[MIM 256 100, 602 088, 604 387, 606 966, 613 159, 613 820, 613 824, 614 377, 614 817, 615 382]

(Familial juvenile nephronophthisis, renal medullary cystic disease)

Incidence estimated at 1/100,000 (1/50,000 births in the Canada). First genetic cause of chronic renal failure before the age of 30 years. Chronic renal tubulo-interstitial disease of autosomal recessive transmission. High variability of the clinical presentation and the genetic origin.

At histology: atrophic tubules with a laminated basal membrane or dilated tubes with a thin basement membrane; interstitial fibrosis; cysts appear later.

Most cases (20-40 %) are due to a mutation of the NPHP1 gene on 2q12-q13, which codes for nephrocystine-1 located in the renal tubular epithelium (intercellular junctions, apical primary cilia).

Other cases are due to a mutation of:

-         the NPHP2 gene on 9q 31 which codes for inversin (1%); infantile form

-         the NPHP3 gene on 3q22: codes for nephrocystine-3 (1%); form occurring at adolescence but also infantile or hepatic fibrosis 

-         the NPHP4 gene on 1p36 that codes for nephrocystine-4 which is present in the connector cilium of the photoreceptors

-         the  NPHP5 gene on 3q21 that codes for protein IQCB1: severe forms of retinopathy. especially in case of Senior-Loken syndrome

-         the NPHP6 or CEP290 gene on 12q21, which codes for a protein of the centrosome of the basis of the primary cilium; severe retinopathy, Joubert syndrome

-  the NPHP7 gene on 16p that codes for the protein GLIS2: Oji-Cree Indians in Canada

-         the  NPHP8 gene on 16q that codes for the protein RPGRIP1-L, a protein localized at the base of the cilia of tubular cells:  Joubert syndrome and Meckel syndrome

-         the NPHP9 gene on 17q11, which codes for the NEK8 protein.

This pathology leads to a lack of concentration of the urine with loss of NaCl.: the first sign is therefore often polyuria-polydipsia sometimes revealed by secondary enuresis. Progression to chronic renal failure with preserved diuresis without high blood pressure, or proteinuria or hematuria: indication for a kidney transplant. Imaging reveals cysts of variable size at the level of the cortico-medullary junction.

Clinically, there are:

-         infantile form (NPHP2 or 3): progresses to renal failure before the age of 2 years; severe hypertension, in contrast to other forms; early onset of medullary and cortical cysts; large kidneys; sometimes heart disease, hepatic fibrosis or situs inversus (ciliary pathology);

-         juvenile form (5 to 10 % of cases of terminal kidney failure in children) (NPHP1, NPHP3 to NPHP9): polyuria-polydispsia around 4-6 years of age due to a disorder of the concentration of the urine; renal failure between the age of  10 and 20 years; tubular basement membranes anomalies at renal biopsy; late-onset spinal cord cysts

-         form during the adolescence or late (NPHP1, NPHP3 to NPHP9): similar to the juvenile form but renal failure occurs later

Extrarenal conditions may be associated with nephronophthisis :

-         Senior-Loken syndrome (NPHP5): blindness with congenital nystagmus following retinal dystrophy (Retinitis Pigmentosa) but some cases have no clinical repercussion (isolated ERG anomalies)

-         Cogan syndrome type II: oculo-motor apraxia, sometimes associated with cerebellar ataxia (deletion of the NPHP1 gene in some cases)

-         Joubert syndrome or cerebello-oculo-renal syndrome (NPHP7): mental retardation, cerebellar ataxia, retinal degeneration; renal impairment is present in a minority of cases

-         Boichis or Senior-Boichis syndrome: hepatic fibrosis with hepatosplenomegaly; proliferation of bile ducts [MIM 613 550]; one talks of Boichis-Loken syndrome if tapeto-retinal degeneration and mental retardation are also associated

-         Saldino-Mainzer syndrome:  abnormal ribs, cone-shaped epiphyses, severe retinal dystrophy

-         Sensenbrenner syndrome: cranio-ectodermal dysplasia, facial dysmorphism, retinitis

-         Rhyns syndrome [ MIM 602 152]: panhypopituitarism

-         Ellis-Van Creveld syndrome

Anesthetic implications: 

loss of NaCl, chronic renal failure; infantile form: preoperative echocardiography and check for the absence of situs inversus; check liver function.

References : 

-         Salomon R. 
La néphronophtise et les maladies apparentées : hétérogénéité génétique et oligogénisme. 
Journées Parisiennes Pédiatrie 2006, p 1-14.

-         Sikora P, Mejewski M, Kandzierski G et al. 
Juvenile nephronophtisis, short stature, partial odontia and skeletal abnormalities- a new syndromic association. 
Nephrol Dial Transplant 2006; 21: 2335-6

Updated: November 2018