Winter et al. (1986) reported a syndrome of endocrine and exocrine pancreatic insufficiency in 2 brothers who were 'small for dates' at birth and had neonatal-onset insulin-dependent diabetes mellitus. In contrast to cases with absence of the islets ... Winter et al. (1986) reported a syndrome of endocrine and exocrine pancreatic insufficiency in 2 brothers who were 'small for dates' at birth and had neonatal-onset insulin-dependent diabetes mellitus. In contrast to cases with absence of the islets of Langerhans (304790), serum C-peptide and glucagon levels were measurable. Dourov and Buyl-Strouvens (1969) and Lemons et al. (1979) described absence (agenesis) of the pancreas. Intrauterine growth retardation appears to relate to the fact that insulin is a major intrauterine growth factor. Exocrine and endocrine tissues of the pancreas originate from common progenitor cells. Stoffers et al. (1997) stated that only 8 cases of pancreatic agenesis had been reported: Wright et al. (1993); Dourov and Buyl-Strouvens (1969); Mehes et al. (1976); Lemons et al. (1979); Howard et al. (1980); Widness et al. (1982); and Sherwood et al. (1974). Schwitzgebel et al. (2003) studied an infant girl, born of nonconsanguineous parents, who developed hyperglycemia at 12 days of life. She failed to thrive despite being on an insulin pump, and exocrine pancreatic insufficiency was diagnosed; after pancreatic enzyme replacement therapy was begun, she developed normally. Abdominal ultrasound and CT scan revealed no pancreas. There was a family history of type 2 diabetes on both sides (maternal and paternal uncles and grandmothers), and her mother had gestational diabetes. Both her mother and father had high normal fasting blood glucose levels, but no glucose intolerance. Thomas et al. (2009) described an infant boy who within 24 hours of life had elevated glucose levels requiring an insulin drip; at 3 weeks of age he was found to have severe exocrine pancreatic insufficiency. Management was difficult because of wide fluctuations in blood glucose concentrations in quick succession, inconstancy of appetite and feeding schedule, malabsorption, subcutaneous infections at the pump insertion site, and frequent illnesses. Although he had steady weight gain, he had not yet experienced catch-up growth at 18 months of age, with length at the fiftieth percentile for a 12-month-old child, and weight at the fiftieth percentile for a 6 month old. Ultrasound at 2 weeks of age appeared to show structurally normal mid and distal body of the pancreas, although an ultrasound 1 week later was interpreted as showing only the head of the pancreas. CT of the pancreas at 7 months of age was equivocal, and an ultrasound at 1 year of age revealed a small hypoechoic structure in the area of the pancreatic head; due to his small size, however, a definitive conclusion could not be made. His mother had gestational diabetes during both of her pregnancies, and his father had hyperglycemia treated with oral agents; Thomas et al. (2009) stated that both parents were later given a diagnosis of maturity-onset diabetes of the young (see MODY4 (606392) and Fajans et al., 2010). In addition, both maternal and paternal grandparents were being treated for type 2 diabetes. - Clinical Variability Nicolino et al. (2010) reported a boy and girl, first cousins born of consanguineous parents, who had permanent neonatal diabetes treated by insulin pump with excellent linear growth thereafter: both patients' weight, length, and bone age were within normal ranges at 4 years of age. Although there were no clinical signs of exocrine pancreas deficiency, biochemical investigation revealed low or undetectable serum lipase levels, and stool examination showed slightly increased fecal fat excretion, low chymotrypsin, and low elastase levels. In addition, IGF1 levels were very low, and vitamins A, D, E, and K levels were at the lower limits of normal, consistent with some degree of malabsorption. Abdominal ultrasound revealed a normal-sized pancreas in the boy, whereas the girl had a well-individualized and homogeneous head of the pancreas, but the body and tail of the pancreas could not be identified. Both sets of parents were healthy and nondiabetic, and none of the putative obligate carriers in the pedigree were reported to be diabetic. Oral glucose tolerance testing (OGTT) in the parents showed normal fasting plasma glucose and normal glucose tolerance, with preserved first-phase but reduced late-phase insulin secretory responses. With intravenous GTT, the first-phase insulin secretory response tended to be low, and was very low in the 2 fathers. Ultrasonography of the pancreas was normal in the 4 parents, and levels of serum lipase, IGF1, and vitamins A, D, E, and K were within normal ranges.
In a Caucasian female infant who presented with neonatal diabetes mellitus at birth and pancreatic exocrine insufficiency at 18 days of life, originally reported by Wright et al. (1993), Stoffers et al. (1997) identified homozygosity for a 1-bp ... In a Caucasian female infant who presented with neonatal diabetes mellitus at birth and pancreatic exocrine insufficiency at 18 days of life, originally reported by Wright et al. (1993), Stoffers et al. (1997) identified homozygosity for a 1-bp deletion in the PDX1 gene (600733.0001). There was a strong family history of noninsulin-dependent diabetes mellitus. In a later paper, Stoffers et al. (1997) demonstrated that members of the family who were heterozygous for the mutation had early-onset type 2 diabetes mellitus (MODY4; 606392). In an infant girl with pancreatic agenesis, Schwitzgebel et al. (2003) sequenced both exons of the PDX1 gene and identified compound heterozygosity for 2 missense mutations (600733.0008 and 600733.0009). Her parents, who had elevated fasting blood glucose levels but no glucose intolerance, were each heterozygous for 1 of the mutations, and 1 of the mutations was also detected in heterozygosity in a maternal uncle with type 2 diabetes. Thomas et al. (2009) reported a family in which a male infant with pancreatic agenesis, whose parents were later determined to have MODY, was homozygous for the same 1-bp deletion in the PDX1 gene previously identified by Stoffers et al. (1997) (600733.0001) in a similar family, originally reported by Wright et al. (1993). Thomas et al. (2009) suggested that the 2 families might be related. Fajans et al. (2010) restudied the family reported by Thomas et al. (2009), ultimately identifying 110 members of the 5-generation Michigan-Kentucky pedigree; 34 family members were being treated for diabetes, and 10 of those with diabetes carried the 1-bp deletion in PDX1 and were considered to have MODY4. Patients with MODY as well as those with type 2 diabetes (125853) were characterized by obesity and hyperinsulinemia. Fajans et al. (2010) identified a single 2.5-Mb region on chromosome 13 shared by the Michigan-Kentucky pedigree and a Virginia pedigree, originally reported by Wright et al. (1993), that also carried the 1-bp deletion in PDX1. The size of the shared region suggested that the PDX1 frameshift mutation emerged in a recent ancestor common to both probands, and that a complex pedigree structure connected the 2 probands. In a boy and girl, first cousins born of consanguineous parents, who had permanent neonatal diabetes mellitus with subclinical exocrine deficiency mapping to chromosome 13q21, Nicolino et al. (2010) sequenced the candidate gene PDX1 and identified homozygosity for a missense mutation (E178G; 600733.0010). The girl had partial agenesis of the pancreas, with only the head visualized on ultrasound, whereas the boy appeared to have a normal-sized pancreas by ultrasound. The 4 parents, who were all heterozygous for E178G, were asymptomatic and nondiabetic, but showed abnormalities in insulin secretory responses during glucose tolerance testing.