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We herein report a case of SLS type 5 caused by IQCB1 mutation.
A 17-year-old boy came with progressive diminution of vision and photophobia in both eyes since childhood. The visual disability was the same in the daytime as it was at night. He was diagnosed with some nonspecific pigmentary retinal degeneration. Best corrected visual acuity was 6/60, N6 in right eye and 6/60, N8 in left eye. Anterior segment examination was unremarkable. Fundus examination of both eyes showed mid-peripheral retinal pigment epithelium (RPE) alterations and pigment clumps, relatively sparing maculae, and narrowing of retinal arterioles (Figs. 1A and 1B). Fundus autofluorescence (FAF) showed decreased autofluorescence in the mid-periphery and a perifoveal ring of increased autofluorescence, suggesting a bull's-eye maculopathy (Figs. 1C and 1D). Spectral domain optical coherence tomography (SDOCT) revealed a barely detectable inner–outer photoreceptor segment junction in the central macula corresponding to the area inside of the ring of increased autofluorescence (Figs. 2A and 2B). Humphrey visual field 30-2 of both eyes showed constricted fields (Fig. 2C). Electroretinogram was performed under The International Society for Clinical Electrophysiology of Vision (ISCEV) standards. It showed extinguished scotopic and photopic responses (Fig. 2D).
The boy had no family history of similar problems and was born out of a nonconsanguineous marriage (Fig. 3). When inquired about his systemic condition, he disclosed a history of chronic renal failure from childhood, leading to end-stage renal disease and renal transplantation performed 6 years ago. The renal problems started by the age of 2 years old. Parents were not able to comment on delayed milestones. The cause of renal failure was not known despite all laboratory investigations and despite being under the care of pediatric nephrologist from a young age. He received a kidney donation from his father. Both parents gave no history of visual complaints and, suspecting a syndromic association, we examined both the parents. The father had undergone a retinal detachment surgery and the mother had a normal fundus evaluation. There were no features of pigmentary retinal dystrophy in both the parents. The mother was earlier found unsuitable for kidney donation when she was evaluated 6 years back because she had practically one functional kidney and the other kidney was atrophic. The boy was short statured with good intelligence and hearing. He had no other musculoskeletal problems. The systemic features along with the retinal condition brought us to a differential diagnosis of SLS and patient underwent genetic testing. Targeted gene sequencing was done by MedGenome laboratories, Bangalore, India. A heterozygous nonsense variation was detected in exon 13 of the IQCB1 gene (p.Arg461Ter; c.13181C>T) and heterozygous single base pair deletion in exon 4 of the IQCB1 gene (p.Cys62AlafsTer26; c.184del). Heterozygous single base pair deletion in exon 4 of the IQCB1 gene (chr3:g.121547397del;Depth:65x) that results in a frameshift and premature truncation of the protein 26 amino acids downstream to codon 62 (p.Cys62AlafsTer26; ENST00000310864.6) was detected. This mutation was found to be novel. No other variants were noted. This was suggestive of SLS type 5 with retinitis pigmentosa (RP) like picture. The parents refused to be tested to confirm whether each parent carried one mutant allele. The patient was referred back to the nephrologist and internist for complete evaluation for the ciliopathy and underwent low-vision assessment and was provided with a dome magnifier.
Many diseases can present with oculorenal symptoms (Table 1).
SLS is caused mainly by mutation in the IQCB1 gene (also known as NPHP5), located on chromosome 3q21.1. IQCB1 encodes the protein nephrocystin-5, expressed in the connecting cilia of photoreceptors and in primary cilia of renal epithelial cells. In the retina, nephrocystin-5 co-localizes with retinitis pigmentosa GTPase regulator involved in X-linked RP, and it is responsible for epithelial cell integrity, resulting in renal cyst formation in cases of protein dysfunction in the kidneys.
Patients with nephronophthisis usually have polyuria, polydipsia, and nocturia owing to loss of urinary concentration ability. Progressive failure of kidney function occurs because of degeneration or loss of function of the small collecting tubes (tubules) in the kidney. In the present case, the boy had typical ophthalmic and renal presentation of SLS type 5. Patients may present with severe vision loss from infancy with nystagmus and hyperopia Leber congenital amaurosis or may present with progressive vision loss presenting later with RP-like presentation.
Progressive photoreceptor death in RP ultimately causes RPE atrophy at the macula, which can be assessed by FAF and SDOCT. FAF detects abnormal distribution of lipofuscin in RPE derived from photoreceptor's outer segment phagocytosis. SDOCT delineates the junction between the inner and outer segments of the photoreceptors. In our case, inner–outer photoreceptor segment junction was barely detectable in the central macula suggesting initial ciliary junction disorganization before photoreceptor death. These noninvasive investigations can help in monitoring the patients. They may benefit from various visual aids such as a 4X dome magnifier, which was recommended for our patient. Genetic counselling should be done for patients and their families. These patients might require regular follow up with the internist for systemic associations.
The case presents an interesting diagnosis by an ophthalmologist for a multisystem disease, and it stresses the importance of good systemic evaluation along with eye examination.
Footnotes and Disclosure
The authors have no proprietary or commercial interest in any materials discussed in this article.