Saudi Journal of Kidney Diseases and Transplantation

: 2011  |  Volume : 22  |  Issue : 4  |  Page : 788--791

Joubert syndrome with nephronophthisis in neurofibromatosis type 1

Javed Ahmed, Uma S Ali 
 Department of Pediatric Nephrology, B.J. Wadia Hospital for Children, Parel, Mumbai, India

Correspondence Address:
Javed Ahmed
Department of Pediatric Nephrology, B.J. Wadia Hospital for Children, Parel, Mumbai


Joubert syndrome (JS) is a rare developmental disorder of the central nervous system, characterised by brainstem and cerebellar malformations, hypotonia, episodic hyperapnea and apnea and mental retardation. It may be associated other systemic abnormalities like ocular (e.g., retinal dysplasia, etc.), oculomotor, musculoskeletal and renal (e.g., cystic dysplasia, nephronophthisis), with renal failure. We describe a case of JS with nephronophthisis in neurofibromatosis Type 1 leading to end-stage renal disease, a association that has never been described earlier in the medical literature to the best of our knowledge.

How to cite this article:
Ahmed J, Ali US. Joubert syndrome with nephronophthisis in neurofibromatosis type 1.Saudi J Kidney Dis Transpl 2011;22:788-791

How to cite this URL:
Ahmed J, Ali US. Joubert syndrome with nephronophthisis in neurofibromatosis type 1. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2020 Jul 9 ];22:788-791
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Full Text


Joubert syndrome (JS) is an autosomal recessive central nervous system (CNS) malformation characterized by hypoplasia of the cerebellar vermis, hypotonia and impaired psycho-motor development, together with abnormal respiratory pattern and various ophthalmological features. Renal insufficiency is rarely reported with JS. We report a case of nephronophthisis (NPH) in JS as this is rare and probably the first time being described in association with neurofibromatosis type 1 (NF1).

 Case Report

A 12-year-old female child of cerebral palsy was referred to our department for evaluation of anemia and azotemia. The child was born of non-consanguineous marriage and had been admitted in the NICU for birth asphyxia. She developed convulsions on the 2 nd day of life. She was found to have occipital meningocele and underwent meningeocelectomy at two months of age.

The mother recalls that the child had irregular respiration from the beginning, which gradually improved over time. She had severe mental retardation and her language was mainly few primitive sounds. The child was being followed-up, but irregularly, in the physiotherapy department and had developed severe joint contractures.

She was non-oliguric, had anemia, no organomegaly and was normotensive. Her head circumference was normal. She had ptosis of the right eye and pendular nystagmus, but without any coloboma or retinitis pigmentosa. There was depressed nasal bridge and synophrys. The child had multiple café au lait spots and axillary freckling and mother too had multiple neurofibromas and cafe au lait spots (TYPE 1 neurofibromatosis). Tone was increased in all the limbs, with contracture in all major joints. She had an Hb of 5.4 gm% with normocytic normochromic picture and normal serum iron studies. Her BUN was 110 mg%, serum creatinine 9.8 mg%, serum calcium 7.8 and phosphorous 9.8 mg%. USG showed normal kidney sizes with no cyst visualized.

Her MRI of the brain at the age of 12 years showed the classical "molar tooth" sign [Figure 1].{Figure 1}

Renal histopathology showed sclerosing interstitial fibrosis, tubular atrophy with focal lymphocytic infiltrates and few dilated tubules with thick-walled muscular arteries. Basement membrane appeared to be normal. Occasional glomeruli were sclerosed [Figure 2]. Electron microscopy showed normal basement membrane and interstitial fibrosis. The child was started on iron supplementation, phosphate binders and erythropoeitin injection for anemia, and is now on follow-up.{Figure 2}


JS is a rare (incidence of 1:100,000) autosomal-recessive disorder of the central nervous system characterized by brainstem and cerebellar malformations, hypotonia, episodic hyperapnea and apnea, neuro-ophthalmological abnormalities and mental retardation. [1],[2] After the first description by Joubert in 1969, more than 200 cases have been described, [1] but still delineation of the genotypic and phenotypic spectrum of JS remains unresolved, and both intra-and inter-familial variations are seen.

Maria et al [2] have proposed a revised diagnostic criteria for JS. It includes common anomalies like:

Hypotonia (almost always)AtaxiaDevelopmental delay (independent of gross CNS malformation) andNeuroradiological hallmark "Molar Tooth sign" [1],[3]

Other associated anomalies are: [2],[3],[4]

Dysmorphic face (high eyebrow, epicanthal fold, anteverted nostrils)Breathing abnormalities like hyperpnea and apnea episodes (50-75%), more pronounced in the neonatal periodsOcular abnormalities (oculomotor apraxia, retinal dystrophy, coloboma, nystagmus, strabismus, ptosis, blindness) [4] Renal abnormalities described are cystic renal dysplasia and juvenile nephronophthisis

MRI shows vermis hypoplasia, thickening of the superior cerebellar peduncles with a deep midline cleft at the ponto-mesencephalic junction. The absence of decussating superior cerebellar peduncular axons causes the characteristic molar tooth sign in patients with JS. This "molar tooth" sign is not specific of JS as it may be seen in other conditions like Dekaban-Arima Syndrome, Senior-Loken malformation, Cerebellar vermis hypoplasia/aplasia, Oligophrenia, Ataxia, Coloboma, and Hepatic fibrosis (COACH), etc. [3]

As discussed earlier, JS is a heterogeneous group of disorder and inter -and intra-familial variations are common. Our patient has most of the features except hypotonia, which may be due to perinatal asphyxia and, later, leading to formation of contractures.

Saraiva and Baraitser [5] observed that all patients with kidney abnormality had congenital retinal dystrophy. Although this is a frequent association, it is not an obligatory one, [1] as in our patient, who only had ptosis but no retinal abnormality.

Renal abnormality as such is rare in JS, with an incidence ranging from 2% to 20%. [1] Described anomalies are cystic dysplasia and nephronophthisis (NPH), which are grossly and histologically indistinguishable from other variants of NPH and medullary cystic disease complex (NPH-MCKD). [6] Grossly, multiple cysts located at the corticomedullary junction arise from the distal collecting tubules and medullary collecting tubules. On renal histology, NPH-MCKD exhibits a characteristic triad of disruption of renal tubular basement membranes (TBMs), with tubular cell atrophy, tubulo-interstitial fibrosis and cyst formation. Extrarenal manifestations have been described in association with recessive NPH, but are absent from dominant MCKD. [6],[7] NPH is the most common genetic cause of renal failure in the first two decades of life, amounting to 15%. [7] NPH causes ESRD in adolescents and MCKD in adulthood. [6]

Presently, five (and a few more unconfirmed) genes are implicated in JS-like syndrome. They are distinct from the juvenile NPH (NPH1) gene on chromosome 2q12.3, which is present in approximately 85% of the NPH patients [6],[8],[9] without JS. Commonly detected mutation/deletion in JS are AHI1, CEP290 (NPHP6), TMEM67 (MKS3), RPGRIP1L gene and, rarely, NPHP1 deletion. [9],[10],[11]

JS is heterogeneous both phenotypically and genetically. Genotype correlates little with diversity of manifestations seen. Children with AHI1 and NPHP1 gene mutation/deletion tend to have retinal dystrophy and kidney problems in some individuals. The clinical manifestations for the other three genes (CEP290, TMEM67 (MKS3) and RPGRIP1L) are more variable and overlap with Meckel-Gruber syndrome. AHI1& CEP290 mutation are seen in Senior-Loken syndrome. [9] These five causative genes may cause around 10-40% of the total familial JS, [9],[10] and others are yet to be discovered. Till now, association of JS with neuro-fibromatosis type 1 has never been described. We cannot say whether this is a real association or was an apparent association due to the high incidence of neurofibromatosis in the population.

Molecular basis of this renal disease in CNS malformation is unknown. Recent studies point to several factors, including the c-ret proto-oncogene and Glial-derived nerve factor (GDNF). c-ret encodes a receptor, tyrosine kinase, which in mouse transcripts in the Wolffian duct, ureteric bud epithelium and renal collecting ducts as well as cell lineages in the CNS. [12] c-ret is a receptor for GDNF, which is highly expressed in neonatal kidney and developing rat CNS, and is shown to stimulate renal organogenesis and differentiation of CNS neurons. [12]


Mental retardation varies, ranging from severe to normal, but usually development quotient (DQ), is in the range of 70-80. [7],[9],[13] Children display hyperactivity, aggression, dependency and temperament, [13] but they are generally pleasant, friendly and socially integrated. Some of them may have seizure disorder, autism and concomitant other CNS developmental anomalies like occipital encephalocele or meningocele, which our patient had. Breathing abnormalities like hyperapnea and apnea episodes improves with age, and is most pronounced in the neonatal age.

Cystic dysplasia may be present in the newborn period or may develop later. Juvenile NPH often presents in the first or second decade of life, with polydipsia, polyuria, urine concentrating defects, growth retardation and/ or anemia. Progression to end-stage renal disease (ESRD) occurs by an average age of 13 years, [6],[7],[9] as in our case. What makes our case interesting and unique is hypertonia (which may be due to birth asphyxia), association with type 1 neurofibromatosis, no retinitis pigmentosa (uncommon with renal lesion), occipital meningocele without any features of hydro-nephrosis and with normal bladder size indicating normal voiding. Complications of endstage renal disease resulting from cystic kidney disease or NPH often require specific treatments such as dialysis and/or kidney transplantation. Although transplantation is effective with no risk of recurrence, but co-morbid CNS conditions may preclude it.

Genetic Counseling

This is an autosomal-recessive condition and hence there are 25% chances of this occurring in siblings. Carrier testing and prenatal diagnosis for at-risk family members is available if the mutations have been identified in the proband. Prenatal diagnosis using ultrasound examination with or without fetal MRI has been successful. [9] Family screening with minimal urine examination (including specific gravity) and ophthalmological examination is recommended.


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