An unusual cause of hyperglycemiaR Lal1, LA Loomba-Albrecht1, AA Bremer2
1 Department of Pediatrics, University of California Davis School of Medicine, Sacramento, California
2 Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.90092
Source of Support: None, Conflict of Interest: None
A 6-year old African American girl presented to an urgent care clinic with a 3-day history of throat pain and dysuria. She denied fever, difficulty swallowing, excessive thirst, frequent urination, weight changes or fatigue.
Birth history revealed that the patient's mother had diet-controlled gestational diabetes; the pregnancy and delivery were otherwise unremarkable. The patient had no other medical issues, and was growing consistently at the 99 th percentile. She was not taking any medications. Additional family history did not reveal other family members with hyperglycemia or diabetes, though the patient's father was not involved in her care and his medical history is unknown.
Physical examination revealed a well-developed girl with a height of 132.4 cm (99 th percentile), weight 24.1 kg (80 th percentile) and BMI of 13.75 kg/m 2 (10 th percentile). Physical examination was notable for normal vital signs, no acanthosis nigricans, and pre-pubertal development; however, she did have bilateral tonsillar erythema and exudate.
Given the complaint of sore throat and the physical exam findings, a throat culture was obtained; the results suggested streptococcal pharyngitis. A urinalysis did not suggest a urinary tract infection; however, it was positive for glucosuria without ketonuria. Follow-up laboratory testing revealed a random capillary blood glucose level of 180 mg/dl (10 mmol/l) and a hemoglobin A1c (HbA1c), measured using a method certified by the National Glycohemoglobin Standardization Program (NGSP), of 5.4%.
The patient was prescribed antibiotic treatment for streptococcal pharyngitis and home blood glucose monitoring with a glucometer was recommended. Capillary blood glucose monitoring was performed over the next two months; morning fasting glucose concentrations ranged from 118 to 191 mg/dl (6.6 to 10.6 mmol/l) and pre-meal levels from 116 to 193 mg/dl (6.4 to 10.7 mmol/l).
What is the possible diagnosis?
Reply: Childhood diabetes is usually type 1 in nature, caused by the autoimmune destruction of pancreatic beta-cells. Without the exogenous administration of insulin, typically administered by subcutaneous injections, children are considered prone to ketoacidosis and death. However, other forms of diabetes do affect pediatric patients and need to be considered in the differential diagnosis of hyperglycemia. For instance, type 2 diabetes, a syndrome of relative insulin insufficiency in a state of insulin resistance, has increased dramatically in the pediatric population over the past two decades, paralleling the increase in childhood obesity. However, other rare types of diabetes also exist, including monogenic forms and need to be considered in the differential diagnosis.
The importance of considering the differential diagnosis of hyperglycemia in individuals diagnosed with diabetes is paramount since the management of the disorder is contingent upon understanding the condition's etiology. Moreover, since insulin has to be administered via a parenteral route (usually via subcutaneous injections), insulin therapy for diabetes typically imposes a tremendous psychosocial burden on the patient and family, especially when the patient is a child.
Clinical course and final diagnosis
Based on the initial data and clinical symptoms of hyperglycemia, the patient was diagnosed with "early type 1 diabetes mellitus," and long-acting insulin (4 units of ultralente daily) was prescribed. She was then followed regularly in the pediatric endocrinology clinic. Interestingly, five years after her initial presentation, the patient (who now weighed 49.2 kg (76 th percentile)) remained euglycemic on only 4 units of glargine daily. Additionally, she had not required fast-acting insulin to cover carbohydrate-containing foods or to correct for hyperglycemia since the time of her diagnosis. Furthermore, her HbA1c had remained 5.2% over a three year period.
Given her clinical course, the diagnosis of autoimmune type 1 diabetes was questioned and anti-beta cell antibody levels were measured. When the results of the antibody testing returned negative, the patient underwent genetic testing for monogenic forms of diabetes mellitus (performed at Athena Diagnostics, Inc, Worcester, Massachusetts, USA). The testing revealed a substitution mutation in the 5'-untranslated region (UTR) of the IPF-1gene (c.-18C > T), consistent with the diagnosis of maturity-onset diabetes of the young type 4 (MODY4). Given this information, she was transitioned from subcutaneous insulin to an oral sulfonylurea (glipizide 2.5 mg daily). To date, the patient's diabetes continues to be adequately managed on oral agents alone.
What is maturity-onset diabetes of the young and how is it different than other more common types of diabetes?
Reply: Maturity-onset diabetes of the young (MODY) is a group of autosomal dominant monogenic disorders accounting for 2-5% of diabetes mellitus; to date, the Online Mendelian Inheritance in Man (OMIM) database identifies 11 different types of MODY [Table 1]. Classic MODY was used to describe someone under 25 years of age with persistent, asymptomatic hyperglycemia not progressing to ketoacidosis.  This presentation now encompasses many heterogeneous conditions including mitochondrial disorders, genetic defects in insulin action, diseases of the exocrine pancreas, other endocrinopathies and drugs/chemicals. 
When diabetes occurs during childhood, it is routinely assumed to be type 1 diabetes due to autoimmune destruction of pancreatic beta-cells.  Clinically, the patient is generally young, thin and is presumed to develop diabetic ketoacidosis without the administration of exogenous insulin. Following initial stabilization of blood sugar concentrations, patients may experience a "honeymoon period" wherein insulin requirements are reduced due to residual islet cell function. Type 1 diabetes is more common among non-Hispanic whites, followed by African Americans and Hispanic Americans; it is comparatively uncommon among Asians.  Positive autoantibody test results are classically associated with type 1 diabetes mellitus, but may be positive in other forms of diabetes. The autoantibodies are only associative in nature as they do not cause the autoimmune destruction of the beta-cells. 
In the last two decades, type 2 diabetes has been reported among children and adolescents with increasing frequency. Type 2 diabetes is responsible for ~10-20% of cases of diabetes seen in children in the U.S and is more common in African American and Hispanic American populations.  The classic pathophysiology of type 2 diabetes involves insulin resistance with inadequate pancreatic insulin production.  In contrast to the MODY disorders, type 2 diabetes is a polygenic trait; the MODY syndromes also have significant penetrance (80-95%), while type 2 diabetes is far more variable (10-40%). Additionally, the metabolic syndrome associated with type 2 diabetes is not always found in the MODY disorders. 
Despite the heterogeneity of MODY, five major diagnostic criteria are usually accepted: (i) hyperglycemia usually diagnosed before age 25 years in at least one and ideally two family members; (ii) autosomal dominant inheritance, through at least three generations and a similar phenotype shared by diabetic family members; (iii) absence of insulin therapy at least five years after diagnosis or significant C-peptide levels even in a patient on insulin treatment; (iv) insulin levels often in the normal range, although inappropriately low for the degree of hyperglycemia; and (v) development of diabetes rarely associated with obesity.  Certainly, this information is not always available and while we cannot obtain a full family history, our patient meets several criteria. Additionally, the identification of a specific MODY-related mutation has important prognostic and therapeutic implications [Table 1].
What is MODY type 4?
Reply: MODY type 4 (MODY4) is caused by an inactivating mutation in the gene for insulin promoter factor-1 (IPF1), also referred to as pancreas/duodenum homeobox protein-1 (PDX1), leading to defective pancreatic development and b cell maturation. Homozygous mutations in IPF1 lead to pancreatic agenesis, while heterozygous mutations have been associated with early-onset type 2 diabetes.  In the first family studied with a heterozygous IPF1 mutation, the age of onset (range: 17-67, mean: 35) was greater than that of most other types of MODY. None showed ketosis or indications of severe insulin deficiency, and most were treated with diet or oral hypoglycemic agents. 
Our patient has a heterozygous IPF1 mutation (c.-18C > T) previously associated with MODY4.  Interestingly, this mutation is located in the 5' untranslated region (5'- UTR) of the IPF-1gene. As has been well-established, the 5'- UTR promotes the initiation of transcription and serves as a binding site for stabilizing proteins and other non-protein elements.  Although 5'- UTR mutations do not affect the coding sequence of the gene itself, they often affect the quantity transcribed. Thus, we speculate that our patient's mutation caused her MODY4 by negatively affecting IPF1 transcription. In addition, these findings add to the body of literature supporting the role of non-coding mutations in human disease. 
Our patient is the second reported case of an IPF1 mutation in the 5'- UTR associated with hyperglycemia, supporting the role of non-coding mutations in human disease. A good clinician must always ask themselves if a patient's disease course matches the natural history of their diagnosis. If something is amiss one should never be afraid to question and reevaluate. As our case exemplifies, it is critical to consider and screen for other causes of diabetes in thin, non-ketotic children with hyperglycemia. Type 1 diabetes and MODY disorders may both present with hyperglycemia but are very different diseases both in regards to pathophysiology and treatment. Our patient was diagnosed early due to a urinalysis screen; had this not been performed, she may not have been diagnosed until later in life as in prior case studies. While MODY patients may be managed with insulin, many can also be managed with oral hypoglycemic agents. After years of daily subcutaneous injections our patient is now free from daily injections and no longer required to keep insulin and syringes within reach. As expected, our patient demonstrates far greater compliance with her new oral regimen as well. We must always be aware that our diagnosis has a tremendous impact on the lives and well-being of our patients.