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Papillomas in Goltz syndrome: case report, anaesthetic considerations, and review of the literature

Published:January 25, 2019DOI:https://doi.org/10.1016/j.jcjo.2018.12.007
      A 10-year-old Caucasian female with Goltz syndrome (GS) was referred for management of ocular papillomas (Fig. 1A). She was born full-term with multiple congenital dysmorphisms, including syndactyly (Fig. 1B), ear anomalies, hearing loss, generalized vesicular rash, atrial septal defect, and developmental delay. GS was diagnosed clinically and confirmed genetically; parental genetic testing was negative. Surgical history included bilateral myringotomies, tonsillectomy and adenoidectomy for obstructive sleep apnea (OSA), right toe amputation, and multiple papilloma excisions (axilla, ears, and lips).
      Fig. 1.
      Fig. 1Manifestations of Goltz syndrome in our patient. (A) Craniofacial features and dysmorphology demonstrating triangle-shaped facies, atrophic linear skin lesions, low set ears, small pinnae, peg-shaped teeth, left microphthalmos, and medial bulbar conjunctival papillomas with the right significantly larger than left. (B) Right foot syndactyly with lobster claw deformity. (C) Fiberoptic bronchoscopy demonstrating a large papillomatous mass on the right side of her oropharynx, which had increased in size to 3 cm since her last surgery in 2009. (D) Right eye aniridia and palpebral conjunctival papilloma.
      Our patient received eye care since infancy elsewhere, including dacryocystorhinostomy for nasolacrimal duct obstruction; medically controlled congenital glaucoma with drops stopped at age 4, with family reporting no longer necessary; bilateral ectopia lentis, sclerocornea, optic nerve, and macular chorioretinal colobomas; and left eye retinal detachment.
      On examination visual acuity was light perception right eye and no light perception left eye. Both eyes had large conjunctival papillomas causing irritation, and she complained that the right papilloma obstructed her vision, and requested removal.
      Papilloma excision and examination under anaesthesia was planned. Pre-operative anaesthesia consultation was requested due to pre-existing oropharyngeal papilloma enlarging after airway instrumentation for tonsillectomy. Anaesthesiology determined that the patient's airway was reassuring except for a large partially occluding papilloma (Fig. 1C) and multiple small oropharyngeal papillomas; avoidance of endotracheal intubation and airway management with intermittent bag-mask ventilation to minimize further papilloma irritation was recommended. Inhalation induction of general anaesthesia with sevoflurane, maintenance of spontaneous ventilation, and avoidance of airway instrumentation proceeded as planned. With absence of a definite airway, anaesthesia was maintained intravenously with propofol and remifentanil, and intermittent bag-mask ventilation support to provide the surgical access. Paper tape and padding were used to prevent injury to her fragile skin.
      Ocular examination revealed bilateral aniridia and microcornea, with diffuse corneal haze and thick corneas: 616 and 766 microns right and left eyes. Intraocular pressure was 30 and 15 mm Hg right and left eyes (Perkins tonometry). The right lens had posterior subscapular opacities and was dislocated inferonasally with visible zonules superotemporally. The left lens was completely dislocated in the posterior segment. Fundus examination of the right eye showed a chorioretinal coloboma inferiorly and inferonasally; due to corneal haze, cataract, and dislocated lens, retina and optic nerve visualization was difficult. No posterior structures were clearly delineated in the left eye. B-scan ultrasonography confirmed dislocated lenses bilaterally, a right eye chorioretinal coloboma, and left eye chronic retinal detachment. Axial lengths measured 24.33 mm right eye and 13.30 mm left eye.
      The right eye had a large palpebral conjunctival papilloma inferonasally abutting the caruncle, obscuring the visual axis (Fig. 1D). The left eye had a small caruncular papilloma. The papillomas were excised with no complications. Pathological assessment confirmed conjunctival papillomas with marked subepithelial stroma expansion, proliferating stromal cells, and collagen deposition. Unlike typical conjunctival papillomas, the epithelial lining thickness was mildly hyperplastic. No viral cytopathic effects were identified (Fig. 2). The ocular papillomas have not recurred 1 year postexcision, and the elevated intraocular pressure is managed medically. She subsequently received the HPV-9 vaccine.
      Fig. 2.
      Fig. 2Conjunctival papilloma histopathology slides. (A) Microscopic examination at 12.5 × magnification (hematoxylin, phyloxine, and saffron stain) showing a polypoid lesion with mildly hyperplastic conjunctival epithelium and significant stromal overgrowth. (B) Focal stumpy papillary cores at 25 × magnification. (C) High-power view of an area of stromal overgrowth, containing proliferating bland spindle-shaped stromal cells and increased collagen deposition (arrows).
      Goltz syndrome (also known as focal dermal hypoplasia or Goltz-Gorlin syndrome) is a rare multisystem disorder characterized by anomalies of skin (atrophy, linear pigmentation and fat herniation, papillomas, ridged dysplastic nails), skeletal system (limb hypoplasia, syndactyly, polydactyly, oligodactyly), teeth (hypoplastic teeth), and face (facial asymmetry, pointed chin, small underfolded pinnae) due to dysplasia of ectodermal and mesenchymal derived tissues.
      • Gisseman J.D.
      • Herce H.H.
      Ophthalmologic manifestations of focal dermal hypoplasia (Goltz syndrome): a case series of 18 patients.
      • Willetts G.S.
      Focal dermal hypoplasia.
      It is an X-linked dominant disorder caused by PORCN gene mutations (171 different mutations registered in the online PORCN mutation database), with approximately 90% being female and 95% of all cases being de novo mutations; heterozygous nonmosaic male PORCN mutations are presumed lethal.
      • Bostwick B.
      • Fang P.
      • Patel A.
      • et al.
      Phenotypic and molecular characterization of focal dermal hypoplasia in 18 individuals.

      LOVD—Leiden Open Variation Database: porcupine homolog (Drosophila) PORCN. Curators: Maria Paola Lombardi and Raoul CM Hennekam. http://www.lovd.nl/PORCN (accessed Dec. 1, 2018).

      • Lombardi M.P.
      • Bulk S.
      • Celli J.
      • et al.
      Mutation update for the PORCN gene.
      Our case had a de novo c.1021C>T (p.H341Y) mutation, previously reported in only one other patient.

      LOVD—Leiden Open Variation Database: porcupine homolog (Drosophila) PORCN. Curators: Maria Paola Lombardi and Raoul CM Hennekam. http://www.lovd.nl/PORCN (accessed Dec. 1, 2018).

      • Fernandes P.H.
      • Wen S.
      • Suton V.R.
      • et al.
      PORCN mutations and variants identified in patients with focal dermal hypoplasia through diagnostic gene sequencing.
      Approximately 400 GS cases are reported worldwide; prevalence estimates are unavailable.
      • Frisk S.
      • Grandpeix-Guyodo C.
      • Silwerfeldt K.P.
      • et al.
      Goltz syndrome in males: a clinical report of a male patient carrying a novel PORCN variant and a review of the literature.
      Ocular manifestations have been reported with varying incidence between 40% and 77% (Table 1), most commonly ocular colobomas, strabismus, and microphthalmia.
      • Gisseman J.D.
      • Herce H.H.
      Ophthalmologic manifestations of focal dermal hypoplasia (Goltz syndrome): a case series of 18 patients.
      • Tenkir A.
      • Teshome S.
      Goltz syndrome (focal dermal hypoplasia) with unilateral ocular, cutaneous and skeletal features: case report.
      • Thomas J.V.
      • Yoshizumi M.O.
      • Beyer C.K.
      • et al.
      Ocular manifestations of focal dermal hypoplasia syndrome.
      Table 1Ophthalmic findings in Goltz Syndrome.
      Anophthalmia
      Microphthalmia
      Microcornea
      Corneal clouding
      Blue sclera
      Aniridia
      Heterochromia
      Irregularity of the pupils
      Cataract
      Lens subluxation
      Anterior persistent hyperplastic primary vitreous
      Vitreous debris
      Optic atrophy
      Ocular colobomas (retina, choroid, optic nerve)
      Retinal pigment changes
      Retinal neovascularization
      Ectropion
      Ptosis
      Hyperteleorism
      Strabismus
      Nystagmus
      Papillomas of conjunctiva and eyelid
      Blocked lacrimal drainage
      The least commonly reported ocular finding in GS is conjunctival and eyelid papillomas (5% in the largest case series).
      • Gisseman J.D.
      • Herce H.H.
      Ophthalmologic manifestations of focal dermal hypoplasia (Goltz syndrome): a case series of 18 patients.
      Conjunctival papilloma is a benign epithelial tumour with prominent intrinsic vascularity; they frequently show exophytic growth pattern but can exhibit mixed or rarely an inverted growth pattern, the latter having a greater tendency for malignant transformation into transitional cell, squamous cell, or mucoepidermoid carcinoma.
      • Kaliki S.
      • Arepalli S.
      • Shields C.L.
      • et al.
      Conjunctival papilloma.
      A causal relationship between human papillomavirus (HPV) and conjunctival papilloma has been documented in 5%–45% of cases.
      • Kaliki S.
      • Arepalli S.
      • Shields C.L.
      • et al.
      Conjunctival papilloma.
      Conjunctival papillomas are most commonly associated with low-risk HPV strains 6 and 11, especially in children, and rarely with high-risk HPV strains.
      • Kaliki S.
      • Arepalli S.
      • Shields C.L.
      • et al.
      Conjunctival papilloma.
      Treatment options include observation; however if lesions are irritating, cosmetically unacceptable or obscuring vision, they can be excised, with or without use of cryotherapy. Recurrence rate after removal ranges between 3% and 27%, possibly more common in children and limited by adjuvant oral cimetidine and/or topical interferon alfa-2b.
      • Kaliki S.
      • Arepalli S.
      • Shields C.L.
      • et al.
      Conjunctival papilloma.
      HPV-9 vaccine, which includes the serotypes associated with conjunctival papillomas, may reduce papilloma recurrences,
      • Dion G.R.
      • Teng S.
      • Boyd L.R.
      • et al.
      Adjuvant human papillomavirus vaccination for secondary prevention. A systematic review.
      with anecdotal reduced recurrences in GS.
      There is limited information in the literature concerning anaesthesia in GS.
      • Smith S.
      • Gadhok K.
      • Guvakov D.
      An unexpected airway complication in a male patient with Goltz syndrome.
      • Martinez M.A.
      • Mayhew J.F.
      Anesthesia for a child with Goltz syndrome.
      • Holzman R.S.
      Airway involvement and anesthetic management in Goltz's syndrome.
      Papillomas in the airway and hypertrophy of the gums and buccal mucosa
      • Kaliki S.
      • Arepalli S.
      • Shields C.L.
      • et al.
      Conjunctival papilloma.
      can complicate airway management. Irritation of papillomas or tissues in the upper airway can trigger rapid growth of papillomas, making airway instrumentation a concern, as in our patient.
      • Smith S.
      • Gadhok K.
      • Guvakov D.
      An unexpected airway complication in a male patient with Goltz syndrome.
      • Martinez M.A.
      • Mayhew J.F.
      Anesthesia for a child with Goltz syndrome.
      Most previous reports describe unanticipated difficult airway due to unexpected papillomas. Anaesthetic management of these patients may require preoperative awake fiberoptic airway assessment. Maintenance of spontaneous ventilation and avoidance of airway instrumentation can minimize airway trauma, thus preventing new papilloma formation. Children with GS are prone to OSA. A case series of 18 GS patients demonstrated that 93% reported OSA symptoms, with 87% requiring tonsillectomy, similar to our case.
      • Bostwick B.
      • Fang P.
      • Patel A.
      • et al.
      Phenotypic and molecular characterization of focal dermal hypoplasia in 18 individuals.
      Presence of fragile skin with chronic scarring in GS requires careful tissue handling and intravenous line placement.
      In summary, we describe conjunctival papillomas, a less commonly recognized ophthalmic finding in GS. Our case report emphasizes the anaesthetic risks an ophthalmologist may otherwise unknowingly encounter in bringing a patient with GS to the operating room. We recommend a mandatory pre-operative anaesthetic consultation for all GS patients to limit possible anaesthetic complications in this population who often require multiple surgeries.

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