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Finding Modifier Genes in Turner Syndrome

Dr. Pinnaro

Turner syndrome (TS) is a karyotype disorder in which the sex chromosomes consist of an intact X chromosome and partial-to-complete loss of the other sex chromosome. TS includes a number of phenotypic features, including many that have variable expression. The degree of second sex chromosome loss explains the risk of some but not all TS features. Modifier genes are one possible explanation for TS features whose risk is not explained by karyotype. In this case, the modifier genes would be polymorphisms on autosomal chromosomes. This postulate served as the basis for a recent research study by Dr. Cat Pinnaro. Specifically, she sought to determine whether autosomal genes might influence the risk of cardiovascular malformations in TS. She focused on genes involved in pathways already known to impact cardiac development. The identified that specific variants in the CRELD1 gene were associated with risk of having a bicuspid aortic valve in TS. This study serves as proof-of-concept that modifier genes impact TS phenotype, and paves the way for future studies searching for additional modifier genes that might impact other aspects of phenotype in TS and other karyotype disorders. The work is published in the journal Human Genetics (pubmed link here).

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Dr. Tuttle Receives International Interest for His New Approach to Teach Physicians How to Manage Diabetes in Hospitalized Patients

The 11th International Meeting of Pediatric Endocrinology was held March 4-7 2023 in Buenos Aires, Argentina. This meeting allows pediatric endocrinology physicians from around the world opportunity to share their experiences, advances and best practices. This year the meeting was attended by over 1200 pediatric endocrinologists. Dr. Tuttle, a 3rd year pediatric endocrinology fellow in our division, presented his fellowship scholarly project at the meeting. He has created an interactive e-Book designed to more effectively teach pediatric resident physicians how to manage diabetes in hospitalized patients. Diabetes is difficult to manage, especially during illness and hospitalization. Mismanagement can lead to excessive hyperglycemia, elevated ketones, and/or hypoglycemia. Efficiently and effectively teaching learning physicians the complexities of management is challenging. Dr. Tuttle has met this challenge by creating new teaching approaches and materials and is currently working to optimize these new tools. An abstract of his poster presentation can be found here (link – note: this content may not be freely available at this external website).

Dr. Tuttle attends his poster at the 2023 International Meeting of Pediatric Endocrinology in Buenos Aires, Argentina .
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Diabetes in Turner Syndrome

Dr. Catherina Pinnaro
Dr. Eirene Alexandrou

Although it has long been known that persons with Turner syndrome have increased risk of developing diabetes, the reasons are not well understood. Relatedly, there are no known preventative strategies and no directed therapies. Dr. Pinnaro and Dr. Alexandrou from our Division have teamed up to review published knowledge in this area and map out critical gaps in understanding. Their review, entitled “Hyperglycemia in Turner syndrome: Impact, mechanisms, and areas for future research” has just been published in the peer reviewed literature. Also contributing to the manuscript were student Cameron Mitsch and division member Dr. Norris. The paper appears in the journal Frontiers in Endocrinology and can be found here (doi: link or pubmed link ). Dr. Pinnaro is leading a team working to find the root causes of diabetes linked to Turner syndrome. It remains important for persons with Turner syndrome to receive expert endocrine care, such as can be obtained from Dr. Alexandrou; see this link for contact information for her Turner syndrome clinic .

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Patient Choice Award Recipients

We are pleased to report that 6 of the pediatric endocrinology providers in our division have received Patient Choice Awards. These awards are given out by UI Health Care to recognize physicians for consistently providing patients with an excellent healthcare experience. The recipient physicians were:

  • Lauren Kanner
  • Katie Larson Ode
  • Julie Osterhaus
  • Liuska Pesce
  • Catherina Pinnaro
  • Mike Tansey

The Award was given to only 174 providers across the entire institution. The Award recognizes those who scored in the top 10% nationally in response to patient surveys asking whether the physician showed concern for patient questions or worries, gave explanations about problem or condition, made efforts to include the patient in care decisions, discussed proposed treatments (options, risks, benefits, etc), and whether they would be likely to recommend the care provider to others. Our division is fortunate to have these Award winning physicians on our team. We thank each of them for their wonderful work. Find more about the awards at this link.

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Turner Syndrome Clinic Opens

Dr. Eirene Alexandrou
Dr. Catherina Pinnaro

Teaming up, Dr. Alexandrou and Dr. Pinnaro from our division have worked hard to create the first dedicated clinic in the region for persons with Turner syndrome (TS). TS is a genetic condition that occurs when one of the X chromosomes is fully or partially lost from cells before birth. Symptoms of TS almost always include short stature and lack of pubertal progression. Both of these conditions can benefit from expert treatment from a pediatric endocrinologist. Additionally, TS symptoms often also include subtle structural body changes such a webbed neck, structural heart defects, autoimmune disorders, hearing loss, frequent ear infections, kidney defects, and selective learning difficulties. For this reason, it is crucial to have other pediatric sub-specialty services involved and/or available. The new clinic includes pediatric endocrinology, pediatric cardiology, clinical psychology, medical genetics, pediatric nephrology, reproductive endocrinology, dietician services, and a clinical pharmacist. In addition, Dr. Pinnaro is involved with clinical trials for which some patients may qualify. The current (2023) website for the clinic, including contact information, can be found here : https://uihc.org/childrens/services/turner-syndrome .

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New Data on Overcoming Genetic Forms of Growth Hormone Resistance

Dr. Eirene Alexandrou

Growth hormone is required for children to realize their full potential to grow taller. Those children who are unable to make normal amount of growth hormone do not grow well. Fortunately, daily growth hormone injections are an available therapy and robustly restore growth in these children. More rarely, some children can make growth hormone but can not respond to it properly due to various genetic reasons. One such reason is mutation of a gene termed PAPPA2. This gene produces a protein required for growth hormone to work. Specifically, the PAPPA2 protein liberates IGF-1 — the major growth hormone induced growth factor — to allow it to promote growth. Persons who lack a proper PAPPA2 gene thus do not grow well. An active question in the field regards whether giving IGF-1 supplements might overcome this issue and promote growth in children with this condition. Dr. Eirene Alexandrou from our Division was part of a team that studied this question and have now published their findings. Their results suggest that indeed IGF-1 can improve growth in children with genetic mutations in PAPPA2, but that the therapy may not completely normalize growth. Because IGF-1 therapy can have side effects, they suggest weighing pros and cons with each family when considering treatment. Their findings have been published in the journal Hormone Research in Paediatrics. The abstract has been indexed in Pubmed and can be found here.

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New Practice Guidelines for Care of Cystic Fibrosis-Related Diabetes

Dr. Larson Ode

The treatments available for persons with cystic fibrosis and for persons with diabetes have both been advancing rapidly over the past half-decade. It is no surprise therefore that care for persons with both conditions, termed cystic fibrosis-related diabetes (CFRD), is advancing as well. An updated set of treatment guidelines for CFRD have been issued by the International Society for Pediatric and Adolescent Diabetes. The guidelines have been indexed in Pubmed (pubmed link) and can be found here (doi: link). The lead author of the guidelines is Dr. Katie Larson Ode from our division. Her co-authors include CFRD experts from Minnesota, Colorado, Indiana, Philadelphia, Australia, Canada, Italy, and Germany. We are fortunate to have Dr. Larson Ode’s expertise and leadership in this field.

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New Clues in the Pursuit to Understand the Fatty Acid Imbalance of Cystic Fibrosis

Dr. Norris

Persons with cystic fibrosis typically have an imbalance in their fatty acid levels. A prominent aspect of this imbalance is a deficiency of linoleic acid, which is one of the so-called essential fatty acids. Despite decades of research, the mechanisms of the imbalance are not fully understood. To better understand this fatty acid imbalance, a group of researchers at the University of Iowa, Kansas State University, and the Karolinska Institutet in Stockholm Sweden worked together to study pigs and ferret with cystic fibrosis. The results showed that the imbalance exists at birth even before first feeding. This result argues strongly against one of the leading prior hypotheses which was that the imbalance might stem from the nutrient malabsorption that occurs in cystic fibrosis. Instead, the results suggest that several molecular mechanisms might be responsible for the imbalance, including excess metabolism of arachidonic acid, oxidative isomerization of unsaturated fatty acids, and/or biliary loss of phospholipids containing unsaturated fatty acids. The senior author of the resulting manuscript describing the findings was Dr. Norris from our Division. The work can be found published in the journal Clinical Science (link).

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Highly Effective Modulator Therapy for Cystic Fibrosis Impacts Body Mass Index and Insulin Sensitivity

  • Dr. Larson Ode
  • Dr. Norris

Cystic fibrosis is a genetic disease that causes dysfunction in multiple systems, but especially in the lungs which progressively deteriorate. The past few years have seen massive progress in the medical treatment of cystic fibrosis. Drugs have come to market that correct the basic molecular defects that cause cystic fibrosis. These drugs are classified as “highly effective modulator therapies”. These therapies must be tailored to each person, by matching to the different mutations that cause cystic fibrosis. In 2019, a blend of three modulators was approved for treatment of the most common form of cystic fibrosis involving the “F508del” mutation. This therapy combines elexacaftor, tezacaftor, and ivacaftor (“ETI”). This therapy dramatically improves lung dysfunction in persons with cystic fibrosis due to F508del mutation. Persons with cystic fibrosis are at very high risk to develop diabetes. For example, those who have only have F508del mutation have an over 80% chance of developing diabetes by middle age. It is currently not known if ETI-therapy for cystic fibrosis will impact diabetes risk. To address this knowledge gap, investigators from 5 institutions conducted a study of twenty persons with cystic fibrosis. Each person underwent an oral glucose tolerance test before and roughly 10 months after starting ETI-therapy. Interestingly, there was not a significant change in glucose levels after starting ETI. However, C-peptide levels increased with ETI therapy, consistent increased insulin secretion. Accordingly, an insulin resistance index significantly increased as did body mass index. Taken together, these results suggest that ETI therapy produces a degree of insulin resistance, likely related to an increase in body mass index. The longer term impact of ETI and related therapies on diabetes risk and body weight will need careful ongoing study. The faculty investigators involved in the study from our division were Dr. Larson Ode and Dr. Norris. The publication describing the study and results can be found at this Pubmed link.

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Double Jeopardy: Two Dangerous Medical Emergencies Associated with Type 1 Diabetes Can Occur Simultaneously

  • Dr. Parra Villasmil
  • Dr. Tansey

Medical emergencies associated with diabetes include diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), and severe hypoglycemia. DKA occurs when the body’s insulin levels are too low, allowing excessive ketone production to the point that acidosis occurs in the blood. HHS occurs when blood glucose levels rise to extremely high levels and the body becomes dehydrated causing body fluids to become concentrated to the point that brain function declines. Children with type 1 diabetes are often susceptible to the development of DKA. Although HHS can occur in children with type 1 diabetes, it is not common. Importantly, both conditions are reversible with proper medical treatment, even though both conditions can be fatal if treatment is not started promptly. Occasionally, a child with type 1 diabetes can develop both DKA and HHS simultaneously. This is a very dangerous predicament, requiring immediate and expert/judicious treatment. Dr. Parra Villasmil and Dr. Tansey from our Division, in conjunction with members of the Pediatric Intensive Care Unit team, have just published a report of such a case. In this publication, they describe the critical condition of the child on arrival to the hospital and the subsequent careful interventions that were made to resolve the two conditions. The report can be found in the journal Cureus (Pubmed link).