Neonatal Autoimmune Diseases: Neonatal type I diabetes mellitus

Neonatal autoimmune diseases are distinctly rare. Most neonatal autoimmune diseases result from the transplacental transfer of maternal antibodies directed against fetal or neonatal antigens in various tissues. While autoantibodies have been detected in patients with neonatal autoimmune disease, the pathogenic role of autoantibodies has not been well defined. Other mechanisms may play a role in the development of neonatal autoimmunity, including fetal/maternal microchimerism and aberrant apoptosis of fetal cells.

The pathophysiologic basis for the development of neonatal autoimmunity is not entirely clear, but differences in the neonatal immune system compared with the adult immune system, as well as unique characteristics of target antigens in the newborn period may be important factors.

Neonatal Autoimmune Disease

1. Neonatal lupus
2. Neonatal anti-phospholipid syndrome
3. Behcet’s disease
4. Neonatal autoimmune thyroid disease
5. Neonatal polymyositis and dermatomyositis
6. Neonatal scleroderma
7. Neonatal type I diabetes mellitus.

The autoinflammatory syndromes are a completely different category, but are also included in discussion of neonatal autoimmune diseases. The autoinflammatory syndromes include which all share a common pathophysiologic mechanism.

The autoinflammatory syndromes include :

1. The cryopyrin associated periodic syndromes (CAPS)
2, Familial cold autoinflammatory syndrome (FCAS)
3. Neonatal onset multisystem inflammatory disease (NOMID)
4. Muckle-Wells syndrome, which all share a common pathophysiologic mechanism.

Neonatal type I diabetes mellitus.

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes that occurs in the first 6 months of life. It is a rare disease, occurring in only one in 100,000 to 500,000 live births. Infants with NDM do not produce enough insulin, leading to an increase in blood glucose. NDM can be mistaken for the much more common type 1 diabetes, but type 1 diabetes usually occurs later than the first 6 months of life. In about half of those with NDM, the condition is lifelong and is called permanent neonatal diabetes mellitus (PNDM). In the rest of those with NDM, the condition is transient and disappears during infancy but can reappear later in life; this type of NDM is called transient neonatal diabetes mellitus (TNDM). Specific genes that can cause NDM have been identified.

Transient (TNDM) and Permanent (PNDM) Neonatal Diabetes Mellitus are rare conditions occurring in about 1: 300,000 live births. In TNDM growth retarded infants develop diabetes in the first few weeks of life only to go into remission in a few months with possible relapse to a permanent diabetes state usually around adolescence, often around the time of adolescence. Pancreatic dysfunction in this condition is maintained throughout life with relapse initiated at times of metabolic stress such as puberty or pregnancy. The mechanisms involved in this rare condition may inform on fetal pancreatic development, islet cell physiology and predisposition to type 2 diabetes. In PNDM, insulin secretory failure occurs in the early postnatal period. A number of conditions are associated with PNDM, some of which have been elucidated at the molecular level. Insulin therapy is difficult to manage in the neonatal period, and in experienced hands, the insulin pump may provide a valuable tool to administer insulin.

Pancreatic dysfunction in this condition is maintained throughout life with relapse initiated at times of metabolic stress such as puberty or pregnancy. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. A number of conditions are associated with PNDM, some of which have been elucidated at the molecular levels. Among those, the very recently elucidated mutations in KCNJ11 and ABCC8 gene, encoding the Kir6.2 and SUR1 subunit of the pancreatic K(ATP) channel involved in regulation of insulin secretion accounts for one third to a half of the PNDM cases. Patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. In TNDM, patients are younger at the diagnosis of diabetes and have lower initial insulin requirements. Considerable overlap occurs between the two groups, so that TNDM cannot be distinguished from PNDM based on clinical features. Very early onset diabetes mellitus seems to be unrelated to autoimmunity in most instances.

Diabetes mellitus is uncommon in infancy and newborn period. The two common forms seen are the transient and permanent forms of diabetes mellitus of the newborn. They have to be differentiated from the transient hyperglycemic states (Blood sugar > 125 mg/dl) seen in newborns who receive parenteral glucose infusions and in those with septicemia and CNS disorders. Transient diabetes mellitus of the newborn (TDNB) is defined as hyperglycemia occurring within the first month of life lasting at least 2 weeks and requiring insulin therapy. Most of these cases resolve spontaneously by 4 months. It has a reported incidence of 1 in 45,000 to 60,000 live births.

The most likely etiology is a maturational delay of cAMP mediated insulin release. The clinical features include small for datedness, proneness for birth asphyxia, open-eye alert facies, dehydration, emaciation, polyuria and poydipsia. These children are prone to septicemia and urinary tract infections. They have hyperglycemia, glucosuria, absent or mild ketonuria, low basal insulin, C-peptide and IGF-1 levels. Treatment consists of hydration and judicious administration of insulin with close monitoring. Thirty percent of these children are likely to develop permanent neonatal diabetes. Compared to transient form, permanent diabetes mellitus is uncommon. It is usually due to pancreatic dysgenesis often associated with other malformations and rarely due to type 1 diabetes mellitus. The diagnosis is based on the demonstration of both exocrine and endocrine pancreatic dysfunction. These children are managed as type 1 diabetes mellitus. They are prone to develop the vascular complications of diabetes at an earlier date.

Recurrent diabetes is common in patients with “transient” neonatal diabetes mellitus and, consequently, prolonged follow-up is imperative. Molecular analysis of chromosome 6 anomalies, the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provide a tool to identify transient from permanent neonatal diabetes mellitus in the neonatal period. This analysis also has potentially important therapeutic consequences leading to transfer some patients, those with mutations in KCNJ11 and ABCC8 from insulin therapy to sulfonylureas. Realizing how difficult it is to take care of a child of this age with diabetes mellitus should prompt clinicians to transfer these children to specialized centers. Insulin therapy and high caloric intake are the basis of the treatment. Insulin pump may offer an interesting therapeutic tool in this age group in experienced hands.

Symptoms of NDM include thirst, frequent urination, and dehydration. NDM can be diagnosed by finding elevated levels of glucose in blood or urine. In severe cases, the deficiency of insulin may cause the body to produce an excess of acid, resulting in a potentially life-threatening condition called ketoacidosis. Most fetuses with NDM do not grow well in the womb and newborns are much smaller than those of the same gestational age, a condition called intrauterine growth restriction. After birth, some infants fail to gain weight and growth as rapidly as other infants of the same age and sex. Appropriate therapy improves and may normalize growth and development.

Neonatal diabetes, which may be transient or permanent, is rare. Most patients are full-term but small- for-date infants. Typical symptoms of diabetes mellitus occur within the first 4 weeks of life, requiring insulin therapy and very strict blood glucose monitoring. Subsequent growth and psychomotor development are usually normal. In about 33% of these patients the diabetes remains permanent; the transient cases, however, often develop permanent diabetes mellitus later in life. Exocrine pancreatic insufficiency is present in some patients. Neonatal diabetes differs from type-I diabetes in many aspects and seems to form a distinct entity of inborn pancreatic malfunction.

Diabetes mellitus diagnosed during the first 2 years of life differs from the disease in older children regarding its causes, clinical characteristics, treatment options and needs in terms of education and psychosocial support. Over the past decade, new genetic causes of neonatal diabetes mellitus have been elucidated, including monogenic β-cell defects and chromosome 6q24 abnormalities. In patients with KCNJ11 or ABCC8 mutations and diabetes mellitus, oral sulfonylurea offers an easy and effective treatment option.

Type 1 diabetes mellitus in infants is characterized by a more rapid disease onset, poorer residual β-cell function and lower rate of partial remission than in older children. Insulin therapy in infants with type 1 diabetes mellitus or other monogenic causes of diabetes mellitus is a challenge, and novel data highlight the value of continuous subcutaneous insulin infusion in this very young patient population. Infants are entirely dependent on caregivers for insulin therapy, nutrition and glucose monitoring, which emphasizes the need for appropriate education and psychosocial support of parents. To achieve optimal long-term metabolic control with low rates of acute and chronic complications, continuous and structured diabetes care should be provided by a multidisciplinary health-care team.

Pancreatic agenesis is a rare cause of neonatal diabetes mellitus and the knowledge about the clinical features is sparse. A patient with pancreatic agenesis and double outlet right ventricle is reported.

Pancreatic agenesis is a clinical entity characterized by severe intrauterine growth retardation, early onset of permanent neonatal diabetes mellitus without ketoacidosis, failure to thrive due to pancreatic exocrine dysfunction and associated malformations mainly of the biliary system or of the heart. Because of the high neonatal mortality, awareness of pancreatic agenesis as a possible cause of severe intrauterine growth restriction is important for the optimal treatment of diabetes mellitus, exocrine pancreatic insufficiency and the associated malformations.

Permanent neonatal diabetes mellitus

Permanent neonatal diabetes mellitus (PNIDDM) is a rare form of IDDM with unclear etiology and pathogenesis. We determined the incidence and prevalence rates and studied the clinical and biochemical features of PNIDDM in the Sultanate of Oman.

The mean incidence rate during the study period from January 1989 to December 1994 was 1.788 +/- 0.82 per 100,000 live births per year. At the end of December 1994 the prevalence rate was 2.4 per 100,000 children below the age of 5 years. They constituted 41.6% of all cases of IDDM in this age group. Diarrhoea, fever, lethargy, poor feeding and failure to thrive were the most common presenting symptoms. Dehydration and tachypnoea were the most common signs.

All patients who developed IDDM during the neonatal period had intrauterine growth retardation and 4.5 presented with diabetic ketoacidosis (plasma glucose 37 +/- 9 mmol/L, pH 7.12 +/- 0.1). Hypertriglyceridemia was a constant feature (19.4 +/- 4.8 mmol/L). They were products of consanguineous marriage with significantly high prevalence of IDDM and NIDDM in their family members. None of the infants had clinical or immunological evidence of congenital viral infection. Three of the five children had HLA-DR2, the diabetes resistance alleles. C-peptide secretion was absent during and after metabolic control of hyperglycemia in all the studied infants and none had circulating islet cell antibody at presentation or during the first year after diagnosis.

Despite marked growth retardation at birth, there was a significant improvement of growth after initiating insulin therapy. Four of the 5 patients had normal developmental milestones, one had mild developmental delay following a severe and prolonged attack of hypoglycemia. None of the patients had exocrine pancreatic deficiency. In summary, the very high rate of parental consanguinity, occurrence in both sexes and in two siblings in the same family, absence of islet cell antibodies and the presence of HLA-DR2 loci in 3/5 of patients suggest that PNIDDM is a different disease process to standard IDDM in childhood and an autosomal recessive mode of transmission.


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  • Polak M, et al. Neonatal Diabetes Mellitus — genetic aspects 2004. Pediatr Endocrinol Rev. 2004 Dec;2(2):193-8.
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