Nephronophthisis (NPHP) is recognized as the most common inherited cause of renal failure in children (1). According to the age of onset of end-stage renal disease (ESRD), NPHP can be classified as infantile, juvenile and adolescent forms. Among them, juvenile NPHP is the most common. Typical clinical features include polyuria, polydipsia and isosthenuria due to renal concentration function impairment, no hematuria, proteinuria, hypertension and other manifestations. If the disease progresses to a higher stage of chronic kidney disease (stage III and above), fatigue may occur. Fever, fatigue, skin itching, nausea, vomiting, uremic gastritis, anemia, and growth retardation may occur (2). Approximately 10%–20% of cases involve NPHP patients also display additional extrarenal abnormalities, such as Senior-Loken syndrome (SLS), Joubert syndrome, Mainzer-Saldino's syndrome, and liver fibrosis, situs inversus, etc. Among these, the eye is the most commonly affected extrarenal organ in NPHP, with retinitis pigmentosa being the most common (3).

Genes that have been found to be associated with the disease encode proteins involved in the functioning of primary cilia, basal bodies, and centrosomes, and mutations can lead to renal damage, as well as extrarenal manifestations associated with NPHP. Mutations in the nephrocystin-1 gene (NPHP1) on chromosome 2q13, the most common cause of the disease, are either pure or compound heterozygous mutations (4). In this report, we describe the case of a child with renal wasting disease caused by a pure deletion of NPHP1 and analyze and summarize the manifestations of NPHP in this child, to provide a reference for the diagnosis and treatment of similar children in the future and to enhance the understanding and identification of the disease in clinical practice, thus providing timely diagnosis and treatment.

Nephronophthisis (NPHP) is one of the most common causes of monogenic single-gene renal failure (CKF), with over 25 genes have been associated with NPHP. These genes encode proteins involved in the functioning of primary cilia, the matrix, and the centrosome, leading to kidney diseases and extrarenal manifestations (7, 8). Among them, the most common cause of juvenile NPHP is a mutation in the NPHP1 gene, which accounts for 20%–25% of reported NPHP cases; 10 cases of renal wasting disease have been found to be caused by homozygous deletion of a large fragment of NPHP1, with the onset of the disease occurring at around 9–13 years old (9). Due to renal concentrating function, most patients exhibit typical symptoms of nephronophthisis, such as polydipsia, polyuria, enuresis, and significantly decreased urine osmolality. Moreover, ultrasound examinations of patients with nephronophthisis caused by NPHP1 gene deletion have consistently shown renal cysts, but the child in this case only suggests that the echo of the parenchyma of both kidneys is enhanced, the boundary between cortex and medulla is blurred, and the blood flow of both kidneys is less.

Renal cortical cysts may appear in the late stage of the disease. These are primarily caused by the NPHP1 protein (also known as renal capsule protein) which is expressed on the surfaces of primary cilia and renal tubular epithelial cells, and can interact with molecules involved in cell adhesion and signal transduction, as well as other capsule proteins. Fibronectin is an important component of the extracellular matrix and is involved in cell proliferation, apoptosis, and polarization (10). Mutations in NPHP1 can prevent its binding to fibronectin, thus restricting its function. Apart from the appearance of a series of extrarenal manifestations, renal cysts develop as the disease progresses. It has been reported that the initial imaging results of patients with NPHP may be non-specific, while the normal shape of the kidney can be assessed by ultrasound, indicating a loss of corticomedullary differentiation. However, with disease progression, ultrasound imaging conducted at later stages may show smaller atrophic kidneys with obvious corticomedullary cysts (11). Therefore, it is thus important to pay active attention to the manifestations associated with renal cysts in such children.

Renal tubulointerstitial damage in renal wasting disease is often characterized by medullary cystic changes. Myelocystic nephrotic include juvenile renal wasting disease (JN), medullary cystic kidney disease (MCKD), and medullary sponge kidney (MSK) (12). MSK is a kind of congenital, benign renal developmental abnormality, primarily characterized by spindle-shaped or small cystic dilation of the collecting ducts within one or more renal pyramids in both kidneys. Clinical manifestations often include kidney stones, renal calcification, tubular concentrating dysfunction, and recurrent urinary tract infections. The prognosis is relatively good, with rare cases causing renal function abnormalities during adolescence. Ultrasound (ultrasound examination) may show small anechoic areas and echogenic foci radiating around the renal pelvis. In this case, no relevant ultrasound findings were observed in the patient's kidneys, so this diagnosis is not considered for now. JN and MCKD share similarities in clinical and pathological manifestations, collectively referred to as the JN-MCKD syndrome. JN-MCKD is a group of cystic kidney diseases characterized by the formation of medullary cysts and occult chronic renal insufficiency, with pathological features consistent with chronic tubulointerstitial nephritis. The two can be distinguished based on inheritance pattern, age of onset, and clinical presentation: renal wasting disease is an autosomal recessive disorder, commonly seen in children and adolescents, and may be accompanied by other extrarenal manifestations. Medullary cystic disease, which is more common in adults, is an autosomal dominant inheritance, mainly with renal lesions and less extrarenal manifestations. Both are genetic diseases, which are often diagnosed by genetic testing.

Feng Chen mentioned that the clinical diagnosis of atypical NPHP is challenging, proposed NPHP1 deletion in Chinese twins with nephronophthisis, and demonstrated in the text the superiority of whole exome sequencing (WES) for diagnosing this type of disease (13). This case patient is also an atypical NPHP patient. Given that the average age of onset of ESRD in juvenile NPHP is 13 years, with only a few cases entering ESRD around age 6, the diagnosis of this patient is even more difficult. This reaffirms the importance of genetic testing for diagnosing atypical NPHP patients.