Pediatr Nephrol DOI 10.1007/s00467-015-3117-3

MANAGEMENT DILEMMA

Management dilemmas in pediatric nephrology: Cystinosis Martine T. P. Besouw 1 & Maria Van Dyck 2 & David Cassiman 3 & Kathleen J. Claes 4 & Elena N. Levtchenko 2

Received: 17 December 2014 / Revised: 13 April 2015 / Accepted: 15 April 2015 # IPNA 2015

Abstract Background Cystinosis is a rare, inherited autosomal recessive disease caused by the accumulation of free cystine in lysosomes. It is treated by the administration of cysteamine, which should be monitored by trough white blood cell (WBC) cystine measurements to ensure effective treatment. Case-Diagnosis/Treatment The index case had an older brother who had previously been diagnosed with cystinosis, allowing early diagnosis of the index case at the age of 5 months. Cysteamine therapy was started at the age of 3 years; however, monitoring of WBC cystine levels did not occur on a regular basis during most of his life. Growth retardation improved after correction of electrolyte disturbances, the initiation of cysteamine therapy and treatment with recombinant human growth hormone. Renal replacement therapy was started at the age of 11 years, and renal transplantation was performed at the age of 12 years. Extra-renal cystine accumulation caused multiple endocrinopathies (including adrenal insufficiency, hypothyroidism and primary hypogonadism), neurological symptoms, pancytopenia owing to splenomegaly and portal hypertension due to nodular regenerative hyperplasia, aggravated by splenic vein thrombosis and partial portal

* Martine T. P. Besouw [email protected] 1

Department of Pediatric Nephrology, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium

2

Department of Pediatric Nephrology, University Hospitals Leuven, Leuven, Belgium

3

Department of Hepatology, University Hospitals Leuven, Leuven, Belgium

4

Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium

vein thrombosis. The patient died of diffuse intra-abdominal bleeding caused by severe portal hypertension. Conclusion Cysteamine treatment should be started as early as possible, and dosage should be monitored and adapted based on trough WBC cystine levels. Relevant international guideline Emma F et al. (2014) Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant 29:iv87–iv94. Keywords Cystinosis . Cysteamine . Renal Fanconi syndrome . Renal transplantation . Chronic kidney disease . Complications . Follow-up

Case report A flow diagram of the index case is shown in Fig. 1. This case report focuses on a male patient who was born as the fourth child in a family that already had one child with cystinosis. The affected sibling, an older brother, was diagnosed with cystinosis 2.5 years before the index case was born; the other two siblings were healthy. The patient was born term by caesarean section with a birth weight of 3100 g. The pregnancy was complicated by diabetes gravidarum (requiring insulin) and a placenta praevia. Since the older brother had already been diagnosed with cystinosis, regular screening of the index case was performed by a pediatric nephrologist at 2-month intervals after birth. At the age of 4 months he was found to have both glucosuria and proteinuria and was subsequently admitted for further investigations. Clinical examination at admission showed mild craniotabes, but was otherwise unremarkable. Growth parameters were within the normal range, with a weight of 7.160 kg (−0.2 standard deviation score [SDS]), height of 69 cm (+1.5 SDS) and head circumference of 42.5 cm (−0.4 SDS). Further

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Fig. 1 Flow diagram of case report. DD differential diagnosis, rhGH recombinant human growth hormone

examinations confirmed the presence of renal Fanconi syndrome with glucosuria, proteinuria, hyperphosphaturia, hypercalciuria and generalized aminoaciduria. No signs of rickets were visible on the X-ray images. Ophthalmological examination did not find corneal crystals, but the cornea was not transparent (subsequent examinations later in life did confirm the presence of corneal crystals). Electron microscopic studies revealed the presence of cystine crystals in leucocytes and bone marrow, as well as marked cystine accumulation in fibroblasts obtained from a conjunctival biopsy (Fig. 2). The diagnosis of cystinosis was made at the age of 5 months. Since cysteamine was not available in Belgium at the time of diagnosis, treatment was limited to the administration of potassium phosphate, vitamin D and vitamin C. During the first years of life, the patient was hospitalized repeatedly due to dehydration and vomiting associated with infectious episodes. Treatment with cysteamine hydrochloride was initiated immediately when it became available in Belgium, at the age of 3 years and 3 months; it was also started simultaneously in his brother, who was then 8 years and 11 months old. After the initiation of cysteamine treatment, the patient developed several oval, red, exfoliating lesions on the shoulders and the extensor surfaces of the upper and lower arms, which periodically disappeared and reappeared. At that time the lesions

were diagnosed as lichen spinulosus, and an ointment containing urea was prescribed. In the meantime, phosphocysteamine had found to be equally effective in the treatment of cystinosis while having a better taste and smell than cysteamine hydrochloride [1]. Thus, 1 month after the diagnosis of the skin lesions, when the patient was aged 4 years and 7 months, treatment with cysteamine hydrochloride was replaced by phosphocysteamine. Within the next months, the skin lesions completely disappeared. The patient’s renal function progressively declined, and at the age of 11 years and 2 months he was started on hemodialysis, followed by a deceased-donor kidney transplantation at the age of 12 years and 1 month. His immunosuppression therapy after kidney transplantation consisted of prednisolone, cyclosporine A and azathioprine. During the period of endstage renal disease (ESRD), treatment with phosphocysteamine was suspended for 21 months due to hyperphosphatemia. It was restarted after successful renal transplantation. Orthopaedic evaluation in the years after renal transplantation showed moderate genua valga, as well as pedes plani. During that period, monitoring on a regular basis showed that the levels of intact parathyroid hormone (iPTH) remained within normal limits (8.5–19.0 pg/mL; normal range 3–40 pg/mL), as did those of 25-hydroxy vitamin D3 (14.6–

Pediatr Nephrol Fig. 2 Electron microscopy of fibroblasts obtained from conjunctival biopsy of the index patient. Fibroblasts can be seen to be packed with cystine crystals (asterisks)

39.6 ng/mL; normal range 7–80 ng/mL) and 1,25-dihydroxy vitamin D3 (36.6–43.7 pg/mL; normal range 20–80 pg/mL). There was no history of bone fractures, and bone mineral density remained normal with z-scores above −1.99. The young patient had meanwhile experienced significant stunting of the longitudinal growth, and at the age of 13 years and 7 months he was started on treatment with recombinant human growth hormone (rhGH). At the moment of treatment initiation, his height was 137.7 cm (−3.2 SDS), and the pubertal Tanner stage was A1P2G2 with a testicular volume of 6 mL. Treatment with rhGH continued until the age of 18 years and 10 months; his final height was 165.6 cm (−2.1 SDS; Fig. 3a), and the final Tanner score was A2P5G5 with a testicular volume of 15–20 mL. In contrast, his brother, who had not been treated with rhGH, only achieved a final height of 148.2 cm (−4.8 SDS; Fig. 3b). The expected target height for both boys based on the parental length was 176.7 cm (±8.5 cm). In the years following renal transplantation, the patient developed severe and refractory pancytopenia associated with splenomegaly. A bone marrow biopsy showed the preservation of all three lines of hematopoiesis without signs of myelodysplasia. Therefore, at the age of 22 years, a splenectomy was performed with concomitant liver biopsy. Histopathological examination of the spleen showed atrophy of the white pulp with a pseudovascular expansion of the red pulp, as well as the presence of multiple cystine crystals. The liver biopsy showed nodular regenerative hyperplasia as the cause of his (non-cirrhotic) portal hypertension and the presence of numerous cystine crystals. The splenectomy was complicated by a thrombosis of the splenic vein and a partial thrombosis of the portal vein system (including the main portal vein and the bifurcation). Subsequently, portal

hypertension caused ascites directly post-surgery and recurrent bleeding episodes from esophageal varices in the years thereafter, for which multiple endoscopic variceal ligations were needed. The pancytopenia, however, gradually resolved after the splenectomy. In the post-operative period, the patient developed fever of unknown origin. There was no increase of infectious parameters, and all cultures remained negative. An adrenocorticotropic hormone test was subsequently performed, which confirmed the clinical suspicion of adrenal insufficiency; the fever disappeared after the initiation of hydrocortisone. Later, at the age of 28 years, a routine blood examination showed an increased thyroid stimulating hormone (TSH) level (21.35 mIU/ L; normal range 0.27–4.20 mIU/L), indicating hypothyroidism. Supplementation with thyroid hormone was started. A few years later, at the age of 31 years, he developed a painful one-sided gynecomastia. Subsequent investigations showed high levels of luteinizing hormone (LH; 51.8 IU/L; normal range 1.7–8.6 IU/L) and follicle stimulating hormone (FSH; 60.4 IU/L, normal range 1.5–12.4 IU/L) with low testosterone levels (155 ng/dL; normal range 300–1000 ng/dL) and low free testosterone levels (1.22 ng/dL; normal range 5.0020.00 ng/dL), indicating primary hypogonadism and he was started on testosterone injections. In retrospect it was found that prolactin levels at that time were 57.9 (normal 2-16) µg/L, increasing over the next year to 246 µg/L. The recovery after polyethylene glycerol precipitation was >60 %, thus excluding the presence of macroprolactin. During the first 20 years of life this patient was treated with cysteamine; however, white blood cell (WBC) cystine levels were not routinely available, and measurements were only performed sporadically. The few measured values were all

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Fig. 3 Growth curves. a Growth curve of the index patient. Note the initial normal growth after birth, with decreased growth velocity during the first months of life. A temporary improvement in longitudinal growth can be seen to have occurred after the initiation of cysteamine therapy. The initiation of rhGH hormone therapy after renal transplantation resulted in catch-up growth after a period of stunting. b Growth curve

of the index patient’s affected brother, who was diagnosed at an older age. Note the severe growth retardation at diagnosis, which was further aggravated in the years thereafter. Cysteamine administration was no longer efficient to improve longitudinal growth. Renal transplantation did improve longitudinal growth, resulting in growth paralleling the normal growth curves, but there was no catch-up growth

above the advised cut-off level of 1 nmol ½cystine/mg protein, falling within the range of 1.5–5.3 nmol ½cystine/mg protein, and were not used to adjust cysteamine dose, which remained at 60 mg/kg/day. The patient, his parents, and later his partner all confirmed that he was compliant with his treatment. At the age of 31 years, he was switched from

phosphocysteamine to cysteamine bitartrate (Cystagon®). In the same period, genetic testing of the CTNS gene became available. This showed a homozygous 57-kb deletion in both the index patient and his affected brother, which provided molecular confirmation of the diagnosis of cystinosis. During this time the function of the transplanted kidney had gradually

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declined. A kidney biopsy showed chronic transplant glomerulopathy, and at the age of 31 years he was started on peritoneal dialysis (PD). Six months before the initiation of PD, at the age of 30 years, the patient presented with fatigue, vertigo and an uncertain gait for several days, followed by a sudden onset of confusion and disorientation in time and space. Blood tests showed no evidence of an acute infection with either hepatitis B, hepatitis C, cytomegalovirus (CMV), Epstein–Barr virus (EBV), varicella-zoster virus (VZV), human herpesvirus-6, Toxoplasma gondii, Borrelia burgdorferi, Aspergillus or Treponema pallidum, and blood cultures remained negative. Subsequent lumbar punctures showed normal cerebrospinal fluid (CSF) cytology and were also negative for CMV, EBV, VZV, herpes simplex virus, enterovirus, polyomavirus, Borrelia burgdorferi, Cryptococcus and Toxoplasma gondii; bacterial, fungal and mycobacterial cultures remained negative. Serum ammonia was normal. An electroencephalogram was also normal. No intracerebral abnormalities were detected on a computed tomography scan, but a small focal lesion in the right basal ganglia was discernible on an magnetic resonance imaging (MRI) scan (Fig. 4). Differential diagnosis consisted of an infection, lymphoma or cystinotic lesion. An infection seemed unlikely since there was no fever and no increase of infectious parameters in blood, and all serological tests and cultures in blood and CSF were negative. Furthermore, the lesion decreased in size on subsequent MRI scans without the initiation of anti-infectious therapy. Because of this spontaneous decrease in size, the diagnosis of lymphoma was also excluded. Given the position of the lesion, a biopsy to reach a definite diagnosis was considered to be of high risk, and it was ultimately concluded that the lesion was most likely caused by intracerebral cystine accumulation. The disorientation subsided, but the patient remained fatigued with unstable gait and episodes of falling, both with and

Fig. 4 Brain magnetic resonance imaging of the index patient. T2 image showing the contrast-enhanced region in the right basal ganglion (red arrow)

without loss of consciousness, but without tonicoclonic movements, absences, twitching or urine loss. At the same time, it became more apparent that he suffered from severe myopathy. An electromyography (EMG) showed rest activity, arguing against steroid-induced myopathy. At the age of 32 years, he had an episode of massive aspiration, causing a severe pneumonia requiring intubation and mechanical ventilation. Subsequent studies after he recovered from the aspiration pneumonia showed unsafe swallowing of solid foods, for which it was advised to take liquid and pureed foods only. Nonetheless, he had several episodes of aspiration pneumonia thereafter, but none of these required admission to an intensive care unit. Later that year, at the age of 33 years, he was admitted with a hepatic encephalopathy (ammonia 271 μmol/L), most likely due to hepatic shunting caused by the known non-cirrhotic portal hypertension. The disorientation disappeared after the administration of lactulose. A few weeks after discharge, he was readmitted to the intensive care unit with an acute abdomen and blood in the dialysate. A laparotomy showed a massive hemoperitoneum; however, no focus for the bleeding could be found. He subsequently developed multi-organ failure and died 4 days after admission, at the age of 33 years.

Management of cystinosis Background and diagnosis Cystinosis is a rare inherited autosomal recessive disease caused by mutations in the CTNS gene on chromosome 17p13 which lead to intralysosomal cystine accumulation in cells throughout the body. It occurs in approximately 1 in 100, 000–200,000 live births. Children generally present between the age of 6–12 months with polyuria, polydipsia and failure to thrive due to generalized proximal tubular damage, called renal Fanconi syndrome [2]. Cystinosis is the most prevalent cause of congenital renal Fanconi syndrome, but other metabolic conditions should be considered (Table 1). The diagnosis can be made by measuring cystine levels in WBCs, which will be above the upper limit of the normal range for carriers of a CTNS mutation (>1 nmol ½cystine/ mg protein). Analysis of the CTNS gene confirms the diagnosis of cystinosis [3]. To date, more than 100 mutations are known to cause this disorder, of which the 57-kb deletion detected in a homozygous state in both the index patient and his brother is the most prevalent mutation found in Northern European populations [3, 4]. Corneal cystine crystals can be seen by an experienced ophthalmologist in most children aged >12 months and are always present in patients aged >18 months [3]. In countries where WBC cystine measurement and DNA analysis are not widely available, the diagnosis can be made by electron microscopy examination of

CTNS/ autosomal recessive

Cystinosis Nephropathic/219800

Enoyl-CoA hydratase

Idiopathic Fanconi syndrome

Isolated renal Fanconi syndrome

Miscellaneous, including muscular weakness and eye abnormalities

Hepatorenal glycogen accumulation; hepatomegaly; rickets; osteomalacia; developmental delay; growth retardation

OMMIM™a , Online Mendelian Inheritance in Man. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Washington DC)

CK, Creatine kinase; LDH, lactate dehydrogenase; AST, aspartate aminotransferase

Miscellaneous

Miscellaneous Unknown (miscellaneous)

Mitochondrial nephropathies Unknown

GLUT2

Kayser-Fleischer rings in the cornea; hepatitis; cirrhosis; central nerve system abnormalities

ATP7B/autosomal recessive

Fanconi–Bickel syndrome SLC2A2/autosomal recessive (glycogen storage disease type XI)/227810

Hepatomegaly; cirrhosis; nephrocalcinosis; glomerulosclerosis

Fumaryl-acetoacetate-hydrolase Copper transporting ATPase; β polypeptide

FAH/ autosomal recessive

Tyrosinemia/276700

Fructose intolerance; growth retardation Hepatomegaly; liver disease; cataract, developmental delay

Wilson’s disease/277900

Aldolase B Galactose-1-phosphate-urdylyltransferase

ALDOB/autosomal recessive

Hepatocyte nuclear factor 4-alpha

GALT/autosomal recessive

HNF4A/autosomal dominant

Type 4/616026

NaPi-IIa

Growth retardation; rickets

Growth retardation; congenital cataract; developmental delay; fits; arthropathy; increased CK, LDH, AST

Hypercalciuria, nephrocalcinosis, nephrolithiasis, renal insufficiency Elevated levels of creatine kinase, lactate dehydrogenase and aspartate aminotransferase; peripheral cataract; mild retardation in Dent’s type 2

Failure to thrive; rickets; metabolic acidosis; photophobia; renal insufficiency; hypothyroidism

Clinical or biochemical abnormalities

Inherited fructose intolerance/229600

EHHADH/autosomal dominant

Unknown protein

Phosphatidyl-inositol 4,5 biphosphate-5-phosphatase

Phosphatidyl-inositol 4,5 biphosphate-5-phosphatase

Chloride channel 5

Cystinosin

Mutated protein

Galactosemia/230400

SLC34A1/autosomal recessive

Type 3/615605

Unknown gene, 15q15.3/autosomal dominant

Type 2/61338

Fanconi renotubular syndrome Type 1/134600

OCRL1/X-linked recessive

OCRL1/X-linked recessive

Type 2/300555

Lowe’s syndrome 309000

CLCN5/X-linked recessive

Dent’s disease Type 1/300009

Ocular/219750

Juvenile/219900

Gene/inheritance

Differential diagnosis of inherited renal Fanconi syndromes

Disease/OMIM™a

Table 1

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fibroblasts obtained from a conjunctival biopsy [5], which was also performed in our index case (Fig. 2). Screening for cystinosis The screening of newborns for cystinosis is currently not available. The measurement of WBC cystine levels in bloodspots is hampered by the relatively high plasma cystine levels and oxidation of intracellular cysteine, which influence the measurement results [6]. In addition, the disease is unsuitable for genetic screening in bloodspots due to the wide variability of mutations in the CTNS gene that can cause cystinosis [4]. Increased levels of sedoheptulose (caused by the concomitant deletion of the CARKL gene in the common 57-kb deletion) can be measured in bloodspots; however, this test will only detect patients that are homozygous for the 57kb deletion and can therefore not be used as a general screening method [6]. Once a diagnosis of cystinosis is made in a child, prenatal screening can be performed in subsequent pregnancies. If the CTNS mutations of the older sibling are known, specific screening tests on the fetus can be performed to test for the presence of these mutations. Alternatively, the cystine content of chorionic villi or cultured amniotic cells can be measured [7]. After birth, a gradual progression towards renal Fanconi syndrome has been described over the first months, even while WBC cystine levels are still in the range of heterozygote carriers [8]. Therefore, if prenatal investigations were not performed and genetic testing is unavailable, we advise monthly screening of blood and urine to detect renal Fanconi syndrome until the age of 6 months. Once the diagnosis of cystinosis is confirmed, treatment with cysteamine should be started. This strategy allows early detection of the disease and provides the opportunity to start treatment with cysteamine as soon as possible after birth with the aim to slow down disease progression and prevent extra-renal complications from occurring later in life. Since most children with cystinosis present at a young age (generally between the age of 6–12 months) [2], the screening of older siblings is only advised in those with a history of polyuria and polydipsia. Challenges with cysteamine administration Before the discovery of the cystine-depleting effect of cysteamine in 1976 [9], it was thought that vitamin C might decrease intralysosomal cystine accumulation. Hence, our patient was started on vitamin C therapy after the initial diagnosis of cystinosis. In 1979 a trial was published demonstrating the inadequacy of vitamin C in the treatment of cystinosis [10], and this practice was subsequently abolished. At the present time, cysteamine is the only available treatment for cystinosis. The most widely prescribed formulation,

cysteamine bitartrate, has recently also been marketed as an enteric-coated formulation. Since the cystine-depleting effect of immediate-release cysteamine only lasts for 6 h, the drug should be taken 4 times per day around the clock. The entericcoated formulation has a cystine-depleting effect that lasts for 12 h and should be taken 2 times per day [11, 12]. The best strategy to monitor the efficacy of cysteamine to deplete cells from intralysosomal cystine accumulation is to measure trough WBC cystine levels. Unfortunately, this method is laborious and is only available in a few specialized laboratories around the globe [3]. The aim should be to maintain WBC cystine levels within the range of asymptomatic carriers of a CTNS mutation, which is 5 years, indicating that there may not only be an early delay in white matter maturation in these children, but that cystine accumulation may also have a progressive effect on white matter organization and connectivity [41]. Myopathy Myopathy is another complication of cystinosis that is often seen in older patients. Changes in EMG readings can be found even before a decreased muscle strength is noted by the patient

[42]. Moreover, many cystinosis patients have been treated with steroids as part of the renal transplantation immunosuppressive regimen, which can make it clinically difficult to differentiate between steroid myopathy and myopathy due to progression of cystinosis. Steroid myopathy, however, results in a distinct EMG pattern. In the presence of muscle destruction (as in myopathy caused by cystinosis), spontaneous activity can be seen at rest, which is not present in steroid myopathy. Moreover, steroid myopathy mainly affects proximal muscles, while the muscle weakness in cystinosis starts as a distal myopathy [42, 43]. In our index case, resting activity was found on EMG, suggesting that his myopathy was caused by cystinosis and not by the long-term use of corticosteroids. As cystinosis progresses, the myopathy can cause breathing difficulties. Swallowing difficulties due to decreased strength and coordination of oropharyngeal muscles can cause aspiration pneumonia and can thus worsen respiratory difficulties, as was the case in our patient. Respiratory distress aggravated by aspiration pneumonia is a common cause of death in older cystinosis patients. Adequate treatment with cysteamine can prolong the time without myopathy and decrease the progression rate once the myopathy is present, and thus decreases the risk of death [36].

Options for future research There is as yet no full understanding regarding the pathogenesis of cystinosis. Cysteamine is used to deplete cells from excess of cystine molecules. If adequate treatment with cysteamine is started from an early age, it can postpone the development of ESRD and prevent several extra-renal complications of cystinosis. Cysteamine, however, offers no cure, and despite life-long treatment, there is no reversal of renal Fanconi syndrome in cystinosis patients, nor is the progression to ESRD reversed. Also, some of the extra-renal complications can still occur despite adequate treatment with cysteamine [36]. Thus, the absence of cystinosin is thought to have more implications on the cellular function than can be explained by intralysosomal cystine accumulation alone. Using a ctns knockout mouse model, Gaide Chevronnay et al. [44] demonstrated that the ctns−/− genotype causes apical dedifferentiation of proximal tubular cells, before they become atrophic. Throughout the years, several possible mechanisms have been postulated to explain this proximal tubular damage, including decreased ATP production in proximal tubular cells [45], increased apoptosis rate [46], increased oxidative stress [47] and altered autophagy [48]. The exact aetiology of these lesions, however, needs to be studied further to further optimize the treatment of cystinosis. In recent years, much of the research effort has focused on identifying alternatives to cysteamine as a treatment of cystinosis. The ctns knockout mouse model has been

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successfully treated with hematopoietic stem cell transplantation (using stem cells of wild-type littermates) [49] and with gene therapy (using autologous stem cells that were transduced with the human CTNS cDNA sequence ex vivo) [50]. Both of these therapies resulted in a marked decrease of cystine accumulation in the brain, eyes, heart, kidneys, liver, skeletal muscle and spleen of the treated mice. However, these levels were still higher than those measured in asymptomatic heterozygous carriers [49, 50]. Thus far, no clinical trials in humans have been performed to study stem cell transplantation or gene therapy as a possible cure for cystinosis.

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Transition to adult care Transition to adult care facilities poses a variety of problems in many chronic pediatric diseases [51]. Patients with cystinosis have only survived into adulthood since the availability of cysteamine and renal replacement therapy in children in the late 1970s and early 1980s. The transition of these patients is not only complicated due to the switch from the known pediatric environment to the unknown world of adult care, but also because cystinosis is a rare systemic disease. Some patients have reported that they feel that their adult nephrologist is less experienced in treating patients with cystinosis and that some of them do not know or pay little attention to the extra-renal complications of the disease [52]. For the long-term followup, a multidisciplinary approach (including at least a nephrologist, ophthalmologist, endocrinologist and neurologist) should be considered wherever possible, enabling adequate follow-up not only for the renal but also for the most prevalent extra-renal manifestations of the disease. Also, measurement of trough WBC cystine levels to monitor and adjust cysteamine treatment remains important in adulthood in order to prevent complications of cystinosis or to delay their progression [3].

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