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Infantile nephronophthisis(NPHP2)

MedGen UID:
355574
Concept ID:
C1865872
Disease or Syndrome
Synonyms: Nephronophthisis 2; Nephronophthisis 2, infantile; NPHP2
SNOMED CT: Infantile nephronophthisis (444558002)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): INVS (9q31.1)
 
Monarch Initiative: MONDO:0011190
OMIM®: 602088
Orphanet: ORPHA93591

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 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 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).

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).

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.  https://medlineplus.gov/genetics/condition/nephronophthisis

Clinical features

From HPO
Chronic tubulointerstitial nephritis
MedGen UID:
65957
Concept ID:
C0238304
Disease or Syndrome
Chronic inflammation of the kidney affecting the interstitium of the kidneys surrounding the tubules.
Enlarged kidney
MedGen UID:
108156
Concept ID:
C0542518
Finding
An abnormal increase in the size of the kidney.
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).
Absence of renal corticomedullary differentiation
MedGen UID:
342352
Concept ID:
C1849765
Finding
A lack of differentiation between renal cortex and medulla on diagnostic imaging.
Renal cortical microcysts
MedGen UID:
356391
Concept ID:
C1865877
Finding
Cysts of microscopic size confined to the cortex of the kidney.
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.
Hyperechogenic kidneys
MedGen UID:
477530
Concept ID:
C3275899
Finding
An increase in amplitude of waves returned in ultrasonography of the kidney, which is generally displayed as increased brightness of the signal.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Pulmonary valve insufficiency
MedGen UID:
11031
Concept ID:
C0034088
Pathologic Function
The retrograde (backwards) flow of blood through the pulmonary valve into the right ventricle during diastole.
Situs inversus totalis
MedGen UID:
1642262
Concept ID:
C4551493
Congenital Abnormality
A left-right reversal (or "mirror reflection") of the anatomical location of the major thoracic and abdominal organs.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Pulmonary hypoplasia
MedGen UID:
78574
Concept ID:
C0265783
Congenital Abnormality
A congenital abnormality in which the lung parenchyma is not fully developed. It may be associated with other congenital abnormalities.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Hyperkalemia
MedGen UID:
5691
Concept ID:
C0020461
Finding
An abnormally increased potassium concentration in the blood.
Elevated circulating creatinine concentration
MedGen UID:
148579
Concept ID:
C0700225
Finding
An increased amount of creatinine in the blood.
Hyperkalemic metabolic acidosis
MedGen UID:
356106
Concept ID:
C1865880
Finding
Oligohydramnios
MedGen UID:
86974
Concept ID:
C0079924
Pathologic Function
Diminished amniotic fluid volume in pregnancy.

Professional guidelines

PubMed

Raina R, Chakraborty R, Sethi SK, Kumar D, Gibson K, Bergmann C
Am J Kidney Dis 2021 Jul;78(1):125-141. Epub 2021 Jan 6 doi: 10.1053/j.ajkd.2020.10.021. PMID: 33418012

Recent clinical studies

Etiology

Ijaz A, Alfadhli F, Alharbi A, Khan YN, Alhawas YK, Hashmi JA, Wali A, Basit S
Eur J Med Genet 2022 Oct;65(10):104578. Epub 2022 Aug 17 doi: 10.1016/j.ejmg.2022.104578. PMID: 35987473
Penchev V, Boueva A, Kamenarova K, Roussinov D, Tzveova R, Ivanova M, Dimitrova V, Kremensky I, Mitev V, Kaneva R, Beltcheva O
Eur J Med Genet 2017 Jun;60(6):321-325. Epub 2017 Apr 6 doi: 10.1016/j.ejmg.2017.04.002. PMID: 28392475
Sun L, Tong H, Wang H, Yue Z, Liu T, Lin H, Li J, Wang C
Nephrology (Carlton) 2016 Mar;21(3):209-16. doi: 10.1111/nep.12563. PMID: 26184788
Failler M, Gee HY, Krug P, Joo K, Halbritter J, Belkacem L, Filhol E, Porath JD, Braun DA, Schueler M, Frigo A, Alibeu O, Masson C, Brochard K, Hurault de Ligny B, Novo R, Pietrement C, Kayserili H, Salomon R, Gubler MC, Otto EA, Antignac C, Kim J, Benmerah A, Hildebrandt F, Saunier S
Am J Hum Genet 2014 Jun 5;94(6):905-14. Epub 2014 May 29 doi: 10.1016/j.ajhg.2014.05.002. PMID: 24882706Free PMC Article
Tory K, Rousset-Rouvière C, Gubler MC, Morinière V, Pawtowski A, Becker C, Guyot C, Gié S, Frishberg Y, Nivet H, Deschênes G, Cochat P, Gagnadoux MF, Saunier S, Antignac C, Salomon R
Kidney Int 2009 Apr;75(8):839-47. Epub 2009 Jan 28 doi: 10.1038/ki.2008.662. PMID: 19177160

Diagnosis

Ijaz A, Alfadhli F, Alharbi A, Khan YN, Alhawas YK, Hashmi JA, Wali A, Basit S
Eur J Med Genet 2022 Oct;65(10):104578. Epub 2022 Aug 17 doi: 10.1016/j.ejmg.2022.104578. PMID: 35987473
Raina R, Chakraborty R, Sethi SK, Kumar D, Gibson K, Bergmann C
Am J Kidney Dis 2021 Jul;78(1):125-141. Epub 2021 Jan 6 doi: 10.1053/j.ajkd.2020.10.021. PMID: 33418012
Yoshikawa T, Kamei K, Nagata H, Saida K, Sato M, Ogura M, Ito S, Miyazaki O, Urushihara M, Kondo S, Sugawara N, Ishizuka K, Hamasaki Y, Shishido S, Morisada N, Iijima K, Nagata M, Yoshioka T, Ogata K, Ishikura K
Nephrology (Carlton) 2017 Jul;22(7):566-571. doi: 10.1111/nep.12996. PMID: 28621010
Sun L, Tong H, Wang H, Yue Z, Liu T, Lin H, Li J, Wang C
Nephrology (Carlton) 2016 Mar;21(3):209-16. doi: 10.1111/nep.12563. PMID: 26184788
Finer G, Shalev H, Landau D
Pediatr Nephrol 2006 Jul;21(7):910-6. Epub 2006 May 30 doi: 10.1007/s00467-006-0142-2. PMID: 16773401

Therapy

Otto EA, Schermer B, Obara T, O'Toole JF, Hiller KS, Mueller AM, Ruf RG, Hoefele J, Beekmann F, Landau D, Foreman JW, Goodship JA, Strachan T, Kispert A, Wolf MT, Gagnadoux MF, Nivet H, Antignac C, Walz G, Drummond IA, Benzing T, Hildebrandt F
Nat Genet 2003 Aug;34(4):413-20. doi: 10.1038/ng1217. PMID: 12872123Free PMC Article

Clinical prediction guides

Sun L, Tong H, Wang H, Yue Z, Liu T, Lin H, Li J, Wang C
Nephrology (Carlton) 2016 Mar;21(3):209-16. doi: 10.1111/nep.12563. PMID: 26184788

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