Abstract
Background and Aims
Nephronophthisis (NPHP), a ciliopathy which almost always causes end-stage kidney disease (ESKD), may have extrarenal symptoms such as Bardet-Biedl syndrome (BBS) and Senior-Loken syndrome (SLS), and these are called NPHP-related ciliopathies (NPHP-RC). Bardet-Bield syndrome and SLS share similar clinical features, so that definitive diagnosis might depend on genetic analysis. Bardet-Bield syndrome diagnosis is typically based on clinical manifestations, which comprise, for example, renal defects, polydactyly, obesity, retinitis pigmentosa (RP), learning difficulties, in addition to secondary manifestations such as development delay, speech defects, hypertension, among others. Senior-Loken syndrome classical encompasses familial NPHP and RP; additional variable features can include skeletal, liver, neurologic and other visual defects, as well as obesity. NPHP genes are the most commonly affected in NPHP. Although disruption of the NPHP5 and NPHP6 genes are the most frequent cause of SLS, at least variants in ten genes have been reported.
We present a case of a young girl clinically diagnosed with BBS, later known to be a SLS based on genetic analysis, revealing an unusual affected gene.
Method
We reviewed this case based on medical records.
Results
The patient presented with polydactyly at birth and pre-obesity in the first six months of age. At the age of 4 years she was first evaluated by ophthalmology due to reduced visual acuity which evolved unfavorably with severe generalized retinal dysfunction and moderate maculopathy at the age of 9 years. Delayed development and poor social skills were increasingly evident, as wells as short stature, small hands and dysmorphic facial features. At the age of 12 years bilateral transmission hearing loss was diagnosed and two years later she was referred to Endocrinology due to hirsutism, stretch marks and cushingoid facies. In this context, blood work was performed and surprisingly revealed plasma creatinine of 2.19 mg/dL and urea of 65 mg/dL. Kidney ultrasound revealed reduced dimensions and increased parenchymal echogenicity; an obstructive component was excluded. She rapidly progressed to ESKD and dialysis dependence. Bardet-Biedl syndrome was considered. She was referred for transplant assessment and underwent genetic testing. A homozygous likely pathogenic variant was identified in TRAF3IP1 gene, compatible with SLS 9 (autosomal recessive inheritance).
Conclusion
Although phenotype-based diagnosis was common in ciliopathies, genetic testing is now regularly used for definitive diagnosis. Mutations in the geneTRAF3IP1 were only recently described, particularly in patients presenting with NPHP, RP, skeletal defects, hepatic fibrosis and hexadactyly; ESKD is frequent between 3 and 16 years and SLS is formally associated. Our patient had several clinical manifestations suggestive of BBS, and presumptive diagnosis was assumed (although noticeable phenotypic overlap with SLS exists). Genetic analysis was crucial; the identified mutation in TRAF3IP1 justifies some of the extra-SLS/BBS-like manifestations. Patients must be monitored carefully, namely related to ESKD and extrarenal manifestations; there is also the need for segregation analysis (divorced parents and half-brothers). Ultimately this case represents a consequence of genetics evolution, with a wide genetic and clinical variability now described within these syndromes.
Clinical Manifestations and Genetic Analysis of 5 Korean Choroideremia Patients Initially Diagnosed With Retinitis Pigmentosa
