Neonatal diabetes mellitus

INTRODUCTION — Neonatal diabetes mellitus (DM) is characterized by the onset of persistent hyperglycemia within the first six months of life due to impaired insulin function and is frequently caused by a mutation in a single gene affecting pancreatic beta cell function.

The presentation, clinical manifestations, diagnosis, and evaluation for neonatal DM will be reviewed here. An overview of causes and management of neonatal hyperglycemia is discussed separately. (See "Neonatal hyperglycemia".)

TERMINOLOGY — The terminology describing DM in the first year of life is somewhat confusing. Neonatal DM is the commonly used term to describe monogenic forms of DM that present during infancy. Although some patients present within the neonatal time period of the first 30 days of life, infants most often present within the first six months of life, and occasionally present up to 12 months of life [1-3]. In contrast, autoimmune type 1 diabetes is unlikely to present within the first six months of life. Therefore, the term neonatal DM, which is most commonly used in the literature and clinically, will be the term used throughout this topic and refers to patients up to one year of life who present with monogenic DM. (See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents", section on 'Infants' and "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents", section on 'Epidemiology'.)

EPIDEMIOLOGY — DM is a rare cause of neonatal and infantile hyperglycemia with reported incidence ranging from 1 in 90,000 to 160,000 live births [4,5]. Most infants who present with DM in the first six months of life will have a monogenic cause referred to as neonatal DM [1]. (See 'Terminology' above.)

PATHOGENESIS

Overview of gene mutations — Neonatal DM is caused by a single mutation in one of several genes that are involved in the normal development and function of pancreatic beta cells including insulin production and secretion [1]. Clinical manifestations (transient versus permanent diabetes mellitus, extrapancreatic features), prognosis, and treatment depend upon the affected gene and the underlying pathogenesis [2].

Mutations that cause neonatal DM are a result of impaired insulin function due to one of the following mechanisms and affected genes [1]:

●Abnormal beta cell function affecting insulin production and secretion – KCNJ11, ABCC8, INS, GCK, SLC2A2, SLC19A2, RFX6 [6-15].

●Beta cell destruction due to cellular stress or autoimmunity – INS, EIF2AK3, IER3IPI, FOXP3, WFS1, LRBA, STAT1, STAT3 [16-22].      

●Abnormal pancreatic development (pancreatic aplasia or hypoplasia) – PDX1 (IPF1), PTF1A, HNF1B, RFX6, GATA4, GATA6, CNOT1, GLIS3, NEUROG3, NEUROD1, PAX6, NKX2-2, MNX1 [23-34].

The relative frequency of different genetic causes was determined in a large case series of 1020 patients diagnosed with neonatal DM before six months of age [2]. Comprehensive genetic testing identified causal mutation in more than 80 percent of cases. Mutations in KCNJ11 and ABCC8, which encode for subunits of the ATP-sensitive potassium channel (K_ATP) in the pancreatic beta cell, were the most common (n = 390) found in 46 percent of infants with neonatal diabetes from nonconsanguineous families and 12 percent of identified consanguineous families. Mutations in the gene that encodes insulin (INS) had similar rates of 10 percent in patients from nonconsanguineous and consanguineous families (n = 110). In consanguineous families, the most common genetic cause was a homozygous mutation in EIF2AK3 gene causing Wolcott-Rallison syndrome (OMIM#226980, n = 24 percent) (n = 76).

Although neonatal DM may also occur in preterm infants (gestational age <37 weeks), it is more challenging to make a diagnosis in this group of patients. In a second case series, 146 of 750 infants with diabetes diagnosed before six months of age were born preterm [35]. A genetic etiology was identified in 97/146 (66 percent) preterm infants compared with 501/604 (83 percent) term infants [35]. KCNJ11 gene mutations were less common in preterm infants.

Phenotypic expression — Gene mutations that cause neonatal DM are expressed as one of the following clinical subtypes [2,3]:

●Transient diabetes mellitus (eg, due to KCNJ11 or ABCC8 mutations or overexpression of the imprinted region of chromosome 6q24) – 20 percent of cases.

●Diabetes mellitus responsive to oral sulfonylurea (eg, due to mutations of KCNJ11 or ABCC8, which encode subunits of the K_ATP channel) – 40 percent of cases.

●Permanent isolated diabetes mellitus that requires lifelong insulin therapy (eg, due to mutations of INS) – 10 percent of cases.

●Syndromic diabetes mellitus with extra-pancreatic features (eg, Wolcott-Rallison syndrome due to mutations of EIF2AK3) – 10 percent.

●Autoimmune diabetes in infancy associated with other manifestations of immune dysfunction due to rare monogenic mutations in genes important for immune function (eg, FOXP3, LRBA, STAT1, STAT3 mutations).

●No genetic cause identified.

Transient neonatal DM — Twenty percent of patients who present with neonatal diabetes will ultimately be found to have transient neonatal DM that resolves in infancy (usually by 13 to 18 weeks of age) but may recur later in life [1-3,36]. In the previously mentioned large case series, 20 percent of the cohort had a genetic diagnosis of transient neonatal DM [2]. The underlying genetic defects included:

●Overexpression of the imprinted region of chromosome 6q24, which include the genes PLAGL, HYMAI, and ZPF57 [37-41]. The overexpression of this region has been attributed to either a mutation in the zinc finger transcription factor ZPF57 leading to hypomethylation of the imprinted loci, or due to the duplication of 6q24 from either paternal uniparental disomy or an unbalanced duplication of the paternal chromosome 6 [39-41]. Of note, patients may develop hypoglycemia in later infancy or childhood after the initial hyperglycemic phase [36] and 50 percent of patients redevelop hyperglycemia in adulthood.

●Activating mutations of either KCNJ11 or ABCC8 that encode subunits of the K_ATP channel, which are discussed below, can lead to both transient or permanent neonatal diabetes. For patients with these gene mutations, the continued need for therapeutic interventions determines whether diabetes is transient or permanent. (See 'Sulfonylurea therapy' below.)

●Case reports of patients with mutations of INS, which encodes preproinsulin [42-44].

Neonatal DM responsive to sulfonylurea — Approximately 40 percent of patients with neonatal DM are responsive to sulfonylurea treatment caused by activating mutations of KCNJ11 or ABCC8, which may result in either transient or permanent DM [1-3]. For most infants with these genetic mutations, oral sulfonylurea therapy is as effective as subcutaneous insulin in controlling hyperglycemia [45-48]. These mutations are the most common cause of neonatal DM and affect genes that encode subunits of the K_ATP channel [2]. KCNJ11 encodes the inner subunit (Kir6.2) of the K_ATP channel, whereas ABCC8 encodes the outer subunit (SUR1). Mutations in these genes result in inappropriately open K_ATP channels even in the presence of hyperglycemia. Without closure of the K_ATP channels, the cell membrane is unable to depolarize and release insulin. (See 'Sulfonylurea therapy' below.)

K_ATP channels are also found in the brain. Patients with permanent neonatal DM due to activating KCNJ11 mutations may also present with varying degrees of neurodevelopmental and psychiatric difficulties [49-54]. The combination of the most severe developmental delays and epilepsy is referred to as DEND (developmental delay, epilepsy, neonatal diabetes) syndrome. Many but not all studies suggest that early diagnosis and treatment with a sulfonylurea may improve neurologic outcome depending on the specific mutation involved [55-57].

By contrast, inactivating mutations of KCNJ11 or ABCC8 are important causes of congenital hyperinsulinism, which is characterized by persistent hyperinsulinemic hypoglycemia. (See "Pathogenesis, clinical presentation, and diagnosis of congenital hyperinsulinism".)

Permanent isolated neonatal DM requiring insulin — Approximately 40 to 50 percent of infants with permanent neonatal DM will require lifelong treatment with insulin. Mutations of INS, which encodes preproinsulin, account for 10 percent of neonatal DM cases and up to 20 percent of those with permanent neonatal DM [2,14]. Patients with mutations of INS have isolated DM and will require lifelong insulin therapy. In these patients, mutations in the coding regions of the gene lead to misfolding of the insulin protein, which accumulates in subcellular compartments and contributes to beta cell death [12,13]. Noncoding INS mutations in the promoter region lead to changes in chromatin accessibility and transcription factor binding and decreased INS gene transcription [58].

In addition, approximately 10 percent of patients with KCNJ11 mutations causing neonatal DM are not responsive to treatment with sulfonylureas and must be treated with insulin [48].

Neonatal DM associated with genetic syndromes — DM is a clinical feature of many different syndromes that present during infancy caused by mutations in over 17 genes [2]. Syndromic causes of neonatal DM account for approximately 10 percent of neonatal DM cases due to a variety of pathogenetic mechanisms including abnormal pancreatic development, beta cell destruction, and impaired beta cell function and severe insulin resistance syndromes.

The most common syndrome presenting with neonatal DM is Wolcott-Rallison syndrome (OMIM#226980), an autosomal recessive disorder. It is caused by mutations in EIF2A, which encodes the translation initiation factor 2-alpha kinase 3 (important in the regulation of endoplasmic reticulum) [16]. It occurs in almost 30 percent of cases with consanguineous families [2]. Other features include hepatic dysfunction and skeletal dysplasia.

Other more rare syndromes that present with neonatal DM include [1,4]:

●IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), a rare X-linked disorder is caused by mutations to the gene that encodes the transcription factor FOXP3. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked".)

●Fanconi-Bickel syndrome (OMIM#138160), an autosomal recessive disorder, is caused by mutations of SLC2A2 (GLUT2). Other features include liver dysfunction and hypergalactosemia. (See "Other disorders of glycogen metabolism: GLUT2 deficiency and aldolase A deficiency", section on 'GLUT2 deficiency'.)

●Rogers syndrome (OMIM#249270), an autosomal recessive disorder, is caused by mutations of SLC19A2. Other features include thiamine-responsive megaloblastic anemia and sensorineural hearing loss. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Thiamine-responsive megaloblastic anemia (SLC19A2 mutation)'.)

●Wolfram syndrome (OMIM#222300), an autosomal recessive disorder, is caused by mutations of WFS1 [19]. Other features include diabetes insipidus, optic atrophy, and deafness leading to an alternative acronym of DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome. (See "Arginine vasopressin deficiency (central diabetes insipidus): Clinical manifestations and causes", section on 'Wolfram syndrome' and "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Wolfram syndrome'.)

●Donohue syndrome, Rhabson-Mendenhall syndrome (INSR mutations) – Mutations of INSR, which encodes the insulin receptor, result in severe insulin resistance syndromes presenting with post-prandial hyperglycemia, fasting hypoglycemia, poor linear growth, and impaired muscle and adipose development [59].

CLINICAL FEATURES

Presentation — Due to the genetic heterogeneity underlying neonatal DM, the clinical presentation of affected infants varies from incidentally identified asymptomatic hyperglycemia to severe dehydration and diabetic ketoacidosis (DKA) [1,2,4].

Clinical manifestations include [1,4]:

●Small for gestational age – Frequently neonatal DM presents prenatally with intrauterine growth restriction due to a deficiency of functional insulin, which is an in-utero growth factor. Catch-up growth is observed when there is subsequent appropriate postnatal treatment resulting in euglycemia [1,60,61].

●Poor postnatal growth (ie, failure to thrive) for infants who do not receive appropriate therapy.

●Polyuria due to hyperglycemia and glucosuria.

●Diabetic ketoacidosis (DKA) – Infants with neonatal DM are at risk for dehydration and electrolyte abnormalities due to urinary losses and acidosis due to ketogenesis. However, the signs and symptoms of DKA in infants are nonspecific and include irritability, lethargy, tachypnea, and evidence of hypovolemia (eg, sunken eyes and fontanels). The frequency of DKA at presentation varies and is dependent on the specific underlying genetic disorder. DKA is reported to occur in approximately 30 percent of patients with mutations of INS (isolated diabetes mellitus requiring insulin) and ranges from 30 to 75 percent for those with mutations of either KCNJ11 or ABCC8 (DM responsive to sulfonylurea) [4,6]. Patients with transient DM due to overexpression of 6q24 typically do not present with DKA [4]. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis", section on 'Signs and symptoms'.)

●Malabsorptive diarrhea – In some cases, pancreatic exocrine function may be impaired, resulting in malabsorptive diarrhea even in infants without pancreatic agenesis or hypoplasia [29,62,63]. Pancreatic exocrine insufficiency has been described in neonatal DM due to mutations in NEUROG3 and PDX1 [23,24,28,29].

Extra-pancreatic findings — Nonpancreatic findings are commonly seen in association with neonatal DM. They may be helpful in determining the underlying genetic mutation (see 'Neonatal DM associated with genetic syndromes' above) and include:  

●Skeletal abnormalities – EIF2A [16,18].

●Hepatic dysfunction – EIF2A, SLC2A2 [16,18].

●Optic abnormalities – WFS1, PAX6 [19,31].

●Deafness – WFS1, SLC19A2 [19,64].

●Hypothyroidism – GLIS3 [26] (see "Clinical features and detection of congenital hypothyroidism", section on 'Thyroid dysgenesis').

●Cardiac abnormalities – GATA4, GATA6 [27,65] (see "Isolated atrial septal defects (ASDs) in children: Classification, clinical features, and diagnosis", section on 'Genetic disorders').

●Polycystic kidney disease – HNF-1 beta [30] (see "Renal hypodysplasia", section on 'Genetic disorders').

●Immune dysregulations – IPEX, STAT1, STAT3, LRBA [20-22] (see "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked").

●Neurologic abnormalities and neurodevelopment impairment – KCNJ11, NEUROD1, PTF1A, IER3IP1, CNOT1 [6,25,28,33,34,64,66]:

•KCNJ11 mutations can be associated with severe developmental delay, epilepsy, muscle weakness, and dysmorphic features [6]. These findings are also known as the DEND (developmental delay, epilepsy, neonatal diabetes) syndrome [67]. (See 'Neonatal DM responsive to sulfonylurea' above.)

Course — In 20 percent of cases, neonatal DM spontaneously resolves prior to 18 months of age. However, there is often a recurrence of hyperglycemia in adolescence or adulthood. (See 'Transient neonatal DM' above.)

The remaining patients have a permanent disorder and will require lifelong medication either with oral sulfonylurea therapy and/or insulin. (See 'Neonatal DM responsive to sulfonylurea' above.)

DIAGNOSIS — Making a diagnosis of neonatal DM in infants <6 months of age is challenging. A clinical diagnosis of DM is made for infants who have persistent insulin-dependent hyperglycemia beyond three days of life with blood glucose levels >200 mg/dL and in whom alternative causes for elevated blood glucose levels have been excluded. For neonates and infants with DM, neonatal DM due to a monogenic etiology is confirmed when genetic testing identifies a causative gene mutation. (See 'Genetic testing' below and 'Terminology' above.)

DIAGNOSTIC EVALUATION — For infants with persistent hyperglycemia, the following diagnostic evaluation is performed to exclude other causes of neonatal hyperglycemia and to differentiate monogenic neonatal DM from polygenic autoimmune type 1 DM. Further genetic testing is performed for infants with a clinical diagnosis of neonatal DM to determine the causative gene mutation.

●Review of history:

•Is there any evidence of another cause of hyperglycemia (see 'Differential diagnosis' below)?

-Medications associated with elevated blood glucose levels (eg, corticosteroids, beta-adrenergic agents)? If so, consider discontinuation if possible.

-Signs of sepsis?

-Excessive glucose administration through parenteral nutrition?

•Is there any history of diarrhea or loose fatty stools suggesting pancreatic exocrine functional impairment? If so, consider obtaining fecal elastase measurement, as low values suggest pancreatic exocrine insufficiency. (See "Approach to chronic diarrhea in neonates and young infants (<6 months)", section on 'Stool testing' and "Exocrine pancreatic insufficiency", section on 'Fecal elastase-1'.)

●If the patient is on parenteral nutrition, review the rate of glucose infusion. If it is greater than 8 mg/kg per minute, decrease the glucose infusion rate initially to a rate of 6 mg/kg per min if possible and evaluate the subsequent blood glucose level to see if it remains elevated. (See "Neonatal hyperglycemia", section on 'Lowering the GIR'.)

●Laboratory evaluation:

•Obtain blood cultures to rule out sepsis. (See 'Differential diagnosis' below.)

•Serum C peptide and insulin level to determine endogenous insulin production.

•Assessment for acidosis (blood gas) and ketones (beta-hydroxybutyrate) to identify infants with diabetic ketoacidosis.

•Autoimmune panel of antibodies associated with type 1 diabetes – Antibodies to glutamic acid decarboxylase (GAD), islet cell, insulin, the tyrosine phosphatases (insulinoma-associated protein 2 [IA-2] and IA-2 beta), and zinc transporter (ZnT8) generally distinguishes autoimmune type 1 diabetes from monogenic neonatal DM. However, these markers are rarely positive in infants less than 12 months of age. Nevertheless, we obtain an autoimmune panel in infants between 6 to 12 months that includes these antibodies as the presence of any of these autoantibodies is indicative of type 1 diabetes. (See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents", section on 'Distinguishing type 1 from type 2 diabetes'.)

•HbA1C is not recommended to diagnose DM in infants <6 months of age because neonates have a high concentration of fetal hemoglobin (HgbF) and therefore a lower concentration of hemoglobin A (HgbA) [68]. An elevated HbA1C >6.5 percent in an infant <6 months would still be consistent with a diagnosis of diabetes, but a normal HbA1C would not be reassuring if there is clinical suspicion of neonatal diabetes.

●Abdominal ultrasound to determine the presence and size of the pancreas.

Genetic testing — Once the diagnosis of DM has been established in an infant less than 12 months of age, targeted genetic testing to confirm and identify a monogenic etiology is recommended as this can guide treatment recommendations. Genetic testing is cost-effective because management of a high proportion of patients is improved with identification of the underlying defect (eg, patients responsive to oral sulfonylurea therapy). We suggest using screening panels from commercial laboratories that include 15 to 20 candidate genes for neonatal DM, as a cost-effective approach for neonatal DM genetic testing. As bioinformatics support for whole exome sequencing and whole genome sequencing becomes more readily available and more cost-effective, this testing approach will supersede candidate gene testing for neonatal DM. The United States National Center for Biotechnology Information (NCBI) genetic registry lists test services in the United States and other select countries.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for neonatal hyperglycemia is broad and is discussed separately. (See "Neonatal hyperglycemia", section on 'Causes'.)

For persistent hyperglycemia, DM is a diagnosis of exclusion. The most common causes of neonatal hyperglycemia are differentiated from DM as follows (see 'Diagnostic evaluation' above):

●Sepsis: Positive blood cultures

●Parenteral nutrition – Reduction of glucose infusion rate to physiologic glucose requirements. (See "Neonatal hyperglycemia", section on 'Lowering the GIR'.)

●Medications – Discontinuation of hyperglycemic medications, including corticosteroids and beta adrenergic drugs (eg, dopamine, epinephrine, or norepinephrine) once medically appropriate.

MANAGEMENT

Overview — For infants with persistent hyperglycemia, initial management is directed towards correction of fluid and electrolyte abnormalities, and reduction of hyperglycemia by administration of intravenous insulin. Patients with mutations in ABCC8 or KCNJ11 may respond to oral sulfonylurea therapy and not require insulin therapy. Patients with pancreatic exocrine deficiency will require pancreatic enzyme supplementation.

Management should be directed by a clinician with expertise in treating persistent hyperglycemia in neonates and infants.

Fluid and electrolyte management — Infants with evidence of dehydration, and electrolyte abnormalities including acidosis should be initially managed in an intensive care unit with supportive measures for volume repletion with intravenous fluids and correction of electrolyte deficits with electrolyte replacement. If significant dehydration is present at diagnosis, fluid resuscitation should be initiated prior to the start of treatment with insulin. (See "Fluid and electrolyte therapy in newborns".)

Insulin therapy

Initial intravenous insulin — The initial management of persistent hyperglycemia in patients less than 12 months of age is administration of a continuous infusion of intravenous (IV) insulin following fluid repletion, if needed. The starting dose varies between 0.01 to 0.05 units/kg per hour depending on the severity of presentation with regards to degree of hyperglycemia and presence of ketoacidosis [3,69,70]. Dosing is adjusted in small increments of 0.01 units/kg per hour with the goal to slowly decrease and maintain glucose levels between 100 and 200 mg/dL. Frequent blood glucose monitoring provided by continuous glucose monitoring or via handheld glucometer (initially hourly and then up to eight measurements per day) guides subsequent insulin dosing. Optimal management includes insulin dose adjustments based on blood glucose monitoring to avoid complications from hyperglycemia and hypoglycemia. Discussion on the details and administration of insulin therapy are discussed separately. (See "Neonatal hyperglycemia", section on 'Insulin therapy'.)

Subcutaneous insulin therapy — After the infant is stable and has started oral feedings, subcutaneous insulin therapy can be started either through multiple daily injections or as a continuous subcutaneous insulin infusion (CSII) using an insulin pump. Adequate nutrition and subcutaneous insulin will allow for appropriate treatment of hyperglycemia and weight gain. However, administrating subcutaneous insulin in infants with neonatal diabetes is challenging as infants usually have little subcutaneous fat, require small doses of insulin, and are prone to the development of hypoglycemia. The smallest feasible subcutaneous dose of any insulin, including long-acting (glargine) without dilution, is 0.5 units [3]. As a result, dilution of insulin will often be needed for safe administration and consultation with an experienced pediatric pharmacist is recommended.

In our practice, we use CSII to administer insulin along with continuous glucose monitoring because an insulin pump can reliably deliver small doses of insulin (although dilution of the insulin may be needed due to the small size of the infant). CSII is started using basal insulin at a dose between 0.1 to 0.3 units per kg per day depending on the most recent intravenous needs and then titrated based on glucose control with a targeted range of 100 to 200 mg/dL. Correction insulin for preprandial glucose levels over 250 mg/dL may be needed [3,70-74]. Initially, neonates and young infants may not need additional bolus insulin for meals. As the infant grows and eating patterns change this need for prandial insulin may evolve.

Alternatively, multiple daily injections based on preprandial glucose levels can be used with a similar target glucose level of 100 to 200 mg/dL. When using multiple daily dosing, we prefer the use of rapid-acting analog insulins (insulin lispro, aspart, or glulisine) given three to four times per day before a feed. A starting dose of 0.1 to 0.15 units per kg per dose is used when the pre-prandial glucose level is over 200 to 250 mg/dL. Alternatively, long-acting insulins such as glargine may be used at a dose of 0.2 to 0.4 unit/kg per day divided in one to two injections per day [3,69,70]. However, intermediate-acting insulins such as NPH should not be used as they have been associated with an increased risk for erratic control and hypoglycemia.

Sulfonylurea therapy — For patients with neonatal DM due to mutations in ABCC8 or KCNJ11, observational data from large case series showed that treatment with oral sulfonylurea drugs at high doses (up to 2.5 mg/kg per day of glyburide [glibenclamide]) effectively treated hyperglycemia and reduced or eliminated the need for insulin treatment for 80 to 90 percent of patients with these mutations [3,45,47,48,75]. As a result, we recommend oral sulfonylurea therapy for these patients.

The transition from insulin to sulfonylurea treatment should be conducted in an inpatient setting supervised by a clinician with expertise in managing infants with diabetes in order to avoid hypoglycemia because the insulin requirement can decrease rapidly once sulfonylurea treatment has been initiated. For neonatal DM due to mutations in ABCC8 or KCNJ11, the relative doses of sulfonylurea used are much higher compared with doses used to treat patients with type 2 diabetes (0.2 mg/kg per day). Data suggest that the success rate of transfer to sulfonylureas is dependent on the specific mutation present and associated with earlier treatment [48,75,76].

Since the K_ATP channels are also found in the brain, treatment with sulfonylurea drugs can effectively treat some of the neurological symptoms associated with mutations in KCNJ11. There is some evidence that earlier initiation of treatment improves neurological outcomes [49,55,56,76].

Since the treatment approach in neonatal DM depends upon the genetic mutation, it is important to obtain expedited genetic testing as soon as the diagnosis of neonatal DM is made. After establishing euglycemia with insulin therapy, and in the absence of pancreatic hypoplasia/aplasia, consanguinity, or syndromic features, an empiric trial of sulfonylurea is suggested while awaiting the results of genetic testing or if genetic testing is not available, in consultation with a pediatric endocrinologist [3,47,56].

Transient neonatal DM: Discontinuing therapy — If an infant's genetic testing results are suggestive of diagnosis of transient neonatal diabetes, a trial to discontinue therapy may be indicated, with a slow wean of the hypoglycemic agent (insulin or sulfonylurea) with ongoing monitoring of glucose levels. If the infant can be successfully weaned off their therapy while maintaining normoglycemia, glucose levels are monitored every three to six months to detect any development of chronic hyperglycemia. In addition, infants diagnosed with 6q24 transient neonatal diabetes are at risk for hypoglycemia, which typically presents between 6 to 18 months of age [36], and blood sugar monitoring is imperative during this time period even after the infant has been successfully weaned from insulin. (See 'Transient neonatal DM' above.)

Pancreatic enzyme and nutrient supplementation — If the infant has pancreatic exocrine deficiency, pancreatic enzyme replacement similar to that used in patients with cystic fibrosis is required to maximize enteral calorie absorption. In addition, nutrient repletion including fat soluble vitamins may be required. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on 'Pancreatic enzyme replacement therapy' and "Cystic fibrosis: Nutritional issues", section on 'Nutrient deficits and goals'.)

SUMMARY AND RECOMMENDATIONS

●Neonatal diabetes mellitus (DM) is the commonly used term to describe monogenic forms of DM that typically present within the first 12 months of life. Although some patients present within the neonatal time period of the first 30 days of life, infants most often present with neonatal DM within the first six months of life, occasionally up to 12 months of life, and very rarely after 12 months of age. (See 'Terminology' above.)

●Neonatal DM is caused by one of more than 30 identified genetic mutations. (See 'Overview of gene mutations' above.)

●Neonatal DM is expressed as one of several clinical subtypes depending on the specific gene mutation and including transient DM, DM responsive to oral sulfonylurea, isolated permanent DM requiring lifelong insulin therapy, and neonatal DM associated with genetic syndromes also requiring lifelong insulin therapy. (See 'Phenotypic expression' above.)

●Infants with neonatal DM can present with incidentally noted hyperglycemia or symptomatically with clinical findings of dehydration, low birth weight, failure to thrive, glucosuria, ketoacidosis, and osmotic diuresis. (See 'Presentation' above.)

●A clinical diagnosis of neonatal DM is made for infants who have persistent insulin-dependent hyperglycemia beyond three days with blood glucose levels >200 mg/dL and in whom alternative causes for elevated blood glucose levels have been excluded. The diagnosis is confirmed when genetic testing identifies a causative gene mutation. (See 'Diagnosis' above and 'Genetic testing' above.)

●The diagnostic evaluation for neonatal DM focuses on exclusion of other causes of neonatal hyperglycemia including distinguishing monogenic neonatal DM from autoimmune type 1 DM. Further genetic testing is performed for infants with a clinical diagnosis of neonatal DM to determine the causative gene mutation. (See 'Diagnostic evaluation' above.)

●The differential diagnosis of neonatal DM is broad and includes type 1 DM, sepsis, hyperglycemia due to excessive glucose intravenous infusion, and hyperglycemia-inducing medications. (See 'Differential diagnosis' above.)

●For infants with persistent hyperglycemia including those with neonatal DM, management is initially directed towards correction of fluid and electrolyte abnormalities and reduction of hyperglycemia by the administration of a continuous infusion of intravenous insulin. After the infant is stable and has started oral feedings, subcutaneous insulin therapy can be started either through multiple daily injections or as a continuous subcutaneous insulin infusion using an insulin pump.

●After stabilization on insulin therapy and in absence of pancreatic hypoplasia/aplasia, consanguinity or syndromic features, we suggest an empiric trial of oral sulfonylurea while awaiting genetic testing or if genetic testing is not available (Grade 2C). (See 'Management' above and 'Overview of gene mutations' above.)

●For patients with neonatal DM due to mutations in KCNJ11 or ABCC8, we recommend treatment with sulfonylurea drugs (glyburide [glibenclamide]) (Grade 1B). This therapy may effectively treat hyperglycemia and reduce or eliminate the need for insulin treatment in 80 to 90 percent of patients with these mutations. (See 'Sulfonylurea therapy' above.)

●Infants with pancreatic exocrine deficiency may require pancreatic enzyme and nutrient supplementation similar to that used in patients with cystic fibrosis to ensure adequate growth. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on 'Pancreatic enzyme replacement therapy' and "Cystic fibrosis: Nutritional issues", section on 'Nutrient deficits and goals'.)