A Case of a 12-Year-Old Boy With Nephropathic Cystinosis
In this video, James Matera, DO, discusses a case presentation of a 12-year-old patient with nephropathic cystinosis, including the diagnosis, management, follow-up, and ways to coordinate with the care team of specialists.
James Matera, DO, is a practicing nephrologist, Senior Vice President for Medical Affairs, and Chief Medical Officer at CentraState Medical Center (Freehold, NJ).
TRANSCRIPTION:
James Matera, DO: My name is Dr James Matera. I am the Chief Medical Officer and Senior Vice President of Medical Affairs at Central State Medical Center, part of the Atlantic Health System in Freehold, New Jersey. I am a nephrologist by trade and now an administrator.
Today we're going to talk a little bit about a fairly rare disease that we see, but a very important one, which is nephrogenic cystinosis. I call it a rare but important disease. Part of that is because if we don't actively find these patients, and I'll go over a little bit about why it's hard to diagnose them early on, they can progress to end-stage renal disease. And of course, that's an issue we want to try to avoid. I'm going to start with a short case presentation of a patient who had a delayed diagnosis, but ultimately we'll go over some of the pathogenesis, what we expect to see, how we would treat these patients, what our outcomes are going to be.
So, this is a disease and we'll talk a little bit more about the different types. But this patient that I'm presenting today was 12 years old when they finally made a diagnosis, that's a little bit late in the diagnosis. But when you look at it, he had the classic Fanconi syndrome when he was three years old. And we'll talk about what that means as I get into the pathogenesis. However, the official diagnosis of nephrogenic cystinosis was not made until he was about 12 years old. And that was on the finding of some ophthalmological findings where they saw the deposition of cysteine crystals in the patient's cornea. So, the diagnosis was made a little bit late at age 12. Interestingly enough, at that time when we looked at his laboratory results, particularly paying attention to his renal function, he had some mild-to-moderate renal insufficiency for a 12-year-old with an estimated GFR of only 66 milliliters per minute. It should be higher than that.
When we looked at his free cysteine content in his white blood cells, which is one of the diagnostic hallmarks, it was markedly elevated. It was 6.36 nanomoles per half cysteine per milligram of protein. Don't need to worry too much about that, but that's elevated. And the key factor going forward is measuring the deposition by looking at those levels. So, the next step for this patient at age 12 was to have genetic testing, and the gene involved is what's called the CTNS gene, and that showed the diagnosis, and made it clear that he had this form of nephrogenic cystinosis. So, with the GFR that was a little bit lower, he was immediately started on therapy with cysteamine. And we'll talk about that and then we'll go back to the case.
Nephrogenic cystinosis is a fairly rare genetic disease. It's a lysosomal storage disease, which is inherited in an autosomal recessive manner. What happens here is there's a cystine transporter called cystine that has a mutation. So, it starts to develop into this disease state by accumulating, cysteine, deposing, or depositing into the various tissues in the body. The prevalence is one in about 100,000 to 200,000 births. When you look at the literature, it has a predilection for all ethnic groups, so it doesn't single out any specific ethnic groups. And the male to female ratio is slightly higher at one to 1.4. So, females are a little bit higher in this.
When we look at it, there are three types that we can see. The most common form that's responsible for 95% is what we call infantile, and that's going to be seen in the younger patients. They're almost always going to present with Fanconi Syndrome, which we'll talk about.
Another type– juvenile, which we often call Intermediate Cystinosis, is a little bit harder to diagnose, and we'll talk about some of the diagnostic modalities for that. And then a rarer form, which is non-renal or non-nephropathic and affects mainly the eyes. The cornea and the kidney appear to have one of the higher predilections for the deposition of cysteine, although all organs can be evolved as we'll see.
So again, the most common case is the infantile, and that's what we would suspect in our case. But once this free cysteine starts to accumulate in the lysosomes, that's when we start to see the cellular cysteine crystal formation. Think of kidney stones and what happens there. These start to deposit or think of other infiltrative diseases like amyloidosis. These things deposit and start to cause tissue and ultimately end organ damage. And that's where the clinical scenario comes into play. The most common form of this disease with the infantile form, classic syndromes for this type include failure to thrive, which we see often.
So again, the differential that we'll talk about can be quite extensive—Rickets, and then ultimately the true Fanconi Syndrome. Now, I know a lot of people like to forget about Fanconi Syndrome, but we need to remember that because it's one of the earliest manifestations of this and a predictor for chronic kidney disease in these patients. So, other organ systems can be involved and this includes the eye, particularly the cornea, the gastrointestinal tract, the musculoskeletal system, and also the central nervous system. Neonates are classically asymptomatic even though we know they're already starting the deposition in utero. But when they're born, they may have normal birth weight, they may have normal fetal length, but they're already starting to accumulate cysteine. So, there's a window there where we may not see any symptoms, but typically by the time they're one year of age, that's when the symptoms start to come.
And the usual presenting symptom is Fanconi Syndrome. And if you remember Fanconi Syndrome, and I know everybody loves to have their head blow up when we talk about the proximal tubule, but that leads to polyuria, polydipsia, and ultimately the baby may become dehydrated. It forms a proximal renal tubular acidosis. So, all my medical students out there love that. You start to have urinary loss of electrolytes and subsequent electrolyte displacement and then ultimately growth retardation. So, this is a major factor that starts as early as one year of life, and many times we just don't pick up on that. When we look at these kids' urine, we see glucose uria because that's a hallmark of Fanconi's. They're going to have glucose in the urine, and that's one of the ways that we start to look at Fanconi's.
Now, I will tell you with the advent of the SGLT2 inhibitors a few years back, as people were starting to come on these, not of importance in this, but I started to see a lot of people with glucose in their urine. I started to freak out a little bit about why all these people had glucose in the urine. But with the SGLT2s, we know that's a good thing. So, we can just look at those by urinary dipstick to see if there's glucose in the urine. So, that helps to do this as well. So, this may be the very first symptom of cystinosis and we have to pay attention to that. Without treating this disease though, renal failure can occur as early as 10 years of age. So, that is of paramount importance to make the diagnosis early, and you see in our case, he's already a little above that and already has some renal insufficiency. So, when you look at overall childhood renal failure, cystinosis itself accounts for about 5% of our patients who end up needing dialysis or a transplant. When we look at the differential here as we do with other orphan diseases or rare diseases, it can be difficult to pin this down.
Other lysosomal storage diseases, glycogen storage diseases, and Wilson's Disease may all manifest a little bit the same. Some may have some Fanconi's, but of course, whenever we talk about that proximal tubule, we have to bring into things like Bartter Syndrome and diabetes insipidus. So, all of these are going around in your head as you're trying to manifest cystinosis. So again, diagnosis can be delayed and thus bring on the problems with the progression of renal disease. The key component to diagnosis here, a high index of suspicion is warranted. If you have a young patient who has Fanconi's and has the failure to thrive, you have to look into this as a possibility. And the diagnostic way to do that is to do what's called a WBC Cysteine Level, which will be elevated. You would then move on and do genetic testing of that CTNS gene and the two of those coupled are enough to make the diagnosis.
Once you're able to diagnose, you can have an impact on the progression of chronic kidney disease and more importantly, get these kids started on lifelong therapy. So, it's very important to do that. So, other diagnostic considerations, when we're looking at the other forms of cystinosis as well, not just the infantile form outside of the WBC cysteine levels and the genetic testing, focus on the eyes and the kidneys. Remember there's a type that's non-renal that affects the cornea. So, slit lamp examination of the cornea looking for cysteine deposition is very important. And certainly, this particular patient didn't get that slit limp exam until he was almost 10 or 11 years old, and by that time they had missed the nephrogenic portion of this leading to some renal disease. As far as the nephrogenic juvenile form, which we call, it's kind of the intermediate one, sometimes renal biopsy will help us there.
I will tell you that most of the time, because infantile is 95%, you don't need the biopsy. But when you have those intermediate patients, which are much rarer, you may have to resort to renal biopsy and there it's a podocytopathy, if you will. There are some podocyte activities that we would look at. But again, the diagnostic modalities using the white blood cell is very, very important moving forward. So, once you're treating, we really only have one option available to us that's standard of care, and that's cysteamine. And there are two forms of that, and I'll go over a study that just came out last month actually from Norway looking at the various forms of it. So, cysteamine is currently the only cysteine depletion therapy that we have available to us. And what this does is it goes to the lysosomes and converts cystine that's accumulating in those lysosomes.
Remember, it's a lysosomal storage disease, cysteine accumulates, and the cysteamine causes you to release those byproducts from the lysosome, thereby decreasing the burden. You would then measure that on your WBC cysteine levels and see it going down. So, once you do that, you want to start low on these and titrate up. There are some adverse effects, which we'll talk about in a minute. And we set a target for what we want to see that WBC cysteine level, and it should be less than or equal to one. Now remember in our patient, I forget the exact number, but it was up in the six range. So, we want to measure that and we want to measure that frequently. I'll give you some guidelines in a minute. The sooner the diagnosis is made, the sooner the therapy starts, there have been shown good outcomes, improvement in growth, preserving renal function, and preserving deposition of extrarenal organs, particularly the eye. And this has a direct effect on life expectancy, including the non-renal deposition. Treatment for this is for life. These patients have to be on this.
So again, I just want to refer to this study that came out of Norway where they looked at the typical what's called an intermediate release. And you have to take that every six hours for it to be effective. But there's also an extended-release, which limits it down to 12 hours to give some better compliance. And in this particular study, they did not find any difference in whether you use the intermediate or the extended-release of cysteamine. The intermediate release has been around since about 1997. The extended-release is a little bit sooner, but both seem to be equally effective. As far as side effects, the main one that is reported is bad breath–halitosis– from the cysteine. But there can be some minor GI disturbances, overall that does not impact the discontinuation of the therapy.
And there have been some rare cases, again, of interstitial or tubulopathy and colitis after several months of therapy. But overall very well tolerated. But again, the intermediate release has to be given every six hours. And you can imagine a younger child trying to do that. So, we do have those options available to us when we're not able to control their progression of chronic kidney disease and they go on to more progressive or end-stage renal disease, renal transplantation has worked in these patients. It works well. It's highly successful. And interestingly enough, the cystinosis does not occur or recur in the renal allograft. In some other diseases, we see that. But in cystinosis, thankfully it doesn't. Keep in mind though, that all the other organ depositions do not stop with renal transplantation. So, you still get corneal deposits, you still get GI coded in CNS, so you have to keep that in the back of your mind.
So, with that, we have to pay particular attention to the eye disease. In these kids again, as they get older, you may see delayed puberty. Hypothyroidism is another big aspect and we have to work with our endocrinology partners for that. They can also get overt exocrine pancreatic disease including diabetes mellitus and can be insulin dependent. Sometimes there can be infiltration in the liver. Sometimes there can be some swallowing difficulties due to the GI tract in the esophagus. And then sometimes also some rare CNS involvement including pseudotumor and other things. So, even with transplantation, you may do better with your kidney function. You have to remember that the cysteine deposition continues in the other organs. So, let's follow up quickly on our patient. He was started on cysteamine therapy, titrating it as tolerated, and ultimately he was administered about 1.3 grams per day, and after his diagnosis, we were able to get his levels down to under one.
So, his WBC levels were very well followed. The dose administration was titrated every two weeks. And he was also given therapy targeting the effects of his Fanconi Syndrome. That included oral phosphate therapy, potassium citrate therapy, treatment for his hypophosphatemia and acidosis, proximal tubular acidosis, and classic with Fanconi. And after about seven or eight months, this child had an assay that was down to 1.01 nanomoles, per half cysteine per milligram of protein. That's pretty good. So, I think that's good. And more importantly in this young fellow after seven months, his GFR went up 11 points to 77. Still not where I want a 12-year-old to be, but showed that this is the right thing to do to try to slow that progression. So, what else do we need to do for these patients? Once they're diagnosed, how do we follow them?
Most patients really should be cared for by a pediatric nephrologist. He should be the team leader on this. He should undertake the role of the primary care provider because of all the nuances that may occur and the importance of avoiding or slowing the progression of chronic kidney disease. They should be seen regularly. Try not to lose them to follow-up, hand them off to adolescent medicine docs as they get older if need be. The visits should also be coordinated with other subspecialists. And it's so important as the child gets older to involve the child and the parents in shared decision-making. Make sure that they're doing a healthy lifestyle and dietary modifications for chronic kidney disease. We should measure that leukocyte cysteine content about every three months. And again, we want to keep it roughly around one nanomole per half cysteine per milligram of cell protein.
As far as blood chemistries, these patients should be followed usually every week once they start therapy to make sure of renal function and hepatic function. But then once they're stable, about every three to four months would be adequate for basic chemistries. They should be seen in the office approximately every two to three months, and they should also be monitored very closely for their growth charts and their weight gains. Possible electrolyte abnormalities, see how the Fanconi's is doing, and don't ever forget those non-real complications. Those can come up to get you later as far as the eyes because that is an important factor, slit lamp exams should be done every year on these kids. Even if they get transplanted, you should still look for those corneal depositions. If you're not seeing growth improvement and you still have growth retardation, we can work with our pediatric endocrinology partners to consider things like growth hormones. Not a lot of studies out there, but certainly a possibility of doing this.
And we have the recombinant human growth hormone now, which can work very well. Never forget the thyroid. Want to monitor and treat any thyroid complications that may occur. Sometimes you may have some CNS effects, so speech and language therapy is needed. Genetic counseling is very important. This is a genetic disease, it's an autosomal recessive. I think everybody should have, the family should have a genetic conference as well. So, for a rare disease, this is a very important one I think because of the impact that it may have on chronic kidney disease. We don't want our 10, 12, 15 year olds on dialysis. And if we look at the spectrum of this, again, this starts in utero, but there's a little delay before we may be able to make that diagnosis. So, we've got to be ever-vigilant. We have to have a high index of clinical suspicion, and we have to pay attention to what our patients and their disease states are telling us. So, that's a summary and a little case study on nephrogenic cystinosis for Consultant360.
I'm Dr James Matera, and thank you for listening.