Overcoming the Odds of Prenatal Hypophosphatasia

Episode 3


In an examination room, an ultrasound technician moves a wand over a patient’s belly. The patient is 20 weeks pregnant. Usually, these appointments bring good news, but the news this day is devastating: the baby’s bones are broken and bowed. Despite this, the baby is born and does well. After testing, all signs point to hypophosphatasia for Dr. Eric Rush, a clinical geneticist at Children’s Mercy Hospital and the University of Kansas Medical Center, and an Associate Professor of Pediatrics at the University of Missouri-Kansas City, who shares this patient’s story. And thanks to the life-changing treatment of enzyme replacement therapy, today, this child and many others with this rare bone disease are living happy, healthy lives.

Eric T. Rush, MD, FAAP, CCD

Clinical Geneticist, Medical Director, Office of Faculty Affairs and Development, Children’s Mercy Hospital

Professor, Department of Pediatrics, University of Missouri – Kansas City School of Medicine, Kansas City, Missouri

Dr. Rush received Bachelor of Science degrees in Biochemistry and Biology with Concentration in Genetics at the University of Kansas in 2001. He received his medical degree at University of Kansas School of Medicine, Kansas City, KS in 2005. He completed a residency in Internal Medicine and Pediatrics at the University of Nebraska Medical Center in 2009 and Chief Residency in Pediatrics at the University of Nebraska Medical Center in 2010. He finished his training with a Clinical Genetics fellowship at the University of Nebraska Medical Center in 2012.

Among his clinical interests are osteogenesis Imperfecta, hypophosphatasia, X-linked hypophosphatemia, cancer genetics, cardiovascular genetics, dysmorphology, Personalized Medicine, and Genetics of Common Disease. His research interests include extraskeletal manifestations of osteogenesis Imperfecta, best practices in treatment of hypophosphatasia, skeletal pathology in peroxisomal biogenesis disorders, and molecular characterization of rare syndromes. Dr. Rush’s professional affiliations include the American Academy of Pediatrics, the American Society for Bone and Mineral Research, the International Society for Clinical Densitometry, and Alpha Omega Alpha. He is on the Scientific Advisory Board and is the current chair of the Rare Bone Diseases Alliance and is on the Scientific Advisory Board for Global Foundation for Peroxisomal Disease.



Overcoming the Odds of Prenatal Hypophosphatasia

Dr. Raj Bhardwaj: This episode of DDX was produced in partnership with the American Society for Bone and Mineral Research, and sponsored by Alexion, AstraZeneca Rare Disease.

In an exam room, a woman lies back as an ultrasound technician moves a wand over her belly. She’s 20-weeks pregnant. The room is quiet except for the rhythmic thump of the baby’s heartbeat on the monitor.

On the screen, details emerge — tiny fingers, toes, a beating heart.

Dr. Eric T. Rush: On this sort of imaging, 98 times out of a hundred, what parents get are very reassuring pieces of information that the baby’s looking fine, baby’s growing fine. And in most of those cases, you can anticipate a normal pregnancy and normal delivery. So it’s usually good news that people are getting when they have this ultrasound.

Dr. Bhardwaj: But the news this young mom was going to receive about her developing baby was devastating.

This is DDX, a podcast from Figure 1 about how doctors think. I’m Dr. Raj Bhardwaj. This season is all about the treatment of bone diseases.

Today, a case from Dr. Eric Rush, a Clinical Geneticist at Children’s Mercy Hospital and the University of Kansas Medical Center. He is also an Associate Professor of Pediatrics at the University of Missouri-Kansas City. Dr. Rush is a site principal investigator for clinical trials sponsored by Alexion AstraZeneca Rare Disease, which includes the treatment discussed in this episode. He also has consulted and received honoraria from AstraZeneca Rare Disease. He has received no compensation for his participation in this podcast and the views represented are his own.

Dr. Rush: During the mother’s pregnancy on the 20-week anatomy scan that all moms get, they noticed that there were a lot of broken bones. And what bones weren’t broken appeared to be bowed. And so, that really gets us worried when we see a baby that has bowed bones, broken bones, and maybe isn’t growing so well. And so this was, of course, a really scary time for the family, and this is potentially devastating for the family because in some cases, these babies don’t necessarily survive.

Dr. Bhardwaj: For this young family, that kind of uncertainty was terrifying and heartbreaking.

Dr. Rush: Over the course of the next few months, the baby continued to grow, still a lot of concern over bowing of the bones, but not really so much concern over the fractures that didn’t seem to be as many new fractures. But all the doctors were still very concerned about the potential for the baby not being able to breathe on her own when she was born.

Dr. Bhardwaj: The day this young mom went into labor, she and her partner stepped into the hospital, unsure if they’d be leaving with their newborn or facing a different reality.

Dr. Rush: But in this case, the baby was born, the baby was on just room air, did not need any help after delivery for oxygen, and actually did really well.

Dr. Bhardwaj: Everyone was shocked — and relieved.

But there was still a very big problem to be solved.

Dr. Rush: But what we still didn’t have for the baby was a diagnosis. The most common of the brittle bone conditions is one called osteogenesis imperfecta.

We hadn’t really made that diagnosis yet, and upon evaluating the patient, I didn’t really think that diagnosis fit particularly well. I thought it was likely to be a different brittle bone condition that this child had. And so I became much more concerned about a different brittle bone condition called hypophosphatasia.

Dr. Bhardwaj: One of the hallmark signs of hypophosphatasia or HPP is low levels of the enzyme alkaline phosphatase in the blood.

But more tests were needed for a firm diagnosis.

Dr. Rush: And so there are some other fluids within the blood and fluids within the urine that can be measured. And then we can also do genetic testing. And we can get a firmer diagnosis.

Dr. Bhardwaj: The results came back. All pointed to HPP.

The parents were informed that not only was their child expected to live, but with treatment, she may even thrive.

Dr. Rush: So we had a very emotional conversation with this family where we told them, this is not osteogenesis imperfecta, which they were concerned that it was likely to be either what we sometimes will call type two or perinatal lethal osteogenesis imperfecta, or at the very least a very severe form of it. And what we told them is we believe, with good evidence at this point, that your child actually has hypophosphatasia and a form of hypophosphatasia that we call benign prenatal hypophosphatasia.

Dr. Bhardwaj: While HPP is a disease that requires long-term treatment, this type of HPP isn’t fatal.

Dr. Rush: And so we got to give them two really good pieces of news. One is that we believe your baby’s going to live. And two is that we can treat them.

Dr. Bhardwaj: But HPP is unpredictable and requires a nuanced approach to treatment.

Dr. Rush: There are cases where we have patients that will present with very mild disease. We might see patients that aren’t having any fractures, don’t have very much pain, are functionally doing well, keeping up with their friends, not missing school. We know that this is a condition that they have, but those patients, we really wouldn’t have anything to follow. What are you exactly treating? And so unless there’s something really important that’s important to the patient, not necessarily just important to me, unless there’s something really specific to follow, I tend not to treat them. One case where we can see HPP sort of go away, and the term I use is for prenatal HPP is it kinda burns itself out and we’ll often see significant resolution.

Dr. Bhardwaj: The typical treatment for HPP is enzyme replacement therapy. And although it’s not new — it’s been around for nearly 30 years — it’s life changing for patients.

Dr. Rush: Enzyme replacement therapy has been an absolute game changer in the treatment of rare disease. The whole paradigm of enzyme replacement is something that’s been talked about for years, as soon as we really understood that some of these diseases were caused by changes to enzymes within the body. There’s been the hypothesis that one could replace the enzyme, but it took until the early 1990s before we were able to do that. And since that time, a number of conditions have enzyme replacement therapy. So it makes it an exciting time to be practicing genetics.

Dr. Bhardwaj: Meanwhile, Dr. Rush and the patient’s parents adopted a wait and see approach.

The baby was growing and developing normally.

Dr. Rush: One of the things we worry about in babies with HPP is failing to thrive. But this baby thrived. And she had good weight gain, good gain in length, good development overall.

Dr. Bhardwaj: But there was a problem.

Dr. Rush: By the time she was in her late infancy, mid to late infancy, around 7 months of age, we became concerned that she was not able to sit quite normally. We feared that she would not be able to stand quite normally because of her legs.

Dr. Bhardwaj: She had bowed legs and was diagnosed with rickets.

Dr. Rush and his team (along with her parents) decided it was time to put this little girl on enzyme replacement therapy.

Dr. Rush: We knew what we wanted to treat. We knew we wanted to heal her rickets, we knew we wanted her bones to be less soft, and we knew we wanted her to functionally do well, and to be able to walk, talk, run, jump, the things that other kids will be doing.

Dr. Bhardwaj: She started a regime of one injection three times a week. The results were astounding.

Dr. Rush: Yeah, we started to see improvements within probably about three months. She seems stronger. And then about six months is when we really started seeing the bones being straighter. And when we really saw the rickets start to heal. And then by a year we were really seeing continued improvement. And by about 18 to 24 months after starting treatment, rickets were essentially resolved. We really weren’t seeing them anymore. And her bones were quite straight at that point.

Dr. Bhardwaj: Our patient is now 6-years-old.

Dr. Rush: It’s always a cause for celebration and I will say nobody looking at her would know she had HPP today. She walks around, she runs around she plays with friends. She’s a normal little girl at this point. I’m just one that we still have to take some special precautions with, and we have to give special treatment to, but she’s really has been probably one of our biggest success stories.

Dr. Bhardwaj: Dr. Rush says that we can learn two main lessons from this girl’s case …

Dr. Rush: The first is that we really have to be very cautious about how we give a prenatal diagnosis, especially when we don’t have definitive information, so I think we should be a little more nuanced in our approach to prenatal diagnosis when we don’t have all the information. And I think we do that for our own sake, but I also think we do that for the benefit of the families. The second lesson I draw from this is to really follow your patients with HPP carefully.

And sometimes that means bringing them into the clinic more often than you would otherwise. Because this is an unpredictable disease. And we were lucky in this patient, that we caught her as we felt like she was starting to get a little more disease progression. And we started her on treatment before it got significantly worse.

I’m glad we did that. I’m glad we did bring her back frequently. And I’m glad we were able to see her grow during infancy. So we knew when the right time was and that everybody, including the family, felt good about our decision to proceed with treatment. One of the things that I was taught very early in my pediatrics residency was follow up’s your friend.

Dr. Bhardwaj: Follow-up appointments are also super important to prevent patient rebound.

Dr. Rush: We do see patients as they get into adolescence, start to push back a little bit against the medical regimen. When you have a patient that’s in clinic that you’re just a little worried about for whatever reason, sometimes you can’t even put your finger on it. Just bring them back in the clinic, check up on and make sure everything’s okay.

Dr. Bhardwaj: Thanks to Dr. Rush 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.

Head over to figure1.com/ddx where you can find full show notes, speaker bios and photos.

This episode of DDX was produced in partnership with the American Society for Bone and Mineral Research and sponsored by Alexion, AstraZeneca Rare Disease.

Thanks for listening!