Endocrinology, Metabolism & Diabetes Research and Innovations :: Nationwide Children's Hospital, Columbus, Ohio

Endocrinology, Metabolism and Diabetes Research

Clinician scientists within Endocrinology, Metabolism and Diabetes are commited to improving care for children. Clinical-based research studies are informing new treatment strategies involving new technologies. Information about some of the latest research done by our hospital can be found here. 

Delayed Treatment for Unusual Hypophosphatemic Rickets

Despite late initiation of proper therapy, one case of hypophosphatemic rickets-induced genu valgum improved from 24 degrees to 4.

Rickets is not uncommon in young children, especially breastfed infants. In most cases, treatment with concentrated vitamin D resolves early problems with bone growth and deformity. But when extended vitamin D therapy fails to improve skeletal symptoms of rickets, a patient’s soft, weak bones may be caused instead by a calcium or phosphate deficiency or an underlying genetic disorder.

  [read more...]

This is what occurred with a female infant who presented to her pediatrician at 1 year of age with bowed legs. Vitamin D therapy failed to correct her bone growth by the age of 5, at which point she was referred to the Metabolic Bone Clinic at Nationwide Children’s Hospital. Published in December in Case Reports in Pediatrics, the case required physicians in the clinic to correctly identify, treat and resolve hypophosphatemic rickets. The team, comprised of experts from genetics, endocrinology, nephrology and orthopedics, discovered that the patient’s illness was caused by mitochondrial complex I deficiency induced de Toni-Debré-Fanconi (or simply Fanconi) syndrome.

“If bowed legs persist beyond about 2 years of age, the child should be further evaluated radiographically,” explains Allan C. Beebe, MD, an orthopedic specialist at Nationwide Children’s. “It could be Blount’s Disease or an endocrine problem, and specialist referral is important.”

In this case, X-rays showed worsening of the patient’s knees from simple bowed legs at 2 years of age to knock knees at angles of 20 and 24 degrees by the age of 5. Lab tests ordered by the clinic team revealed that the patient had phosphate loss from her kidneys, elevated serum alkaline phosphatase and parathyroid hormone levels and inappropriately normal 1,25 OH vitamin D levels — all classic markers for hypophosphatemic rickets. The patient also had increased thirst and urination and was found to have metabolic acidosis, proteinuria and glycosuria on her urinalysis, which led the clinical team to consider Fanconi syndrome as the rare cause of her hypophosphatemic rickets. 

Additional testing confirmed their suspicion and more advanced lab tests, including a muscle biopsy, revealed that the syndrome was due to a mitochondrial disorder — deficiency of complex I and mild loss of complex III activity.

Although the patient’s condition had finally been accurately diagnosed, the metabolic bone team was unsure whether the severe degree of her skeletal deformity would respond to the appropriate medical therapy or if corrective orthopedic surgery would be necessary.

“She needed calcitriol, adequate dosage of phosphate and alkali therapy to heal her rickets and correct her limb deformity,” says Sasigarn A. Bowden, MD, clinical researcher and endocrinologist for the Section of Endocrinology, Metabolism and Diabetes at Nationwide Children’s.

Despite the delay in accurate diagnosis and initiation of treatment, the patient responded well to medical therapy, illustrating that advanced bone disease due to delayed diagnosis of Fanconi syndrome can still respond to medical treatment and may not need surgical correction. Bone deformity does not typically respond to therapy — particularly when initiated late — in other types of hypophosphatemic rickets, such as X-linked hypophosphatemic rickets.

Following proper treatment, the patient’s bone pain resolved completely. By the age of 10, her bone deformity was corrected with angulations of only 4 and 5 degrees, no fractures had occurred, serum phosphate levels were back to normal and a renal ultrasound showed no nephrocalcinosis or kidney stones. The patient remains under the care of endocrinologists, nephrologists and geneticists at Nationwide Children’s for her bone disease, mitochondrial disorder and Fanconi syndrome.

This case serves as a reminder for physicians that things may not always be what they seem, Dr. Bowden says. “Clinicians should be thorough when evaluating a toddler presenting with bowed legs, investigating a variety of potential causes,” suggests Dr. Bowden. “Proper initial diagnosis will lead to proper treatment and the best outcome.”

Related Citation:
Bowden SA, Patel HP, Beebe A, McBride KL. Successful Medical Therapy for Hypophosphatemic Rickets due to Mitochondrial Complex I Deficiency Induced de Toni-Debré-Fanconi Syndrome. Case Reports in Pediatrics. 2013 Dec 10. 354314.


Working to Prevent Sudden Death with Adenotonsillectomy and Polysomnography among Children with Prader Willi Syndrome

Children diagnosed with Prader Willi syndrome, a congenital disorder that can cause obesity and mental and behavioral delays, may benefit from early treatment with growth hormone. In an effort to prevent sudden deaths caused by breathing abnormalities during sleep—the risk of which is increased among patients with Prader Willi syndrome taking growth hormone—researchers at Nationwide Children’s Hospital examined whether sleep-disordered breathing could be corrected with a surgery called adenotonsillectomy.

  [read more...]

Led by David R. Repaske, MD, PhD, chief of the Section of Endocrinology, Metabolism and Diabetes and co-director of the Prader Willi Center, the interdisciplinary team analyzed pre- and post-surgery polysomnography (PSG) tests for 13 pediatric patients with Prader Willi syndrome. PSG detects sleep-disordered breathing, such as obstructive sleep apnea and obstructive hypoventilation.

Following adenotonsillectomy, eight children had complete resolution of their sleep-disordered breathing and three had partial resolution on the PSG. Only two children, both of whom began with severe obstructive sleep apnea, did not improve following the surgery and required further intervention.

“A surprising result of this study was the finding that curing obstructive sleep apneas by adenotonsillectomy sometimes unmasked a new problem: central apnea, which required additional therapy,” says Dr. Repaske.

Although growth hormone can be extremely beneficial in the treatment of Prader Willi syndrome, it can enlarge the tonsils and adenoids, causing obstructive sleep apnea or hypoventilation. Based on this study, regularly monitoring children with PSG and intervening with adenotonsillectomy when appropriate may help cure or ameliorate sleep-disordered breathing that could otherwise result in death.

Meyer SL, Splaingard M, Repaske DR, Wipf W, Atkin J, Jatana K. Outcomes of Adenotonsillectomy in Patients with Prader-Willi Syndrome. Archives of Otolaryngology-Head and Neck Surgery. 2012 Nov 1, 138(11):1047-51.  PMID:23165379.


Diabetes Awareness and Outcomes

November is American Diabetes Month, and the Endocrinology, Metabolism and Diabetes program at Nationwide Children’s Hospital is working to expand its educational and outreach initiatives. “Diabetes: Protect Our Future” is the theme of World Diabetes Day, Nov. 14, 2013, which will be promoted within the Nationwide Children’s community and beyond. Endocrinology faculty and staff have designed numerous outreach efforts to help improve public knowledge about childhood diabetes, as well as clinical efforts to improve patient education and capacity for self-management.

  [read more...]

Awareness initiatives include public displays ranging from general healthy eating posters and handouts to insulin calculation charts. A separate informational display will discuss self-management the 7 Self-Care Behaviors framework, which according to Diabetes Educator Wynola Wayne, RN, BSN, CDE, aims to empower families to be their own self-managers, using the experts at Nationwide Children’s as resource people when issues arise.

For children who are already diabetes patients at Nationwide Children’s, a number of other patient education and support programs exist, including the High Intensity Clinic. This pilot effort currently provides follow-up care to four pediatric patients, ages 11 to 17, previously admitted to the hospital for problems related to poorly-managed diabetes.

Clinic participants have monthly visits with an endocrinologist or nurse practitioner, social worker, psychologist, diabetes educator and dietitian. The visits last a total of 2.5 hours, and clinic staff meets after each clinic day to discuss patient progress and planning. In addition, families receive weekly or twice weekly phone calls to check in and discuss progress between visits. The staff also communicates regularly with teachers and school nurses to ensure coordinated care and the appropriate accommodations for patients.

The High Intensity Clinic has not only reduced hospital admissions for participants, but it also has improved school attendance records. Bethany King, MSW, a social worker at Nationwide Children’s and member of the clinic team, attributes this success to the continuity of care, personalized attention, and goal-oriented emphasis of the clinic. “We see the families much more frequently, so we catch problems early and can be more proactive than reactive,” says King. “We break things down into small goals directed by patients and their families, and we’re able to take a much more supportive approach with this clinic than with regular quarterly clinic visits.”

Although the clinic is new at Nationwide Children’s Hospital, its staff anticipates most participants will phase out after about a year of care, gradually returning to standard management. The department expects to expand the number of patients that can be seen by the pilot clinic to 20 in 2014 with the addition of new staff.

“Now that we have things underway, we want to know about our impact on patients that can’t be measured by an A1C,” says King, who believes that the variety of support services participants receive at each visit helps connect families to the resources they need to get—and stay—in control of diabetes. “These children have a lot going on in their lives, and we want to make sure we are addressing their needs.”

The High Intensity Clinic offers a level of clinical expertise that is complemented by the advanced research taking place at Nationwide Children’s. Current projects to improve diabetes-related outcomes include a randomized controlled trial assessing the benefits of vitamin D supplementation during the “honeymoon period” following newly diagnosed type 1 diabetes; a project to study the effect of vitamins C and E on endothelial function in adolescent diabetes; a study of diabetes prevention via oral insulin dosing; and an investigation of Alpha-1 Antitrypsin in new-onset type 1 diabetes.


Genetic Variant May Protect Against Some Diabetic Complications, Study Finds

A variant within a gene family involved in the expression of type 1 diabetes may offer some protection against conditions caused by the disease, such as diabetic retinopathy, a new study suggests. The findings, which appear in the May issue of the journal Human Immunology, raise some interesting questions about whether these variants—called alleles—could be exploited to block some of the more devastating long-term complications of type 1 diabetes, which usually develops during childhood or adolescence.

  [read more...]

“If we could find the mechanism for that protection, we might be able to block the specific effects of these alleles on the susceptible tissue before it takes effect,” says neurogeneticist David Greenberg, PhD, senior author of the new study, which was coauthored by William Stewart, PhD. Both are principal investigators in the Battelle Center for Mathematical Medicine in The Research Institute at Nationwide Children’s Hospital.

Scientists have long wondered why complications involving the body’s microvascular system, such as retinopathy, affect some people with type 1 diabetes, but not others. One explanation is an underlying genetic susceptibility to microvascular problems, a possibility Greenberg and his colleagues wanted to explore.

The team began by looking at the Human Leukocyte Antigen (HLA) gene family, an extremely diverse set of genes that helps the immune system recognize proteins made by disease-causing invaders such as viruses and bacteria. HLA genes have hundreds of variations, called alleles, some of which cause type 1 diabetes and other autoimmune diseases. The question is: Do they also affect the microvascular system? In many diabetics, this network of capillaries and tiny blood vessels becomes faulty, leading to such problems as kidney disease, nerve damage and retinopathy—the number one cause of adult blindness in the U.S.

“HLA is the single most important genetic influence on the expression of type 1 diabetes, so it made sense to ask if it was also a factor in complications,” says Greenberg, who also is a professor of pediatrics in The Ohio State University College of Medicine.

Drawing on the Human Biological Data Interchange, a national repository of DNA and cell lines collected from families with type 1 diabetes, Greenberg and his colleagues identified 425 individuals from families in which at least one person was diagnosed before the age of 30 and required insulin treatment. They then divided participants into two groups, those who had experienced at least one microvascular problem and those who had no complications, even after living with diabetes for most of their lives.

The researchers analyzed the tissues, looking for the presence of two HLA alleles in particular—DRB1*03:01 and DRB1*04:01. These alleles have been linked to an increased risk for type 1 diabetes and may also convey susceptibility to a breakdown in the microvascular system. While they found tentative evidence of a link between the expression of DRB1*04:01 and the occurrence of those complications, they found something more surprising. DRB1*03:01actually appeared to offer protection against complications.

“Our data suggest that even when *03:01 and *04:01 occur in the same person, there is a reduced risk for complications. But when *04:01 occurs with any other allele, it may promote the development of complications.” Greenberg says. “Frankly, I was expecting to find that there was no influence of HLA on complications and, if there was, that it would be a different allele. I did not expect to see a protective effect.”

It’s unclear what is causing this protective effect, Greenberg says, but that’s the subject of a study currently under way. Another question he’d like to answer is whether the DRB1*03:01 allele would offer the same protection in people with type II diabetes.

“The DRB1*03:01 in our data set was protective for all complications, but most of the people who had complications in our data set had retinopathy,” Greenberg says. “Knowing that DRB1*03:01is protective, especially for retinopathy, opens up the real possibility of developing a preventive base on how it does what it does. Now we need to find out what that is.”

Full citation:
Lipner EM, Tomer Y, Noble JA, Monti MC, Lonsdale JT, Corso B, Stewart WCL, Greenberg DA. HLA class I and II alleles are associated with microvascular complications of type 1 diabetes. Human Immunology. 2013 May; 74(5): 538-44. doi: 10.1016/j.humimm.2013.01.013.


Vitamin C May Help Prevent Long-Term Complications of Type 1 Diabetes

Diabetic Adolescents Who Received Vitamin C During Infusion Didn’t Experience Endothelial Impairment Caused by Hyperglycemia 

Vitamin C infusions may help prevent and restore endothelial impairment caused by hyperglycemia, according to a study from Nationwide Children’s Hospital.  These findings appear in Pediatric Diabetes.

  [read more...]

Adults and adolescents with type 1 diabetes have impaired endothelial function.  “Specifically, hyperglycemia increases oxygen radicals which decrease the nitric oxide stress response,” says Robert P. Hoffman, MD, member of the Section of Endocrinology and Metabolism at Nationwide Children’s Hospital.

Adenotonsillectomy May Not Resolve Sleep Disordered Breathing in Children with Prader-Willi Syndrome

Not all children with Prader-Willi syndrome receive relief from sleep disorders after undergoing an adenotonsillectomy, suggests a study from Nationwide Children’s Hospital.

Patients with Prader-Willi syndrome are at risk for sleep disordered breathing as a result of their hypotonia, obesity, and/or growth hormone therapy which can cause the tonsils and adenoids to enlarge. 

  [read more...]

At Nationwide Children’s Hospital, Prader-Willi patients undergo an annual sleep study and are evaluated for potential adenotonsillectomy if obstructive apnea events are present.  However, there is limited and conflicting data regarding the benefit of adenotonsillectomy in children with Prader-Willi syndrome.

To evaluate the efficacy of adenotonsillectomy in the treatment of sleep apnea in Prader-Willi syndrome, investigators at Nationwide Children’s performed a retrospective chart review.   Thirteen patients met the study criteria and were categorized based on severe, moderate or mild apnea/hypopnea indexes and obstructive hypoxia.

Findings showed that the 11 patients with mild-to-moderate obstructive sleep apnea or obstructive hypoventilation improved or normalized after receiving adenotonsillectomy.  But of the four children with severe obstructive sleep apnea, two normalized after surgery and two continued to have severe apneas.  Unexpectedly, these patients initially had obstructive sleep apnea and after surgery a central sleep apnea was also unmasked. 

These findings suggest that adenotonsillectomy is effective in most children with Prader-Willi syndrome who demonstrate mild to moderate obstructive sleep apnea, but may not be curative in children with severe forms of the condition.

Investigators stress that patients should receive a repeat sleep study six-to-eight weeks postoperatively to detect central apneas that can occur in some Prader-Willi children after upper airway surgical intervention. 

These findings were presented at the Pediatric Academic Societies (PAS) annual meeting April 28 – May 1, 2012.


Health Literacy and Willingness to Use Online Health Information by Teens with Asthma and Diabetes

This study measured health literacy in a population of teens in treatment for asthma or diabetes.  Finding showed that teens with lower health literacy searched online for health information as often as peers with higher literacy, but were less likely to express the intent to use recommended sites. Belief in the usefulness of a Web site is the strongest attitudinal predictor of intended future use.

  [read more...]

Access an abstract of this study: Health Literacy and Willingness to Use Online Health Information by Teens with Asthma and Diabetes. Telemed J E Health. 2011 Sep 23. [Epub ahead of print]


Early Introduction of Growth Hormone Therapy in Prader Willi Syndrome Yields Positive Results

Recent research from Nationwide Children’s Hospital is showing that early introduction of growth hormone (GH) therapy as early as 3-4 months of age in the Prader-Willi Syndrome (PWS) population is beneficial.  Not only has it resulted in improving body composition and motor skills, but is also showing subsequent improvement in cognition and language development. It is hypothesized that infants with earlier motor development (such as sitting upright) develop improved cognitive and communicative skills due to increased stimulatory interaction with surroundings.

  [read more...]

Both gross motor and language developmental delay are prevalent in children with PWS. Historically, early milestones in children with PWS are achieved on average of double the normal age (e.g., sitting at 12 months, walking at 24 months, and first words at 2 years) 1. Since growth hormone therapy has consistently demonstrated increased muscle tone, muscle strength, and improved body composition in patients with PWS, it can be surmised that these physical changes may precede improvements in cognitive developmental progress.  Although growth hormone therapy is approved for the treatment of PWS, there are no clear guidelines at what age to initiate GH therapy in these children.

The multi-disciplinary PWS clinic at Nationwide Children’s developed a protocol for early initiation of growth hormone therapy in children with PWS.  Four of the five subjects in the early intervention group had formal developmental assessment screening using the Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-3). These formal developmental assessments indicate that early initiation of GH therapy may contribute to much earlier cognitive and language development than what has been historically demonstrated in patients with PWS.
Findings showed that:

  • Patients in the early GH initiation group demonstrated significantly earlier attainment of developmental milestones when compared to the other groups
  • Patients who were started on GH therapy prior to 6 months of age had an earlier age of sitting up, talking  and g-tube removal (indicating improved oral muscle strength, coordination, and improved weight gain).
  • Bayley developmental scores were nearly normal in cognitive, communication, and fine motor categories. This is in contrast to the mild-moderate global developmental delay generally seen in the Prader-Willi population.

The protocol for early initiation of GH therapy has demonstrated that growth hormone can be safe and effective when initiated in early infancy. In addition, our clinic ensures these patients are receiving aggressive developmental therapies (speech, PT/OT) which presumably has contributed to such superb developmental outcomes.


Nationwide Children's Hospital
700 Children's Drive Columbus, Ohio 43205 614.722.2000