Sara Pinney, MD, MS, is the Director of the Monogenic and Atypical Diabetes Program and an attending physician in the Division of Endocrinology and Diabetes at Children's Hospital of Philadelphia. In this Q&A, Dr. Pinney discusses the groundbreaking gene-specific treatment of monogenic diabetes administered within CHOP’s Monogenic and Atypical Diabetes Program.
What is monogenic diabetes, and how does it differ in cause, presentation and management from more common forms such as type 1 and type 2 diabetes?
Among children diagnosed with diabetes, approximately 85% to 90% have type 1 diabetes, an autoimmune condition characterized by destruction of pancreatic beta cells and resulting in lifelong dependence on insulin delivered via injections or pump therapy. Around 5% to 10% of children under 18 are diagnosed with type 2 diabetes, a complex disorder associated with insulin resistance and beta cell dysfunction. Treatment for these types of diabetes may include oral medications, insulin therapy, GLP-1 or GIP receptor agonists, and changes in diet and activity level, or other lifestyle modifications.
Monogenic diabetes — sometimes referred to as maturity-onset diabetes of the young (MODY) — encompasses a group of rare forms of diabetes caused by a pathogenic variant in one of more than 40 genes involved in glucose regulation.
Monogenic diabetes, which accounts for an estimated 1% to 5% of childhood diabetes cases, is identifiable only through genetic testing. Management is highly individualized and depends on the specific gene affected, with some forms more responsive to therapies other than insulin.
What early signs or clinical characteristics of monogenic diabetes in children should prompt providers to consider genetic testing?
Children with developing diabetes may present with increased thirst, increased urinary frequency and unexplained weight loss. These are symptoms of hyperglycemia and appear the same no matter the type of diabetes.
Children with monogenic diabetes often lack the typical clinical features associated with type 1 or type 2 diabetes. Type 1 diabetes is diagnosed through the presence of islet autoantibodies in antibody testing. Children with type 2 diabetes are generally diagnosed after puberty and have a BMI above the 85th percentile.
In the case of monogenic diabetes, genetic testing should be considered when a child presents with
- A negative diabetes autoimmune panel.
- A BMI below the 85th percentile for age.
- A strong multigenerational family history of early-onset diabetes affecting three or more successive generations.
These features increase the likelihood of a monogenic diabetes diagnosis.
What steps does CHOP recommend for screening and accurately diagnosing monogenic diabetes?
The CHOP Monogenic and Atypical Diabetes Program has developed a clinical algorithm to support early identification of children who may have atypical or monogenic diabetes. This tool assists diabetes providers in determining when to refer patients to the Monogenic and Atypical Diabetes Program for specialized evaluation, which often includes comprehensive genetic testing.
How does early identification and intervention influence long-term health outcomes for children?
Identifying the specific genetic cause of monogenic diabetes enables the development of a personalized treatment plan targeted to the underlying defect in glucose regulation. There is evidence — though limited — suggesting that initiating treatment targeted to the specific mutation at an early age may help preserve residual beta cell function for some forms of monogenic diabetes.
Improved glycemic control is critical for reducing the long-term risk of diabetes-related complications, including cardiovascular disease, nephropathy, neuropathy and retinopathy. Additionally, certain forms of monogenic diabetes are associated with comorbidities involving the kidneys, liver, heart or pancreas. Knowing the affected gene allows for proactive screening for these associated conditions with the goal of improving overall health outcomes through earlier detection and intervention.
How does CHOP’s Monogenic and Atypical Diabetes Program deliver multidisciplinary, family-centered care, and what are the benefits of this approach?
Children seen in the CHOP Monogenic and Atypical Diabetes Program receive care from a comprehensive multidisciplinary team. In addition to the attending physician, families meet with a Certified Diabetes Educator (CDE), a clinical dietitian and a nurse specialist dedicated to monogenic diabetes. Patients also have access to psychological services and social work support.
Because some monogenic diabetes forms involve additional organ systems, the program collaborates closely with CHOP specialists in nephrology and gastroenterology who have expertise in related conditions such as kidney disease, liver disease and exocrine pancreatic insufficiency. This integrated, family-centric approach ensures coordinated, holistic care for our patients and their families.
What gene-specific treatment options are available through CHOP, and how do these therapies improve quality of life for children and families?
Once a pathogenic variant causing monogenic diabetes is identified, it is determined whether targeted therapies may improve glycemic outcomes or reduce treatment burden. While many children with monogenic diabetes continue insulin therapy because it remains the most effective treatment, certain monogenic forms respond well to alternative treatments such as sulfonylureas or GLP-1 receptor agonists. For some patients with specific genetic mutations, tailored therapies can improve glucose regulation and, in some cases, decrease reliance on insulin, reducing the daily burden of diabetes management for children and families.
For children with a known genetic variant who have not yet developed diabetes, what monitoring or risk-reduction strategies are recommended?
For children carrying a genetic variant associated with monogenic diabetes but who have not yet developed hyperglycemia, monitoring typically includes periodic measurement of hemoglobin A1c every 3 to 6 months and intermittent home glucose testing of fasting and postprandial values. The optimal frequency of measurement depends on the specific gene involved. If symptoms suggestive of hyperglycemia — such as polyuria, polydipsia, unintended weight loss or poor weight gain — emerge, immediate screening with fasting glucose and HbA1c is recommended.
What changes in glycemic control, treatment burden and quality of life have been observed among children who transition from insulin to tailored therapies following a monogenic diabetes diagnosis?
Following a confirmed diagnosis of monogenic diabetes, the goal is to optimize glycemic control using therapies that specifically address the molecular mechanism impacted by the genetic variant. For some children, this involves continuing on basal-bolus insulin therapy and adding adjunctive agents such as GLP-1 receptor agonists to enhance insulin sensitivity or stimulate glucose-dependent insulin secretion.
In forms known to respond to sulfonylureas, monogenic diabetes patients may be able to discontinue insulin entirely and transition to oral therapy under close medical supervision. For these individuals, the shift to targeted therapy typically results in improved glycemia and a meaningful reduction in treatment burden, contributing to a better overall quality of life.
How can referring providers collaborate with CHOP to ensure timely evaluation and precision care for children with suspected monogenic diabetes?
Referring providers can request a consultation with the Monogenic and Atypical Diabetes Program by contacting CHOP’s Division of Endocrinology at 215-590-3174. To support a timely and accurate evaluation, providers are encouraged to send diagnostic laboratory data, including results from autoimmune antibody testing, any previously completed genetic testing, recent hemoglobin A1c values and details of the child’s current diabetes management regimen.
What current or upcoming research at CHOP is advancing the understanding of monogenic diabetes and expanding treatment possibilities for patients worldwide?
The Monogenic and Atypical Diabetes Program maintains a patient registry, enabling detailed characterization of individuals diagnosed with monogenic diabetes and the evaluation of gene-specific clinical features and treatment responses. The team is also actively investigating patients with strong clinical indicators of monogenic diabetes who have negative genetic testing results, with the goal of discovering new disease-causing genes.
A broader aim of this work is to translate insights from monogenic diabetes into novel therapeutic approaches that may benefit individuals with type 1 or type 2 diabetes. The program anticipates participating in future clinical trials targeting specific genetic defects.
In parallel, CHOP Research Institute investigators Paul Gadue, PhD and Karla Leavens, MD, PhD, are using human stem cell-derived beta cells to study how monogenic variants alter beta cell function. Their research seeks to identify targeted therapies that improve insulin production and may ultimately transform treatment for specific forms of monogenic diabetes.
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Sara Pinney, MD, MS, is the Director of the Monogenic and Atypical Diabetes Program and an attending physician in the Division of Endocrinology and Diabetes at Children's Hospital of Philadelphia. In this Q&A, Dr. Pinney discusses the groundbreaking gene-specific treatment of monogenic diabetes administered within CHOP’s Monogenic and Atypical Diabetes Program.
What is monogenic diabetes, and how does it differ in cause, presentation and management from more common forms such as type 1 and type 2 diabetes?
Among children diagnosed with diabetes, approximately 85% to 90% have type 1 diabetes, an autoimmune condition characterized by destruction of pancreatic beta cells and resulting in lifelong dependence on insulin delivered via injections or pump therapy. Around 5% to 10% of children under 18 are diagnosed with type 2 diabetes, a complex disorder associated with insulin resistance and beta cell dysfunction. Treatment for these types of diabetes may include oral medications, insulin therapy, GLP-1 or GIP receptor agonists, and changes in diet and activity level, or other lifestyle modifications.
Monogenic diabetes — sometimes referred to as maturity-onset diabetes of the young (MODY) — encompasses a group of rare forms of diabetes caused by a pathogenic variant in one of more than 40 genes involved in glucose regulation.
Monogenic diabetes, which accounts for an estimated 1% to 5% of childhood diabetes cases, is identifiable only through genetic testing. Management is highly individualized and depends on the specific gene affected, with some forms more responsive to therapies other than insulin.
What early signs or clinical characteristics of monogenic diabetes in children should prompt providers to consider genetic testing?
Children with developing diabetes may present with increased thirst, increased urinary frequency and unexplained weight loss. These are symptoms of hyperglycemia and appear the same no matter the type of diabetes.
Children with monogenic diabetes often lack the typical clinical features associated with type 1 or type 2 diabetes. Type 1 diabetes is diagnosed through the presence of islet autoantibodies in antibody testing. Children with type 2 diabetes are generally diagnosed after puberty and have a BMI above the 85th percentile.
In the case of monogenic diabetes, genetic testing should be considered when a child presents with
- A negative diabetes autoimmune panel.
- A BMI below the 85th percentile for age.
- A strong multigenerational family history of early-onset diabetes affecting three or more successive generations.
These features increase the likelihood of a monogenic diabetes diagnosis.
What steps does CHOP recommend for screening and accurately diagnosing monogenic diabetes?
The CHOP Monogenic and Atypical Diabetes Program has developed a clinical algorithm to support early identification of children who may have atypical or monogenic diabetes. This tool assists diabetes providers in determining when to refer patients to the Monogenic and Atypical Diabetes Program for specialized evaluation, which often includes comprehensive genetic testing.
How does early identification and intervention influence long-term health outcomes for children?
Identifying the specific genetic cause of monogenic diabetes enables the development of a personalized treatment plan targeted to the underlying defect in glucose regulation. There is evidence — though limited — suggesting that initiating treatment targeted to the specific mutation at an early age may help preserve residual beta cell function for some forms of monogenic diabetes.
Improved glycemic control is critical for reducing the long-term risk of diabetes-related complications, including cardiovascular disease, nephropathy, neuropathy and retinopathy. Additionally, certain forms of monogenic diabetes are associated with comorbidities involving the kidneys, liver, heart or pancreas. Knowing the affected gene allows for proactive screening for these associated conditions with the goal of improving overall health outcomes through earlier detection and intervention.
How does CHOP’s Monogenic and Atypical Diabetes Program deliver multidisciplinary, family-centered care, and what are the benefits of this approach?
Children seen in the CHOP Monogenic and Atypical Diabetes Program receive care from a comprehensive multidisciplinary team. In addition to the attending physician, families meet with a Certified Diabetes Educator (CDE), a clinical dietitian and a nurse specialist dedicated to monogenic diabetes. Patients also have access to psychological services and social work support.
Because some monogenic diabetes forms involve additional organ systems, the program collaborates closely with CHOP specialists in nephrology and gastroenterology who have expertise in related conditions such as kidney disease, liver disease and exocrine pancreatic insufficiency. This integrated, family-centric approach ensures coordinated, holistic care for our patients and their families.
What gene-specific treatment options are available through CHOP, and how do these therapies improve quality of life for children and families?
Once a pathogenic variant causing monogenic diabetes is identified, it is determined whether targeted therapies may improve glycemic outcomes or reduce treatment burden. While many children with monogenic diabetes continue insulin therapy because it remains the most effective treatment, certain monogenic forms respond well to alternative treatments such as sulfonylureas or GLP-1 receptor agonists. For some patients with specific genetic mutations, tailored therapies can improve glucose regulation and, in some cases, decrease reliance on insulin, reducing the daily burden of diabetes management for children and families.
For children with a known genetic variant who have not yet developed diabetes, what monitoring or risk-reduction strategies are recommended?
For children carrying a genetic variant associated with monogenic diabetes but who have not yet developed hyperglycemia, monitoring typically includes periodic measurement of hemoglobin A1c every 3 to 6 months and intermittent home glucose testing of fasting and postprandial values. The optimal frequency of measurement depends on the specific gene involved. If symptoms suggestive of hyperglycemia — such as polyuria, polydipsia, unintended weight loss or poor weight gain — emerge, immediate screening with fasting glucose and HbA1c is recommended.
What changes in glycemic control, treatment burden and quality of life have been observed among children who transition from insulin to tailored therapies following a monogenic diabetes diagnosis?
Following a confirmed diagnosis of monogenic diabetes, the goal is to optimize glycemic control using therapies that specifically address the molecular mechanism impacted by the genetic variant. For some children, this involves continuing on basal-bolus insulin therapy and adding adjunctive agents such as GLP-1 receptor agonists to enhance insulin sensitivity or stimulate glucose-dependent insulin secretion.
In forms known to respond to sulfonylureas, monogenic diabetes patients may be able to discontinue insulin entirely and transition to oral therapy under close medical supervision. For these individuals, the shift to targeted therapy typically results in improved glycemia and a meaningful reduction in treatment burden, contributing to a better overall quality of life.
How can referring providers collaborate with CHOP to ensure timely evaluation and precision care for children with suspected monogenic diabetes?
Referring providers can request a consultation with the Monogenic and Atypical Diabetes Program by contacting CHOP’s Division of Endocrinology at 215-590-3174. To support a timely and accurate evaluation, providers are encouraged to send diagnostic laboratory data, including results from autoimmune antibody testing, any previously completed genetic testing, recent hemoglobin A1c values and details of the child’s current diabetes management regimen.
What current or upcoming research at CHOP is advancing the understanding of monogenic diabetes and expanding treatment possibilities for patients worldwide?
The Monogenic and Atypical Diabetes Program maintains a patient registry, enabling detailed characterization of individuals diagnosed with monogenic diabetes and the evaluation of gene-specific clinical features and treatment responses. The team is also actively investigating patients with strong clinical indicators of monogenic diabetes who have negative genetic testing results, with the goal of discovering new disease-causing genes.
A broader aim of this work is to translate insights from monogenic diabetes into novel therapeutic approaches that may benefit individuals with type 1 or type 2 diabetes. The program anticipates participating in future clinical trials targeting specific genetic defects.
In parallel, CHOP Research Institute investigators Paul Gadue, PhD and Karla Leavens, MD, PhD, are using human stem cell-derived beta cells to study how monogenic variants alter beta cell function. Their research seeks to identify targeted therapies that improve insulin production and may ultimately transform treatment for specific forms of monogenic diabetes.
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