Pancreatic beta cell agenesis

Definition

Pancreatic beta cell agenesis is a rare disorder in which a child is born with no beta cells—the cells in the pancreas that produce insulin—resulting in diabetes.

Description

Diabetes mellitus is a disease caused by elevated blood sugar and can result in numerous medical problems that can affect the kidney, eyes, cardiovascular system, skin, and joints. There are two common types. Type 1 results from destruction of the insulin-producing cells (beta cells) of the pancreas and usually occurs in children of at least one year of age or young adults. Injected insulin is required to allow glucose (sugar) to enter the body's cells to be used for energy. Type 2 diabetes occurs mostly in older, often obese, adults and results from the body's cells' decreased ability to respond to the insulin the body produces. In contrast to these two types, neonatal diabetes is extremely rare. Neonatal diabetes is usually transient, meaning that it goes away after some time. It appears to be caused by immaturity of the beta cells; babies with this form of the disease usually recover and do not require insulin before about three months of age. Fewer than forty cases of permanent neonatal diabetes had been reported as of 2001. Reported causes of neonatal diabetes have included absence of the whole pancreas, absence of the clusters (called islets) that contain the beta cells, and absence of the beta cells themselves. This last form is known as pancreatic beta cell agenesis.

Only one confirmed case of pancreatic beta cell agenesis has been reported (1994). This was an infant girl who had a low birth weight and showed high glucose (sugar) in her blood during a routine test. She was also pale, with a low body temperature, rapid breathing and low muscle tone. Her health was further complicated by a diagnosis of an additional metabolic disorder, methylmalonic acidemia (MMA). She died at the age of 16 days. An autopsy showed that her pancreas had islets, which are the bundles of cells containing insulin-producing cells as well as cells that produce other hormones. However, the islets did not contain insulin-producing cells.

Genetic profile

Pancreatic beta cell agenesis may be an autosomal recessive disorder. This means that a child would have to inherit two abnormal copies of a specific gene , one from each parent, in order to have the disorder. The infant described above had both pancreatic beta cell agenesis and MMA, also known to be an autosomal recessive disorder. A gene causing MMA is located on chromosome 6, and studies of this child's genes and chromosomes showed that she inherited two identical copies of at least part of chromosome 6 from her father, a condition known as paternal uniparental isodisomy, instead of one copy of this region from each parent. The MMA was caused by the inheritance of two identical defective MMA genes from her father and the beta cell agenesis was then believed to have been caused by the inheritance of two abnormal copies of another gene. On other chromosomes, it has been shown that certain genes only work when they come from the mother and others only from the father. Several cases of transient neonatal diabetes have also had two identical copies of paternal chromosome 6 or other abnormalities of chromosome 6. This suggests that there may be a connection between pancreatic beta cell agenesis and transient neonatal diabetes. It is believed that the relevant region of chromosome 6 contains a gene that delays the production of insulin and only works when inherited from the father. As of 2001, there were no reports in the literature describing the status of the beta cells in infants with transient neonatal diabetes. Presumably, this is because a pancreatic biopsy would be required, and this procedure would be too strenuous for a fragile baby.

Demographics

The overall incidence of neonatal, or newborn, diabetes mellitus is approximately one in 400,000 to one in 600,000 live births, and many cases are transient, with the infants requiring insulin for an average of three months. These infants do appear to be at an increased risk of developing type 2 diabetes in young adulthood. As of 2001, fewer than 40 cases of well-documented permanent neonatal diabetes had been reported. Only two infants with neonatal diabetes had been demonstrated (by autopsy) to completely lack the insulin-producing cells in the pancreas at birth. One of these is described above and had both pancreatic beta cell agenesis and another disorder called methylmalonic acidemia. She also had low birth weight, typical of children with neonatal diabetes because of the inability to metabolize glucose. The second child was of normal birth weight, suggesting that she originally had beta cells that were subsequently destroyed, perhaps by an autoimmune process as in type 1 diabetes. Both of these infants died in the newborn period.

Signs and symptoms

Symptoms of neonatal diabetes include lethargy, dehydration, and breathing difficulties. In the laboratory, high levels of glucose (sugar) in the blood and urine are demonstrated. Children with neonatal diabetes, including the child with pancreatic beta cell agenesis, are generally of low birth weight.

Diagnosis

Neonatal diabetes, like other forms of diabetes, is diagnosed by high blood sugar levels. Permanent and transient forms of neonatal diabetes are indistinguishable at initial diagnosis. Determining if the cause of neonatal diabetes is pancreatic beta cell agenesis was done after death in the published cases by studying the pancreas from an autopsy; a pancreatic biopsy would be required to make this diagnosis in a living child.

Treatment and management

Pancreatic beta cell agenesis, like type 1 and some cases of type 2 diabetes mellitus, is treated by insulin injection.

Prognosis

Both children reported to have absence of beta cells were diagnosed on autopsy because they died at birth. The second child's prognosis was complicated by the fact that she had the additional MMA disorder. It is not known as of 2001 if any living children have pancreatic beta cell agenesis.

Resources

PERIODICALS

Abramowics, Marc J., et al. "Isodisomy of Chromosome 6 in a Newborn with Methylmalonic Acidemia and Agenesis of Pancreatic Beta Cells Causing Diabetes Mellitus." Journal of Clinical Investigation 94 (1994): 418–21.

Blum, D., et al. "Congenital absence of insulin cells in a neonate with diabetes mellitus and mutase-deficient methymalonic acidaemia." Diabetologia 36 (1993): 352–7.

ORGANIZATIONS

American Diabetes Association. 1701 N. Beauregard St., Alexandria, VA 22311. (703) 549-1500 or (800) 342-2383. <http://www.diabetes.org>.

Juvenile Diabetes Foundation International (JDF). 120 Wall St., New York, NY 10005. (212) 785-9500 x708 or (800) 533-2873. <http://www.jdf.org>.

Toni I. Pollin, MS, CGC