRS cases. Similar lesions have been described in the course of the trigeminal nerve (Kuechler D et al 2011).

Neural crest cell dysfunction: The presence of cerebral vascular malformations and aneurysms, as well as soft tissue tumors, suggests possible dysregulation of neural crest cell migration (Pichiecchio A et al 2002).

Sympathetic dysfunction: Inflammation or dysfunction of the upper cervical sympathetic nervous system results in ipsilateral facial atrophy, enophthalmos, and bone atrophy-similar to PRS. Of note are observations that ipsilateral sympathectomy leads to arrest of disease progression (Cory RC et al 1997; El-Kehdy J et al 2021).

Hereditary mechanism: Wartenberg described PRS as a hereditary degenerative disease, with only a few familial cases known to date. To date, no specific inheritance pattern or gene has been isolated (Miller MT et al 1995).

Trauma-induced: Online surveys of PRS patients have revealed a non-confirmed association between head injury in early childhood and the onset of symptoms (Stone J 2003). This hypothesis seems unlikely in view of the frequency of trivial trauma to the head, especially in early childhood.

Infectious causes: Previous infections with varicella-zoster virus, herpes simplex virus, and Borrelia burgorferi have been described as risk factors (Sahin MT et al 2004).

PRS is primarily an autoimmune disease with associations to circumscritic scleroderma of linear type or morphea type (see Fign.). The closest relationship is to linear scleroderma en coup de sabre (Orozco-Covarrubias L et al. 2002). The main distinguishing feature is the absence of scarring alopecia and skin induration in "classic" PRS cases. In contrast, scleroderma en coup de sabre shows cutaneous sclerosis of the scalp, hyperpigmentation, and loss of scalp hair and eyebrows.

Biopsy shows almost complete local fat atrophy, minimal sclerosis of the dermis, and only reduced adnexal structures. The characteristic finding is diffuse lympho-plasma cellular dermatitis (Orozco-Covarrubias L et al 2002). A brain biopsy, which by its nature is not routinely performed in PRS, shows lymphocytic interstitial vasculitis.

PR syndrome manifests in the first two decades of life, with a few cases in the older age group (Mendonca J et al 2005). The average age is 13.2 years, with the male population being diagnosed earlier. The disease shows a progressive course, followed by "burnout" within 2 to 20 years and spontaneous remission (Duymaz A et al. 2009).

The simultaneous occurrence of linear circumscritic scleroderma of the "en coup de sabre" type and progressive facial hemiatrophy is described relatively frequently (Jablonska 1975a). In the classification proposed by versch. In the classification proposed by various authors, it is therefore also listed among the linear forms of circumscritic scleroderma.

Furthermore, a combination of progressive facial hemiatrophy with scleroderma of the morphea type is also possible (see Fig.).

Involvement of the central nervous system is not infrequently observed. Antinuclear antibodies are detected in this subtype in up to 50% of patients.

The eyes are affected in up to 35% of cases (Ahmed S et al. 2020). Neurologic symptoms occur in 15 to 20% of cases (Stone J 2003).

Atrophy of the face with onset in childhood or early adolescence. Progressive facial asymmetry due to atrophy of the subcutaneous fat, muscles and underlying bones. Furthermore, pigmentation disorders, hypo- or hyperpigmentation in facial and the ipsilateral neck region. Lesional decreased sweat secretion has been demonstrated.

Alopecia: Infestation of eyebrows and eyelashes.

Opthalmologic findings: Enophthalmos: Progressive enophthalmos secondary to atrophy of retrobulbar adipose tissue and changes in orbital anatomy due to bone atrophy.

Eyelid changes: Pseudoptosis secondary to enophthalmos, eyelid retraction, lagophthalmos, eyelid atrophy, and late stage pseudocoloboma of the eyelids (Smith B et al 1977).

Orbital tumors: Orbital neurinoma - an incidental finding on magnetic resonance imaging (MRI)( Derex L et al 1995).

Extraocular muscle (EOM) changes: Thinning or fibrosis of the EOM, sudden horizontal or vertical strabismus, nystagmus, and diplopia.

Conjunctival pigmentation: Abnormal pigmentation of the conjunctiva.

Scleral findings: Spontaneous scleral melting (Hoang-Xuan T et al 1991).

Corneal manifestations: Decreased corneal sensitivity, reduced stromal nerve fibers on confocal microscopy, keratopathy with secondary infectious keratitis, stromal edema, band-like keratopathy, and mealy deposits in the corneal stroma (Moloney G et al 2014).

Uveal changes: Acute uveitis with iritis, iridocyclitis, vitritis, panuveitis, iris atrophy, crystalline deposits in the iris and heterochromic iridocyclitis according to Fuchs (La Hey E et al 2003).

Lens findings: cataract and lens shift.

Changes in intraocular pressure (IOP): IOP rise in acute trabeculitis or end-stage neovascular glaucoma and ocular hypotension in iridocyclitis, ciliary body hypotrophy or atrophy.

Retinal findings: retinal vasculitis, neuroretinitis, telangiectasias, pigment epithelial changes, retinal folds, exudative retinal detachment (RD), central retinal artery occlusion, chorioretinal atrophy, and retinitis pigmentosa-like changes

Neuro-ophthalmological (optic nerve involvement): Optic neuropathy and papillitis

Anisocoria: Horner's syndrome and tonic pupil - due to disturbances of the autonomic system.

Neurological: Epilepsy: Focal, generalized seizures or status epilepticus.

Pain: headache, trigeminal neuralgia and facial pain

Cerebro-vascular events: Ischemic stroke, cerebral hemorrhage, microinfarcts, microhemorrhages, and subsequent cerebral atrophy

Vascular malformations: aneurysms, cavernomas, hypoplastic or stenotic vessels

Movement disorders: muscle spasms, synkinesia, pyramidal symptoms, dystonia, torticollis and gait disturbances

Speech anomalies: aphasia and dysarthria

Limb abnormalities: limb weakness, pain or in rare cases atrophy (Stone J 2003).

Neuropsychiatric manifestations: cognitive disturbances, hallucinations, and psychiatric disorders

Maxillofacial: Bony changes: hypoplasia of the maxilla, zygomatic bone, mandible, temporal bone and rarely frontal bone.

Oral manifestations: unilateral atrophy of tongue, atrophy of gums, atrophy of hard palate and abnormal development of teeth

Cardiac changes: Hypertrophic cardiomyopathy and rheumatologic heart disease.

Endocrine disorders: Hashimoto's thyroiditis and metabolic disorder.

The diagnosis "PRS" is primarily a clinical diagnosis. In order to exclude overlaps with similar syndromes, different examination methods can be used.

Ophthalmologic examinations: best corrected visual acuity, refraction and assessment of pupillary response.

General examination of facial symmetry, head posture, extraocular muscle movements and strabismus; orbital examination, evaluation of eyelid abnormalities and treatment of ptosis; careful examination with slit lamp; measurement of intraocular pressure; detailed fundus examination

Orbital ultrasound: In cases of media opacities due to vitritis, cataract or corneal opacity, this procedure helps to diagnose the corresponding pathology of the posterior segment. Ultrasound biomicroscopy is used to screen for changes in the ciliary body.

Orbital imaging: Computed tomography (CT) of the orbit is used to evaluate for changes in the bony orbit.

Neurological examinations: Electroencephalogram: Used to clarify cases of epilepsy and to localize cerebral lesions.

Analysis of cerebrospinal fluid (CSF): CSF examination is usually normal. Oligoclonal bands and increased IgG index are associated with T2 hyperintense lesions on MRI (Vix J et al 2015).

Neuroimaging: Computed tomography shows bony deformity of the skull, thinning of the diploe, and intracranial calcifications. MRI T1 sequence localizes patches of cerebral atrophy. The MRI T2 sequence localizes the hyperintense foci in the subcortical area. MR angiogram shows the extent and location of vascular malformations. Spectral photoemission CT (SPECT) of the brain can reveal subclinical CNS lesions in PRS (Grosso S et al 2003).

Dental evaluation: Monitoring of progressive jawbone deformation and dental abnormalities by serial orthopantomograms and photographs.

Dermatologic examination: Skin biopsy is not routinely performed. However, the histopathological findings help to differentiate PRS from LSCS.

Serological investigations: Anti-nuclear antibodies (ANA): The most commonly associated serologic finding in 25% to 52% of cases (Sommer A et al 2006).

Rheumatoid factor: Elevated titers in cases of localized scleroderma and LSCS (Zulian F et al 2006).

Other serologic tests: C-reactive protein, HLA-B27 typing, extractable nuclear antigen, anti-Scl-70, anti-cardiolipin, and anti-dsDNA antibodies are of limited value.

Rassmussen's encephalitis (RE): It manifests as unilateral cerebral involvement and intractable seizures. Focal neurologic deficits and subsequent atrophy resemble the picture of PRS. Histopathologic findings of lymphocytic vasculitis in both RE and PRS may complicate the diagnosis. PRS may be associated with RE and develop progressive hemifacial atrophy.

Barraquer-Simons syndrome: This is an acquired progressive lipodystrophy affecting the face, neck, thorax, abdomen, and rarely the extremities. Central nervous system involvement is suggested by epilepsy and bilateral cerebral atrophy. Gradual, symmetric, bilateral loss of subcutaneous adipose tissue with renal involvement helps distinguish this syndrome from PR syndrome.

Hemifacial hypertrophy: This condition is an asymmetric enlargement of the face and head instead of hemiatrophy and is an important clinical differential diagnosis for asymmetric facial deformities.

Hemifacial fat necrosis: Causes range from bulbar poliomyelitis to connective tissue disease to trauma. The absence of cutaneous, muscular, or bony involvement helps distinguish this entity from PRS.

Congenital deformities: Conditions such as congenital hemiatrophy or torticollis can mimic facial asymmetry caused by PRS. A careful history helps to differentiate these entities.

Ophthalmologic complications

• Corneal opacity
• Glaucoma
• Restrictive strabismus
• Retinal detachment
• Loss of vision
• Phthisis bulbi or atrophic bulbi
• Constricted orbit

Neurologic complications:

• Recurrent epileptic seizures and status epilepticus
• Subarachnoid hemorrhage due to rupture of cerebral aneurysms[9].
• Spontaneous carotid-jugular fistula and carotid dissection due to cerebral vascular malformations
• Cerebral infarction due to focal stenosis of the cerebral vasculature

Fundamental:

• Interruption of active disease progression and induction of remission.
• Treatment of acute exacerbations such as seizures and uveitis
• Cosmetic rehabilitation after complete remission

The standard treatment is systemic immunosuppression:

• Methotrexate (MTX) - the preferred agent. The dose is 0.3 to 1 milligram/kilogram/week (mg/kg/week). MTX is administered in oral or parenteral form. Therapy is continued for 12 to 24 months to prevent relapses.
• Corticosteroids - MTX is combined with oral prednisolone or intravenous methylprednisolone (IVMP).[30] Oral prednisolone is given at a dose of 1 mg/kg/day for two months, then the dose is reduced in the third month. IVMP is administered as pulse therapy at a dose of 1000 mg/day three days per month for six months.
• Alternative: Mycophenolate mofetil, cyclophosphamide, hydroxychloroquine and cyclosporine are used for resistant cases.
• Psoralen and ultraviolet A (PUVA) - varying efficacy in curbing disease activity (Gambichler T et al 2003).

Ophthalmologic Management:

• Acute uveitis: Topical cycloplegics, topical and systemic steroids are the mainstay of therapy. Acute trabeculitis is treated with topical antiglaucoma medications. Relapses are common and aggressive treatment is the norm.
• Corneal opacification: Optical penetrating keratoplasty provides a good visual outcome for severely opacified corneas due to exposure keratopathy, infectious keratitis, and primary endothelial failure.
• Scleral fusion: The scleral patch graft is the preferred treatment option.
• Glaucoma: Antiglaucoma medications can be used to control IOP in early cases. In severe cases where IOP cannot be adequately controlled with topical medications, trabeculectomy is required.
• Restrictive strabismus: The small angle deviations are corrected by prism glasses. Strabismus with large angles requires definitive surgical correction.
• Retinal vasculitis: Active disease shows vascular lesions in the midperipheral retina and mild vitritis. Primary treatment is topical and systemic immunosuppression. Advanced disease shows neovascularization, vitreous hemorrhage (VH), or tractional retinal detachment (TRD). For neovascularization in the posterior segment, the visible retina, which is not perfused, is lasered. Vitreoretinal surgery with intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) is required for unresolvable VH and TRD.

Neurologic Therapy Management:

• Seizures: Antiepileptic drugs are titrated according to response for long-term treatment.
• Neuropsychiatric disorders: Consultation with a consultant psychiatrist is essential.

Rehabilitation strategies: Cosmetic rehabilitation is attempted when disease progression has halted for at least one to two years - Schultz KP et al 2019). The most commonly used treatment options are:

Oculoplastic therapy management:

• Enophthalmos: Intraorbital injection of fillers such as silicone gel, hyaluronate derivatives, or autologous fat grafts with adipose-derived stem cells produces good cosmetic results.
• Ptosis: Primary correction of enophthalmos often produces satisfactory cosmetic results. Frontalis sling surgery is reserved for severe cases.
• Retracted eyelids: Treated surgically with levator recession or levator lengthening with relaxing myotomy technique.
• Lagophthalmos: Persistent lagophthalmos requires surgical correction with permanent lateral tarsorrhaphy.
• Drooping eyebrow: Browpexy or Z-plasty are good treatment options.
• Atrophy/phthisis bulbi: A painless, involutional eyeball with adequately formed conjunctival fornices requires an initial attempt with the prosthetic shell. Painful phthisic eye may require enucleation surgery with a silicone implant.
• Constricted orbit: Complete surgical reconstruction of the orbit in severe cases with constricted fornices requires mucosal and fat grafts. A healthy orbit is then fitted with a prosthetic shell on a trial basis.

Facial corrections by plastic reconstructive surgery:

• Synthetic tissue fillers: Minimally invasive method of correcting facial asymmetries. The most commonly used fillers are silicone gel, polyethylene, hydroxyapatite, and poly-L-lactate (Ortega VG et al. 2015), which have excellent results in mild to moderate conditions.
• Autologous fat grafting: The Coleman technique produces acceptable cosmetic results in most cases (Coleman SR et al 2015).

Skeletal reconstruction:

• Bone paste cranioplasty, bone implants, bone/cartilage grafts, and orthognathic surgery have variable success rates.

Free soft tissue grafting:

• Commonly used for large volume reconstructions. Commonly used flaps include the greater omentum, lateral femur, parascapular muscles, latissimus dorsi muscle, and dorsal thoracic adipofascial flap. Satisfactory cosmetic results are achieved with this procedure.

The disease reaches the "burn-out phase" within 2 to 20 years after active disease activity. Facial asymmetry is often significant and results in severe disfigurement. Ocular manifestations, ranging from uveitis to keratitis to retinal pathology, require active management. Repeated episodes of uveitis or retinal vasculitis can lead to secondary glaucoma, with variable visual prognosis. The neurologic manifestations are often well controlled and cause little disability.

PRS cases may present in ophthalmology, neurology, or dermatology clinics. These cases require multidisciplinary evaluation and treatment. Therefore, a coordinated team approach involving neurologists, ophthalmologists, rheumatologists, dermatologists, radiologists, plastic surgeons, pharmacists, and other concerned specialties is essential depending on the needs of the patient.

This disease is characterized by primary atrophic transformation of the affected subcutaneous tissue, muscle and bone. Fibrosis is not or rarely observed. This disease often begins in adolescence and childhood in the head region (see section "Features in childhood") and then increasingly affects cheek muscles, bones and also the tongue (Sommer et al, 2006; Tollefson 2007). This results in a sometimes pronounced asymmetry of the face. The simultaneous occurrence of linear circumscritic scleroderma of the "en coup de sabre" type and progressive facial hemiatrophy is described relatively frequently, with a coincidence of up to 40% (Jablonska 1975a). In the classification proposed by the authors, it is therefore also listed among the linear forms, although in the case of pure involvement of extracutaneous structures, classification as a "deep form" is also possible. Involvement of the central nervous system is not infrequently observed (see section on "Apparative Diagnostics"). Antinuclear antibodies are detected in this subtype in up to 50% of patients.

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