Does this patient have autosomal recessive familial juvenile nephronophthisis?

Nephronophthisis comprises a group of genetic tubulointerstitial disorders with autosomal recessive pattern of inheritance (Figure 1) that progress to end-stage renal failure and that are clinically sub-classified by the variability in age of occurrence and the presence of syndromatic extrarenal manifestations. Historically, the term “juvenile nephronophthisis-medullary cystic disease complex” was created to describe two histopathologically similar diseases: familial juvenile nephronophthisis (FJN) and medullary cystic kidney disease (MCKD). However, the past two decades brought a revolution in genomic medicine, leading to a new taxonomy that is based more on genetic than on clinico-pathologic determinants.

Figure 1.

Pedigree of a family affected with familial juvenile nephronophthisis.

In clinical pathology, the term “Nephronophthisis” describes a congenital tubular cystic malformation syndrome that entails cysts, arising at the level of the corticomedullary junction, accompanied by peritubular fibrosis and inflammation, tubular basement membrane disruption and atrophy of the tubular epithelia. The kidney size is typically not enlarged, and regressive changes occur throughout later development that lead to small-sized kidneys. Unlike in ADPKD, the cysts do not appear as enlarging cystic space occupying lesions, expanding in a concentric fashion, but rather as “punched-out” empty spaces within the kidney parenchyma.

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The clinical course is highly dependent on the presence of syndromatic extrarenal manifestations and on the degree of renal function compromise. In severe cases, renal failure in utero gives rise to oligohygramnios and a Potter sequence, and among many secondary malformations, pulmonary hypoplasia and postpartum respiratory failure represent the most important cause of morbidity and mortality. On the milder end of the spectrum, there is isolated nephronophthisis without extrarenal malformations, and slow progression of CKD leading to ESRD in adulthood. With increasing utilization of unbiased genetic tests, like whole exome sequencing, more and more unusual presentations of nephronophthisis with mild disease-causing mutations are identified in adults with otherwise undefined early CKD, with or without renal cysts.

Classic clinical presentations of nephronophthisis include urinary concentrating defects that result in clinical symptoms of polyuria, constant thirst, secondary enuresis, and drinking through the night. Other “textbook“-features include early onset renal failure, usually prior to age 30; reduced kidney function in adolescence or childhood, lack of significant hypertension or detectable proteinuria and bland urine sediment, normal to reduced kidney size on ultrasound with increased echogenicity and loss of the corticomedullary junction. Small cysts (1-15 mm in diameter) are irregularly distributed at the corticomedullary junction and in the medulla. Cysts may be observed on ultrasound examination at a late stage, but is not required for diagnosis. One third of patients with nephronophthisis will become anemic before the onset of renal insufficiency.

Unlike patients with polycystic kidney disease, patients with nephronophthisis rarely develop flank pain, hematuria, hypertension, urinary tract infections (UTIs), or renal calculi.

In the classification of Nephronophthisis and nephronophthisis-like syndromes, the major distinctions are the presence or absence of extrarenal manifestations, the age of onset and the mode of inheritance. Autosomal-recessive disease that is limited to the kidneys is then subclassified as infantile, juvenile or adolescent nephronophthisis, depending on the age of symptoms.

In juvenile nephronophthisis (type 1), children develop polyuria and polydipsia and start to drink regularly during the night at about age 6 years. CKD progresses inevitably and leads to ESRD around a median age of 13 years. This entity is typically associated with mutations in the NPHP1 gene.

In infantile nephronophthisis (type 2), children are more severely affected and reach ESRD within the first three years of life. Genetic analysis of this entity gave rise to the identification of the inversin gene (INVS) as a disease gene.

In adolescent nephronophthisis (type 3), ESRD is reached at a median age of 19. This entity was initially associated with mutations in the NPHP3 gene.

It is noted, however, that beyond those three forms of pediatric kidney disease, mutant alleles of all NPHP1-3 genes are being found in more severe, syndromic cases of nephronophthisis, with catastrophic multiorgan malformations. For example, severe homozygous mutations in NPHP3 may give rise to a Meckel-Gruber-like syndrome and lead to intrauterine or early postnatal lethality.

Apart of this, there is autosomal-dominant tubulointerstitial kidney disease (ADTKD) that was previously referred to as medullary cystic kidney disease (MCKD) and often grouped together with Nephronophthisis as the “NPH-MCKD complex”. This is now revised as ADTKD and clinically characterized as an autosomal-dominant group of diseases with slowly progressive CKD and ESRD in adulthood, the presence or absence of medullary cysts, the progressive lack of concentration capability leading to polydipsia, polyuria and enuresis, the absence of early onset hypertension, the absence of a pathologic urine sediment, none or very mild proteinuria and normal or small-sized kidneys on ultrasound. Histopathologic features are similar to nephronophthisis, with interstitial fibrosis and infiltration, tubular atrophy and basement membrane disruption, as well as cystic dilatation of the tubules. According to the KDIGO consensus report of 2015, ADTKD is subclassified into four different entities, depending on the causative gene mutation:

ADTKD-UMOD is caused by mutations in the Uromodulin gene (encoding for the Tamm-Horsfall protein), and is characterized by hyperuricemia, early onset gout, rare presentation in childhood, and occasional findings of renal cysts. This entity was previously called medullary cystic kidney disease type 2 (MCKD2).

ADTKD-REN is the rarest form of ADTKD, caused by mutations in the renin gene, presenting frequently in childhood with anemia, mild hypotension and risk for AKI, hyperuricemia, hyperkalemia, and it may be medically treated by fludrocortisone. This entity was previously referred to as familial juvenile hyperuricemic nephropathy type 2 (FJHN2).

ADTKD-MUC is caused by mutations in the MUC1 (mucin) gene and is rarely associated with kidney cysts. It is characterized by progressive CKD, but no unique clinico-pathologic or laboratory features. It was previously called medullary cystic kidney disease type 1 (MCKD1).

ADTKD-HNF1B is caused by mutations in the gene for hepatocyte nuclear factor 1?. The phenotypic spectrum is very wide, and it may include CAKUT-type abnormalities, renal cysts sometimes resembling ADPKD, pancreatic cysts and/or atrophy, liver cysts and LFT abnormalities, autism, hypokalemia, hypomagnesemia and diabetes (maturity onset diabetes of the young; MODY type 5). There is no single defining feature and some of the described defects may be present or absent even within the same family with the same disease allele.

Within the nephronophthisis spectrum of disorders, there are further, rare autosomal-recessive complex multiorgan malformation syndromes:

In Senior-Løken syndrome, nephronophthisis is associated with Leber congenital amaurosis.

In Joubert syndrome, nephronophthisis is associated with cerebellar vermis aplasia (giving rise to the so-called “molar tooth sign” on brain MRI) and retinitis pigmentosa, and can also include a cleft lip (or palate) and postaxial polydactyly.

In Meckel-Gruber syndrome, nephronophthisis is associated with hepatic fibrosis, severe CNS patterning defects often manifesting with occipital encephalocele, retinitis pigmentosa, postaxial polydactyly and perinatal lethality.

In Bardet-Biedl syndrome, there are variable manifestations, often including nephronophthisis, postaxial polydactyly, childhood obesity, retinitis pigmentosa, hypogonadism, and other defects.

In Alström syndrome, a nephronophthisis-like presentation is associated with retinitis pigmentosa, sensorineural hearing loss, childhood obesity, insulin-resistant diabetes, hypertriglyceridemia and dilated cardiomyopathy.

All the above disorders are ciliopathy-spectrum disorders, with protein products of the respective disease genes localizing to and/or exerting their biological function at the primary cilium and its support apparatus.

Many other rare ciliopathy disorders include nephronophthisis as the primary renal manifestation.

Given the potential syndromic relationships, a new diagnosis of nephronophthisis should motivate the clinical screening for other associated disease phenotypes. A screen for retinal disease, liver ultrasound, echocardiogram and neurologic/developmental abnormalities is indicated. In this context, more ciliopathy manifestations, like L/R-asymmetry perturbations (situs inversus), congenital heart defects, bronchiectasis etc. may be identified.

Glomerulocystic kidney disease (GCKD) is a set of diseases that have the common features of cystic dilation of Bowman’s capsule and the initial proximal convoluted tubule. A biopsy may be necessary to distinguish nephronophthisis and ADTKD from GCKD. GCKD can also be inherited in an autosomal-dominant fashion.

Autosomal-recessive polycystic kidney disease (ARPKD) is characteristic by renal enlargement, often detected in utero, and ectatic dilatation of the distal collecting ducts, leading to renal cysts. ARPKD is also associated with biliary duct malformations, cystic liver disease and periportal hepatic fibrosis.

What tests to perform?

The laboratory evaluation of nephronophthisis patients includes a urine dipstick and microscopic urinalysis, which usually is normal except for a low specific gravity reflection a significant urinary concentration defect. The absence of proteinuria or of hematuria may differentiate nephronophthisis from other heritable kidney diseases, such as focal segmental glomerulosclerosis and Alport’s syndrome, respectively.

Plasma or serum analyses: Complete blood count (CBC) diff platelets and comprehensive chemistry panels with phosphorus: provides all biochemical information, such as electrolytes, creatinine, phosphate, and parathyroid hormone levels.

Vit D 25 and Vit D 1,25: for those with advanced renal insufficiency (chronic kidney disease [CKD] Stage 3 or 4) are also indicated.

Lipid panel: All patients with underlying renal disease will need a lipid panel since they are at higher risk for cardiovascular disease.

For individuals with extrarenal manifestations, such as retinitis pigmentosa, ophthalmologic examination (visual acuity, slit lamp biomicroscopy, ophthalmoscopy, and retinal electrophysiology) are necessary.

The most relevant diagnostic test is the ultrasound examination of the kidneys (Figure 2), which demonstrates normal to slightly reduced kidney size, increased echogenicity, and loss of corticomedullary differentiation. Cysts, when present, maybe observed at the corticomedullary junction, but cysts visible on imaging are not required for the diagnosis of nephronophthisis. Thin-section CT is more sensitive than sonograph in detecting these cysts.

Figure 2.

Ultrasound of a patient with familial juvenile nephronophthisis.

Typically a biopsy is not necessary for a diagnosis. However, in unclear cases, it may be of assistance.

In the differential diagnosis of nephronophthisis, neither renal imaging nor histopathology can unequivocally confirm the clinical diagnosis. Genetic analysis is highly indicated in order to identify causative mutations, assist with further syndromatic workup and help with prognosis. This is often conducted on a research basis and may involve whole exome sequencing not only of the patient, but also of the parents and affected or unaffected siblings.

Due to the pediatric nature of nephronophthisis, once diagnosed, the parents should understand that they are most likely a carrier of the disease and every one of their children has a 25% chance to inherit the disease gene.

Given the rarity of the disease, sporadic cases are common.

Geneticists may provide counseling on family planning. Each at-risk family member should be informed of the availability of diagnosis. However, before a diagnostic test is performed, every subject also needs to be informed about the consequences of diagnostic screening, particularly regarding insurability, to permit informed judgment.

Nephronophthisis has long been recognized as a rare cause of ESRD worldwide and is one of the most common genetic causes of ESRD in the pediatric population. The prevalence has been quoted as between 1/50,000 to 1/100,000 live births.

An affected sibling or affected relatives on family history suggest the diagnosis, however, the parents of an affected individual are not affected, and are rather carriers because the disease is inherited in an autosomal-recessive pattern. Therefore, imaging of parents of an affected individual should be negative. In contrast the ADTKD-spectrum disorders follow an autosomal-dominant mode of inheritance and are present in every generation of a given pedigree. In the case of ADTKD-HNF1B, because of the pleiotropic nature, variable penetrance and expressivity, the identical disease allele may lead to very variable phenotypic presentations in the affected family members.

In summary, the diagnosis of nephronophthisis should be entertained when an individual presents in the first three decades of life with reduced kidney function, a bland urine sediment, normal to small kidneys on ultrasound with increased echogenicity and loss of the corticomedullary junction. Cysts may be observed on ultrasound examination of the kidneys, but that finding is not required for the diagnosis.

How should patients with nephronophthisis be managed?

No disease-specific therapy is recommended. Conservative therapies known to slow the progression of kidney disease and those appropriate to treat the attendant manifestations of reduced kidney function (including anemia, acidosis, and hyperparathyroidism, urinary tract infections, hypertension if present) remain the standard of care.

Due to the nature of the pediatric condition, growth retardation should be addressed.

There is no evidence of recurrent disease after successful transplantation.

What happens to patients with nephronophthisis?

Patients with nephronophthisis will experience urinary concentrating defects, frequent urination and constant thirst. Decline in kidney function usually results in ESRD in adolescence. Renal replacement therapy is required in this stage. Disease reoccurrence is not observed after transplant.

How to utilize team care?

Specialty consultations

Genetic Counselors: At the point of diagnosis, a geneticist /genetic counselor plays an important role in determining the disease and its mutation. Family members of patients with nephronophthisis should receive patient education regarding the inheritance pattern of the disease and risk for progression for affected individual if possible.

Due to the pediatric nature of nephronophthisis, once diagnosed, the family proband needs to be carefully examined. In familial cases, patients’ parents should understand that they are carriers of the gene and have a 25% chance to pass the gene to every child they have. Geneticists may provide counseling on family planning.

Each at-risk family member should be informed of the availability of diagnosis. Before a diagnostic test, family members need to be informed about the consequences of diagnostic screening, particularly regarding insurability.


Nurses should educate their pediatric and adult patients to take adequate water and sodium supplementation appropriately.

Nurses should help with performing blood pressure checking, remind patients to have the right dose of medication, and assist physician-patient communication. Home blood pressure monitoring is an important feature of management/administration of required subcutaneous and intravenous medications such as erythropoietin will be supported by nurses


Conservative therapies known to slow the progression of kidney disease and those appropriate to treat the attendant manifestations of reduced kidney function (including hypertension, anemia, acidosis, and hyperparathyroidism) remain the standard of care. In case of growth retardation, appropriate methods should be employed.


Dietitians should help individuals with nephronophthisis understand the role of renal diet in helping preserving kidney function, reducing the amount of phosphate, protein, sodium and acid in the diet.

Therapists (physical, occupational, speech, other)

Patients who develop ESRD and require renal replacement therapy will need their nephrologists and transplant team to cooperate well for a successful transplant. A physical therapist may be involved in post-surgery care. For those patients with RP and blindness, occupational or physical therapy may improve quality of life.

Are there clinical practice guidelines to inform decision making?


An autosomal recessive inheritance pattern in the family history helps diagnosis and provides parents at risk for additionally affected children. A geneticist may explain that in nephronophthisis, as an autosomal recessive disease, 25% of children would be expected to be affected. Each of the carrier parents’ children will have a 25% possibility to develop the disease regardless of the child’s gender. Given the rareness of the disease, current clinical practices lack evidence-based guidelines for this condition.


Given the rare prevalence of the disease, spontaneous individual cases (no previous case occurred /diagnosed in family history) are often observed.

Other considerations

  • ICD-9 codes: 753.16 – Nephronophthisis

  • MIM code: 256100