Unilateral High Intraocular Pressure, Cataract, and Retinal Detachment in Waardenburg Syndrome

Waardenburg syndrome was first described in 1951 by Dutch ophthalmologist Petrus Johannes Waardenburg (1886-1979). It is an auditory-pigmentary syndrome that results from a lack of melanocytes in the hair, skin, eyes, or stria vascularis of the cochlea. It accounts for more than 2% of congenitally deaf individuals [1]. Affected people usually have neurosensory hearing loss, forelock pigmentation loss, iris heterochromia, and medial canthus dystopia, and their first-degree relatives have the same features of this syndrome [2]. There are now four types of Waardenburg syndrome, each with its own set of clinical characteristics. Dystopia canthorum, sensorineural hearing loss, iris pigmentary abnormalities, and hair hypopigmentation are all features of type 1. The presence or absence of dystopia canthorum distinguishes Waardenburg syndrome types 1 and 2, respectively. Type 3 (Klein Waardenburg syndrome) is similar to type 1 with added musculoskeletal abnormalities. The presence of an aganglionic megacolon characterizes type 4 (Shah Waardenburg syndrome, also known as Waardenburg Hirschsprung disease). It can be difficult to make a definitive diagnosis of Waardenburg syndrome because it appears in a multitude of ways [3]. PAX3 gene mutations are responsible for type 1 and type 3 while MITF or SNAI2 gene mutations are responsible for type 2 Waardenburg syndrome. Type 4 Waardenburg syndrome is due to mutations in the SOX10, EDN3, or EDNRB genes [4]. Most cases of Waardenburg syndrome types 1 and 2 are inherited as autosomal dominant, type 3 could be sporadic or autosomal dominant, and type 4 is inherited as autosomal recessive [5]. Waardenburg syndrome has a distinctive diagnostic criterion. To diagnose Waardenburg syndrome, five major and five minor diagnostic criteria should be established. The major criteria include sensorineural hearing loss, a white forelock, dystopia canthorum, iris pigmentation disturbance, and first-degree relatives diagnosed with Waardenburg syndrome. Minor criteria include congenital skin hypopigmentation, medial eyebrow flare (synophrys), hypoplastic alae nasi, prominent broad nasal root, and premature graying of hair before the age of 30 years. The clinical diagnosis of Waardenburg syndrome requires at least two major criteria or one major and two minor criteria [6]. Studies that report the ocular manifestations in Waardenburg syndrome are few. We report a case of a 25-year-old male who presented with characteristic features of Waardenburg syndrome along with high intraocular pressure (IOP), cataract, and retinal detachment (RD) in one eye.

A 25-year-old male presented for eye examination due to gradual loss of his left eye visual acuity over the last few years. According to the patient and his family, these findings were present since early childhood when it was noticed that he was unable to fixate with the left eye. The patient had now presented hoping that intervention at this age would help. The patient reported no history of trauma or ocular surgery or intervention of any sort. Family mentioned that he has had poor vision since childhood. On examination, he had distinctive facial and body abnormalities. The patient had abnormal skin coloration with areas of hypopigmented hair on both his forearms. His face showed synophrys with high nasal root, a prominence of the root of the nose and a white forelock of hair (Fig. 1a). His mouth showed a high-arched palate with dental aberrations (microdontia, oligodontia, and conical teeth). The patient did not have any hearing deficit and family history was negative. The patient has lateral displacement of the inner canthi (dystopia canthorum). The patient had 6/6 vision in the right eye and no light perception in the left eye. At presentation, the IOP was 21 mm Hg in the right eye and 41 mm Hg in the left eye. Pupil examination was normal in the right eye, however, the left eye showed a small constricted pupil. Slit lamp examination of the right eye showed normal conjunctiva, sclera, and anterior chamber depth with segmental heterochromia (without iris transillumination defect) and clear crystalline lens (Fig. 1b). Slit lamp examination of the left eye showed clear cornea, deep and quiet anterior chamber with complete iris hypochromia, a small area of iris transillumination defect and mature cataract. There were no signs of previous trauma or intraocular inflammation (Fig. 1c). Gonioscopy showed an open angle without peripheral anterior synechiae (PAS) and with normal angle pigmentation of the left eye (Fig. 1d). Fundus examination was normal in the right eye with a cup/disc ratio of 0.1 but there was no view to the left eye fundus due to mature cataract. B scan of the left eye showed RD (Fig. 1e). Right eye visual field examination and optic disc optical coherence tomography were within normal limit, the high IOP of the left eye was controlled by topical aqueous suppressants eye drops on the next clinic follow-up visit. Due to financial reasons, genetic testing could not be performed.

Waardenburg syndrome is a rare genetic disorder characterized by varying degree of neurosensory hearing loss, hypopigmentation, and defects in structures that originate from neural crest cells. It affects 1 in 42,000 people in the population. Studies that reported the ocular manifestations in Waardenburg syndrome are few. Cortés-González et al. reported an association between posterior microphthalmos and Waardenburg syndrome type 2A while Meire et al. [3] reported a case of Marcus Gunn ptosis with jaw-winking in Waardenburg syndrome. Turkish Waardenburg syndrome type 2 family members showed a distinctive fundus picture with ipsilateral connections between iris, fundus, and perhaps, inner ear pigmentation which could be a result of a failure of pigmented melanocytes distribution within their anatomical sites [7]. Glaucoma is another reported association with this syndrome. Open-angle glaucoma has been reported, as well as bilateral open-angle glaucoma with bilateral iris hypochromia. Kadoi and Hayaska in 1996 reported a case with elevated IOP and branch retinal vein occlusion while Nork et al. reported a case with advanced bilateral glaucoma and narrow iridocorneal angles in Waardenburg syndrome [8, 9]. Juvenile open-angle glaucoma has also been reported in a 20-year-old Egyptian man with Waardenburg syndrome [10]. Although glaucoma has not been considered as an associated characteristic of Waardenburg syndrome, a possible mechanism could be that ocular melanocytes may be derived from the neural crest and that a defect in pigmentation may therefore lead to developmental abnormalities in these structures. The iridocorneal angle structures are largely of neural crest origin, which may support the association of glaucoma with Waardenburg syndrome [3]. Congenital cataract is not a usual association with Waardenburg syndrome, but bilateral lamellar cataract was the presenting feature in 1 patient with Waardenburg syndrome that required surgical intervention [11]. All types of Waardenburg syndrome are usually associated with iris and choroidal hypopigmentation, but choroidal malignant melanoma and fundus vasoproliferative tumors have also been reported in Waardenburg syndrome [12‒14]. RD was a B scan finding. RD is not known to be associated with Waardenburg syndrome. All possible causes of RD were excluded by history, examinations, and investigations. Persistent fetal vasculature defects include glaucoma, cataract, falciform retinal folds, funnel- or stalk-shaped RD, spontaneous fundus hemorrhage, and a congenitally small eye [15]. Neogenin is a transmembrane receptor critical for multiple cellular processes, including neurogenesis, astrogliogenesis, endochondral bone formation, and iron homeostasis. Selective loss of neogenin in neural crest cells results in a dysregulation of neural crest cell migration or delamination, exhibiting features of PHPV-like pathology (e.g., elevated retrolental mass), unclosed retinal fissure, and microphthalmia [16]. Waardenburg syndrome originates from neural crest cells as PHPV. The patient presented with cataract, glaucoma, and stalk-shaped RD which are common in PHPV. This case exhibits what is most probably a variant of PHPV in a Waardenburg syndrome patient. Due to the guarded prognosis, a joint decision with the patient was made to avoid surgical intervention. Even though elevated IOP, lamellar cataracts and RD have been reported before with Waardenburg, this is the first case report to our knowledge of a patient presenting with both these findings and a dense cataract. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see www.karger.com/doi/10.1159/000529278).

Waardenburg syndrome is a rare genetic disorder characterized by varying degree of neurosensory hearing loss, hypopigmentation and defects in structures that originate from neural crest cells. Studies that report the ocular manifestations in Waardenburg syndrome are few. We report a case of a 25-year-old male who presented with characteristic features of Waardenburg syndrome along with high IOP, cataract, and RD in one eye.

The assistance provided by Ms. Rana Mahjoub is greatly appreciated.

Research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. This study protocol was reviewed and approved by Saggaf Eye Center Research Ethics Committee; approval number 399. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

There are no conflicts of interest.

The authors did not receive any funding.

All authors contributed to the conception or design of the work and acquisition of the data; drafting the work and revising it critically for intellectual content; final approval of the manuscript for publication and approved the final version of the manuscript to be published. Yahya Al-Najmi wrote the concept and design, Khalid Alsaggaf and Albatool Alghamdi collected the data, Yahya Al-Najmi and Maram E. A. Abdalla Elsayed performed the data analysis and interpretation, and Mohammed Albeedh contributed to critical review of the article and reviewed the manuscript for final approval.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.