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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2014  |  Volume : 25  |  Issue : 3  |  Page : 630-633
A family with five siblings affected with nephronophthisis

1 Department of Pediatrics, Jordan University Hospital, Amman, Jordan
2 Department of Pediatrics, The Hashemite University, Zarka, Jordan
3 Department of Medicine, Jordan University Hospital, Amman, Jordan

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Date of Web Publication9-May-2014


Nephronophthisis is an autosomal recessive disease that leads to end-stage renal disease. These days, molecular genetic analysis is used pre-emptively for making a definitive diagnosis in patients who have clinical and radiological data suggestive of the disease. Herein, we are reporting a 12-year-old girl who was genetically diagnosed to have juvenile nephronophthisis, which explained the mystery of the chronic kidney disease in her four affected siblings.

How to cite this article:
Albaramki J, Akl K, Hamed R, Wahbeh A. A family with five siblings affected with nephronophthisis. Saudi J Kidney Dis Transpl 2014;25:630-3

How to cite this URL:
Albaramki J, Akl K, Hamed R, Wahbeh A. A family with five siblings affected with nephronophthisis. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2021 Oct 19];25:630-3. Available from: https://www.sjkdt.org/text.asp?2014/25/3/630/132218

   Introduction Top

Nephronophthisis is a genetic disease that leads to end-stage renal disease (ESRD). It is characterized by polyuria and polydipsia. The prevalence of nephronophthisis in Jordan is not known. Genetic testing leads to a definitive diagnosis. [1] We herewith present a 12-year-old girl with a strong family history of ESRD in her family who had renal impairment and in whom genetic analysis revealed the diagnosis of nephronophthisis.

   Case Report Top

A 12-year-old girl presented to the pediatric nephrology clinic with vomiting and abdominal pain of few weeks duration along with increased thirst and nocturia. Her height was 151 cm (at the 50 th centile) and her weight was 39 kg (between 25 th and 50 th centile). Blood pressure was 90/60 mm Hg. On physical examination, no abnormalities were detected; detailed ophthalmological assessment was also normal. Laboratory results showed a serum creatinine of 224 μmol/L, urea of 16 mmol/L, sodium of 140 mmol/L, potassium of 3.8 mmol/L, calcium of 1.5 mmol/L, phosphate of 1.75 mmol/L and hemoglobin of 9.57 g/L. The parathyroid hormone level was 625.7 pg/mL (normal up to 54 pg/mL) and urine osmolality was 131 milli osmoles. Urine analysis and liver function tests did not show any abnormality.

Family history revealed that the patient had an older brother who died at the age of six years from renal failure of unknown etiology. He was on peritoneal dialysis for a year before his death. His kidney biopsy showed interstitial fibrosis and tubular atrophy.

The study patient has two other brothers and one sister who underwent kidney transplantation. An elder brother aged 28 years was diagnosed to have renal impairment at the age of 10 years and his renal function deteriorated with time. He was put on hemodialysis for a few months and subsequently underwent a living unrelated donor transplantation at the age of 13 years; presently, he has normal graft function 15 years post-transplant [Figure 1].
Figure 1: Family pedigree showing five affected family members with juvenile nephronophthisis.

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The eldest sister of the study patient is 27 years old at the time of reporting. She was diagnosed to have renal impairment at the age of ten years and was on peritoneal dialysis for nine months. Subsequently, she underwent living unrelated donor transplantation at the age of 11 years. Currently, 16 years post-transplant, her graft function is normal. Her younger brother is now 19 years. He had renal impairment at the age of seven years. He underwent a pre-emptive kidney transplant, the donor being his father at the age of 14 years. Currently, five years post-transplant, he has stable graft function. One brother, who is now 29 years, has been reported as healthy. Her parents are first-degree cousins.

Our patient underwent a renal ultrasound that revealed bilateral small echogenic kidneys. The family refused a kidney biopsy. Genetic testing of nephronophthisis gene NPHP1 was performed and showed a homozygous deletion in the NPHP1 gene confirming the diagnosis of JN. She is now being followed-up regularly at the clinic and her last serum creatinine was 265 umol/L, with an estimated glomerular filtration rate (GFR) of 25 mL/min/1.73 m 2 (chronic kidney disease stage IV). Currently, she is on anti-hypertensive medications, erythropoietin, phosphate binders, iron supplements and calcitriol. The family has opted for pre-emptive kidney transplantation in the future.

   Discussion Top

Nephronophthisis is an autosomal recessive disorder characterized by chronic tubulointerstitial nephritis progressing to ESRD. It was first described in 1951 by Fanconi. [1] There are three types according to the age of onset: Infantile, juvenile and adolescent forms.

The prevalence of nephronophthisis in Jordan is not known. A retrospective study from Jordan regarding etiology of chronic renal failure in 202 patients revealed that 3.96% had nephronophthisis. [2] More than 300 cases of nephronophthisis have been published in the literature thus far. [3]

JN is the most common type; children present around the age of seven years with polyuria and polydipsia secondary to reduced urinary concentrating ability demonstrating low urine osmolality and progressing to renal failure by the age of 13 years. [4] Renal ultrasound usually reveals normal-sized kidneys with increased echogenicity and loss of corticomedullary differentiation. Cysts may be seen at later stages. [5]

Light microscopy usually shows interstitial fibrosis and tubular damage in the form of tubular atrophy and tubular basement membrane anomalies such as thickening and disintegration of the basement membranes. [6]

Eleven different genes have been identified in JN. [7] The most frequent of these gene mutations is homozygous deletion of NPHP1, which causes approximately 20% of cases. Other mutations contribute to less than 3% each. [8] NPHP1 is one of the earliest genes identified in 1993 on chromosome 2q13 by positional cloning in consanguineous families. [9],[10] Homozygous deletions of 250 kb in this gene was detected in 70% of cases of nephronophthisis in 1997. [11],[12]

A cohort of 20 Egyptian children with nephronophthisis were studied and homozygous deletion in NPHP1 gene was indentified in 29.4% of patients, and this is similar to what has been reported from the Western countries. [13]

The NPHP1 gene encodes a protein called nephrocystin that is present at the cell-cell junction and the cell-matrix interface, suggesting important functions in the tubular epithelium. [14] It is also localized at the primary cilia-like proteins. [15]

Extra-renal symptoms are seen in 10-20% of cases, and these include retinitis pigmentosa (Senior-Loken syndrome), cerebellar ataxia in Joubert syndrome, bone anomalies, mental retardation and liver fibrosis. [16]

The majority of patients with NPHP1 mutation have no extra-renal symptoms, although moderate forms of retinal degeneration and Joubert syndrome have been reported in some cases. Medullary cystic kidney disease has similar clinical features and pathology to JN, but has an autosomal dominant pattern of inheritance and leads to renal failure at the age of 50 years. [17],[18]

Our patient had a history of polyuria and progressive familial renal disease. She was diagnosed by genetic analysis that revealed homozygous deletion of NPHP1, indicating that her parents were carriers. This family was quite unlucky to have five affected members. The high rate of consanguinity in Jordan increases the prevalence of such inherited autosomal recessive diseases.

To the best of our knowledge, this is the first case report from Jordan where genetic testing confirmed the diagnosis of JN. Also, genetic analysis will enable prenatal diagnosis in subsequent siblings. In conclusion, based on clinical and radiological findings, JN can be diagnosed by genetic studies.

   References Top

1.Fanconi G, Hanhart E, von Albertini A, Uhlinger E, Dolivo G, Prader A. Familial, juvenile nephronophthisis (idiopathic parenchymal contracted kidney). Helv Pediatr Acta 1951;6:1-49.   Back to cited text no. 1
2. Hamed RM. The spectrum of chronic renal failure among Jordanian children. J Nephrol 2002;15:130-5.   Back to cited text no. 2
3. Waldherr R, Lennert T, Weber HP, Födisch HJ, Schärer K. The nephronophthisis complex. A clinicopathologic study in children. Virchows Arch A Pathol Anat Histol 1982;394:235-54.  Back to cited text no. 3
4.Hildebrandt F, Strahm B, Nothwang HG, et al. Molecular genetic identification of families with juvenile nephronophthisis type 1: Rate of progression to renal failure. APN Study Group. Kidney Int 1997;51:261-9.  Back to cited text no. 4
5.Blowey DL, Querfeld U, Geary D, Warady BA, Alon U. Ultrasound findings in juvenile nephronophthisis. Pediatr Nephrol 1996;10:22-4.  Back to cited text no. 5
6.Zollinger HU, Gaboardi F, Imbasciati E, Lennert T. Nephronophthisis (medullary cystic disease of the kidney). A study using electron microscopy, immunofluorescence, and a review of the morphological findings. Helv Paediatr Acta 1980;35:509-30.  Back to cited text no. 6
7.Wolf MT, Hildebrandt F. Nephronophthisis. Pediatr Nephrol 2011;26:181-94.  Back to cited text no. 7
8.Hildebrandt F, Attanasio M, Otto E. Nephronophthisis: Disease mechanisms of a ciliopathy. J Am Soc Nephrol 2009;20:23-35.  Back to cited text no. 8
9.Antignac C, Arduy CH, Beckmann JS, et al. A gene for familial juvenile nephronophthisis (recessive medullary cystic disease) maps to chromosome 2p. Nat Genet 1993;3:342-45.  Back to cited text no. 9
10.Hildebrandt F, Singh-Sawhney I, Schnieders B, et al. Mapping of a gene for familial juvenile nephronophthisis: Refining the map and defining flanking markers on chromosome 2. APN Study Group. Am J Hum Genet 1993;53: 1256-61.  Back to cited text no. 10
11.Hildebrandt F, Otto E, Rensing C, et al. A novel gene encoding an SH3 domain protein is mutated in nephronophthisis type 1. Nat Genet 1997;17:149-53.  Back to cited text no. 11
12.Saunier S, Calado J, Heilig R, et al. A novel gene that encodes a protein with a putative src homology 3 domain is a candidate gene for familial juvenile nephronophthisis. Hum Mol Genet 1997;6:2317-23.  Back to cited text no. 12
13.Soliman NA, Hildebrandt F, Allen SJ, Otto EA, Nabhan MM, Badr AM. Homozygous NPHP1 deletions in Egyptian children with nephronophthisis including an infantile onset patient. Pediatr Nephrol 2010;25:2193-4.  Back to cited text no. 13
14.Hildebrandt F, Zhou W. Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 2007; 18:1855-71 .   Back to cited text no. 14
15.Fliegauf M, Horvath J, von Schnakenburg C, et al. Nephrocystin specifically localizes to the transition zone of renal and respiratory cilia and photoreceptor connecting cilia. J Am Soc Nephrol 2006;17:2424-33.  Back to cited text no. 15
16.Salomon R, Saunier S, Niaudet P. Nephronophthisis. Pediatr Nephrol 2009;24:2333-44.  Back to cited text no. 16
17.Scolari F, Ghiggeri GM. Nephronophthisis-medullary cystic kidney disease: From bedside to bench and back again. Saudi J Kidney Dis Transpl 2003;14:316-27.  Back to cited text no. 17
[PUBMED]  Medknow Journal  
18.Hildebrandt F, Otto E. Molecular genetics of nephronophthisis and medullary cystic kidney disease. J Am Soc Nephrol 2000;11:1753-61.  Back to cited text no. 18

Correspondence Address:
Dr. Jumana Albaramki
Department of Pediatrics, Jordan University Hospital, Faculty of Medicine, Jordan University, P.O. Box 1459, Amman 11821
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DOI: 10.4103/1319-2442.132218

PMID: 24821164

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