The earliest clinical symptom of NPHP is polyuria, which is caused by renal resistance to vasopressin and impairment of urine concentration. During the disease progression, anemia may occur earlier. Loss of sodium through urine may also occur, which is often accompanied by developmental retardation and osteopathy. Disease progression is slow in many patients, and renal insufficiency is difficult to detect clinically until they are diagnosed with uremia.
About 15% of patients could exhibit extrarenal phenotypes affecting the eyes, liver, skeleton, central nervous system, etc. Eye damage is mainly manifested as retinopathy in NPHP, and patients may exhibit coarse nystagmus, retinal degeneration, optic atrophy, retinal defects, and even blindness [19]. A small number of patients may also have abnormal manifestations such as liver fibrosis and conical epiphyseal separation. Therefore, it is very difficult to diagnose NPHP based on clinical phenotypes, and it is easy to be overlooked and misdiagnosed.
It’s well known that the disease is associated with relatively clear pathogenic genes, and WES has helped clinicians enhance their understanding of the disease and improve the detection rate of the disease. For example, in children with end-stage renal disease (ESRD), NPHP accounts for 5% [19] of cases in the United States and 6.5% [20, 21] of cases in the United Kingdom. However, there arelimited reports on NPHP cases in China. In recent years, with the widespread application of genomics technology, the genotype data of NPHP patients is increasing lyused for diagnosis in China.
The cause of the present case was not easy to identify. The proband was admitted to hospital with renal failure; at the time of admission, the kidney size was consistent with age, and renal failure was considered as an acute onset. Routine urine analysis indicated presence of urinary protein (+++), suggesting a possible history of chronic renal disease. To determine the causes of proteinuria, renal biopsy was recommended. Due to the family members refused a renal biopsy. The patient showed characteristics, such as acromegaly facies, and thick, short, and flat phalanges. The family had a history of marriage between close family members for three generations. After multiple disciplinary team (MDT) discussion, we decided to make a definite diagnosis by sequencing the whole exome. The results revealed c.497del (p.Lys166Serfs) and c.2323-3T>A mutations in the TTC21B gene; the genotype was highly correlated with the clinical phenotype of the patient. Further, sanger sequencing was performed to verify that the two variants of the mutation in the patient were inherited from herparents, who were compound heterozygous in dividuals, this was consistent with the autosomal recessive inheritance model. The two mutation sites were retrieved from databases including PubMed, EMBASE, HighWire, the Cochrane Library, and CNKI. The retrieval time was from January 1992 to January 2020. The search terms included “NPHP”, “ciliopathies”, “TTC21B”, and “adolescent kidney depletion disease”. Retrospective retrieval and citation retrieval of references were carried out. Manual retrieval was also carried out when necessary. It was finally confirmed that the two genetic loci of the patient carried mutations.
This case highlights three major points: 1. genetic testing should be carried out as early as possible for children in high-risk family to facilitate early diagnosis, especially those who have lost the chance of renal biopsy; 2. the understanding of NPHP has been significantly improved by WES, although only about 30% of NPHP patients have identifiable mutations [22]. This suggests that more NPHP genes are yet to be discovered. The NPHP genes will give us a better understanding of the pathological mechanisms of this disease and the relationship between cilia and cyst development. In addition to conventional treatment and renal replacement therapy, the new therapies are expected to replace the old ones; 3. it is very important to strengthen prenatal education and premarital examination in poverty-stricken areas and avoid the transmission of inherited metabolic diseases.
Although 25 genetic loci related to NPHP are reported, they are only found in approximately 30% of NPHP cases [22]. Different gene loci have different clinical manifestations, which are related to the pathogenesis of gene loci. However, the same gene loci may have different clinical manifestations, such as different TTC21B loci mutations resulting in clinical manifestations with significant differences. A heteromorphic allele of TTC21B may cause Jeune asphyxiating thoracic dystrophy (JATD), while a similar genotype (c.2758-2A>G-het; p.Pro209Leu-het or p.Cys552X-het; p.Pro209Leu-het) leads to early onset of NPHP; however, homozygous p.Pro209Leu leads to significantly isolated NPHP [23]. Moreover, the same p.Pro209Leu allele can also exist in the heterozygous in dividuals with BBS having cystic nephropathy (BBS prevalence < 24% ) [24].
NPHP1 is the first identified NPHP gene, accounting for the majority of known NPHP cases (20-25%) [25, 26]. NPHP2 is observed in infants, and may lead to established renal failure (ERF) [27]. Mutations in NPHP3 may lead to a variety of phenotypes, including adolescent NPHP, NPHP with liver fibrosis, NPHP with retinitis pigmentosa (RP), infantile NPHP, and MKS [28, 29]. NPHP4 mutation is most frequently associated with retinal phenotypes [30]. In patients with NPHP5 and NPHP10, abnormal expression of renal cyst protein connecting cilia may increase the risk of retinitis pigmentosa by 100% and 80% respectively. In addition, NPHP5 and NPHP6 were also found to be directly related to the function of the retinitis pigmentosa GTPase regulator (RPgr) [31, 32]. Other reported NPHPs that can be detected in photoreceptors include NPHP-1, 8, 11, and 12 [23, 33-35]. NPHP7 is associated with Gli-similar protein 2 transcription factor, and the deletion of this transcription factor results in an increased risk of fibrosis and apoptosis [36]. The deletion of NPHP9 is associated with increased DNA damage in the pathogenesis of NPHP [37]. NPHP-5, 6, 9, 10, 13, and 15 have been reported in SLS syndrome case reports [38-41]. Mutations in NPHP-6 and NPHP-11 may cause Joubert syndrome [42]. In some cases, the type of mutation in the disease may affect the phenotype, for example, the reported truncation mutations of NPHP11 [43, 44] and NPHP5 [45] often lead to a clinical phenotype that is more severe than that caused by missense mutations.
In conclusion, the two novel mutations in TTC21B gene, c.497del and c.2323-3T>A, identified in a Chinese patient. The deletion mutation in the TTC21B gene resulted in a change of the 3D structure of the protein, which may have impaired the functions. And, this study highlighted the importance of genetic testing in the diagnosis of this disease. The related gene mutation review contributed to the spectrum of known pathogenic variants of TTC21B, expanded the current understanding on the NPHP.