DEND syndrome (ORPHA:79134)
A rare form of neonatal diabetes mellitus characterized by a triad of Developmental delay, Epilepsy, and Neonatal Diabetes (DEND syndrome), with a generally severe course. This form of neonatal diabetes is not associated with abnormal pancreatic development.
Epidemiology
Fewer than 60 cases have been reported to date.
Clinical description
DEND syndrome represents the most severe end of the neonatal diabetes mellitus spectrum. Birth-weight is below the 10th percentile in approximately half of the cases. Patients have hyperglycemia requiring insulin therapy that presents within 12 months of birth. The onset is usually before 6 months of age and before 1 month of age in about 1/3rd of the patients. Remission from the hyperglycemia happens in about half of the patients (median age 39 weeks, but may not occur until 5 years old), however, relapse frequently occurs during puberty. The associated neurologic features range from mild to severe developmental delay (psychomotor and cognitive). Attention deficit or language disorder (dyslexia) is found in 100% of cases. Patients also present with intractable epilepsy and muscle hypotonia. A less severe, intermediate form has been described and is known as intermediate DEND syndrome.
Etiology
DEND syndrome is caused in most cases by gain of channel function mutations in the KCNJ11 gene (11p15.1), encoding a subunit of the ATP-sensitive potassium (KATP) channel. Mutations in this gene also cause permanent neonatal diabetes mellitus (PNDM). Only 20% of individuals with mutations in this gene develop DEND or the intermediate DEND form. Rare reports of specific mutations in the ABCC8 gene (11p15.1) have also been associated with DEND.
Diagnostic methods
DEND syndrome should be suspected when there is onset of diabetes mellitus before 6 months, or before 1 year of age with no pancreatic involvement or no evidence of autoimmune disorder, or with unusual family history and associated neurological complications. The diagnosis is confirmed by genetic testing which should be performed as soon as possible in order to prescribe the appropriate treatment and follow up. Diagnosis should be established before the onset of complications and should not wait for a potential remission of the hypoglycemia.
Differential diagnosis
The differential diagnosis includes the less severe intermediate DEND syndrome and other forms of neonatal diabetes mellitus, permanent and/or transient.
Antenatal diagnosis
Non-invasive prenatal testing of fetal genotype can be performed for monogenic diabetes and give highly accurate results before the third semester.
Genetic counseling
The mode of inheritance of DEND syndrome is usually dominant (50% of transmitting the disease by an affected couple) and rarely recessive (25% chance of transmitting the disease by an affected couple), however, most diagnosed cases occur from a de novo mutation, in which case chances of recurrence in siblings are close to zero.
Management and treatment
Treatment must begin as soon as the diagnosis is established using hypoglycemic sulfonylureas, which act by binding to the regulator SUR1 subunit of the potassium channel, and provide a better metabolic equilibrium than insulin. The clinician should aim to optimize the treatment to the maximum possible dose without causing hypoglycemia (preprandial target: 70-120 mg/dL - postprandial target: 100-145 mg/dL) in order to optimize the drug's beneficial effect on the central nervous system. Calorie and carbohydrate intake must be carefully balanced (15-18 g/kg/d of carbohydrates) to allow for weight gain while avoiding the risk of future insulin resistance. Restriction below the nutritional recommendations for children with low birth weight isn't recommended. Blood glucose must be monitored with as little amount of blood as possible (0.3 microliter) either with an appropriate blood glucose meter or a continuous glucose monitor.
Prognosis
In the neonatal period, the prognosis of the disease is linked to the severity of the symptoms. Rapid diagnosis and treatment with hypoglycemic sulfonylureas after metabolic control has been restored with insulin are critical to improve the prognosis and reduce neurological complications. Later in life, the prognosis depends on the metabolic control which determines the timing of appearance of the long-standing diabetes complications.

                            Last update: 
                            July 2024


                            - Expert reviewer(s): 
                            Pr Michel POLAK | Endo-ERN*


                                * European Reference Network