Hi, this is Dr. Bart Clark from Mayo Clinic, Rochester, Minnesota, coming to you to present about hypoparathyroidism in children. This is an Endocrine Society presentation. The hope is that you'll get an idea about the life cycle considerations in patients with hypoparathyroidism, many of whom develop this in childhood, some don't, some develop it later in life. As an adult endocrinologist, I see mostly patients who develop this later in life after surgery, anterior neck surgery in particular. But of course, we do see adult survivors of childhood presentations of many things, including hypoparathyroidism. So turning to hypoparathyroidism in children, this is a condition that we don't see very often, but we oftentimes see these children as they mature past age 16, at least in my institution, we're oftentimes referred these patients as long as they're willing to give up on their pediatrician. That's not an easy transition, usually in children with this condition oftentimes don't transfer to the adult side, even until the 30s. But whenever they show up, we have the responsibility of caring for them. So point out things that we expect to occur in children who develop this condition. Certainly, some of these patients will develop dental enamel hypoplasia shown on the top left of this slide. The teeth look funny. And typically, there are short blunted roots in the premolars, there's delayed or absent eruption in teeth, and the teeth generally are hypoplastic and prone to caries. So this is oftentimes recognized by the pediatricians, but if they show up in our clinic later, and it was missed or somehow didn't get diagnosed, of course, this should prompt some consideration of that. cataracts are also more common in this condition in children, the cataract that occurs usually leads to clouding or opacity of the lens, this leads to visual blurring. And of course, in this condition, the classic teaching is that the cataracts in hypoperithroidism are what they call posterior subcapsular cataracts. This is a very specific type of cataract that could be identified on slit lamp examination, usually by ophthalmologists. But that if it's found should prompt consideration of this condition. The basal ganglia calcifications that we see usually on CT head imaging, but can be seen on other images as well, including x rays, in some cases can vary, it can vary from punctate as shown in the left hand panel on the bottom left, with the arrows pointing to this, there's definitely calcification there that shouldn't be there. But at the same time, as adults, we oftentimes see patients with more expensive, extensive basal ganglia calcification. So you can see that in the three panels on the right showing three different patients at different stages of disease with different appearance of the basal ganglia calcification. These findings usually are picked up on by the radiologist right away. And of course, it's not a mystery by the time they make it to our office that they have this condition. Now, what about the commonality of this condition? It's interesting that there's been a number of studies done in different countries around the world, showing various prevalence incidents and mortality from this. This is from my own institution with studies added from other countries, you can see the range of the prevalence of hypoparathyroidism in general from the country's specific data. At the same time, you can see that the difference between surgical and non-surgical hypoparathyroidism, the last two columns on the right is quite variable. And as you'd expect, it's more common to find surgical hypoparathyroidism. These studies were done mostly of adult patients, of course, and that's what we're finding. It's more common to be post-surgical. If you look at the incidence figures in Denmark and India, you see that the total overall incidence is much less than the prevalence, as you'd expect, 0.8 per 100,000 to 2.6 per 100,000, some variation in that between Denmark and India. Finally, mortality, there's now five studies out that show no evidence of increased mortality. And three of those, two of the studies from Tayside, Scotland, and I believe India have shown a slight increase in mortality. So there's some debate yet as to what this really is. But in general, these patients do very well. They live a long time. And sometimes, of course, they can die of complications, but that's uncommon. The risk of complications is shown in this slide. This comes from data collected at the Aarhus by Lars Reinmark, one of the investigators there. And they found differences between post-surgical and non-surgical hypoparathyroidism in terms of the complications that these patients were hospitalized for. You can see in the left column, the different types of complications, renal insufficiency, kidney stones, ischemic cardiovascular disease, neuropsychiatric disease, seizures, cataracts, upper extremity fractures, and intracranial calcifications being the main ones. And if you look at the differences in terms of hazard ratios, HR for short, showing the percentage of these patients who were found to have increased risk, for example, renal insufficiency 3.1 fold increased with a confidence interval shown. For non-surgical hypoparathyroidism, it was actually more frequent than in the post-surgical patients. And of course, the non-surgical patients in the series had been followed for longer than the patients who had post-surgical. So it's not clear that this isn't due to duration of disease or severity of disease. The assumption is it's probably a combination of both. As you go down through the list, you notice that there's no kidney stone risk seen in their patients who had non-surgical hypoparathyroidism. Other complications are shown. Seizures, for example, are fairly common and moderately increased, I would say, certainly 10 fold increased in the non-surgical patients. And the rest of it you can see. Frequency of intracranial calcifications, the basal ganglia calcification we've talked about is fairly common as well. Now, we hear a lot about symptoms from the patients. They seem to be anxious, sometimes depressed. And if you said, what about anxiety? The next two slides, we'll talk a little bit about what's been published on this. This very first paper is coming from Germany, where they looked at the difference in terms of anxiety scores using SF36 in this case. But looking at these in patients who had hypoparathyroidism, 25 women with that, that was all post-surgical. Comparing this to 25 age and sex match controls who had had thyroidectomy but had intact parathyroid glands. So a very useful comparison group. Most scales were worse in the patients who had the post-surgical hypoparathyroidism. And that's generally the sense you get with all these different symptoms, some of which are more psychiatric as opposed to more physical symptoms. Now, other studies have been done in the U.S. looking at SF36 again. Other instruments are now out there that they're used in various clinical trials. But in this case, Cusano at Columbia, Cho at Harvard, and SickJR at the Aarhus in Denmark have looked at this in some detail. And basically, most of these studies show similar findings where the scores are worse in all the domains compared to normative data. For example, scores were lower in the Cho study as well, a bigger study with 340 patients evaluated. And then SickJR using their instrument with a 62-fold study, 62-patient study, showed significantly reduced quality of life. And that's what our patients tell us they have in general when we ask about that. Now, management of chronic hypoparathyroidism is shown here. Maria Luisa Brandi has published on this in the JCENM as far back as 2016. You can see the various guidelines that have been produced so far. The European Society has published on their guidelines. There's an international conference that was published on the management of hypoparathyroidism in late 2022. And then finally, there's a disease state clinical review published by the ACE organization that looks at post-operative hypoparathyroidism in particular. All of these guidelines agree that the treatment targets should be low normal serum calcium, high normal serum phosphorus, 24-hour urine calcium in the normal range, less than 300 milligrams by the milligram calculation or less than 7.5 millimoles by SI units. Calcium phosphate product, everybody pretty much agrees so far that this should be less than 55 based on the renal data. But there's some sense that this may be too high for these patients and eventually this number may reduce. But this is the current recommendations. Conventional management does involve replacement with calcium citrate most commonly because of better absorption but carbonate works well in many patients. You can use anywhere between one and nine grams a day in divided doses. Most patients take at the lower end of that range but some need more. Calcitriol is given usually at low to medium doses, 0.25 to two micrograms a day. Again, at least twice a day, sometimes three times a day where that is given. Vitamin D2 or D3 is recommended also simply because some tissues in the body need regular vitamin D2 or D3 and they cannot use calcitriol. These tissues will convert the circulating vitamin D2 or D3 into calcitriol inside the tissue because they have a one alpha hydroxylase enzyme to do this and it's not just the kidneys that are affected. Thiazide diuretics and a low salt diet are recommended if the patient has hypercalciuria in spite of the best efforts to control serum calcium into the range that we want. And then, of course, phosphate binders, low phosphate diets can be recommended if necessary to bring down hyperphosphatemia that doesn't respond. This last slide shows the monitoring that's recommended for certainly adults. This is reasonable for children as well. Certainly, checking serum calcium, phosphorus, magnesium, creatinine, BUN, and EGFR are recommended during the initial treatment phase or with change in therapy over time. Weekly to monthly is reasonable at the beginning and then after treatment stabilization, twice yearly to once yearly can be recommended. 24-hour urine, calcium, and creatinine are recommended yearly or as clinically indicated. Many times this will be checked in the middle of the year because doses have changed and we need to know did the urine calcium go up unanticipated or unexpectedly but would have to be treated if it did. Finally, the other various things shown here, renal imaging looking for kidney stones either by ultrasound, CT, or other ophthalmology evaluation for cataracts when patients are symptomatic. That makes sense. Otherwise, they're not usually sent just for asymptomatic status. CNS imaging for basal ganglia and other intracerebral calcification can be done by choice, most often without neurologic symptoms accompanying it. That wouldn't be recommended right off the bat. But bone density testing, the patients want to know we expect high bone density in these patients. And once that the status is known, those things could be checked as needed clinically and this is subject to investigator or clinician judgment. Thank you very much for your attention.

hypoparathyroidism

children

symptoms

management

complications