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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2012  |  Volume : 23  |  Issue : 4  |  Page : 804-809
ARC syndrome with complex renal problems: Nephrocalcinosis, proximal and hyperkalemic distal RTA and nephrogenic diabetes insipidus

1 Department of Pediatric Nephrology, Tabriz University (Medical Sciences), Tabriz, Iran
2 Department of Pediatric Gasteroenterology, Tabriz University (Medical Sciences), Tabriz, Iran
3 Department of Pediatric Cardiology, Tabriz University (Medical Sciences), Tabriz, Iran

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Date of Web Publication9-Jul-2012


We present a female neonate with arthrogryposis, renal tubular abnormalities and cholestasis syndrome and complex renal structural and functional abnormalities that include medul­lary nephrocalcinosis, hydronephrosis, nephrogenic diabetes insipidus, Fanconi syndrome, proximal and distal hyperkalemic renal tubular acidosis, near-nephrotic range proteinuria, hypercalciuria and severe hypovitaminosis D.

How to cite this article:
Malaki M, Mandana R, Ghaffari S. ARC syndrome with complex renal problems: Nephrocalcinosis, proximal and hyperkalemic distal RTA and nephrogenic diabetes insipidus. Saudi J Kidney Dis Transpl 2012;23:804-9

How to cite this URL:
Malaki M, Mandana R, Ghaffari S. ARC syndrome with complex renal problems: Nephrocalcinosis, proximal and hyperkalemic distal RTA and nephrogenic diabetes insipidus. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2021 Jun 21];23:804-9. Available from: https://www.sjkdt.org/text.asp?2012/23/4/804/98165

   Introduction Top

Arthrogryposis, renal tubular abnormalities and cholestasis (ARC) syndrome was first described in two siblings from a consanguineous family in 1973. [1] It is not uncommon among popula­tions with a high consanguinity rate and now over 60 cases have been reported in the world. [2],[3] Because of the variability in signs and symp­toms, they have been divided into incomplete and complete forms. [4]

The major renal manifestation of this syn­drome is a severe Fanconi syndrome together with nephrogenic diabetes insipidus [3],[5] in some patients. Other features of renal involvement seen are small dysplastic kidneys, nephrocalcinosis, interstitial nephritis and multicystic dysplasia. [3]

In this case report, we present a female neo-nate admitted with severe dehydration, non-anion gap acidosis, Fanconi syndrome, signi­ficant proteinuria, and hyperkalemic distal re­nal tubular acidosis, nephrocalcinosis, arthrogryposis of left ankle, cholestasis and icthyosis that come together to form a rare syndrome named as ARC.

   Case Report Top

A 14-day-old female neonate from a consan­guineous family born near term (36 th week) with a birth weight of 2000 g presented to us with severe dehydration due to polyuria. Her parents had noticed jaundice and she was ad­mitted for correction of dehydration and eva­luation of jaundice.

General physical examination showed that she had leathery skin and severe icthyosis of the whole body [Figure 1]a and b. She was icteric but her liver and spleen sizes were normal. Her mother complained that she had clay-colored stools. She had arthrogroposis in the left ankle [Figure 2]a and b and cardiac examination, re­vealed a mild secundum atrial septal defect (ASD). Platelets were in the normal range with normal shape and size. No coagulation abnor­malities were seen.
Figure 1: a: Pustule and wrinkling of the skin.
Figure 1: b: Diffuse icthyosis and jaundice on the back.

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Figure 2: a: Arthrogryposis of left ankle and the large big toe is evident.
Figure 2: b: Left ankle arthrogryposis, wrinkled skin and icthyosis are seen.

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At the first imaging of the kidney, renal size was 40 mm with medullary nephrocalcinosis and mild hydronephrosis [Figure 3]a and b, liver size was 50 mm and spleen was also of normal size. Her diethyliminodiacetic acid scan (DIDA) scan showed no excretion of radio­tracer after 24 h and was suggestive of extra-hepatic stasis [Figure 4]. Her laboratory tests on arrival showed pH = 7.2, base excess (BE) = -11 and serum bicarbonate = 14 mEq/L, blood urea = 65 mg/dL and creatinine = 1.8 mg/dL. Her urine output was 660 mL daily, her urine pH was 7 and urinary specific gravity was 1010 in spite of severe dehydration and acidosis.
Figure 3: a: Sagittal view after hydration showing medullary nephrocalcinosis and cystic dilatation.
Figure 3: b: Another view showing medullary nephrocalcinosis and cystic dilatation.

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Figure 4: After 1mCi Tc99diethyliminodiacetic acid (DIDA scan): Early images show proper perfusion of liver. There was no radiotracer excretion and visualization of biliary ducts, gallbladder and intestine up to 24 h, suggestive of extrahepatic biliary obstruction.

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Free calcium was high, 1.87 mg/dL and se­rum albumin was low, as low as 2 g/dL [Table 1]. Liver enzymes were mildly elevated. Serum phosphorous was 3.2 mg/dL, uric acid 2.4 mg/ dL and alkaline phosphatase 787 IU/L. Serum sodium was normal but serum potassium was 5.7 mmol/dL in spite of high urine output and administration of alkali and thiazide therapy.
Table 1: Comparison of laboratory findings at entry and during treatment.

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Her urine dipstick was positive for glucose, protein and reducing substances. Urine cal­cium to creatinine ratio was 3 and, after the­rapy with thiazide, it reached to 1 (normal for age <0.8). The protein to creatinine ratio was 8 and measured proteinuria in 24 h was 90 mg daily (23 mg/m 2 /h; normal <4 mg/m 2 /h), urine sodium was 75 meq/dL, potassium 15 meq/dL and chloride 80 meq/dL (anion gap was posi­tive). During management, she needed bicar­bonate therapy above 12 meq/kg/d. Her HCO 3 reached 18 meq/L and BE 6 after treatment. On the 60 th day after birth, her urine output with thiazide decreased to 450 mL daily and, with aggressive nutrition, she gained a weight of 400 g in two months. Serum albumin reached 3.5 from 1.9 g/dL, total calcium was normal (9.2 mg/dL) and total PTH in the sample after 10 am was 45 pg/mL, but she had severe hypovitaminosis D 3 (2.5 ng/mL, nor­mal: 15-25 ng/mL).

   Discussion Top

Arthrogryposis, renal dysfunction and cholestasis are the major components of ARC syndrome. But, variable phenotype association with this rare syndrome has been recognized, such as icthyosis, absent corpus callosum, recurrent infections that lead to metabolic acidosis and, rarely, liver failure. [6]

Arthrogryposis is an important finding of this syndrome, although it may be absent in some cases or may have atypical pattern like hip dislocation. [7] Cholestasis in ACR syndrome is associated with conjugated hyperbilirubinemia that fluctuates between normal to very high values and normal γ-glutamyl transpeptidase (GGT) and mildly elevated AST/ALT and, mostly, non-excreting isotope studies. Also, thrombocytopenia with abnormal morphology and/or function may occur in these patients. Other features of this syndrome that may be seen include hypotonia, structural heart di­sease, deafness and ichthyosis, hirsutism and some other dysmorphic features. [6]

In this case, arthrogryposiseas affected the left ankle joint. She was born from consan­guineous parents near term with a weight of 2000 g, and obvious jaundice appeared after the first week, with her liver enzymes fluctuating from normal to slightly high. Prothrombin time and platelet count as well as platelet morpho­logy were normal. Liver size and spleen were normal, but isotope scan showed extrahepatic biliary obstruction. Our patient could hold up her neck at the second month, but she was in­sensitive to sound and also had a mild cardiac defect (ASD secundum) and generalized ichthyosis with leathery skin.

Renal problems in ACR patients are complex and highlighting them is the purpose of our discussion. Arhan described glomerulocystic appearance in a case affected by ARC syn­drome in addition to many abnormalities that are described for these patients. [3],[6],[7] In a series of six cases, proteinuria (60 times of normal) was seen in four patients, and four of them had hypernatremic dehydration. In one patient, nephrogenic diabetes insipidus (NDI) was en­countered

Imaging studies showed small dysplastic kid­neys in two of six patients. Two had nephro-calcinosis and loss of corticomedullary diffe­rentiation, although in one of these cases in whom the imaging studies suggested nephrocalcinosis, biopsy showed cystic dilation of tubules only. [3] Hypercalciuria, proteinuria and hypoalbuminemia are other findings in ARC syndrome patients. Measured calcium to creatinine ratio (2.2) or urine albumin to creatinine reached 0.7 (normal up to 0.1), and their serum albumin could reach a nadir of 20 g/L. [6]

Another finding in this patient who also had renal tubular acidosis (RTA) is that we expec­ted hypokalemia to resolve by volume correction, which reduces aldosterone secretion, [8] but it remained high. Hypercalciuria and hyper-echoic kidneys associated with medullary nephrocalcinosis is in keeping with the recent re­ports about these patients being predisposed to nephrocalcinosis and lithiasis [6] .

In our case, isonatremic dehydaration was most probably due to NDI and Fanconi syn­drome. Her significant proteinuria (in the nephrotic range or 50 mg/kg/d) was associated with hypoalbuminemia, revealed after hydration but without hyperlipidemia.

In our patient, in spite of polyuria, potassium was normal (4.8 meq/dL, normal: 3.5-5.5 meq/dL), but it increased to 5.7 meq/dL after rehydration in spite of administration of alkali, hydrochlorothiazide therapy and reduction of creatinine levels. Her positive urine anion gap and hypercalciuria may be due to both pro­ximal and hyperkalemic distal RTA, probably due to voltage defect, an observation that has not been mentioned before.

Hyperparathyroidism is another associated problem that has been reported in cases of ARC syndrome, [6] which may be due to meta­bolic acidosis that is associated with an in­creased excretion of calcium and phosphorous. [9] On the other hand, decreased citrate excretion ultimately leads to decreased luminal citrate, nephrocalcinosis and metabolic bone disease, which is a universal finding in distal RTA (DRTA), unless early base therapy is instituted for prevention of bone buffering. [10] Some pa­tients with DRTA also have reduced absorp­tion of calcium from the gastrointestinal tract. [11] This results in hypocalcemia, hypophosphatemia and hyperparathyroidism and rickets in un­treated patients. [12] Also, metabolic acidosis may impair vitamin D metabolism that can lead to calcium malabsorption and appearance of ra­diographic evidence of rickets in these patients. [13],[14] Acidosis causes decreased produc­tion and increased clearance of 1-25(OH)vit D 3 . [15]

In our patient, in spite of administration of alkali and thiazide, hypercalciuria was above normal and parathorme hormone was in the normal level of 44 pg/dL, but her 25-(OH) Vit D 3 was low at the level of 2.5 ng/mL (normal 15). This shows that hyperparathyroidism in these patients is due to prolonged metabolic acidosis, hypercalciuria and malabsorption, which impair the production of 1-25(OH) vit D 3 .

ARC syndrome has complex signs and sym­ptoms, but renal problems include NDI, hyper-calciuria, proximal and distal hyperkalemic RTA and proteinuria near the nephrotic range (50 mg/kg/d) due to tubular and overflow proteinuria and severe hypovitaminosis D. Hyper-calciuria and metabolic acidosis can lead to hyperparathyroidism although in ARC, renal size is normal but renal insufficiency persists in some grades in spite of rehydration. Medul­lary nephrocalcinosis and hydronephrosis that became evident after adequate hydration are interesting findings of this case.

   References Top

1.Lutz-Richner AR, Landolt RF. Familiare Gallengansmissbildungen mit tubularer Neireninsurfizienz. Helv Paediatr Acta 1973; 28:1-12.  Back to cited text no. 1
2.Nili F, Akbari-Asbaghe P, Oloomi-Yazdi Z, et al. Wide spectrum of clinical features in a case of arthrogryposis-renal tubular dysfunction-cholestasis syndrome. Arch Iran Med 2008;11: 569-72.  Back to cited text no. 2
3.Eastham KM, McKiernan PJ, Milford DV, et al. ARC syndrome: an expanding range of phenotypes; Arch Dis Child 2001;85:415-20.  Back to cited text no. 3
4.Bull LN, Mahmoodi V, Baker AJ, et al. VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype. J Pediatr 2006;148:269-71.  Back to cited text no. 4
5.Coleman RA, Van Hove JL, Morris CR, Rhoads JM, Summar ML. Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: Additional findings or a new syndrome (ARCC-NDI)? Am J Med Genet 1997;72:335-8.  Back to cited text no. 5
6.Gissen P, Tee L, Johnson CA, et al. Clinical and molecular genetic features of ARC syn­drome. Hum Genet 2006;120:396-409.  Back to cited text no. 6
7.Arhan E, Yusufoglu AM, Sayil TR. ARC syn­drome without arthrogryposis, with hip dislo­cation and renal glomeroulocystic appeaance: A case report. Eur J Pediatr 2009; 68:995-8.  Back to cited text no. 7
8.Han JS, Kim GH, Kim J, et al. Secretory defect in renal tubular acidosis in associated with transporter defect in H(+)ATPase and anion exchanger-1. J Am Soc Nephrol 2002;13:1452-3.  Back to cited text no. 8
9.Lemann J Jr, Litzow JR, Lenon EJ. Studies of the mechanism by which chronic acidosis augments urinary calcium excretion in man. J Clin Invest 1967;46:1318-28.  Back to cited text no. 9
10.Goodman AD, Lemann J Jr, Lennon EJ, Relman AS. Production, excretion and net ba­lance fixed acid in patients with renal acidosis. J Clin Invest 1965;44:495-506.  Back to cited text no. 10
11.Greenberg AJ, McNamara H, Mcrory WW. Metabolic balance studies in primary renal tubular acidosis: Effects of acidosis on external calcium and phosphor balances. J Pediatr 1966;69:610-8.  Back to cited text no. 11
12.Mcsherry E, Morris RC Jr. Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. J Clin Invest 1978;61: 09-27.  Back to cited text no. 12
13.Chensey RW, Kaplan BS, Phlep M, et al. Renal tubular acidosis doesnot alter circulating values of calcitrol. J Pediatr 1984;104:51-5.  Back to cited text no. 13
14.Cunningham J, Fraher LJ, Clements TL, Revell PA, Papapoulos SE. Chronic acidosis with metabolic bone disease. Am J Med 1982; 73:199-204.  Back to cited text no. 14
15.Portale AA, Halloran BP, Harris ST, et al. Metabolic acidosis reverses the increase in serum 1,25(OH)2D in phosphor restricted men. Am J Physiol 1992;263:E1164-70.  Back to cited text no. 15

Correspondence Address:
Majid Malaki
Department of Pediatric Nephrology, Tabriz University (Medical Sciences), Tabriz
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DOI: 10.4103/1319-2442.98165

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

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