BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive disorder with a subset of patients presenting with extrarenal manifestations such as retinal degeneration, cerebella ataxia, liver fibrosis, skeletal abnormalities, cardiac malformations, and lung bronchiectasis. However, the involvement of other organ systems has also been documented. Extrarenal manifestations occur in approximately 10-20% of patients. In developed countries, it has been reported as one of the most common causes of monogenic chronic kidney failure (CKF) during the first three decades of life, with more than 25 genes associated with this condition. The current treatment options for managing NPHP include supportive care, management of complications, and kidney replacement therapy when necessary. The index patient is a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain. Her elder sister, TN, who was 17 years old, was diagnosed with CKF and noted to have persistently elevated liver enzymes (gamma-glutamyl transferase, alanine, and aspartate transaminases). Following genetic testing, her elder sister was shown to have Nephronophthisis Type 3, and a liver biopsy showed early fibrotic changes. Subsequent genetic testing confirmed the index patient as having NPHP Type 3. A kidney biopsy showed focal sclerosed glomeruli with patchy areas of tubular atrophy and related tubulointerstitial changes in keeping with NPHP. We present the first confirmatory case of NPHP from South Africa based on histopathology and genetic testing in a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain, whose elder sister also presented with CKF and early liver fibrosis, confirmed on biopsy and genetic testing.
CONCLUSIONS: In low-middle-income countries, genetic testing should be undertaken whenever possible to confirm the diagnosis of NPHP, especially in those with a suggestive biopsy or if there is CKF of unknown aetiology with or without extra-renal manifestations.

UNASSIGNED: Caroli syndrome or Caroli disease is characterized by focal dilation of the intrahepatic bile ducts, with or without congenital liver fibrosis. Mutations in the WDR19 gene can result in nephropathy, an autosomal recessive cystic kidney disease. However, this genetic mutation is clinically associated with Caroli syndrome or disease. We hypothesize that WDR19 gene mutations may contribute to extrarenal phenotypes such as Caroli disease or syndrome.
UNASSIGNED: The outpatient department received a 1-year-old male patient with persistent dilated bile ducts for over four months. Subsequent ultrasound examination revealed liver cirrhosis, splenomegaly, and cystic dilatation of the intrahepatic bile duct. He was subsequently admitted for comprehensive diagnosis and treatment. Accordingly, we performed computed tomography (CT)-hepatic portal venography, magnetic resonance-cholangiography, and the plain liver scan, the results revealed liver cirrhosis, splenomegaly, cystic dilatation of the intrahepatic bile duct, as well as atypical hyperplasia nodules in the right posterior lobe of the liver and lymphatic hyperplasia and enlargement in the porta hepatis and the space between the liver and stomach. As the possibility of early small liver cancer could not be excluded due to the presence of nodules, surgical resection was performed followed by pathological examination and whole genome exome testing. The pathological findings revealed hepatocyte swelling, hydropic degeneration, and sporadic necrosis. Fibrous tissue hyperplasia was observed in the portal vein area, along with local pseudolobule formation. Also, numerous small bile duct hyperplasia was observed with lymphocyte infiltration, which is consistent with cirrhosis. Moreover, the hepatocytes of the small focal area showed atypical hyperplasia. Considering the above findings, Caroli syndrome was diagnosed. The genetic results showed two heterozygous mutations in the WDR19 gene, c.2290delC (p.Q764Nfs*29) and c.2401G>C (p.G801R). Therefore, the child\'s intrahepatic bile duct dilatation and cirrhosis were considered as the manifestations of Caroli syndrome caused by mutations in the WDR19 gene.
UNASSIGNED: Mutations in the WDR19 gene can manifest as Caroli disease or Caroli syndrome. For the definite diagnosis of liver diseases of unknown etiology, whole exome sequencing may be more conducive.

UNASSIGNED: Nephronophthisis (NPHP) is a rare autosomal recessive inherited tubulointerstitial nephropathy, the most prevalent genetic cause of end-stage renal disease (ESRD) in children. Convincing evidence indicated that the overall prevalence of NPHP in adult-onset ESRD is very likely to be an underestimation. Therefore, understanding the genetic background and clinicopathologic features of adult-onset NPHP is warranted.
UNASSIGNED: we reported one intriguing case with concurrent NPHP3 c.2694-2_2694-1delAG (splicing) variant and c.1082C > G (p.S361C) variant. A 48-year-old male was admitted to our hospital, complained about renal dysfunction for 10 years, and found right renal space-occupying lesion for 1 week. One of the most interesting clinical features is adult-onset ESRD, which differs from previous cases. Another discovery of this study is that the NPHP harboring NPHP3 deletion may be associated with clear cell renal cell carcinoma.
UNASSIGNED: In conclusion, we report two mutations in the NPHP3 gene that cause NPHP with adult-onset ESRD and renal clear cell carcinoma in a Chinese family, enriching the clinical features of NPHP.

Mainzer-Saldino syndrome (MSS) or conorenal syndrome (CRS) is a rare autosomal recessive ciliopathy characterized by multiorgan affection, typically presents with a triad of nephronophthisis (NPHP), retinitis pigmentosa (RP), and cone-shaped epiphysis (CSE) with varying degrees of severity. A 20-month-old male is experiencing recurrent pneumonia attacks, an elevated serum creatinine level, proteinuria, and high anion gap partially compensated metabolic acidosis were incidentally discovered during one of his hospitalizations. A biopsy was performed, and the results supported the diagnosis of Alport syndrome. However, a subsequent genetic test suggests the presence of MSS. Aside from NPHP, RP and CSE tested positive. Based on the fact that MSS is not a common cause of end-stage renal disease (ESRD) in pediatrics, physicians should bear in mind genetic testing as a decisive tool. In this context, we highlighted a case of an accidentally discovered impaired renal function from first presentation to final diagnosis, with a valuable comparison with previously published similar cases.

Senior-Loken syndrome (SLS) is a rare autosomal recessive disorder affecting the eyes and the kidneys. It is an extremely rare disorder with an incidence of 1/1,000,000. Like most hereditary disorders, it is more commonly seen in families with consanguineous marriages. Here, we present a case of a 35-year-old male with a complicated past medical history, who presented to us in the outpatient department for kidney transplant consideration. The patient was diagnosed case of Senior-Loken syndrome with a family history of autoimmune diseases, renal disease, and multiple unexplained miscarriages. He also had multiple dialysis access-related complications requiring frequent access changes. He previously had an unrelated pre-emptive renal transplant which resulted in graft failure within 48 hours. In view of his history, a prothrombotic condition was suspected and the patient was started on warfarin. Workup was positive for lupus anticoagulant and hematology recommended lifelong anticoagulation. The patient had a related renal transplant that was successful. He is now on apixaban and has not had any thrombotic complications to date. This patient had antiphospholipid syndrome leading to multiple thrombotic events and a failed graft, but was never worked up for autoimmune disorders despite having a strong family history. His renal disease was presumed to be secondary to a rare condition - Senior-Loken syndrome and he was not investigated for a co-existing condition (e.g., antiphospholipid syndrome {APLS} in this case) which led to early graft failure. Hence when considering a patient for transplant, care should be taken to rule out autoimmune diseases and not ignore possible co-existing conditions in the presence of a renal pathology.

Nephronophthisis (NPHP) is a common pediatric cystic kidney disease, accounting for approximately 10% of end-stage renal failure cases in children. NPHP is primarily diagnosed through the identification of indel mutations and copy number variants (CNVs), and patients carrying NPHP1 mutations usually progress to renal failure at a mean age of 13 years old. However, the association between CNVs containing NPHP1 variations and the progression of NPHP-induced disease remains unclear. Here, we report three NPHP patients in a family. The proband had developed stage 4 chronic kidney disease (CKD) at 9 years old, and her younger brother and older sister had developed renal failure at 8 and 10 years old, respectively. A genetic diagnosis showed that they carried two rare CNVs, including homozygous loss of NPHP1, MALL, ACTR1AP1, MTLN, and LOC100507334. Heterozygous deletions mainly consisted of non-coding RNA genes on both sides of the CNVs. The proband was in stage 4 of CKD while her brother had progressed to renal failure, probably due to more extensive heterozygous deletion of a 67.115 kbp fragment, which included LIMS3-LOC440895, LOC440895, GPAA1P1, ZBTB45P1, and LINC0112 genes. This report demonstrates that larger CNV deletions, including homozygous NPHP1, MALL, and MTLN mutations and heterozygous deletions, presumably accelerate disease progression. Therefore, early genetic diagnosis plays a crucial role in the intervention and prognosis of these patients.

Nephronophthisis type 12 (NPHP 12) is a rare cilia-related cystic kidney disease, caused by TTC21B mutation, mainly involving the kidneys, which generally occurs in children. Our study aimed to illustrate its clinical, pathological and genetic characteristics by reporting an adult-onset case of NPHP 12 caused by a single heterozygous nonsense mutation of TTC21B confirmed by renal histology and whole exome sequencing and reviewing related literature with a comparative analysis of the clinical features of each case. It will further increase the recognition of this rare kidney genetic disease, which sometimes can manifest as an adult disease.
A 33-years-old man showed a chronic disease course, and he exhibited slight renal dysfunction (CKD stage 3, eGFR = 49 ml/[min* 1.73 m2]) with renal tubular proteinuria, without any extrarenal manifestations, congenital malformation history of kidney disease, or family hereditary disease. Renal histological findings showed substantial interstitial fibrosis with some irregular and tortuous tubules with complex branches and segmental thickening and splitting of the tubular basement membrane. The patient was diagnosed with chronic interstitial nephritis for an unknown reason clinically. Further genetic analysis revealed a single heterozygous nonsense mutation in the TTC21B gene and NPHP 12 was diagnosed finally.
A single heterozygous mutation in the TTC21B gene may cause atypical NPHP12, which had a relatively later onset and milder clinical symptoms without developmental abnormalities. Therefore, for unexplained adult-onset chronic interstitial nephritis with unusual changes of renal tubules and interstitial fibrosis, even without a clear history of hereditary kidney disease, genetic testing is still recommended. The correct diagnosis of this rare adult-onset hereditary nephropathy can avoid unnecessary treatment.

Nephronophthisis (NPHP) is a chronic tubular interstitial disorder that exhibits an autosomal recessive genetic form and causes progressive renal failure in children. Patients with NPHP rarely show urinary abnormalities, edema, or hypertension. Thus, NPHP is often detected only when renal failure becomes advanced. NPHP can be divided into three types based on the age of end-stage renal failure, i.e., infant type (approximately 5 years old), juvenile type (approximately 13-14 years old), and adolescent type (approximately 19 years old). Here, we report a case of NPHP diagnosed by genetic analysis at 26 years of age with atypical histological abnormalities.
A 26-year-old woman showed no growth disorders or urinary abnormalities in annual school physical examinations. However, at a check-up at 26 years old, she exhibited renal dysfunction (eGFR 26 mL/min/1.73 m2). Urine tests indicated low specific gravity of urine, but not proteinuria or microscopic hematuria. Urinary β2-microglobulin was high (805 μg/L), and renal biopsy was performed for definitive diagnosis. Histological findings showed no significant findings in glomeruli. However, moderate fibrosis was observed in the interstitial area, and moderate atrophy was observed in the tubules. There were no significant findings in immunofluorescence analysis, and no electron dense deposits were detected by electron microscopy. Although cyst-like expansion of the tubules was unclear, tubular atrophy was dominantly found in the distal tubule by cytokeratin 7 staining. Genetic analysis of the NPHP1 gene showed complete deletion of this gene, leading to a definitive diagnosis of NPHP.
NPHP is not merely a pediatric disease and is relatively high incidence in patients with adult onset end-stage of renal disease. In this case, typical histological abnormalities, such as cyst-like expansion of the tubular lesion, were not observed, and diagnosis was achieved by genetic analysis of the NPHP1 gene, which is responsible for the onset of NPHP. In patients with renal failure with tubular interstitial disease dominantly in the distal tubules, it is necessary to discriminate NPHP, even in adult cases.

Secondary hyperparathyroidism (HPT) is a common complication of end-stage renal disease (ESRD) and may be an important precipitating factor for the development of myelofibrosis. However, there have been only a few reports on myelofibrosis caused by secondary HPT in children. We describe a case of a 15-year-old boy with myelofibrosis due to secondary HPT who was successfully treated with hemodialysis, erythropoietin, phosphate binders, and activated vitamin D agents. The patient had no past medical history and had been admitted to the hospital for abdominal pain. Routine blood examination revealed pancytopenia combined with renal impairment. Hyperphosphatemia, decreased 1,25-dehydroxyvitamin D, decreased serum calcium, and increased parathyroid hormone (PTH) levels were observed. Bone marrow biopsy confirmed myelofibrosis and renal biopsy revealed nephronophthisis (NPHP). The possibility of renal osteodystrophy and myelofibrosis due to secondary HPT was considered. Hemodialysis and erythropoietin were initiated and combined therapy with a phosphate binder and an active vitamin D agent achieved greater reduction of PTH levels, along with improvement of pancytopenia. As medical treatment for secondary HPT can lead to a reversal of myelofibrosis and avoid parathyroidectomy in children, prompt recognition of this condition has major implications for treatment. Therefore, despite its rarity, pediatricians should consider myelofibrosis due to secondary HPT as a cause of pancytopenia in patients with chronic kidney disease.

Patients with genetic disorders are potentially more susceptible to present vascular abnormalities compared to the general population. For these patients, unusual difficulties could appear during a CVC placement procedure that could lead to major complications if venous abnormalities are undiagnosed. Ultrasound and fluoroscopy guidance should be used routinely for all patients in order to avoid complications and catheter misplacement.