Heterotaxy syndrome is a rare congenital disorder characterized by abnormal arrangement of the thoracic and abdominal organs and is classified into polysplenia (left isomerism) and asplenia (right isomerism) syndromes. Polysplenia is associated with multiple splenic nodules, bilobed lungs, vascular anomalies, and organ malpositioning. In contrast, asplenia features bilateral trilobed lungs and eparterial bronchi, and is commonly associated with severe cardiac defects and high neonatal mortality. Here, we report 2 cases that illustrate the clinical spectrum of heterotaxy syndrome. The first case involved a 59-year-old female presenting with vague abdominal pain that was incidentally found to have features of polysplenia syndrome, including multiple splenules, malpositioned liver, partial pancreatic agenesis, and bilobed lungs. The second case was a 26-hour-old neonate who presented with cyanosis and respiratory distress and was diagnosed with right isomerism and complex congenital heart disease, including right ventricular outflow tract (RVOT) stenosis, atrioventricular canal defect, situs inversus, and asplenia. These cases highlight the varied presentations and anatomical complexity of heterotaxy syndrome, emphasizing the role of imaging in its diagnosis and clinical management.

The pancreas regulates metabolic homeostasis through exocrine and endocrine pathways. Dysfunction or loss of pancreatic β-cells causes diabetes. Here we explore the role of Polo-like kinase 1 (PLK1) in the pancreas using a pancreatic-lineage specific knockout (Plk1PKO) mouse model. Plk1PKO leads to partial pancreatic agenesis, diminishing pancreatic mass. Adult Plk1PKO mice exhibit diabetic syndromes including hyperglycemia, glucose intolerance, and insulin hypersensitivity. Plk1PKO mice also exhibit growth retardation and reduced skeletal muscle and adipose tissue masses. Furthermore, Plk1PKO mice develop metabolic adaptation towards fatty acid utilization, manifested by elevated oxygen consumption (VO2), reduced respiratory exchange ratio (RER), and more oxidative myofibers. These findings reveal a key role of PLK1 in pancreas development.

To report a case of diabetes mellitus (DM) associated with partial pancreatic agenesis and congenital heart disease (CHD) in a patient found to have a nonsense mutation of the GATA6 gene. We present the imaging, laboratory, and genetic findings, and describe the clinical course of a patient with an atypical presentation of DM as well as CHD, who was found to have partial pancreatic agenesis on computed tomography (CT) imaging. Genetic testing was performed to identify monogenic DM. A 30-year-old nonobese female with a waxing and waning pattern of insulin-dependent DM diagnosed at the age of 20 was found to have partial pancreatic agenesis on CT scan. It was unclear whether the patient was experiencing undetected hyperglycemia prior to initial diagnosis of DM. She had no history of diabetic ketoacidosis (DKA) despite poorly-controlled diabetes and years without insulin treatment. The patient also had congenital tricuspid atresia, ventricular septal defect, and transposition of the great vessels with surgical correction in childhood. Partial pancreatic agenesis and CHD with atypical DM prompted genetic testing for monogenic DM, and a nonsense mutation of the GATA6 (c.1242C>A, p.C414*) gene was found. GATA6 mutations are associated with a broad spectrum of diabetic phenotypes, pancreatic agenesis, and a variety of CHDs. This case highlights the importance of considering monogenic diabetes in young, nonobese patients with diabetes, particularly with negative pancreatic antibodies and no history of DKA. Further, this case demonstrates the importance of testing for GATA6 mutations in any young patient with diabetes and CHD.

Mutations in GATA6 are the most frequent cause of pancreatic agenesis. Most cases present with neonatal diabetes mellitus. The case was a female born after an uncomplicated pregnancy and delivery in a non-consanguineous family (3.59 kg, 70th percentile). Severe cardiac malformations were diagnosed at two and a half months old. No hyperglycaemic episodes were recorded in the neonatal period. Diabetes was diagnosed at 21 years due to the detection of incidental glycosuria. She had a low but detectable C-peptide level at diagnosis. Anti-GAD and Islet-cell antibodies were negative and she failed oral hypoglycaemic therapy and was started on insulin. Abdominal MRI revealed the absence of most of the neck, body, and tail of pancreas with normal pancreas elastase levels. Criteria for type 1 or type 2 diabetes were not fulfilled, therefore a next generation sequencing (NGS) panel was performed. A novel heterozygous pathogenic GATA6 mutation (p.Tyr235Ter) was identified. The GATA6 variant was not detected in her parents, implying that the mutation had arisen de novo in the proband. Rarely GATA6 mutations can cause adult onset diabetes. This report highlights the importance of screening the GATA6 gene in patients with adult-onset diabetes, congenital cardiac defects and pancreatic agenesis with no first-degree family history of diabetes. It also emphasizes the importance of genetic counselling in these patients as future offspring will be at risk of inheriting the variant and developing GATA6 anomalies.