Congenital ankyloblepharon in a newborn with an IRF6 mutation

Abstract

We present the case of a boy born at 41 weeks’ gestational age who was found to have multiple anatomic anomalies, including abnormalities of the oral cavity, eyelids, and digits. He had ankyloblepharon that was localized to the lateral portion of the palpebral fissure bilaterally. Genetic testing confirmed a mutation in the interferon regulatory factor 6 (IRF6) gene, a known etiology for a spectrum of rare disorders that includes eyelid abnormalities. We present a novel surgical technique for bedside ankyloblepharon repair and describe the relevant clinical features of this case.

Case Report

A boy born at 41 weeks’ gestational age by Caesarean delivery was noted to have multiple anatomic abnormalities, including bilateral ankyloblepharon, oral adhesions, incomplete cleft palate, webbing of the fourth and fifth toes, and excess tissue folds on the great toes. No genitourinary or gastrointestinal abnormalities were noted; the patient was hospitalized for nutritional support. The ophthalmology service was consulted on the patient’s third day of life for bilateral interrupted ankyloblepharon, partial fusion of the eyelids by webs of skin between the upper and lower eyelids (Figure 1). On examination, the patient blinked to light and the eyes were soft to palpation bilaterally. The anterior and posterior segment examinations were otherwise unremarkable.

FIG 1.

Right (A) and left (B) ankyloblepharon prior to surgical removal. Tissue adhesions are evident in the lateral palpebral fissures. Skin folds over the nail beds (C) and oral adhesions (D) were also present at birth. Both eyes immediately following ankyloblepharon repair (E).

Multiple specialty teams worked collaboratively to address his anatomic anomalies, provide nutritional support, and identify the underlying genetic etiology. Genetic testing ultimately identified a mutation of the interferon regulatory factor 6 (IRF6) gene (c.250C>T, p.Arg84Cys, heterozygous), resulting in a diagnosis of popliteal pterygium syndrome. Of note, this patient’s parents are nonconsanguineous, and there is no known family history of orofacial anatomic anomalies. Parental genetic testing has not yet been completed.

Ankyloblepharon removal was indicated to allow palpebral excursion, avoid corneal irritation, and prevent deprivation amblyopia. Bedside removal of ankyloblepharon was performed (Video 1, available at jaapos.org). Both eyes and eyelids were anesthetized with topical proparacaine drops and topical lidocaine to the eyelid margin and tissue adhesions. The eyelid and surrounding periorbital skin were prepared with povidone-iodine 5% sterile ophthalmic prep solution. Two 6–0 polyglactin 910 sutures with needle removed were threaded simultaneously and passed posterior to each adhesion using a Weber Lewis lens loop. An alternative instrument for this maneuver is the Gass muscle hook, especially if there is limited space between the ankyloblepharon adhesions and the canthus. The two sutures were then hand tied at the point of connection between the web and the lid margin, at both the upper and lower eyelid. On the left eyelid, the sutures cheese-wired through the thin adhesions. On the right eyelid, the adhesions were thicker, and after suture tying, blunt-tipped Westcott scissors were used to cut the web between the upper and lower sutures. Bleeding was noted on the left side following the cheese-wire incision, which resolved quickly with localized pressure using cotton tipped applicators. The right eyelid, with suture hemostasis prior to Wescott incision, had no bleeding and no residual skin tags. The patient was able to open his eyes spontaneously immediately following the procedure.

The patient was examined 3 months following the procedure to assess vision and postoperative healing. At this visit, the patient was doing well, with age-appropriate vision and tracking and normal dilated fundus examination and cycloplegic refraction.

Discussion

Ankyloblepharon includes a range of phenotypes, from complete lid fusion to sparse tissue strands between the eyelids. It can be classified into five types based on associated anomalies: none, central nervous system and/or cardiac, ectodermal syndromes, cleft lip and/or palate only, or chromosomal syndromes.^1,2 Ankyloblepharon in neonates is frequently addressed with bedside removal, as in our own patient.³ In the surgical video, we demonstrate a novel technique using suture hemostasis prior to ankyloblepharon removal. This approach may be favorable for removal of ankyloblepharon involving thicker webs of tissue adhesions. For thin webs, simple lysis is appropriate.

The IRF6 gene encodes a transcription factor involved in craniofacial and skin development. Mutations in IRF6 can lead various disorders, including Van Der Woude and popliteal pterygium syndromes.⁴ Van Der Woude syndrome is autosomal dominant and involves mild anomalies of the oral cavity, most notably cleft lip and palate. Prevalence estimates range from 1 in 30,000 to 1 in 100,000.⁵ Popliteal pterygium syndrome can be sporadic or autosomal dominant, with incomplete penetrance, and manifests with abnormalities in orofacial, ocular, limb, digit, and genital development. These include popliteal webbing (known as “popliteal pterygium” and not to be confused with pterygia of the ocular surface), cleft lip and palate, syndactyly, skin folds over the nail beds, and defects of the external genitalia (scrotum or labia). Popliteal pterygium syndrome is strongly associated with ankyloblepharon. This syndrome is estimated to have an incidence of 1 in 300,000 live births with marked phenotypic variability.^6,7 Our patient did not have a family history of ankyloblepharon or associated findings, suggesting that the patient likely has a de novo mutation.

Similar clinical presentations have been associated with other disorders including BartsocasPappas, Hay-Wells, and CHAND syndromes. The unique clinical features, associated genes, and severity are illustrated in Figure 2.

FIG 2.

Ankyloblepharon-associated diseases inheritance patterns and associated features, based on increasing overall severity.

Although diverse genetic mutations underlie the ankyloblepharon-related syndromes summarized in Figure 2, all of the genes implicated are critical for proper cell signaling and fetal development. Mutations in the RIPK4 gene, which encodes a receptor serine-threonine kinase can cause type 1 Bartsocas-Pappas and CHAND syndromes.⁸ CHUK encodes a protein that regulates ubiquitous transcription factors ⁹. Mutations in CHUK can cause type 2 Bartsocas Pappas syndrome. Tumor protein 63 (TP63) gene, a transcription factor involved in cell growth and differentiation, can cause Hay-Wells syndrome when mutated. Therefore, all of the underlying genetic causes of this family of diseases have key roles in cell differentiation and development. Despite this common genetic theme, there are clinically important differences. For example, Bartsocas-Pappas is often lethal in utero or in the neonatal period because of extensive ectodermal abnormalities and growth restriction. Patients with less lethal ankyloblepharon-related syndromes face nutritional and respiratory challenges associated with varying degrees of orofacial abnormalities. Popliteal pterygium syndrome, in which children are more likely to survive the neonatal period, causes mobility issues due to webbing across a major joint.

Genetic counseling is essential to help patients understand the implications of the syndromes outlined above. For example, some forms of popliteal pterygium, Van der Woude, and Hay-Wells syndromes are autosomal dominant, although with variable expressivity. Penetrance is higher and better studied in Van der Woude syndrome (>80% penetrance) compared with popliteal pterygium and Hay-Wells syndromes, which are simply known to have incomplete penetrance.¹⁰ A thorough family history and interpretation of genetic testing can help families understand the implications of a given diagnosis and how traits may be passed on in future generations.

Interdisciplinary collaboration optimizes patient care in complex ankyloblepharon-associated systemic disease. Pediatric genetic subspecialists suggested custom genetic testing, which yielded the diagnosis of popliteal pterygium syndrome. They also recommended a skeletal survey (which was within normal limits), given the possible disorders that could account for our patient’s clinical presentation. Genetic counselors provided information about testing, prognosis, and family planning. Otorhinolaryngology performed lysis of oral adhesions and lingual frenulotomy and continued monitoring of his incomplete cleft palate. The patient’s primary care pediatrician, in conjunction with pediatric otorhinolaryngology, is closely monitoring his nutritional intake and growth trajectory. Pediatric development specialists are involved in his care to follow his neurodevelopmental and social needs.