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1 These authors have contributed equally to this work and share first authorship
Affiliations
Department of Plastic and Reconstructive Surgery, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United KingdomInstitute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom
1 These authors have contributed equally to this work and share first authorship
Fiona N. Smith
Footnotes
1 These authors have contributed equally to this work and share first authorship
Affiliations
Department of Plastic and Reconstructive Surgery, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom
1 These authors have contributed equally to this work and share first authorship
Chang W. Lee
Footnotes
1 These authors have contributed equally to this work and share first authorship
Affiliations
Department of Plastic and Reconstructive Surgery, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom
Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne NE1 7RU, United KingdomDepartment of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom
Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne NE1 7RU, United KingdomDepartment of Paediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom
Department of Plastic and Reconstructive Surgery, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency, typically associated with clinical features of intractable diarrhoea, type 1 diabetes mellitus and eczema. We present a case of IPEX syndrome referred to our regional facial palsy service for smile restoration surgery. The patient presented with dissatisfaction of facial appearance, including mask-like facies and no functional smile. Pre-operative electromyography confirmed normal temporalis muscle activation. Consequently, the patient was offered single-stage bilateral lengthening temporalis myoplasties. The patient reported improved satisfaction with facial appearance. Surgery resulted in good early resting and voluntary symmetry. Oral commissures were elevated at rest improving oral incompetence. This is the first description of facial animation surgery in the context of IPEX syndrome. With careful consideration and patient selection, successful surgical restoration of resting symmetry and dynamic commissural smile can be achieved in this complex cohort of patients.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency caused by hemizygous mutations of the forkhead box protein 3 (FOXP3) gene, a critical regulator of regulatory T cells (Tregs) which is associated with typical clinical features of intractable diarrhoea, type 1 diabetes mellitus and eczema.
Here we present our experience of facial reanimation surgery to improve oral competence and reconstruct active smile in an adolescent post-haematopoietic stem cell transplant (HSCT) patient with IPEX syndrome complicated by a bilateral developmental facial palsy. To our knowledge, this is the first report of facial reanimation surgery for this specific atypical feature of IPEX syndrome - providing evidence of successful smile reconstruction in this complex patient group.
Case report
Our patient was well known to the regional pediatric immunology service - originally presenting shortly after birth with intractable diarrhea, recurrent infections, eczema and failure to thrive. Features of generalized low muscle tone and weakness were noted at this time, including notable “myopathic facies”. Initial investigations revealed haemolytic anaemia, eosinophilia and raised IgE levels. Small bowel biopsies demonstrated typical features of villous atrophy and lymphocytic infiltration. An “IPEX-like” syndrome was suspected and at age 10 months the patient received a successful HSCT from an unrelated female donor.
Enteral feeding via a percutaneous endoscopic gastrostomy (PEG) tube was commenced, as well as fundoplication for significant gastro-oesophageal reflux. The PEG tube was eventually reversed aged 13 years with the patient on soft diet. Despite these interventions his facial muscle weakness and fatigue persisted (without significant progression) post-HSCT. Over subsequent years, extensive investigations were carried out to exclude an underlying congenital myopathy. However, peripheral nerve conduction and electromyography (EMG) studies, thigh muscle biopsies and genetic screening studies all appeared normal. Subsequent genetic profiling confirmed a truncating nonsense mutation of FOXP3 (c.*876A>G (5)) and a definitive diagnosis of IPEX syndrome was made.
The patient was referred to the regional facial palsy service aged 17 years, for consideration of facial reanimation surgery. His ongoing complaints were psychosocial and aesthetic in nature – namely low mood and social withdrawal, as well as dissatisfaction with facial appearance. Additional functional complaints included drooping of the lower lip, with associated drooling of saliva and poor vocal projection. Clinical examination revealed a mask-like facial appearance with malar flattening, absent facial creases and permanently exposed teeth (Figure 1A.). There was bilateral absence of eyebrow raise, lip pucker and smile (Figure 1B.), but notable preservation of orbicularis oculi muscle function and asymmetrical preservation of lower lip depressor function bilaterally - preserving functional eyelid closure and contributing to lower lip ptosis, respectively. Composite scores using the Sunnybrook Facial Grading System were consistent with significant palsy of mimetic facial nerve innervated muscles bilaterally (Composite score of 21 (Scale 0-100: 100 = normal facial function)). There was bilateral preservation of extraocular muscle function, including lateral recti muscles, as well as active temporalis and masseter muscle function - indicating no clinically apparent 3rd to 6th cranial nerve involvement. Subsequent EMG studies revealed abnormal distant activity of orbicularis oculi and orbicularis oris, with normal and independently activating temporalis.
Figure 1(A-B) Upper row. Pre-operative images of bilateral developmental facial palsy demonstrating appearance at rest (A) sand during voluntary smile (B). There was minor asymmetry with preservation of orbicularis oculi and lower lip depressor function, indicating an incomplete facial palsy. (C-D) Lower row. Post-operative images at 3 months following bilateral lengthening temporalis myoplasties demonstrating improved malar contour, nasolabial fold and oral commissure position at rest (C) with improved symmetry on voluntary movements; including smile (D).
The patient's goal was to improve facial appearance - exploring options to improve facial expression in general and create active smile. As he had no functional smile muscles, he was counselled about the two main surgical options used for importing functional muscle and creating a dynamic commissural smile – a single-stage bilateral regional muscle transfer (lengthening temporalis myoplasties) or a two-stage free muscle transplant (microneurovascular gracilis muscular transfer, coapted to the nerve to masseter on each side). The advantages of lengthening temporalis myoplasties include a single operative procedure, shorter operative time, quicker post-operative recovery and earlier visible surgical results. The major disadvantages of microneurovascular gracilis muscular transfer include two operative procedures, longer operative time and post-operative recovery and, specifically in this case, a dependence on quality nerve re-innervation in a patient with clinical and neurophysiological features suggestive of developmental facial nerve palsy. The patient opted for single-stage bilateral lengthening temporalis myoplasties.
Following thorough pre-operative assessment, the patient underwent single-stage facial reanimation surgery with bilateral lengthening temporalis myoplasties under general anaesthetic (as previously described
). Unexpected intraoperative findings included abnormally short and weak temporalis tendons, which required bilateral zygomatic arch osteotomies for exposure and fascia lata grafts from the left thigh in order to augment and lengthen them. The fascia lata grafts were weaved into the temporalis muscle and temporalis tendons and sutured distally to the oral commissure and upper lip. The remainder of the procedure was uneventful.
The patient was discharged on day 4 post-operatively following a planned and uneventful post-operative admission to the surgical high dependency unit for nasal non-invasive ventilation. Soft diet was recommended for 7 days post-operatively. Specialist physiotherapy-directed facial re-training was commenced at 4 weeks - to overcome trismus, optimize symmetry and encourage contraction of temporalis muscles without teeth clenching. At 3 months, good early resting and voluntary symmetry were noted - with marked improvements in malar flattening, nasolabial fold definition and lower lip ptosis (Figure 1C-D.). Post-operative elevation of the oral commissures at rest, compared to the pre-operative state, improved oral incompetence (Figure 1C.). Subjectively, the patient reported improved satisfaction with facial appearance at this early stage.
Discussion
A plethora of atypical features of IPEX syndrome have been described,
A retrospective, multicenter review by Barzaghi et al identified 16% (16/96) patients with neurological findings, including: peripheral neuropathy, myopathies/hypotonia, hemi-diaphragmatic paralysis, eosinophilic meningitis, neurodevelopmental delay, seizures, and benign intracranial hypertension.
Clinical, immunological, and genetic features in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like syndrome.
Tregs isolated from CIDP patients express lower levels of FOXP3 mRNA and active phases of CIDP are associated with reduced numbers of Tregs and suppressed Treg function.
In addition, Treg deplete mouse models of experimental autoimmune neuritis have demonstrated an inverse relationship between Treg levels and severity in the early stages of neuritis.
Taken together, these findings could indicate that, in our patient, HSCT may have been adequate to stem further progression of his developmental facial palsy but without subsequent recovery of any pre-existing weakness. This observation, together with more generalized features of muscle weakness (which also failed to progress further into adulthood), suggest that the facial features may be part of more generalized neuro-myopathic consequences of early Treg depletion in this individual. Why the facial nerve innervated muscles were more sensitive in this case is not known, but this hypothesis may also explain the surgical findings of shortened and underdeveloped temporalis tendons bilaterally.
Conclusion
We report the first description of facial reanimation surgery in the context of IPEX syndrome. With careful consideration and patient selection, successful surgical restoration of resting symmetry and dynamic commissural smile can be achieved in this patient cohort. The lengthening temporalis myoplasty offers the advantages of a single surgical procedure, shorter operative times, a relatively short in-patient stay and predictable outcomes
Lengthening temporalis myoplasty versus free muscle transfer with the gracilis flap for long-standing facial paralysis: A systematic review of outcomes.
Clinical, immunological, and genetic features in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like syndrome.
Lengthening temporalis myoplasty versus free muscle transfer with the gracilis flap for long-standing facial paralysis: A systematic review of outcomes.
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