Alternative titles; symbols
ORPHA: 2805; DO: 0061003;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q12.2 | Pancreatic agenesis 1 | 260370 | Autosomal recessive | 3 | PDX1 | 600733 |
A number sign (#) is used with this entry because of evidence that pancreatic agenesis-1 (PAGEN1) is caused by homozygous or compound heterozygous mutation in the PDX1 gene (600733) on chromosome 13q12.
Pancreatic agenesis-1 (PAGEN1) is an autosomal recessive disorder characterized by intrauterine growth retardation. Both endocrine and exocrine pancreatic insufficiency become apparent in the first few weeks or months of life (Winter et al., 1986; Schwitzgebel et al., 2003). Some patients exhibit subclinical exocrine deficiency (Nicolino et al., 2010).
Genetic Heterogeneity of Pancreatic Agenesis
Pancreatic agenesis-2 (PAGEN2; 615935) is caused by mutation in a distal enhancer of the PTF1A gene (607194), and pancreatic agenesis-3 (620991) is caused by mutation in the ZNF808 gene (620970).
Pancreatic and cerebellar agenesis (PACA; 609069) is caused by mutation within the PTF1A gene itself. Pancreatic agenesis associated with congenital heart defects (HDCA; 600001) is caused by mutation in the GATA6 gene (601656). Partial agenesis of the dorsal pancreas has also been reported (167755).
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.
Wildling et al. (1993) reported agenesis of the dorsal pancreas in a woman with diabetes mellitus and in both of her sons.
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.
The transmission pattern of PAGEN1 in the family reported by Stoffers et al. (1997) was consistent with autosomal recessive inheritance.
In a pedigree in which a boy and girl, first cousins born of consanguineous parents, had permanent neonatal diabetes mellitus with subclinical exocrine deficiency, Nicolino et al. (2010) performed a genome scan and identified a single 4.4-Mb region compatible with linkage to chromosome 13q12 (lod score, 3.24), between SNPs rs943721 and rs723918.
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.
Dourov, N., Buyl-Strouvens, M. L. Agenesie du pancreas: observation anatomo-clinique d'un cas de diabete sucre, avec steatorrhee et hypotrophie, chez un nouveau-ne. Arch. Franc. Pediat. 26: 641-650, 1969. [PubMed: 5802058]
Fajans, S. S., Bell, G. I., Paz, V. P., Below, J. E., Cox, N. J., Martin, C., Thomas, I. H., Chen, M. Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60. Transl. Res. 156: 7-14, 2010. [PubMed: 20621032] [Full Text: https://doi.org/10.1016/j.trsl.2010.03.003]
Howard, C. P., Go, V. L., Infante, A. J., Perrault, J., Gerich, J. E., Haymond, M. W. Long-term survival in a case of functional pancreatic agenesis. J. Pediat. 97: 786-789, 1980. [PubMed: 7000995] [Full Text: https://doi.org/10.1016/s0022-3476(80)80270-8]
Lemons, J. A., Ridenour, R., Orsini, E. N. Congenital absence of the pancreas and intrauterine growth retardation. Pediatrics 64: 255-257, 1979. [PubMed: 471619]
Mehes, K., Vamos, K., Goda, M. Agenesis of pancreas and gall-bladder in an infant of incest. Acta Paediat. Acad. Sci. Hung. 17: 175-176, 1976. [PubMed: 1027315]
Nicolino, M., Claiborn, K. C., Senee, V., Boland, A., Stoffers, D. A., Julier, C. A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency. Diabetes 59: 733-740, 2010. [PubMed: 20009086] [Full Text: https://doi.org/10.2337/db09-1284]
Schwitzgebel, V. M., Mamin, A., Brun, T., Ritz-Laser, B., Zaiko, M., Maret, A., Jornayvaz, F. R., Theintz, G. E., Michielin, O., Melloul, D., Philippe, J. Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J. Clin. Endocr. Metab. 88: 4398-4406, 2003. [PubMed: 12970316] [Full Text: https://doi.org/10.1210/jc.2003-030046]
Sherwood, W. G., Chance, G. W., Hill, D. E. A new syndrome of pancreatic agenesis: the role of insulin and glucagon in somatic cell growth. Pediat. Res. 8: 360 only, 1974.
Stoffers, D. A., Ferrer, J., Clarke, W. L., Habener, J. F. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. (Letter) Nature Genet. 17: 138-141, 1997. [PubMed: 9326926] [Full Text: https://doi.org/10.1038/ng1097-138]
Stoffers, D. A., Zinkin, N. T., Stanojevic, V., Clarke, W. L., Habener, J. F. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nature Genet. 15: 106-110, 1997. [PubMed: 8988180] [Full Text: https://doi.org/10.1038/ng0197-106]
Thomas, I. H., Saini, N. K., Adhikari, A., Lee, J. M., Kasa-vubu, J. Z., Vazquez, D. M., Menon, R. K., Chen, M., Fajans, S. S. Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 pro63fsX60 mutation. Pediat. Diabetes 10: 492-496, 2009. [PubMed: 19496967] [Full Text: https://doi.org/10.1111/j.1399-5448.2009.00526.x]
Widness, J. A., Cowett, R. M., Zeller, W. P., Susa, J. B., Rubenstein, A. H., Schwartz, R. Permanent neonatal diabetes in an infant of an insulin-dependent mother. J. Pediat. 100: 926-929, 1982. [PubMed: 7045311] [Full Text: https://doi.org/10.1016/s0022-3476(82)80517-9]
Wildling, R., Schnedl, W. J., Reisinger, E. C., Schreiber, F., Lipp, R. W., Lederer, A., Krejs, G. J. Agenesis of the dorsal pancreas in a woman with diabetes mellitus and in both of her sons. Gastroenterology 104: 1182-1186, 1993. [PubMed: 8462806] [Full Text: https://doi.org/10.1016/0016-5085(93)90290-s]
Winter, W. E., Maclaren, N. K., Riley, W. J., Toskes, P. P., Andres, J., Rosenbloom, A. L. Congenital pancreatic hypoplasia: a syndrome of exocrine and endocrine pancreatic insufficiency. J. Pediat. 109: 465-468, 1986. [PubMed: 3746536] [Full Text: https://doi.org/10.1016/s0022-3476(86)80119-6]
Wright, N. M., Metzger, D. L., Borowitz, S. M., Clarke, W. L. Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis. Am. J. Dis. Child. 147: 607-609, 1993. [PubMed: 8506821] [Full Text: https://doi.org/10.1001/archpedi.1993.02160300013005]