Antenatal diagnoses of congenital cataracts and related surgical complications in a familial case of Nance-Horan Syndrome

Nance-Horan Syndrome (NHS) was initially reported in 1974 by Walter E. Nance in the United States and Margaret B. Horan in Australia [1]. As a rare X-linked hereditary disorder, NHS is characterized by a constellation of ophthalmologic features, dental anomalies, facial dysmorphism, and intellectual delay [1,2]. With fewer than 70 NHS families described in the existing literature, the disease prevalence and incidence remain elusive. Mutations in the causative NHS gene, mapping to chromosome region Xp22.13, impair regulation of midbrain, retina, lens, tooth, and craniofacial development [1,4].


Nance-Horan Syndrome (NHS) was initially reported in 1974
by Walter E. Nance in the United States and Margaret B. Horan in Australia [1]. As a rare X-linked hereditary disorder, NHS is characterized by a constellation of ophthalmologic features, dental anomalies, facial dysmorphism, and intellectual delay [1,2]. With fewer than 70 NHS families described in the existing literature, the disease prevalence and incidence remain elusive.
Ocular fi ndings include dense congenital cataracts involving the fetal nucleus and posterior Y-suture with irregular tethering of the zonular fi bres onto the posterior cortex [5].
There is little to no published ophthalmology literature, that provides expansive knowledge on clinical presentation, diagnosis, and management of surgical complications in NHS patients. Here, we present the fi rst ophthalmological case

Genetic evaluation and investigation
In the initial assessment by Genetics at two weeks of age, the proband measured at the 75 th percentile, 50 th percentile, and 25 th percentile for height, weight, and head circumference, respectively. Micrognathia was noted on physical examination with no other evidence of dysmorphic facial features. A comprehensive physical examination of all major systems was unremarkable.
A review of the family history revealed that the proband's mother, of Scottish and Ukrainian ancestry, was diagnosed with bilateral sutural VY cataracts at six years of age. Regular follow-up by ophthalmology has not identifi ed cataract progression or changes to visual acuity in the mother. Aside from a history of myopia, the mother had no relevant past medical history. Interestingly, on physical examination, she displayed screwdriver-shaped central incisors and small lateral incisors. The family medical history was otherwise insignifi cant. There were no additional cases of congenital or childhood cataracts in either parental lineage. Paternal family roots originated from Switzerland and Germany and had an unremarkable medical and ocular history. There was no consanguinity reported. There was no known family history of intellectual disability, congenital anomalies, inherited disorders, miscarriages, stillbirths, or sudden infant deaths.
Family history was unremarkable for renal anomalies.
A side from NHS, other differential diagnoses for a newborn with antenatal diagnosis of hyperechoic lenses and renal pyelectasis and postnatal fi ndings of microphthalmia and microcornea included: (1) Lowe syndrome, characterized by mutations in OCRL1 and clinical features of aminoaciduria, failure-to-thrive, and intellectual disability; (2) Lenz syndrome, associated with alterations in NAA10 and a triad of dental, renal, and digital anomalies. Genomic analysis was performed at 18 months old to sequence genes related to congenital cataracts.
Whole exome sequencing and Sanger sequencing analysis identifi ed a pathogenic variant of the NHS gene in the proband, while the proband's mother was heterozygous for the variant, confi rming her carrier status. In both patients, entry wounds into the anterior chamber were tight with 20G cutter during all procedures. Anterior chamber maintainer was used continuously throughout the surgery, and care was always taken to maintain adequate depth in the anterior chamber. Viscoelastic was used sparingly. Postoperative care in both patients included tobramycin eye drops for a week, and prednisolone eye drops for six weeks. Atropine eye drops were used for 4 to 5 days after surgery.

Discussion and concl usion
Congenital cataract is among the primary drivers of preventable childhood blindness and vision impairment worldwide [11]. More than 50% of all cataract presentations at birth or during early childhood have been attributed to a heterogeneous array of genetic conditions [12]. While inheritance have been described [13]. The study presented here depicts the genetic, clinical, and surgical and post-surgical details of a family diagnosed with Nance-Horan Syndrome (NHS), an X-linked inherited disorder.
Albeit genetic mapping is not routinely performed in cases of congenital cataracts, the display of dental anomalies and diagnosis of childhood cataracts in the proband's mother was suggestive of a genetic disorder in the context of the proband's presentation. As syndromic features were absent in the proband at that point, and he was too young to manifest potential features such as dental anomalies, whole-exome sequencing followed by Sanger sequencing of variants was performed at 18 months of age. Initially, the proband's parents were not interested in pursuing genetic testing as they felt it would not change his clinical management or their family planning, particularly as the mother did not have a history of progressive cataract complications or require surgical interventions. However, as the proband experienced multiple capsulectomies with anterior vitrectomy and a retinal detachment by 15 months of age, the potential benefi ts of a genetic diagnosis were discussed to guide monitoring and management of possible future comorbidities. By the time genetic testing was agreed upon, the mother was pregnant with the next child. In our study, the genetic analysis identifi ed the proband to be hemizygous for a pathogenic variant of the NHS gene, while his mother was a heterozygous carrier for the same mutation. When genetic testing confi rmed NHS, the family was provided with full genetic counselling, which included an explanation regarding the milder symptoms in the mother as compared to the severe presentation in the children, as well as the 25% recurrence risk in future pregnancies. Additionally, the family was made aware of available prenatal diagnoses for future pregnancies.
Despite cataract surgery in infancy, affected males in Nance-Horan Syndrome have pronounced reduced visual acuity, likely secondary to aberrant development of ocular structures and related predispositions for surgical complications [5,8] In the presented report, our NHS patients neither demonstrated high intraocular pressures or poorly developed anterior chamber angles with gonioscopy during pre-and post-operative assessments. Nevertheless, approximately half of the males diagnosed with NHS are expected to develop severe and unrelenting glaucoma [6]. While secondary glaucoma has been described as an innate consequence of cataract extraction in infants, glaucoma development in NHS patients may also be interceded by aberrancies in the trabecular meshwork anatomy and aqueous humour drainage system [3]. As such, clinicians must present patients with routine follow-up appointments for judicious IOP monitoring.