Callum & Nora’s Story – United States

Callum & Nora’s Story as told by their mother Christine

In 2010, our son Callum was born unexpectedly at 25 weeks gestation, weighing only 1 pound 9 ounces. He had a difficult NICU stay with several complications including chronic lung disease, extremely low blood pressure, and infection. We almost lost him several times. He remained in the NICU for 118 days until finally we were able to bring him home.

At home Callum continued to struggle with the effects of prematurity. He required oxygen support due to chronic lung disease, and he struggled with feeding issues, eventually requiring the placement of a g-tube when he was 11 months old. Around this time, we also noticed that he would cry in pain when we would put on or take off his shirt. At a NICU follow-up appointment, the neonatologist recommended seeing an orthopedic surgeon. The orthopedic doctor made note that Callum definitely had reduced range of motion in both shoulders, with the right being worse than the left. At first, it was suggested that Callum had possibly suffered an injury during birth, and that his shoulders may improve with time.  We continued with twice weekly physical therapy at home for several months. When we saw no improvement, imaging was ordered to investigate further. Callum had x-rays, an MRI, and an ultrasound of his shoulders. The imaging revealed calcium deposits in both shoulder joints, but nobody knew what had caused it.

When Callum was 17 months old, the orthopedic surgeon performed surgery to removed as much of the calcification as possible from Callum’s right shoulder. This, combined with intensive physical therapy, restored functional range of motion to his right shoulder. When he was 26 months old, Callum had surgery on his left shoulder. We continued PT all along and we saw significant improvements.

During one of the follow-up MRIs to look at Callum’s shoulders, a radiologist noted “tortuousity of the vertebral arteries”, which was indicative of a connective tissue disease. This got Callum a referral to cardiology and genetics. We met with the cardiologist when Callum was 27 months old and they performed an echocardiogram which revealed a dilated aortic root (also known as an aneurysm). Blood samples were taken and genetic testing was performed. We had to wait several weeks for the results. In January 2013, we finally got the answer. Callum was diagnosed with Loeys-Dietz Syndrome (LDS).

LDS is a life-threatening genetic disorder that affects the connective tissue in the body. It can affect many different body systems including cardiovascular, musculoskeletal, skin, and gastrointestinal. We were heartbroken. We were told that in 75% of cases, the disease is caused by a spontaneous genetic mutation. In 25% of cases, the child has inherited it from a parent. My husband Michael and I were both tested. We were shocked when my husband’s results came back positive, and an echocardiogram revealed an aneurysm of operable size at his aortic root.
At this point, I was nearly 9 months pregnant with Callum’s younger sibling. Now that we knew Michael had Loeys-Dietz Syndrome, we knew that there was a 50% chance that the baby would also have it. I requested a fetal echocardiogram to look for signs of LDS in the baby. The radiologist found none. But I will never forget the somber look she gave me as she delivered the news that our unborn baby’s aorta appeared “echogenic”, or bright. They recommended that we go to the Advanced Fetal Care Center at Boston Children’s Hospital.

I returned home and started searching the internet for “echogenic arteries on fetal ultrasound”. The results were devastating. All of the results were for something called Generalized Arterial Calcification of Infancy… a rare disease with a high mortality rate. I was in shock. I immediately contacted Callum’s cardiologist and filled him in. He scheduled us for a fetal echo at the Advanced Fetal Care Center. It was there that our worst fears were confirmed. Less than 3 weeks after learning our 2 year old son had a life-threatening genetic disease that would affect him for the rest of his life, we were now facing an even scarier diagnosis for our new baby.

The plan was made to deliver our baby 2 days later at just over 38 weeks gestation. The NICU team was present for delivery as we did not know in what shape the baby would be at birth. Our daughter Nora was born pink and screaming, weighing in at 6 pounds 3 ounces. She had a full head of beautiful brown hair with blonde highlights. I got to hold her for a few minutes before she was whisked away to the NICU for evaluation.

Nora’s prenatal diagnosis was confirmed based on clinical presentation. An echocardiogram performed shortly after her birth showed significant calcification throughout all of her major arteries and many smaller vessels. The NICU team had actually treated one other baby with GACI just two years prior. Her story of survival was a bright light during one of our darkest hours. The medical team pored over research articles, and came up with a treatment plan for our sweet girl.

At this same time, Callum’s cardiologist and endocrinologist let us know that they suspected that Callum may also suffer from GACI. Blood samples were sent for testing, and within a couple of weeks we had our answers. Both Callum and Nora had identical mutations on their ENPP1 genes. They had each inherited a faulty copy of the gene from me and their father. We finally had the answer as to what had caused Callum’s periarticular calcification. He was fortunate in that he never appeared to have any arterial calcification.

When she was 7 days old, Nora received her first bisphosphonate infusion. We were fortunate that she didn’t seem to experience any side effects. We were able to take her home 2 days later. We went straight from the NICU across the street to Children’s Hospital’s cardiology clinic for her first outpatient appointment.

The plan was for Nora to receive weekly bisphosphonate infusions for the foreseeable future.  Every Wednesday, we would make the journey into Children’s Hospital.  I would hold Nora in my arms while the medication slowly made its way through the IV pump and into her little body.  When she was 5 weeks old, Nora had a central venous line placed to make her infusions less traumatic.

Initially, Nora had echocardiograms every week or so. They didn’t show any worsening of the calcification, so we stretched out the time between echos to allow for a greater opportunity to view the possible changes. When she was 4 months old, we finally got the news we had been waiting for. Nora’s echocardiogram revealed significant reduction of the calcification. For the first time in months, it felt like we could breathe again.

This happy news led the medical team to decide to decrease Nora’s infusions from 4 times a month to twice a month. She remained on this schedule until she was 11 months old, when she was able to transition to a twice daily oral bisphosphonate that we could administer at home.

In addition to the arterial calcification present on echocardiogram, Nora also suffered from painful gastrointestinal complications. At first it was suspected that she had a milk/soy protein intolerance. As Nora was exclusively breastfed and refused all bottles, I had no choice but to begin a total elimination diet in an attempt to ease her discomfort. It helped a little bit, but her tummy troubles persisted. Apparently, Nora was suffering from ischemia of the bowel which was causing her pain and distress. As she grew, so did her blood vessels, and her GI issues began to abate with time. By the time she was 18 months old, her GI issues were completely resolved.

Around this time, Callum – who was nearly 4 years old- was diagnosed with hearing loss. He had prior normal hearing tests as a toddler, so we were overwhelmed and distressed to learn that hearing loss was sometimes associated with GACI. Callum’s hearing loss initially presented as progressive, but has fortunately stabilized for the most part. He received his first pair of hearing aids shortly after his 4th birthday, and I will never forget the smile on his face when he realized that he could hear the birds in the trees again.

A few months later, when Callum was almost 4.5 years old and Nora was 22 months old, we made our first visit to the NIH to meet with the medical team there that was studying GACI. It was during this trip that we learned of the connection between GACI and ARHR2. Callum was diagnosed with rickets during our visit. Upon our return to Boston, his medical team was informed of the update, and they came up with a treatment plan for him. Nora also went on to develop ARHR2 around the same age as Callum. Today both kids are on the same medication schedule to manage their rickets- phosphorus every few hours around the clock and active vitamin D twice daily.

Today Callum and Nora are followed by several specialists regularly. They see an endocrinologist to manage their treatment for ARHR2. They see an orthopedic specialist to make sure their bones are growing properly. They see a cardiologist to regularly check for any cardiovascular issues. They have routine x-rays, echocardiograms, blood tests, EKGs, etc. Callum has aortic stenosis (narrowing of his aorta) as a complication of GACI that is monitored closely. They may have more doctor appointments than most kids, but they don’t let that hold them back.

Both kids love to play outside, ride bikes, and use their amazing imaginations. They dote on their baby sister Maren (who was born without being affected by LDS or GACI). I read a quote somewhere once that said, “Some people live their whole lives and never get to meet their hero. I gave birth to mine.” No quote has ever resonated so perfectly with me. We know that we are lucky. Not every family affected by GACI gets the chance to experience a happy ending and we are mindful of this every day.