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PubMed This is a summary of 16 peer-reviewed journal articles Updated
Nephrology

Extra-Renal Manifestations: Beyond the Kidneys

At a Glance

While Nephronophthisis (NPHP) is primarily a kidney disease, 10% to 20% of children experience symptoms affecting the eyes, brain, or liver. Early multi-system screening for syndromic forms like Senior-Løken and Joubert syndromes is essential for comprehensive care.

While Nephronophthisis (NPHP) primarily affects the kidneys, it is important to understand that in about 10% to 20% of cases, the condition can involve other parts of the body [1][2]. Because NPHP is a ciliopathy—a disease of the cell’s “antennae”—and these antennae are found on almost every cell in the body, other organs can sometimes be affected by the same genetic mutation [3][4].

When NPHP occurs alongside symptoms in other organs, doctors refer to it as a syndromic form of the disease [1].

Senior-Løken Syndrome: Eye Involvement

The most common syndromic form of NPHP is Senior-Løken syndrome [5]. This condition combines kidney disease with retinal degeneration, specifically a condition called retinitis pigmentosa [5][6].

  • What happens?: The light-sensing cells in the back of the eye (the retina) slowly break down [6].
  • What to expect at the eye doctor: At this visit, the doctor will use eye drops to dilate the pupils and look closely at the retina. It is safe and does not hurt, though your child’s eyes may be sensitive to light afterward.
  • What to look for at home: Early signs may include “night blindness” (difficulty seeing in the dark) or a loss of side (peripheral) vision [7].
  • The Genetic Link: Mutations in the NPHP1 gene are the most frequent cause of this syndrome [5].

Because vision changes can be gradual, children with NPHP should have regular, specialized eye exams with a pediatric ophthalmologist to monitor for any signs of retinal changes [5].

Joubert Syndrome: Neurological Involvement

Another important syndromic form is Joubert syndrome [8]. This involves the brain and can affect a child’s physical and cognitive development.

  • The “Molar Tooth Sign”: This is a characteristic shape seen on a brain MRI [9]. It is caused by the underdevelopment of a part of the brain called the cerebellar vermis and is a hallmark of Joubert syndrome [9][10].
  • Symptoms: Children may experience ataxia (problems with balance and coordination), hypotonia (low muscle tone or “floppiness”), and global developmental delays [11][8].
  • Kidney Connection: Up to one-third of children with Joubert syndrome will also develop NPHP, especially those with mutations in the CEP290 or TMEM67 genes [12].

Other Potential Areas of Involvement

While less common, other organs can occasionally be involved:

  • Liver: Some children develop liver fibrosis (scarring of the liver) [1]. This is often “silent” and found through blood tests or ultrasounds [13]. It can sometimes lead to cholestasis (a condition where bile flow from the liver is reduced) [13].
  • Skeletal/Heart: Rarely, NPHP can be associated with bone abnormalities or heart defects [1][14].

The Importance of Multi-System Screening

Because these extra-renal symptoms can appear at different times—sometimes before and sometimes after the kidney diagnosis—early and ongoing screening is vital [15]. Once a diagnosis of NPHP is made, your medical team will likely recommend a “baseline” evaluation of these other systems to ensure your child receives comprehensive care [16]. This often includes eye exams, liver function tests, and, in some cases, a brain MRI or neurological evaluation [5][13].

Common questions in this guide

Does Nephronophthisis only affect the kidneys?
No, while it primarily affects the kidneys, in about 10% to 20% of cases Nephronophthisis can affect other parts of the body, such as the eyes, brain, and liver. Because it is a disease of the cells' antennae (cilia), which are found throughout the body, multiple organs can be impacted.
What is Senior-Løken syndrome?
Senior-Løken syndrome is the most common syndromic form of Nephronophthisis. It combines kidney disease with a breakdown of the retina in the eye, which can lead to night blindness and gradual loss of peripheral vision.
What are the signs of Joubert syndrome in a child with NPHP?
Children with Joubert syndrome may experience balance and coordination issues (ataxia), low muscle tone (hypotonia), and developmental delays. It is diagnosed by identifying a specific 'molar tooth sign' on a brain MRI.
How can I tell if my child's NPHP is affecting their liver?
Liver involvement, such as liver fibrosis or scarring, is often silent and does not cause immediate outward symptoms. Your child's doctor will likely use routine blood tests and ultrasounds to monitor for any reduced bile flow or liver changes.
Why does my child need to see an eye doctor if they have kidney disease?
Because Nephronophthisis can cause gradual retinal degeneration, regular, specialized eye exams are crucial. A pediatric ophthalmologist can monitor your child's eyes to detect and manage any vision changes as early as possible.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Which specific genetic mutation was identified in my child, and does it carry a higher risk for Senior-Løken or Joubert syndrome?
  2. 2.Should my child have a baseline brain MRI to look for the 'molar tooth sign'?
  3. 3.How often should my child see a pediatric ophthalmologist for dilated eye exams to check for retinal degeneration?
  4. 4.What liver-related blood tests or ultrasounds do you recommend to monitor for potential liver fibrosis?
  5. 5.If my child has developmental delays, should we consult with a pediatric neurologist as part of their care team?

Questions For You

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References

References (16)
  1. 1

    Novel pathogenic MAPKBP1 variant in a family with nephronophthisis.

    Al-Hamed MH, Alzaidan H, Hussein M, et al.

    Clinical kidney journal 2021; (14(2)):728-730 doi:10.1093/ckj/sfaa090.

    PMID: 33623699
  2. 2

    Renal Pathology of Ciliopathies.

    Sekar T, Sebire NJ

    Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 2024; (27(5)):411-425 doi:10.1177/10935266241242173.

    PMID: 38616607
  3. 3

    NPHP proteins are binding partners of nucleoporins at the base of the primary cilium.

    Blasius TL, Takao D, Verhey KJ

    PloS one 2019; (14(9)):e0222924 doi:10.1371/journal.pone.0222924.

    PMID: 31553752
  4. 4

    Non-classical functions of nuclear pore proteins in ciliopathy.

    Chen Y, Zhang Y, Zhou X

    Frontiers in molecular biosciences 2023; (10()):1278976 doi:10.3389/fmolb.2023.1278976.

    PMID: 37908226
  5. 5

    Defective INPP5E distribution in NPHP1-related Senior-Loken syndrome.

    Ning K, Song E, Sendayen BE, et al.

    Molecular genetics & genomic medicine 2021; (9(1)):e1566 doi:10.1002/mgg3.1566.

    PMID: 33306870
  6. 6

    Potpourri of retinopathies in rare eye disease - A case series.

    Pawar N, Manayath GJ, Verghese S, et al.

    Indian journal of ophthalmology 2022; (70(7)):2605-2609 doi:10.4103/ijo.IJO_3002_21.

    PMID: 35791168
  7. 7

    NPHP1 FULL DELETION CAUSES NEPHRONOPHTHISIS AND A CONE-ROD DYSTROPHY.

    Tauqeer Z, O'Neil EC, Brucker AJ, Aleman TS

    Retinal cases & brief reports 2023; (17(4)):352-358 doi:10.1097/ICB.0000000000001208.

    PMID: 36913617
  8. 8

    Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family.

    Khan MI, Latif M, Saif M, et al.

    The journal of gene medicine 2021; (23(1)):e3279 doi:10.1002/jgm.3279.

    PMID: 32989887
  9. 9

    Whole exome sequencing reveals novel CEP104 mutations in a Chinese patient with Joubert syndrome.

    Luo M, Cao L, Cao Z, et al.

    Molecular genetics & genomic medicine 2019; (7(12)):e1004 doi:10.1002/mgg3.1004.

    PMID: 31625690
  10. 10

    Late-onset hydrocephalus in a child with Joubert syndrome: a case report.

    Fehrenbach MK, Nestler U, Meixensberger J, et al.

    Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 2018; (34(7)):1423-1425 doi:10.1007/s00381-018-3767-0.

    PMID: 29508057
  11. 11

    Neuroimaging Characteristics as Diagnostic Tools in Joubert Syndrome and Related Disorders: A Case Report and Literature Review.

    Alhashimi I, Zoghoul S, Khalil SK, et al.

    Cureus 2024; (16(9)):e69872 doi:10.7759/cureus.69872.

    PMID: 39435230
  12. 12

    Prospective Evaluation of Kidney Disease in Joubert Syndrome.

    Fleming LR, Doherty DA, Parisi MA, et al.

    Clinical journal of the American Society of Nephrology : CJASN 2017; (12(12)):1962-1973 doi:10.2215/CJN.05660517.

    PMID: 29146704
  13. 13

    Genotype and phenotype analysis and transplantation strategy in children with kidney failure caused by NPHP.

    Li J, Su X, Zhang H, et al.

    Pediatric nephrology (Berlin, Germany) 2023; (38(5)):1609-1620 doi:10.1007/s00467-022-05763-3.

    PMID: 36227438
  14. 14

    Nephronophthisis-Pathobiology and Molecular Pathogenesis of a Rare Kidney Genetic Disease.

    Gupta S, Ozimek-Kulik JE, Phillips JK

    Genes 2021; (12(11)) doi:10.3390/genes12111762.

    PMID: 34828368
  15. 15

    [Clinical phenotype characteristics and genetic analysis in children with nephronophthisis and related syndromes caused by different gene mutations].

    Zhao X, Jiang LJ, Rong ZH, et al.

    Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2023; (25(8)):831-836 doi:10.7499/j.issn.1008-8830.2303020.

    PMID: 37668031
  16. 16

    Case Report: A Novel In-Frame Deletion of GLIS2 Leading to Nephronophthisis and Early Onset Kidney Failure.

    Al Alawi I, Powell L, Rice SJ, et al.

    Frontiers in genetics 2021; (12()):791495 doi:10.3389/fgene.2021.791495.

    PMID: 34917135

This page provides educational information about extra-renal manifestations of Nephronophthisis (NPHP). Always consult your child's medical team for specific screening, diagnosis, and care recommendations.

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