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At a glance

This extremely rare condition results in early-onset insulin-dependent diabetes mellitus (IDDM) and exocrine pancreatic insufficiency.

Synonym

Congenital Pancreatic Hypoplasia.

Incidence

Unknown. Approximately 10 cases of complete pancreatic agenesis and slightly more than 100 cases with partial pancreatic agenesis have been reported.

Genetic inheritance

Autosomal recessive. The genetic defect in Pancreatic Agenesis Type 1 results from mutations in the PDX1 (Pancreas/Duodenum Homeobox Protein 1; also known as IPF1 (Human Insulin Promoter Factor-1) gene, which is located on chromosome 13q12.2. Pancreatic Agenesis Type 2 is caused by mutations in the PTF1A (Pancreas Transcription Factor 1, Subunit Alpha) gene, which has been mapped to chromosome 10p12.2. An autosomal dominant inherited and most common form of pancreatic agenesis is caused by mutations in the GATA6 (GATA-Binding Protein 6) gene located on chromosome 18q11.2 and is associated with significant cardiac defects (in over 80% of patients; eg, truncus arteriosus, tetralogy of Fallot). Additional defects, that can include other endocrine disorders (pituitary agenesis, hypothyroidism), gastrointestinal malformations (gallbladder agenesis, biliary atresia, intestinal malrotation, microcolon), uterus bicornis, neurocognitive deficit, and seizures.

Pathophysiology

The neck, body, and tail of the pancreas develop from the dorsal bud and excrete through the accessory duct of Santorini and the minor papilla into the duodenum. The ventral bud forms the major part of the head and uncinate process, which excrete through the main duct of Wirsung and the major papilla into the duodenum. The PDX1 protein is critical for the development of the pancreas and is a key factor in the regulation of the insulin gene in the β-cells of the endocrine pancreas. Targeted disruption of the gene encoding PDX1 results in failure of the pancreas to develop (pancreatic agenesis). Intrauterine growth retardation appears to be related to the fact that insulin is a major intrauterine growth factor.

Diagnosis

Exclude ☞Mucoviscidosis, which is the most common cause of exocrine pancreatic insufficiency in childhood. The findings of intrauterine growth retardation (insulin is a known prenatal growth factor that does not cross the placenta in clinically significant amounts) and early-onset IDDM combined with clinical and biochemical evidence of pancreatic exocrine insufficiency may fit the diagnosis of congenital pancreatic aplasia/hypoplasia. In contrast to cases with absence of islets of Langerhans or complete pancreatic aplasia, serum levels of C peptide and glucagon may be measurable in partial aplasia. The diagnosis of pancreatic agenesis is difficult to establish in the newborn period. Abdominal ultrasound can be used as a screening tool. The size of the infant makes endoscopic retrograde cholangiopancreatography (ERCP) challenging (and hazardous) in inexperienced hands, and magnetic resonance cholangiopancreatography (MRCP) can be used instead. Clinical clues pointing to the diagnosis include intrauterine growth retardation, failure to thrive, persistent hyperglycemia, polyuria, glycosuria, and steatorrhea.

Clinical aspects

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