Short Stature & Other Endocrine Symptoms Of Mucopolysaccharidoses

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Introduction

Dr Alessandro Cattoni: Good afternoon, everybody. Please let me thank the organizers of the Excellence in Pediatrics Education Program for inviting me today. I am Alessandro Cattoni and I work as a pediatric endocrinologist at San Gerardo Hospital in Monza, Italy. As a part of the misdiagnosis course about metabolic disorders in childhood, I would like to take you through the endocrine - presenting signs and symptoms of mucopolysaccharidoses in children.

I am obviously speaking about short stature, but I would also like to present some additional endocrine issues for which an endocrinologist, a pediatric endocrinologist, may be involved in the management of these patients. The organizers of the course asked me to remember that taking any screenshots and reproducing any of the slides presented today is forbidden and feel free to ask any questions during the presentation, but we have a short span of time at the end, five minutes, to try to answer to all the questions you may raise.

MPS and its varied presentations

As you all know, mucopolysaccharidoses represents a heterogeneous group of inborn error of metabolism disorders. The incidence of this condition ranges from 3.5 to 4.5 per 100, 000 live births, and as you know, lots of function mutations, monogenic mutations, of the genes involved in the codification for the lysosomal enzymes, which are involved in the degradation of glycosaminoglycans, leads to the pathological accumulation of chondroitin, dermatan, heparan, and keratan sulfate within the lysosomes.

As a result, cellular function is severely impaired, and this is the most important biological cause for the onset of the clinical presentation of the signs and symptoms, which are related to mucopolysaccharidoses. As you know, 11 deficient enzymes may result in seven different clinical disorders. MPS I, which includes Hurler, Scheie and Hurler- Scheie syndromes, MPS II - Hunter syndrome, MPS III - Sanfilippo syndrome, MPS IV - Morquio syndrome, MPS VI - Maroteaux Lamy syndrome, and MPS VII- Sly syndrome, plus an additional MPS IX disorder.

This patient is a patient diagnosed with MPS IV. I would like just to present now a general overview of the clinical feature that a patient with MPS, not MPS IV, but in general any kind of MPS, may present. So, first of all, these patients may present with macrocephaly. They may present with CNS disorders, such as hydrocephalus and mild mental retardation.

They may present coarsening of facial features, corneal clouding, cardiomyopathy, several kinds of ENT disorders, like hearing loss, recurrent ear infections, and upper airways obstruction. They may present with inguinal or umbilical hernias, hepatosplenomegaly and a wide range of musculoskeletal disorders, from multiple dysostosis of the bones, decreased articular range of motion, kyphosis, scoliosis, and short stature, above all. Everybody who has met one of these patients in his or her career would immediately recognize this patient as being affected by mucopolysaccharidoses, or, however, an inborn error of metabolism.

But the issue is that also this other patient is diagnosed with mucopolysaccharidosis. So a skilled pediatrician and a skilled pediatric endocrinologist should be aware that the clinical spectrum of the clinical presentation of a patient with mucopolysaccharidosis may be extremely variable, ranging from a classical presentation to a mild, non- classical musculoskeletal presentation. So we always have to remember to keep a high index of suspicion when we have to evaluate a patient with a suspect for an MPS.

Just to show you some of the pictures of patients followed here in Monza, these patients present clear clinical features, which immediately raise the suspicion of mucopolysaccharidosis, or however, pathological storage disease. These other patients present much milder clinical features, so it may be much more difficult to recognize patients with this condition being affected by mucopolysaccharidosis. In addition, patients with mucopolysaccharidosis tend to present a progressive evolution of the clinical picture.

So, like in this case, a patient with very overt and very clear clinical features in adulthood may have been a patient with just mild clinical signs in early childhood. So, always remember to follow up patients once you have a suspicion because the clinical picture may change very importantly in time. Let's now focus on the main part of this presentation, that's to say growth and growth impairment in patients with mucopolysaccharidosis .

Why patients with MPS have short stature

Why do patients with MPS experience short stature? Firstly, many of these patients experience joint contractures, which prevent them from keeping a proper standing position. So, this is mostly the result of an abnormal proliferation of the cell within the cartilage, within the articular cartilage, and a complete abnormality in the thickening of the cartilage layers. In addition, a damage may occur and involve the growth plates, always as a result of a pathological accumulation of GAGs within the epiphyseal cartilages.

This is the result of a distortion of the arrangement of the cells within the epiphyseal cartilage and an abnormal, again, thickening of the growth plates. In addition, these patients tend to present multiple dysostoses. This is the result of an impairment in the osteoblast function and a loss of the trabecular bone and a pathological thickening of the cortical bone.

So, this patient may present important abnormalities in the structure and architecture of the bones. Some recent papers have also demonstrated that an important inflammation, an important phlogosis occurs and involves the cartilages both of the joints and of the growth plates. So, also inflammation is part of the causes which leads to an abnormality in the cartilages of these patients.

I would like now to show you some of the pictures which may make you understand what I said before. The patient on the left presents with an important joint contractures involving the knees. As you can see, this patient can't keep a proper standing position and it means a loss of several centimeters in terms of the height achieved.

The second picture shows an important kyphosis which often affects patients with MPS. The third picture shows you important abnormalities of the shape of the bones presented by this patient with a typical bullet- shaped phalanges which may be found in the x- rays of the hands of these patients. And finally, also genu valgum is found in a high percentage of these patients and it now an additional cause for further loss of centimeters in terms of final height achieved at the end of growth.

Growth charts and patterns across MPS types

Now, what is normal and what is not? I was speaking about the growth in patients with MPS I. Let's see how growth occurs in patients with different MPS disorders. Growth in a patient with MPS I tends to be normal with a normal height, Z- score height, standard deviation score, during the first 24 months of life and then a drop, a progressive decrease of height, standard deviation score, occurs in these patients although the final height achieved may be extremely variable in patients with MPS I. The second chart shows growth for patients with MPS II.

The red line represents the third centile for the general population and as you can spot, growth tends to be normal in patients with MPS II within normal ranges up to the age of 6 to 7 years and then it starts to drop later on in time. As you can see, the physiological pubertal spurt is completely absent in these patients.

This chart represents the growth in patients with MPS IVA, so patients with Morquio syndrome. As you can see, the red line represents the 50th centile for the general pediatric population. Growth tends to be normal during the first three to four years, and then it starts to drop with 50th centile final height being around 120 centimeters. Final height in patients with MPS IV may be extremely variable, ranging from 85 centimeters, which is the third centile for patients with MPS IV, and to 175 centimeters, which represents the 97th centile.

So final height may be extremely variable in patients with MPS IVA. Speaking about patients with MPS VI, we have to subdivide this cohort of patients into subgroups, patients with a rapidly progressing disorder and with slowly progressing disorders. The first patient will present the most severe clinical condition, grow up until the age of 9 to 10 years, and then height tends to achieve a plateau.

Patients with MPS VI, with a slowly progressing and thus a milder form of disease, keep on growing until the end of their teenage ages. The final height achieved is 110 centimeters for the 50th centile for the first group, and 145 centimeters as the 50th centile for the second group. So in order to summarize what I've told you before, all the patients with MPS tend to present with normal length and weight at birth, but then a drop in length and height SDS occurs later on in life, during the first years of life.

The time of onset of this drop in height standard deviation score is extremely variable, and it depends on the severity of the disease itself and on the severity of the specific severity of the clinical picture of each patient we are analyzing. As a general rule, we may say that patients who present the most important impairment in terms of final height achieved are patients with MPS IV, followed by MPS VI, MPS I, and MPS II at last.

It's very important that most of these patients do not present at all a pubertal spurt. So pubertal spurts tend to be reduced or completely absent, and so an endocrinologist may be involved in the care of these patients, or anyway, a patient with an undiagnosed MPS may be referred due to an endocrinologist due to one or more of the following reasons, short stature, pubertal delay, or absent or attenuated pubertal spurt.

So as I said before, we have to focus on the patient on the left. So an endocrinologist may come across during his or her career a patient with a non- classical and attenuated form of MPS, and it's very important because the endocrinologist may be the only clinician who may across this patient, and so who should arise the suspicion of an inborn error of metabolism disorder, just starting from short stature or a lack of pubertal spurt.

Just to show you some potential growth patterns for this patient, a patient with an attenuated MPS may present a progressive drop in SDS, followed by an absent pubertal spurt or an attenuated pubertal spurt on the left, and on the right, a patient may just grow normally, striking the same centile, but then he or she do not present any pubertal spurt at the end of puberty.

Features that should raise suspicion

So we are now ready to list the features that should raise a suspicion in a pediatrician and an endocrinologist when approaching a patient just referred due to short stature. Firstly, a patient, as I said before, who does not present a pubertal spurt and who presents a consistent growth chart should raise this kind of suspicion. Patients presented with joint stiffness, that is to say a patient with an important impairment of the fine motor tasks achieved, a patient with recurrent joint pain, or with a limited range of motion, so a patient with one or more of these features and with short stature should prompt further analysis.

A patient with complaining about numbness of the hands, which may be the first sign of a possible carpal tunnel syndrome, and again a patient with a long- standing surgical history, so surgery involving the ENT sphere, or a patient who underwent multiple hernioplasty should raise this kind of suspicion. A patient with important and recurrent ENT disorders, with cardiomyopathy, hepatosplenomegaly, or with orthopedic disorders and short stature should be taken into account as potentially affected with attenuated MPS.

In particular, a patient with kyphosis, scoliosis, or a long- standing history of surgery due to a femoral pathology like the Legg–Calvé–Perthes syndrome should be immediately referred to an involvement of metabolism unit. As endocrinologists, we are really fond of hand and wrist X- ray for bone age, and we know that the bone age assessment falls within the workup for approaching patient with short stature.

So, which kind of information and which rate of reflex may we find when analyzing an X- ray of the hand and the wrist for a patient referred just due to short stature? Firstly, these patients, as I said before, tend to present a typical bullet- shaped phalanges. In addition, we may find a thickening of the metacarpal bones. Another very typical feature is a delayed carpal bone.

We can find an important gap between the bone age of the terminal of the distal bones of the hand and the proximal bones of the hand, which tends to be much more delayed in terms of bone age achieved. And finally, we can find these typical down- slanting features of radius and ulna. So, if we found one or more of these features, we should think about attenuated MPS.

A diagnostic approach

So, which kind of algorithm may be proposed when approaching a patient with short stature? Anytime we find a patient with a consistent growth pattern plus one or more of the red flags listed before we should perform a skeletal survey involving hands and the spine. If the skeletal survey is normal, then we just should think a different potential diagnosis.

If the skeletal survey is suggested, then we should perform a urinary GAGs collection and an analysis of the enzyme activity of the enzymes potentially involved in MPS. Which kind of abnormalities may we find when approaching a skeletal survey in these patients? We may find some spinal abnormalities like kyphosis, scoliosis, or rounded vertebral bodies. Or, we may find some abnormalities involving the hip with a verticalized femoral neck or a acetabular dysplasia.

Treatment effects on growth, bone and puberty

So, now we say that these patients tend to present also extremely severe short stature. What can we do in terms of treatment for our patients? We all know that enzyme replacement treatment and hematopoietic stem cell transplantation have remarkably improved the final outcomes achieved in these patients. So, most of the complications experienced by patients with MPS, different kind of MPS, may be improved due to, thanks to these weapons that we have and we can use as treatment options.

But we know that the effectiveness of hematopoietic stem cell transplantation and ERT for our patients in terms of musculoskeletal symptoms and signs tends to be quite poor. So, some authors have started to think about the use of recombinant human growth hormone in these patients. In particular. Paul Green, in 2010, had started to present some data about the use of growth hormone in a population of patients with MPS.

We know that in most of these patients, the results in terms of increased height velocity was quite poor. Rogers, in 2014, published a single patient with an important improvement in height velocity after the start of a recombinant human growth hormone.

It's important that we are not aware, anyway, about the long- term side effects and the long- term efficacy of recombinant human growth hormone in a population of patients with MPS. So our advice is to use, so far, growth hormone just in patients with demonstrated growth hormone deficiency. When growth hormone secretion is demonstrated as being normal, there is no indication, so far, for using growth hormone in these patients.

In addition, we have to remember that patients who underwent bone marrow transplantation or hematopoietic stem cell transplantation may present a worse response to recombinant human growth hormone due to the chemotherapy and especially the radiotherapy administered before bone marrow transplantation. I would like now just to present some other endocrine issues for which an endocrinologist may be involved. The first thing is low bone mineral density.

These patients tend to present low bone mineral density. It's important that patients with a short stature tend to present an overestimation of the incidence of low bone mineral density. This is just because Z- score for BMD has to be adjusted for high Z- score. So actually, short statures tend to falsely present with a lower bone mineral density.

But actually, also when we adjust bone mineral density Z- score for high Z- score, we tend to find a higher incidence of low bone mineral density in the cohort of patients with MPS. How to treat this condition? Bisphosphonates are used in children with MPS just when an overt osteoporosis is demonstrated. That's to say just patients with multiple fractures or vertebral body fractures.

But we are not allowed to use bisphosphonates in patients who just present with low bone mineral density but without a long- standing history of these kind of fractures. So we just have to provide some substantive treatment, like growth hormone treatment in patients with growth hormone deficiency, and estrogen or testosterone in patients with sexual hormone deficiency.And we have to provide and to grant an appropriate approach of vitamin D levels and calcium intake with the diet.

In addition, as a pediatric endocrinologist, I'm often called to manage premature ovarian insufficiency in these patients, not because patients with MPS present with premature ovarian insufficiency due to the pathology itself, but just because we have to remember that some of these patients underwent hematopoietic cell transplantation, and so these patients may have undergone chemotherapy and radiotherapy as a part of the conditioning schemes undertaken before hematopoietic stem cell transplantation.

These kinds of treatments may be quite gonadotoxic, and so sometimes these patients may not be able to go through puberty just because they present with a premature onset of primary ovarian insufficiency, or sometimes, in most cases, they go through puberty normally, but then they present a later onset of ovarian insufficiency. How should we deal with this condition?

Just induce puberty through estradiol patches in puberty, and just provide a proper amount of estradiol later on in life as hormone replacement therapy, so we are speaking about HRT. But this represents just a small group of patients with MPS, just those who underwent, as I said before, bone marrow transplantation. So my presentation is over, and I would like to thank again the organizers of this interesting meeting and all the audience for your patience in listening to me, so thank you.

Questions and answers

We're now ready to listen to some of your questions, if you have any. So while you're dialing, okay, some questions. So the first question that I get is the following. Is hand and wrist X- ray a reliable tool in patients with MPS when assessing bone age? Well, the answer is quite easy, and it's no. Hand and wrist X- ray provide just extremely variable results, and assessing bone age in this patient is extremely difficult due to two different reasons.

The first one is that the shape and the architecture of the bones we may find at an X- ray is completely subverted, is completely distorted, so it may be very difficult to see the different bones at the different levels of progression throughout puberty and growth. And the second reason is that there is, as I said before, an important gap in the bone age as found between the distal bones and the proximal bones of the hands.

So sometimes, in Italy, we tend to use the Greulich and Pyle atlas to assess bone age, but it's very difficult because I find patients with an advanced bone age involved with the phalanges, but a very delayed carpal and metacarpal bone age. What we tend to do is using some other scoring system, like the Tanner–Whitehouse system, which consists in assessing with a score which goes from A to I, the bone age of each bone, and then an algorithm provides a final result.

So this is the only way we can try to provide the most reliable X- ray assessing for bone age. So do we have any other questions? No? No other questions? Okay, another one. Okay, so which is the safety profile of growth hormone in patients with multiple dysplasia, like MPS? So this is a good question and with a quite difficult answer, but actually we don't know it.

What we know is that we need much more wide, much wider studies to assess the safety of growth hormone in this cohort of patients. Some studies have been held about different disorders related to multiple dysplasias. For example, patients with severe scoliosis in Prader–Willi syndrome or other rare conditions, genetic rare conditions, leading to multiple dysplasia. But just a few data are available in patients with MPS.

We know that, for example, in patients with scoliosis and Prader- Willi syndrome, the use of growth hormone is considered as overall safe. But we also know that patients with MPS tend to present much more severe multiple dysplasia. So actually, what Paul Green and also our study says is that we did not meet any short- term severe complications related to the use of growth hormone.

But obviously, we need much more and much longer- standing studies to assess safety in the use of growth hormone in this specific subset of patients. Any other questions? Okay, another one. Which are your suggestions for screening these patients for low bone mineral density? Like, for example, the time of testing, the type of DEXA scan performed? Okay, good question.

What we tend to do is performing a DEXA scan in patients older than six to seven years. And we start to perform a long- standing follow- up. And we tend to perform a DEXA scan every one to two years. It's very, just two things to remember. Firstly, always remember to perform both a total body and a lumbar spine DEXA scan for these patients.

And second, always remember to adjust, as I said before, BMD- Z score for height Z score. Finally, I would like to remember that the best kind of scan to be taken is a total body less than head DEXA scan. What does it mean? It means that we should consider all the body, but not the head. Because in children who tend to present a higher ratio head to body, the bones of the head tend to overestimate the values of Z score from BMD.

These patients tend to present a thickening of the cortical bones, so also the head bones. And in addition, they tend to present with macrocephaly. So if you perform a total body with head included, this may overestimate the levels of BMD- Z score when we perform a DEXA scan. Do you have any other question? Which growth chart should we use for determining growth in these patients?

So a good question. So the issue is that for some of these patients like MPS I, we do not have a disease- specific growth chart. In patients with MPS IV, MPS VI, for example, we tend to follow up growth using the normal growth charts for the disease. So the disease- specific growth charts. In patients with MPS I, we tend to use the WHO growth charts or eventually the Italian growth chart, the nation- specific growth chart to follow up growth in these patients.

These charts are also very useful to follow up these patients once a treatment like growth hormone is undertaken because you can really see whether an improvement in height standard deviation score for height and for height velocity are actually improved according to the general population and according to the specific population with this kind of disorders. So overall, I would say if you have specific disease- related growth charts, then use these charts.

Otherwise, rely on the WHO growth charts. So another question, question number five. Is it common to have hypothyroidism in children with MPS? Yeah, many children have features we may be confused with hypothyroidism. Okay, this is a very interesting question. Especially, it's true, especially in newborn patients or, you know, patients during the first year of life may present with macroglossy, very coarsening of facial features which may be actually confused with features belonging to the clinical picture of hypothyroidism.

Actually, some post- mortem studies performed on the thyroid of patients with MPS showed a pathological accumulation of glycosaminoglycans in the thyroid of these patients. Actually, in my experience, I do not find an importantly increased, an importantly raised incidence of thyroid disorders of these patients. Although, you know, the numbers are really very small because these kind of disorders are very rare.

But I would say that literature does not report as hypothyroidism being specifically related to a mucopolysaccharidosis. Anyway, it's a good point. You got a good point saying that you have always to check thyroid function in a patient presented with, you know, umbilical hernia, coarsening of facial features, and so on. So, good point. Any other questions? Okay, how can I understand when it is the right time for starting growth hormone treatment?

Okay, it's absolutely a good question. So, first of all, as I said before, if you, my suggestion, our institution suggestion is that if you want to start with growth hormone, be sure to test the patient for growth hormone. So, you should have both auxological features, x- ray, delayed x- ray for bone age, and at least two dynamic tests showing a pathological peak for growth hormone achieved.

So, the question may be switched to when it is the right time to test these patients for a suspicion of growth hormone deficiency. So, my advice is to use, as we said before, the growth, the specific growth chart for patients with these kinds of disorders. For example, in a patient with Morquio syndrome, we tend to see an important reduction in growth velocity and height velocity after the age of five to six years.

So, if I use these charts, I can see that it's quite normal for a patient with Morquio syndrome to experience a drop in height velocity at this age. And so, in that case, I would not perform a dynamic testing for growth hormone because I know it's part of the disease.

I would test for growth hormone and eventually start the treatment when patients experience a complete growth arrest before time, a forehead. So, when it's not expected according to the general charts for patients with these kinds of disorders. And in addition, I would think about growth hormone deficiency when this patient presents an impaired growth also if I use the disease- specific growth charts.

So, for example, a patient with Morquio syndrome with a height which is below the third centile for Morquio - specific growth charts. Could polyuria be part of the glycosaminoglycan deposition?

We have a patient with MPS IV and chronic diabetes insipidus. Yes, it is described and also we have a patient with diabetes insipidus and MPS as well. It is know that MPS increases the risk of developing central diabetes insipidus due to the pathological deposition of GAGs within the neurohypophysis. So the answer is quite clear- Yes, so if a patient with MPS presents with polyuria or polydipsia immediately rule out diabetes insipidus.

It's a good question. So, no more questions. I would really like to thank all the audience for all the questions you made and for participating in the discussion about MPS and growth and for your patience in listening to my presentation. So, thank you, everybody. And I think that the webinar is over. Good afternoon, everybody.

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