Juvenile Open-angle Glaucoma With Waardenburg Syndrome: A Case Report

Waardenburg syndrome (WS) is a genetic disorder resulting in anomalies of derivatives of neural crest cells during development. Patients tend to have variable degrees of pigmentary defects affecting skin, hair, and irides in addition to hearing loss and possible systemic neurological associations. Elevation of the intraocular pressure has been reported in several adult patients with WS. We report the first case of WS to be associated with juvenile open-angle glaucoma in a 20-year-old Egyptian man thus expanding the spectrum of the types of glaucoma that can coexist with the syndrome.

(J Glaucoma 2021;30:e1-e4) W aardenburg syndrome (WS) is a rare genetic disorder characterized by anomalies in some of the structures developing from the neural crest. 1 Clinical findings of the disease involve different degrees of pigmentary defects of the hair, skin, and irides in addition to sensorineural hearing loss. 2 Depending on the presence or absence of certain phenotypic variations, WS was further divided into 4 main types (WS1, WS2, WS3, and WS4) according to the Arias classification in 1971, 3 whereas identification of genetic mutations subdivided some of these types such as types 2A to 2E and types 4A to 4C. 4 In his first report of the syndrome in 1951, Petrus Johannes Waardenburg described 6 main features including telecanthus (which differentiates WS1 from WS2), broad nasal root, synophrys, white forelock, various degrees of heterochromia irides, and finally deaf-mutism. 5 Type 3 WS is associated with limb anomalies, mainly of upper limbs 6 while in type 4 the patient suffers from Hirschsprung disease. 7 Most types of WS show autosomal dominant inheritance with some showing autosomal recessive pattern. 4 Additional ophthalmic features that have been recorded include various degrees of fundus depigmentation, refractive errors, and glaucoma. [8][9][10] The latter has been reported in some patients, [11][12][13] including the first patient, yet it has never been classified as one of the features of the disease. 5 Whether it is an association or a mere coincidence is yet to be determined through detailed studying of a large series of patients which is difficult due to the rare nature of the disease (estimated prevalence of about 1 in 42,000). 14 Glaucomas in previous WS patients' reports were of open-angle glaucoma in adults. 5,[11][12][13] Here we report a case of juvenile open-angle glaucoma (JOAG) in a 20-year-old man with WS which, to date, has never been reported before.  Fig. 2A), which was expected with such degrees of myopia that the patient had, with some embryonic features in some quadrants in the form of high iris insertion obscuring the trabecular meshwork and pathologic long iris processes (Fig. 2B). The quadrants of significantly hypopigmented trabecular meshwork coincided with the sectors of iris hypochromia (superiorly). Dilated examination revealed bilateral clear lenses and advanced glaucomatous cupping of almost 1.0. Both fundi were of albinotic appearance with diffuse hypopigmentation throughout the choroid without localized areas of selective color changes.

CASE REPORT
Systemic history taking revealed congenital, profound, bilateral sensorineural hearing loss with zero repeat diminution resulting in a deaf-mute state. There was no history of any neurological or gastrointestinal problems. The patient denied steroids intake as well as previous ocular trauma or surgery. Apart from a positive family history of glaucoma in the father only, there were no other family members with known history of glaucoma or phenotypic features suggestive of WS which agrees with the de novo mutation patterns seen in some of the families of affected patients. 15,16 On systemic examination, there were no signs of skin or hair hypopigmentation or hyperpigmentation or any limb structural anomalies. Taking into consideration the sensorineural hearing loss, the striking sectoral irides pigmentary defects and the lack of telecanthus and intestinal motility problems, a diagnosis of WS2 was reached. The high myopia does not come as a surprise in this patient since different refractive errors have been described with the syndrome including anisometropia, astigmatism and high myopic errors associated with albinotic fundi. 17,18 The superior sectoral irides hypopigmentation have been recorded before in the literature 13,19,20 and in some of the cases was associated with a superior corresponding sector of choroidal depigmentation. 20 In our case, it was the superior angle that showed similar pigmentary defects and not the choroid. The patient's glaucoma was categorized as JOAG owing to the age of presentation, the lack of features suggestive of congenital glaucoma such as megalocorneas and Haab's striae 21 and the absence of any cause for secondary glaucoma such as inflammation, steroids or trauma. Also, the embryonic-like features of some quadrants on gonioscopy agrees with angle anomalies seen in a subset of JOAG patients. 22,23 The patient was scheduled for sequential nonpenetrating sutureless deep sclerectomy surgeries in both eyes which were uneventful. Postoperative IOPs have been stable since the surgeries DOI: 10.1097/IJG.0000000000001676 at an average of 18 and 16 mm Hg in the right and left eyes respectively on prostaglandin analogue drops.

DISCUSSION
WS is caused by genetic mutations that affect the division and migration of Neural Crest Cells (NCCs) during embryonic stages of development. 15 The NCCs give rise to melanocytes as well as structures in the inner ear, cartilage, and bone. 24 Type 1 of WS, which is the most common type, is caused by mutations of the PAX3 gene resulting in telecanthus, complete or sectoral heterochromia iridum (giving characteristic bright blue appearance), high nasal bridge, flat tipped nose, small alae of nostrils, unibrow, and patches of skin depigmentation. 25 According to the criteria needed for diagnosis of WS, 26 our patient has 2 major criteria and lacks the abnormal increased distance between both medial canthi which categorizes him as WS2, the second most common type of WS. 4 Most of these cases are caused by a mutation in MITF gene 27 where sensorineural hearing loss is more common and more profound compared with WS1. 28 Reports of WS2 due to mutations of SOX10 gene described patients with multiple neurological deficits such as nystagmus and muscle tone anomalies which were not present in the patient discussed here. Type 3 of WS, also known as Klein-Waardenburg syndrome, represents a more severe form of WS1 PAX3 gene mutation characterized by prominent limb and muscular anomalies in addition to microcephaly and developmental delays. Type 4 WS, Shah-Waardenburg Syndrome, is the least common form in which there is congenital lack of intestinal nerves leading to bowel dysfunction. 15 Glaucoma has not been listed as one of the main findings in WS. 5 On reviewing the literature, there has been previous reports of open-angle glaucomas in adult WS patients [11][12][13] but there has been no reports of JOAG in association with WS. JOAG is known to be associated with positive family history of glaucoma and an early age of onset beyond the age of 5 years which explains the absence of buphthalmos findings seen in congenital glaucomas. 21,22 The patient discussed in this report presented late with diminution of vision due to advanced cupping from prolonged periods of elevated IOP which is very characteristic of JOAG patients. 28,29 The insidious onset and asymptomatic nature of the disease make routine, regular full ophthalmological examination of children mandatory for early detection of the disease. Gonioscopic examination of JOAG is usually normal, yet anomalies such as long iris processes with dysplastic trabecular meshwork 23 can be occasionally seen like the patient described above.
Unlike the primary open-angle glaucoma seen in adults, surgical reduction of the IOP is the ultimate solution for persistently elevated IOP in JOAG where medical therapy represents a temporary measure til the date of the surgery. 21 Nonpenetrating deep sclerectomy in such patients has been proven to be successful in controlling the IOP 30 while avoiding  the hypotony and bleb-related complications seen with trabeculectomy in young patients. 31 The patient was referred for genetic counselling.
To date, gene mutations affecting the MYOC 32,33 and CYP1B1 34 genes have been identified as causative factors of JOAG. The genetics behind WS and JOAG are still unravelling. Due to lack of previous reports or studies on both diseases occurring together, it is not known if the 2 disease entities are connected or if it is just a coincidence of 2 unrelated diseases coexisting in the same patient. During embryonic development, NCCs share in the development of the trabecular meshwork. 35 It is now known that NCCs disruption, which is responsible for phenotypic features of WS, 1 is also the cause behind development of anterior segment dysgenesis syndromes and primary congenital glaucoma. 35 The stromal iris hypoplasia and dysmorphic features of the superior angle of our patient, which are seen in some kinds of anterior segment dysgenesis syndromes, 35 may be suggestive of a similar developmental anomalies related to NCCs disruption and angle dysgenesis. Therefore, mutations affecting such cells may result in multiple disorders throughout the body simultaneously. Regarding the patient in concern, one of the parents had primary open-angle glaucoma yet there were no other members of the family suffering from glaucoma or having any features of WS. The modes of inheritance of the 2 diseases (JOAG 22 and first 3 types of WS 4 ) are similar (autosomal dominance) and a connection between the 2 is yet to be determined through further genetic studies that screen for glaucoma gene mutations (MYOC and CYP1B1) in WS patients.

CONCLUSION
WS is a rare genetic disorder affecting the development of neural crest cells during embryonic stages of development resulting in various degrees of pigmentary albino-like defects and hearing loss. Over the past decades, documentation of reported cases revealed a considerable range of phenotypic variations among the affected patients according to different genetic mutations. Even though it is not a main feature of the disease, yet glaucoma has been reported in several WS cases in the literature, namely bilateral open-angle glaucoma with no secondary cause. In our work, we report a novel finding of JOAG coexisting with signs of WS in a 20-year-old Egyptian man. In any documented WS case, even if it is in the pediatric age group, routine follow-up for IOP monitoring is mandatory for early detection and management of glaucoma if present. JOAG is becoming an increasingly recognized cause of significant optic nerve dysfunction among teenagers due to late presentation.