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Nephronophthisis 4(NPHP4)

MedGen UID:
339667
Concept ID:
C1847013
Disease or Syndrome
Synonyms: NEPHRONOPHTHISIS 4, JUVENILE; NPHP4
 
Gene (location): NPHP4 (1p36.31)
 
Monarch Initiative: MONDO:0011752
OMIM®: 606966

Authors:
Marijn Stokman  |  Marc Lilien  |  Nine Knoers   view full author information

Additional descriptions

From GeneReviews Overview
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recognized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype, inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
From MedlinePlus Genetics
Nephronophthisis eventually leads to end-stage renal disease (ESRD), a life-threatening failure of kidney function that occurs when the kidneys are no longer able to filter fluids and waste products from the body effectively. Nephronophthisis can be classified by the approximate age at which ESRD begins: around age 1 (infantile), around age 13 (juvenile), and around age 19 (adolescent).

Nephronophthisis is a disorder that affects the kidneys. It is characterized by inflammation and scarring (fibrosis) that impairs kidney function. These abnormalities lead to increased urine production (polyuria), excessive thirst (polydipsia), general weakness, and extreme tiredness (fatigue). In addition, affected individuals develop fluid-filled cysts in the kidneys, usually in an area known as the corticomedullary region. Another feature of nephronophthisis is a shortage of red blood cells, a condition known as anemia.

Nephronophthisis can occur as part of separate syndromes that affect other areas of the body; these are often referred to as nephronophthisis-associated ciliopathies. For example, Senior-Løken syndrome is characterized by the combination of nephronophthisis and a breakdown of the light-sensitive tissue at the back of the eye (retinal degeneration); Joubert syndrome affects many parts of the body, causing neurological problems and other features, which can include nephronophthisis.

About 85 percent of all cases of nephronophthisis are isolated, which means they occur without other signs and symptoms. Some people with nephronophthisis have additional features, which can include liver fibrosis, heart abnormalities, or mirror image reversal of the position of one or more organs inside the body (situs inversus).  https://medlineplus.gov/genetics/condition/nephronophthisis

Clinical features

From HPO
Polyuria
MedGen UID:
19404
Concept ID:
C0032617
Sign or Symptom
An increased rate of urine production.
Nephronophthisis
MedGen UID:
146912
Concept ID:
C0687120
Disease or Syndrome
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recognized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype, inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Renal tubular atrophy
MedGen UID:
388054
Concept ID:
C1858395
Finding
The presence of renal tubules with thick redundant basement membranes, or a reduction of greater than 50% in tubular diameter compared to surrounding non-atrophic tubules.
Renal corticomedullary cysts
MedGen UID:
409631
Concept ID:
C1968619
Disease or Syndrome
The presence of multiple cysts at the border between the renal cortex and medulla.
Tubulointerstitial fibrosis
MedGen UID:
370652
Concept ID:
C1969372
Disease or Syndrome
A progressive detrimental connective tissue deposition (fibrosis) on the kidney parenchyma involving the tubules and interstitial tissue of the kidney. Tubulointerstitial injury in the kidney is complex, involving a number of independent and overlapping cellular and molecular pathways, with renal interstitial fibrosis and tubular atrophy (IF/TA) as the final common pathway. However, IF and TA are separable, as shown by the profound TA in renal artery stenosis, which characteristically has little or no fibrosis (or inflammation). For new annotations it is preferable to annotate to the specific HPO terms for Renal interstitial fibrosis and/or Renal tubular atrophy.
Stage 5 chronic kidney disease
MedGen UID:
384526
Concept ID:
C2316810
Disease or Syndrome
A degree of kidney failure severe enough to require dialysis or kidney transplantation for survival characterized by a severe reduction in glomerular filtration rate (less than 15 ml/min/1.73 m2) and other manifestations including increased serum creatinine.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Polydipsia
MedGen UID:
43214
Concept ID:
C0085602
Sign or Symptom
Excessive thirst manifested by excessive fluid intake.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.

Professional guidelines

PubMed

Luo F, Tao YH
Nephrology (Carlton) 2018 Oct;23(10):904-911. Epub 2018 Jun 21 doi: 10.1111/nep.13393. PMID: 29717526Free PMC Article

Recent clinical studies

Etiology

Wang J, Li S, Jiang Y, Wang Y, Ouyang J, Yi Z, Sun W, Jia X, Xiao X, Wang P, Zhang Q
Am J Ophthalmol 2023 Aug;252:188-204. Epub 2023 Mar 27 doi: 10.1016/j.ajo.2023.03.025. PMID: 36990420
Otaki Y, Watanabe T, Sato J, Kobayashi Y, Aono T, Saito Y, Goto J, Takahashi H, Arimoto T, Sato H, Konta T, Ueno Y, Watanabe M
Heart Vessels 2022 Apr;37(4):673-682. Epub 2021 Sep 30 doi: 10.1007/s00380-021-01953-5. PMID: 34591160
Luo F, Tao YH
Nephrology (Carlton) 2018 Oct;23(10):904-911. Epub 2018 Jun 21 doi: 10.1111/nep.13393. PMID: 29717526Free PMC Article

Diagnosis

Kayser N, Zaiser F, Veenstra AC, Wang H, Göcmen B, Eckert P, Franz H, Köttgen A, Walz G, Yakulov TA
Hum Mol Genet 2022 Dec 16;31(24):4143-4158. doi: 10.1093/hmg/ddac160. PMID: 35861640Free PMC Article
Otaki Y, Watanabe T, Sato J, Kobayashi Y, Aono T, Saito Y, Goto J, Takahashi H, Arimoto T, Sato H, Konta T, Ueno Y, Watanabe M
Heart Vessels 2022 Apr;37(4):673-682. Epub 2021 Sep 30 doi: 10.1007/s00380-021-01953-5. PMID: 34591160
Hudson R, Patel C, Hawley CM, O'Shea S, Snelling P, Ho G, Holman K, Bennetts B, Crawford J, Francis L, Simons C, Mallett A
Am J Kidney Dis 2020 Aug;76(2):282-287. Epub 2019 Dec 4 doi: 10.1053/j.ajkd.2019.08.031. PMID: 31810733
Luo F, Tao YH
Nephrology (Carlton) 2018 Oct;23(10):904-911. Epub 2018 Jun 21 doi: 10.1111/nep.13393. PMID: 29717526Free PMC Article
Maron JL, Hwang JS, Pathak S, Ruthazer R, Russell RL, Alterovitz G
J Pediatr 2015 Feb;166(2):282-8.e5. doi: 10.1016/j.jpeds.2014.10.065. PMID: 25620512Free PMC Article

Prognosis

Luo F, Tao YH
Nephrology (Carlton) 2018 Oct;23(10):904-911. Epub 2018 Jun 21 doi: 10.1111/nep.13393. PMID: 29717526Free PMC Article
Maron JL, Hwang JS, Pathak S, Ruthazer R, Russell RL, Alterovitz G
J Pediatr 2015 Feb;166(2):282-8.e5. doi: 10.1016/j.jpeds.2014.10.065. PMID: 25620512Free PMC Article

Clinical prediction guides

Wang J, Li S, Jiang Y, Wang Y, Ouyang J, Yi Z, Sun W, Jia X, Xiao X, Wang P, Zhang Q
Am J Ophthalmol 2023 Aug;252:188-204. Epub 2023 Mar 27 doi: 10.1016/j.ajo.2023.03.025. PMID: 36990420
Kayser N, Zaiser F, Veenstra AC, Wang H, Göcmen B, Eckert P, Franz H, Köttgen A, Walz G, Yakulov TA
Hum Mol Genet 2022 Dec 16;31(24):4143-4158. doi: 10.1093/hmg/ddac160. PMID: 35861640Free PMC Article
Maron JL, Hwang JS, Pathak S, Ruthazer R, Russell RL, Alterovitz G
J Pediatr 2015 Feb;166(2):282-8.e5. doi: 10.1016/j.jpeds.2014.10.065. PMID: 25620512Free PMC Article
Bakkaloğlu SA, Kandur Y, Bedir-Demirdağ T, Işık-Gönül İ, Hildebrandt F
Turk J Pediatr 2014 Jul-Aug;56(4):423-6. PMID: 25818963Free PMC Article

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