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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2013  |  Volume : 24  |  Issue : 2  |  Page : 338-344
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC): Report of three cases with a novel mutation in CLDN19 gene


1 Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates
2 University Children's Hospital, Department of General Pediatrics, Munster, Germany
3 Department of Surgery, Division of Ophthalmology, Tawam Hospital, Al Ain, United Arab Emirates
4 Department of Pediatrics, Faculty of Medicine and Health Sciences, Sheikh Khalifa Medical City, United Arab Emirates
5 Department of Pediatrics, Sheikh Khalifa Medical City, United Arab Emirates

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Date of Web Publication26-Mar-2013
 

   Abstract 

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder that is caused by mutation in the genes coding for tight junction proteins Claudin-16 and Claudin-19. Affected individuals usually develop nephrocalcinosis and progressive renal failure; some of them may have ophthalmologic involvement as well. Phenotypic description of three affected individuals from the same Middle Eastern kindred (two sisters and their cousin) is presented. This includes both clinical and laboratory findings upon initial presentation and subsequent follow-up. Molecular analysis of the CLDN19 gene was performed on the three cases and one set of parents. A novel homozygous missense mutation in CLDN19 (c.241C>T, p.Arg81Cys) was detected in all three affected children. The parents were heterozygous. Clinical and laboratory data in the three children with renal and ocular manifestations of FHHNC are described. Genetic analysis revealed a novel mutation in the CLDN19 gene. FHHNC is a rare cause of nephrocalcinosis, and we believe that it should be considered in the presence of nephrocalcinosis with hypercalcuria and hypermagnesuria.

How to cite this article:
Al-Shibli A, Konrad M, Altay W, Al Masri O, Al-Gazali L, Al Attrach I. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC): Report of three cases with a novel mutation in CLDN19 gene. Saudi J Kidney Dis Transpl 2013;24:338-44

How to cite this URL:
Al-Shibli A, Konrad M, Altay W, Al Masri O, Al-Gazali L, Al Attrach I. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC): Report of three cases with a novel mutation in CLDN19 gene. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2019 Dec 14];24:338-44. Available from: http://www.sjkdt.org/text.asp?2013/24/2/338/109601

   Introduction Top


Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive disorder characterized by excessive renal magnesium (Mg 2+ ) and calcium (Ca 2+ ) wasting, bilateral nephrocalcinosis and progressive renal failure. [1],[2] Fifty percent of the cases usually require renal replacement therapy in the 2nd decade of life. [3],[4],[5] The initial symptoms may include recurrent urinary tract infections, polyuria and polydipsia, in addition to marked hypomagnesemia. All patients exhibit hypercalciuria and nephrocalcinosis. Additional symptoms may include nephrolithiasis, abdominal pain, convulsions, muscular twitches, failure to thrive, incomplete distal renal tubular acidosis and hypocitraturia. [3],[5]

Ocular abnormalities (severe myopia, nystagmus and chorioretinitis) and hearing impairment have been reported as inconsistent extra-renal symptoms. [2] Renal function declines progressively in the majority of FHHNC patients, and many of these patients reach end-stage renal disease in their teenage or young adult years. [5],[6],[7],[8]

FHHNC is caused by mutations in the CLDN-16 gene (which encodes the tight junction protein claudin-16). [9] Mutations in Claudin-19, which is another member of the claudin family, were identified in a subset of patients with FHHNC with visual impairment. [10]

Claudins belong to the family of tight junction proteins that define the intercellular space between adjacent endo- and epithelial cells. [11] Claudin-16 and claudin-19 play an important role in the regulation of paracellular cation permeability in the thick ascending loop of Henle (TAL) of the renal tubule [12] and in the distal convoluted tubule (DCT). Loss of function of either claudin-16 or claudin-19 results in renal wasting of magnesium and calcium. [12],[13]

Here, we report a consanguineous family with three children affected with FHHNC. Molecular analysis revealed a novel homozygous missense mutation in CLDN-19.


   Case Reports Top


Case 1

A 4-year old female was referred to our Pediatric Nephrology clinic for evaluation of polyuria and polydipsia. There was no history of urinary tract infections. On initial evaluation, the patient was having normal vital signs; the growth parameters were on the 50 th centile for weight and height. She had myopia with divergent squint with bilateral retinal dystrophy. Fundus examination revealed right foveal yellowish patch with tilted disc, left macular retinal pigment epithelial (RPE) atrophy as shown in the fundoscopy [Figure 1] and optical coherence tomography (OCT) [Figure 2], ocular motility showed left eye exotropia of 20-25 prism diopter Base-out. Other systemic examinations were normal. She was the sixth child to her consanguineous parents (first cousins). One of her sisters, who was eight years old (case 2), had kidney failure and was transplanted two years earlier. Her cousin (case 3) was diagnosed with nephrocalcinosis and renal impairment. Summary of the clinical, laboratory and radiological features are shown in [Table 1]. Abdominal ultrasound (US) examination showed evidence of bilateral medullary nephrocalcinosis [Figure 3].
Figure 1: Fundoscopy showing macular retinal pigment epithelial (RPE) atrophy in case 1.

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Figure 2: Chorioretinal degeneration with retinal pigment epithelial atrophy (arrow) of the left eye.

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Figure 3: Renal ultrasonographic appearance of nephrocalcinosis in the right kidney of case 1.

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Table 1: Summary of the clinical, laboratory and radiological features of the three cases.

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The patient was maintained on Mg 2+ supplements along with potassium citrate and hydrochlorothiazide. Estimated GFR decreased from 65 mL/min/1.73 m 2 on presentation to 48 mL/ min/1.73 m 2 after two years. She had normal serum electrolytes, Ca 2+ and Mg 2+ (on replacement) and no significant progression of nephrocalcinosis on renal US.

Case 2

An 8-year-old female was referred to our hospital after presentation of an acute on chronic renal failure of unknown etiology. She is the cousin of case 1 [Figure 4]. Renal US showed bilateral small kidneys with evidence of nephrocalcinosis. The patient was not compliant with the follow-up, and she finally presented with manifestations of advanced renal failure. There was a past medical history of recurrent urinary tract infection. She developed bilateral cataract and lens implantation was done bilaterally. She had horizontal nystagmus. Fundus examination showed bilateral chorioretinal degeneration in the peripapillary area. She is now in her third year post-kidney transplant.
Figure 4: Showing the family pedigree; Probands (affected sibs, cases 1 and 2 and their cousin, case 3) are assigned by arrows. Parents of cases 1 and 2 are proven heterozygous carriers; probable carriers were not analyzed molecularly.

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Case 3

A 3-year-old female was referred to the Pediatric Nephrology clinic after the detection of impaired kidney function during an episode of acute gastroenteritis. The patient's growth was in the 25 th centile with normal vitals. She was wearing eye glasses for myopia. Other systemic examinations were normal. She was the sixth child to her consanguineous parents. All of her siblings were healthy. There was a positive family history for chronic kidney disease in two of her cousins (cases 1 and 2). Estimated GFR decreased from 55 mL/min/1.73 m 2 on presentation to 50 mL/min/1.73 m 2 after one year. She was maintained on potassium citrate and magnesium 2+ supplements.

Mutation analysis of the Claudin-19 was done for the three cases

DNA analysis from peripheral blood leukocyte sample was done for CLDN19 after informed consent had been taken from the patients' guardians. In the three patients presented above, a missense mutation, Arg81Cys in CLDN-19, in a homozygous state was detected [Figure 5]. This mutation is novel and has not been described previously, but in silico analysis (SIFT, POLYPHEN) strongly suggests its pathogenicity.
Figure 5: Showing the missense mutation Arg81Cys in Claudin-19.

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Genetic analysis for parents of cases 1 and 2 showed that the familial CLDN19:c.241C>T variant was present in a heterozygous state.


   Discussion Top


Nephrocalcinosis in FHHNC is characterized by the deposition of calcium as oxalate/phosphate or urate in the kidney parenchyma and tubules. [14] There are several causes for nephrocalcinosis [Table 2]. [15] The underlying pathological condition is not always evident and requires a detailed history and work-up. The presence of nephrocalcinosis in the absence of hyperuricosuria and hyperoxaluria makes Oxalate, Purine/pyrimidine-induced nephrocalcinosis unlikely. Serum calcium was normal in the presence of hypercalciuria, indicating tubular Ca handling disorders. Normal serum levels of electrolytes, bicarbonate and pH levels with hypomagnesemia and hypermagnesuria should raise suspicion of FHHNC.
Table 2: The differential diagnosis of nephrocalcinosis with its phenotype.[23]

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FHHNC was first described by Manz et al in 1978. [16] It is usually caused by mutations in the tight junction genes CLDN-16[8],[9] or CLDN-19. [13] Frequent initial urinary symptoms of FHHNC include recurrent UTIs, polyuria and polydipsia in addition to marked hypomagnesemia. All patients exhibit hypercalciuria, hypermagnesuria and nephrocalcinosis. Additional symptoms may include nephrolithiasis, abdominal pain, convulsions, muscular twitches, failure to thrive, incomplete distal renal tubular acidosis and hypocitraturia. [5],[6],[7],[8],[9] In a multicenter study that correlated the genotype with phenotype of 25 families with FHHHC, Weber et al described that UTIs were the most common clinical manifestation (43%), followed by polyuriapolydipsia (27%) and hematuria (20%). [10] Our three cases have different manifestations of the disease, including recurrent UTIs, polyuria and nephrocalcinosis with impaired kidney function.

Ocular abnormalities can occur in FHHNC, and include severe myopia, nystagmus and coloboma. Moreover, bilateral keratoconus, corneal calcifications or chorioretinitis have also been reported. [4],[10] Our cases showed severe ocular involvement that includes retinal changes in addition to cataract and squint that was described in one of the patients.

Konrad et al showed that normal CLDN-19 is important in the organization and development of the retina. [10] Fetal human retinal pigment epithelium (RPE) is a claudin-19 dominant epithelium that has regional variations in claudin expression in the retina. [17] Cataract was reported by Al-Haggar et al, [18] which may indicate that CLDN-19 is expressed in the lens as well.

There are other extrarenal features that were described in CLDN-16 case reports that include short stature. [19] Mehmet et al describe other congenital abnormalities (horseshoe kidney, neonatal teeth, atypical face, cardiac abnormalities including coarctation of the aorta associated with atrial and ventricular septal defects, umbilical hernia and hypertrichosis) in a patient who was diagnosed to have FHHHC at the age of two months. [20] Faguer et al reported exercise intolerance with pain, weakness and electromyographical alterations mimicking a Ca +2/ K + channelopathy that persisted even after normalization of K + and Mg 2+ in patients with CLDN-19 mutations; [21] however, all of these symptoms were described in case reports, but are uncommon manifestations of FHHNC.

Konrad et al [10] demonstrated two different homozygous missense mutations in the CLDN-19 gene in families with renal magnesium wasting, renal failure and severe ocular involvement. In seven of eight Spanish/Hispanic families, they found a gly20-to-asp mutation in the first transmembrane domain of claudin-19. In a Swiss family, they detected a gln57-to-glu substitution in the first extracellular loop.

In the Middle East, CLDN-19 mutation was identified in a consanguineous Turkish family with a homozygous leu90-to-pro substitution in two affected children. [22]

Our patients have another missense mutation (Arg81Cys) in CLDN-19 in a homozygous state. This mutation is novel and has not been described previously, and in silico analysis (SIFT, POLYPHEN) suggests its pathogenicity.

Our cases were treated with oral citrate, thiazide diuretics and magnesium replacement apart from case 2, who already presented with low GFR that required dialysis. Medications usually help to normalizing the biomedical changes and may delay the progression of renal failure. [23],[24]

In conclusion, we described in this report the clinical and laboratory data of three related children with renal and ocular manifestations of FHHNC. Genetic analysis revealed a novel mutation in CLDN19 gene. FHHNC is a rare cause of nephrocalcinosis, and it should be considered in the presence of nephrocalcinosis with hypercalcuria and hypermagnesuria.

Conflict of Interest: None

 
   References Top

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3.Manz F, Scharer K, JankaP, Lombeck J. Renal magnesium wasting, incomplete tubular acidosis, hypercalciuria and nephrocalcinosis in siblings. Eur J Pediatr 1978;128:67-79.  Back to cited text no. 3
    
4.Weber S, Hoffmann K, Jeck N, et al. Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis maps to chromosome 3q27 an disassociated with mutations in the PCLN-1 gene. Eur J Hum Genet 2000;8:414-22.  Back to cited text no. 4
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10.Konrad M, Schaller A, Seelow D, et al. Mutations in the tight-junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet 2006;79:949-57.   Back to cited text no. 10
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11.Hou J, Renigunta A, Konrad M, et al. Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex. Clin Invest 2008;118:619-28.  Back to cited text no. 11
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12.Haisch L, Almeida JR, Abreu da Silva PR, Schlingmann KP, Konrad M. The role of tight junctions in paracellular ion transport in the renal tubule: lessons learned from a rare inherited tubular disorder. Am J Kidney Dis 2011;57:320-30.  Back to cited text no. 12
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13.Hou J, Renigunta A, Gomes AS, et al. Good enough, claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium. Proc Natl Acad Sci USA 2009;106:15350-5.   Back to cited text no. 13
    
14.Hoppe B, Kemper MJ. Diagnostic examination of the child with urolithiasis or nephrocalcinosis. Pediatr Nephrol 2010;25:403-13.  Back to cited text no. 14
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15.Sayer JA, Carr G, Simmons NL. Nephrocalcinosis: Molecular insights into calcium precipitation within the kidney. Clin Sci (Lond) 2004;106:549-61.  Back to cited text no. 15
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16.Manz F, Scharer K, Janka P, Lombeck J. Renal magnesium wasting, incomplete tubular acidosis, hypercalciuria and nephrocalcinosis in siblings. Eur J Pediatr 1978;128:67-79.  Back to cited text no. 16
    
17.Peng S, Rao VS, Adelman RA, Rizzolo LJ. Claudin-19 and the barrier properties of the human retinal pigment epithelium, Invest Ophthalmol Vis Sci 2011;52:1392-403.  Back to cited text no. 17
    
18.Al-Haggar M, Bakr A, Tajima T, et al. Familial hypomagnesemia with hypercalciuria, and nephrocalcinosis: Unusual clinical associations and novel claudin16 mutation in an Egyptian family. Clin Exp Nephrol 2009;13:288-94.  Back to cited text no. 18
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21.Faguer S, Chauveau D, Cintas P, et a. Renal, ocular, and neuromuscular involvements in patients with CLDN19 mutations. Clin J Am Soc Nephrol 2011;6:355-60.  Back to cited text no. 21
    
22.Peru H, Akin F, Elmas S, Elmaci AM, Konrad M. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: Report of three Turkish siblings. Pediatr Nephrol 2008;23: 1009-12.  Back to cited text no. 22
    
23.Wolf MT, Dötsch J, Konrad M, Böswald M, Rascher W. Follow-up of five patients with FHHNC due to mutations in the paracellin-1 gene. Pediatr Nephrol 2002;17:602-8.  Back to cited text no. 23
    
24.Tajima T, Nakae J, Fujieda K. Two heterozygous mutations of CLDN16 in a Japanese patient with FHHNC. Pediatr Nephrol 2003; 18:1280-2.  Back to cited text no. 24
    

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Correspondence Address:
Amar Al-Shibli
Consultant Pediatrician,Tawam Hospital, P.O. Box 15258, Al-Ain
United Arab Emirates
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DOI: 10.4103/1319-2442.109601

PMID: 23538362

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]

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