A toddler is taken to his pediatrician because his parents are concerned he might be small for his age. The pediatrician diagnoses him with knock knees, but there’s no cause for alarm.
Although the child doesn’t have any other known medical conditions, something is happening in secret, inside his DNA that won’t be discovered until a diagnosis of hypophosphatemia is discovered some time later. And if this disease is ignored, it can quickly become deadly.
But back to that first appointment. “At that time, he had a rather normal diet, was taking [multivitamins] so his intake of vitamin D was at the recommended daily allowance,” shares Dr. Michael Levine, a pediatric endocrinologist at the Children’s Hospital of Philadelphia. “And because he had no other medical disorders and no other conditions that were of concern, his pediatrician decided that they would just watch him to see whether he could outgrow his knock knees, and whether this might improve his overall growth.”
At the age of 7, there is little to no progress. He visits an endocrinologist. Nothing significant is found. At 10, an orthopedic surgeon operates on the child’s knock knees.
Two years later, he visits Dr. Levine for the first time. “When we first saw him, we were impressed by his prior history of knock knees, which had its onset in his toddler years, and we looked carefully at the evaluation that his pediatric endocrinologist had performed some years prior that disclosed normal levels of serum calcium, normal levels of PTH, normal alkaline phosphatase, and a normal serum 25-hydroxy vitamin D, which in the mind of the first pediatric endocrinologist had effectively ruled out rickets or osteomalacia.”
But one test hadn’t been done — a test for serum phosphorus level, and when the results come back showing hypophosphatemia, this becomes a key to the child’s diagnosis.
“When you have a child that doesn’t respond as you might expect to calcium and vitamin D,” advises Dr. Levine, “you have to take that next step and begin to ask, could this be due to a genetic defect in the vitamin D system, or could it be a genetic defect in phosphate metabolism?”
As it turned out, the child’s disease was genetic, and this unlocked the path to treatment. And while everything worked out in the end, it’s hard not to think about how this story could have been very different had one simple test been run, or if genetics had been considered sooner.
Dr. Michael A. Levine has been compensated by Inozyme Pharma for his participation in partnership with The American Society for Bone and Mineral Research.
Dr. Michael A. Levine is Chief Emeritus of Endocrinology and Diabetes and Director of the Center for Bone Health at The Children’s Hospital of Philadelphia. Dr. Levine holds the Lester Baker Endowed Chair and is Professor Emeritus of Pediatrics and Medicine at the University of Pennsylvania Perelman School of Medicine.
Dr. Levine completed his clinical training at the Johns Hopkins University School of Medicine and took dual fellowship training in Endocrinology and Genetics at the National Institutes of Health.
His research interests focus on the genetic basis of endocrine signaling defects. His primary clinical interests are endocrine diseases that affect bone and mineral metabolism, particularly osteoporosis, primary hyperparathyroidism, and hypoparathyroidism. Dr. Levine has an active laboratory research program that complements and extends his clinical studies. He has identified and characterized the molecular basis of various inherited disorders of mineral metabolism, including familial hypoparathyroidism, pseudohypoparathyroidism, the McCune Albright syndrome, and novel forms of vitamin D dependent rickets.
Dr. Levine is a member of numerous professional societies, including the American Society for Bone and Mineral Research, American Society for Clinical Investigation, Association of American Physicians, the American Pediatric Society, and the Johns Hopkins Society of Scholars, and has received awards that include the Distinguished Endocrinology Award from the American College of Endocrinology; the Frederic C. Bartter Award from the American Society of Bone and Mineral Research; the International Award from the European Society for Pediatric Endocrinology; and the Judson Van Wyk Prize and the inaugural Senior Investigator Award from the Pediatric Endocrine Society.
DDx SEASON 6, EPISODE 3
Hypophosphatemia and the Secret Locked in a Child’s DNA
RAJ: This episode of DDx was produced in partnership with The American Society for Bone and Mineral Research, and sponsored by Inozyme Pharma.
RAJ: A toddler is taken to his pediatrician because he’s small for his age.
His parents are concerned he’s not growing at the rate he should.
And although this child was born healthy and doesn’t have any known medical conditions, something is happening in secret, inside this little boy’s DNA.
A disease is beginning to express itself in ways which will shape his life.
And if it’s ignored, it could quickly become deadly.
RAJ: This is DDx, a podcast from Figure 1 about how doctors think.
I’m Dr. Raj Bhardwaj.
This season is all about rare bone diseases.
Today, a case from Dr. Michael Levine, a pediatric endocrinologist at the Children’s Hospital of Philadelphia.
CHAPTER 1 – MISDIAGNOSIS
RAJ: During this first visit to the pediatrician, the boy’s condition didn’t raise any alarms.
Dr. Levine: His pediatrician identified knocked knees.
RAJ: Although vitamin D deficiency is to blame for most growth issues, this didn’t seem to be the case with our patient.
Dr. Levine: At that time, he had a rather normal diet, was taking Multivites so his intake of vitamin D was at the recommended daily allowance and because he had no other medical disorders and no other conditions that were of concern, his pediatrician decided that they would just watch him to see whether he could outgrow his knock knees, and whether this might improve his overall growth.
RAJ: But this wasn’t something that would simply resolve with time.
Dr. Levine: Over the next several years, he continued to grow poorly, and at age seven years, he was referred to a pediatric endocrinologist for an evaluation.
RAJ: The pediatric endocrinologist looked at the child’s growth chart.
Dr. Levine: The child was growing poorly around the third percentile with parents whose heights would’ve predicted him to be growing closer to the 50th percentile.
RAJ: The specialist reviewed his medical history and found nothing of note.
The patient’s bone age was assessed and was consistent with his chronological age.
A complete growth evaluation was performed.
Dr. Levine: X-rays of his knees showed them to be enlarged, and there were no particular features that struck any bells for rickets.
Thyroid function tests were normal. IGF-1, a marker of growth hormone action, was also normal. There was no evidence of celiac disease, no evidence of renal or liver disease, and the child’s physical exam with the exception of short stature and knock knees was otherwise normal. And at that point, the decision was made to continue to observe the child.
RAJ: At age 10, our patient’s physical growth was still slow.
He was referred to an orthopedic surgeon for an evaluation of his knock knees.
At that time, the boy underwent a series of x-rays to diagnose any bone abnormalities.
The specialist suspected skeletal dysplasia – a blanket term for genetic conditions which affect bone, joints and cartilage health – or a metabolic bone disease, which is a disorder related to bone strength.
Surgery was performed to correct the patient’s knock knees.
The child was referred to the Children’s Hospital of Philadelphia department of genetics and pediatric endocrinology.
Two years later, he was in the care of Dr. Levine.
Dr. Levine: When we first saw him, we were impressed by his prior history of knock knees, which had its onset in his toddler years, and we looked carefully at the evaluation that his pediatric endocrinologist had performed some years prior that disclosed normal levels of serum calcium, normal levels of PTH, normal alkaline phosphatase, and a normal serum 25-hydroxy vitamin D, which in the mind of the first pediatric endocrinologist had effectively ruled out rickets or osteomalacia. And looking at these labs, one would agree that there’s no evidence biochemically for calcipenic or vitamin D deficiency rickets.
RAJ: But there was a test that wasn’t done, which would turn out to be the key to this boy’s diagnosis.
CHAPTER 2 – DIAGNOSIS
Dr. Levine: What was missing from the evaluation was a serum phosphorus level.
But it turns out that in metabolic bone disease, it’s a critically important test for us to evaluate. So when somebody evaluates a child for a metabolic bone disease, such as rickets or osteomalacia they need to know not only the serum calcium and the serum alkaline phosphatase, but they need to know the serum phosphorus level. So we always order that, and it turns out to be a separate order, which clearly makes it a little bit more complicated than checking a single box for a comprehensive metabolic profile. But it’s critically important in the evaluation of metabolic bone disease. In fact, we call it the holy trinity of metabolic bone disease: calcium, alkaline phosphatase and phosphate. Well, it’s what’s needed to make a proper diagnosis. And if you know the calcium, the phosphorus, and the alkaline phosphatase, you can diagnose 80 to 90% of metabolic bone conditions without then requiring additional laboratory testing.
RAJ: Dr. Levine and his team repeated the labs and added serum phosphorus.
CHAPTER 2: DIAGNOSIS
RAJ: An important discovery was made when the results came in.
Dr. Levine: The child had hypophosphatemia and at this point, the alkaline phosphatase was clearly elevated and within the overall context of his knock knee skeletal deformity, poor growth, and now biochemical evidence, we felt comfortable that in fact, the child did have hypophosphatemic rickets.
RAJ: Hypophosphatemic rickets is a disorder caused by low levels of phosphate – which is crucial for bone health – in the blood. It causes soft bones and a host of other related health issues.
Now that Dr. Levine had the diagnosis, he wanted to drill down into possible causes.
Were this boy’s rickets a result of environmental or genetic issues?
Dr. Levine: So with the diagnosis of hypophosphatemic rickets, we are aware that there are several different genetic as well as environmental causes. And so we did a careful analysis of his history, of his diet, and there was no evidence that he was ingesting foods or medications that reduce his ability to absorb phosphorus. But we still wanted to go the extra mile, and that is to determine the genetic basis for his hypophosphatemic rickets.
RAJ: Genetic testing was done.
Dr. Levine was taken aback by the results.
Dr. Levine: And we were surprised when we saw the results, which revealed that this child carried two pathogenic mutations in the gene including ENPP1. And as I said, 90% of kids with hypophosphatemic rickets will carry a mutation of the FEX gene on the X chromosome. But in this case, we had a completely different form of hypophosphatemic rickets, a condition called autosomal recessive hypophosphatemic rickets type two due to biallelic mutations in the ENPP1 gene. Now, one would ask, what difference does this make to our management of the child?
RAJ: In this case the treatment needed to be tailored to the genetic cause.
This child had a mutation in his ENPP1 gene.
Over 70 percent of cases with an ENPP1 mutation will develop into Generalized Arterial Calcification of Infancy GACI. GACI is a rare genetic disease that causes calcium to build up on the walls of arteries, restricting blood flow organs which can result in a stroke or heart attack.
We go into detail about GACI in another episode.
But even though this patient had no evidence of having developed GACI in infancy or otherwise, there was a risk that it might surface later in life. So his treatment had to take that into consideration.
Dr. Levine: So in this child, we treated with slightly reduced doses of calcitriol and phosphorus, less than we use as our initial therapy in children with X-linked hypophosphatemic rickets. And we were very careful to avoid giving too much phosphorus. And over time, we saw the alkaline phosphatase level return to normal, and we saw healing of rickets on the radiographs. So we knew that we were treating the rickets, we felt comfortable that we weren’t aggravating the underlying tendency to arterial calcification. So that went well.
CHAPTER 3: LESSONS
Dr. Levine: I think there are important lessons here because there are new therapeutics available and under development for these distinct causes of hypophosphatemic rickets.
I’ll remind everyone that the most common cause of rickets in a child is vitamin D deficiency and this is a problem that we thought by the middle of the 20th century, we had left to the history books. But it’s a problem that continues to cause significant clinical problems for growing kids.
RAJ: And as Dr Levine said, most cases of rickets can be easily diagnosed and treated with vitamin D.
Dr. Levine: But not every form of rickets is vitamin D deficiency rickets. And when you have a child that doesn’t respond as you might expect to calcium and vitamin D, you have to take that next step and begin to ask, Could this be due to a genetic defect in the vitamin D system, or could it be a genetic defect in phosphate metabolism?
And I think at age seven, if this child had that simple serum phosphorus level added to the battery of tests that were performed, the proper diagnosis of hypophosphatemic rickets would’ve been made and then additional therapeutics could have been considered.
So I think that understanding the genetics will provide the opportunity to practice precision medicine. Understanding the exact genetic pathophysiology enables us to identify the most appropriate therapy.
RAJ: Thanks to Dr. Levine for speaking with us.
This is DDx, a podcast by Figure 1.
Figure 1 is an app that lets doctors share clinical images and knowledge about difficult to diagnose cases.
I’m Dr. Raj Bhardwaj, host and story editor of DDx.
You can follow me on Twitter at Raj BhardwajMD.
Head over to figure one dot com slash ddx, where you can find full show notes, photos and speaker bios.
This episode of DDx was produced in partnership with The American Society for Bone and Mineral Research and sponsored by Inozyme Pharma.
For more information please visit Inozyme Pharma dot com.
Thanks for listening.