Published online June 2, 2008
PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1541-e1547 (doi:10.1542/peds.2007-3543)
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ARTICLE

Neonatal and Late-Onset Diabetes Mellitus Caused by Failure of Pancreatic Development: Report of 4 More Cases and a Review of the Literature

Rongrong Chen, MSca, Khalid Hussain, MDb,c, Maryam Al-Ali, MDd, Mehul T. Dattani, FRCPCHb,c, Peter Hindmarsh, FRCPCHb,c, Peter M. Jones, PhDa and Phil Marsh, PhDa

a Beta Cell Development and Function Group, Division of Reproduction and Endocrinology, King's College London, London, United Kingdom
b London Centre for Paediatric Endocrinology and Metabolism, Great Ormond Street Hospital for Children, National Health Service Trust, London, United Kingdom
c Institute of Child Health, London, United Kingdom
d Department of Paediatric Endocrinology, Hamad Hospital, Doha, Qatar


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Permanent neonatal diabetes mellitus caused by developmental failure of the pancreas is rare. Thus far, only a few genetic causes have been reported. We now report the clinical and genetic aspects of 4 more cases of permanent neonatal diabetes mellitus caused by pancreatic agenesis or hypoplasia.

PATIENTS AND METHODS. All 4 of the patients were from consanguineous kinships, and all presented with diabetes mellitus and pancreatic exocrine insufficiency. Three patients had pancreatic agenesis, and 1 had pancreatic hypoplasia on computed tomography scan. DNA was extracted from blood samples of patients and unaffected family members. Specific genes were amplified by polymerase chain reaction and characterized by DNA sequencing.

RESULTS. Several genes that encode transcription factors that have known roles in pancreas development were characterized in the affected children and unaffected family members. These genes include Pdx1, the master regulator of pancreas development and β-cell differentiation, and other transcription factors that are expressed early in pancreas development, namely, Ptf1a, Sox9, Sox17, Hnf6, and HlxB9. Several novel polymorphisms were found in our patients. However, these were also present in unaffected individuals. No disease-causing mutations were found in any of these genes.

CONCLUSIONS. These findings add to the 4 cases already in the literature in which the Pdx1 structural gene has been found to be normal in patients with pancreatic agenesis or hypoplasia. The analysis here has been extended to include the screening of 4 other candidate genes in addition to promoter elements upstream of the Pdx1. Two of the cases occurred in a sibling pair, and 2 were isolated, so there may be more than 1 etiology in the cases reported here.

Key Words: pancreatic agenesis • pancreatic hypoplasia • neonatal diabetes mellitus • pancreatic insufficiency • Pdx1 gene • Ptf1a gene • Sox9 gene • Sox17 gene • Hnf6 gene • Hlxb9 gene

Abbreviations: IUGR—intrauterine growth retardation • CT—computed tomography • PCR—polymerase chain reaction

Neonatal diabetes mellitus can be either transient or permanent. The transient form of the disease, in the majority of cases, is attributable to an abnormality in an imprinted region of chromosome 6.1 Permanent neonatal diabetes mellitus may occur as a result of developmental abnormalities of the pancreas (such as pancreatic agenesis or hypoplasia) or defects in the genes encoding the pancreatic β-cell ATP-sensitive potassium channels.2,3 Permanent neonatal diabetes mellitus has also been reported to be caused by mutations in the glucokinase gene4 and in association with some rare syndromes.5

There are 19 reports of permanent neonatal diabetes mellitus caused by pancreatic agenesis in the literature. We add to those existing reports an additional 3 cases of pancreatic agenesis and 1 of pancreatic hypoplasia.

In 6 of the 19 cases, the genetic cause has been reported. Two were caused by mutations in a homeodomain transcription factor, Pdx1,6,7 that normally functions in the pancreas development, as well as in insulin gene expression.8 The parents were found to be mutation carriers, whereas the affected children had 2 mutant copies of the Pdx1 gene. In the case reported by Stoffers et al,6 the mutations led to the synthesis of a truncated protein that lacked the homeodomain and failed to bind its target sequence on DNA. A compound heterozygous mutation in Pdx1 was found in the case described by Schwitzgebel et al7 to yield PDX1 protein with a reduced half-life. Both patients with defective Pdx1 developed normally after treatment with insulin and pancreatic enzymes.

Four cases of neonatal pancreatic agenesis were reported by Sellick et al,9 who identified mutations in the transcription factor Ptf1a gene as the genetic defect. In these cases that occurred in 2 consanguineous families, other congenital malformations were seen. The affected children also had cerebellar agenesis, and none survived infancy. The affected subjects had inherited 2 copies of the mutant gene, the parents being carriers for a shared ancestral mutation.

The causes of the remaining 13 clinical cases of pancreatic agenesis remain unknown, but in 4 of the subjects, mutations in the coding sequence of the Pdx1 gene, the master regulator of pancreas development and β-cell differentiation, have been excluded.10–12 These cases suggest that mutations in other genes may be responsible for defective pancreatic development. Much of what is currently known about the genetic control of pancreas formation in development (reviewed in refs 13–15) has been gained from animal models. The gut endoderm cells that develop into the pancreas are characterized by the expression of lineage-restricted transcription factors in addition to Pdx1. In the early stages, where the precursor cells are specified and then transitioned to pancreatic bud, transcription factors including Ptf1a,16 Sox17,17 Hlxb9,18 and Hnf619 have all been shown to have important roles. Subsequent bud growth and differentiation into the component pancreas cells is characterized by expression of genes later in the transcriptional cascade, including Hes1, Delta1, Isl1, Ngn3, NeuroD1, Nkx2.2, Nkx6.1, Brn4, and Pax6 (reviewed in refs 13–15). In mice, Sox9 expression has been shown to maintain embryonic pancreatic precursor cells by inhibition of apoptosis.20

In the cases we report here, 2 of the patients with pancreatic agenesis occurred as siblings in 1 family. The third was an apparently isolated case in a separate pedigree, although from the same area in Qatar. The 3 patients with pancreatic agenesis presented with neonatal diabetes mellitus pancreatic exocrine insufficiency and low birth weight. The fourth patient had pancreatic hypoplasia and presented with diabetes mellitus and pancreatic exocrine insufficiency at the age of 1.5 years. None was diagnosed with any other developmental abnormality, and all came from consanguineous families. In these circumstances, the likely cause is a mutation, homozygous in affected individuals, that specifically affects pancreas development. The pancreas-specific nature of the developmental defect restricts the number of known candidate genes that could be responsible and we describe here characterizing those candidates by DNA sequence analysis.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
All of the patients had been referred to Great Ormond Street Children's Hospital National Health Service Trust with neonatal diabetes mellitus, 3 of the 4 with intrauterine growth retardation (IUGR). Their clinical data are summarized in Table 1.


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  		TABLE 1 Clinical Data Summary for the 4 Patients

 
Patient 1 (boy) and patient 2 (girl), were both diagnosed with neonatal diabetes mellitus in the first 4 weeks of life. They had marked hyperglycemia with undetectable serum insulin/C-peptide levels. Computed tomography (CT) scans confirmed pancreatic agenesis. The parents are first cousins with no symptoms of diabetes and normal fasting blood glucose concentrations. In the family history, a previous child with what were reported as "similar problems" died at age 89 days. Blood samples were obtained from the 2 probands, as well as 6 unaffected close relatives, 4 siblings and both parents.

Case 3 is an apparently isolated case of a girl who presented with diabetes mellitus and pancreatic exocrine insufficiency at the age of 1.5 years. Her weight at birth was 3 kg, and she presented with polyuria, polydipsia, pale stools, and weight loss. The diagnosis of pancreatic hypoplasia was based on ultrasound and CT scans of the abdomen, which showed the pancreas as a tiny bud. Her parents are first cousins, with no symptoms of diabetes mellitus. In the family, 2 brothers and 1 sister are healthy with a normal fasting blood glucose level.

Case 4 is an apparently isolated case of a 3-year-old boy who was diagnosed with neonatal diabetes mellitus in the first 2 weeks. Ultrasound and CT scans indicated pancreatic agenesis. An abdominal CT scan of this patient is shown in Fig 1. His parents are first cousins with normal fasting blood glucose concentrations. A previous child in the family miscarried.


Figure 1
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  		FIGURE 1 Abdominal CT scan of patient 4. The CT scan was performed through the abdomen after intravenous contrast in arterial and portal venous phases. No pancreatic tissue was identified in the retroperitoneum, consistent with a diagnosis of pancreatic agenesis.

 
Isolation of Genomic DNA
The blood samples were obtained with informed consent from the patients in Qatar through Great Ormond Street Children's Hospital National Health Service Trust, and genomic DNA was isolated by using a QIAamp DNA blood mini kit (Qiagen, Crawley, West Sussex, United Kingdom) according to the maker's protocol.

Gene-Specific Amplification
Candidate genes were polymerase chain reaction (PCR) amplified by using 50 to 100 ng of genomic DNA template. The primers for the 5 genes tested are listed Table 2 below.


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  		TABLE 2 Primers Used for Gene Amplification and Sequencing

 
DNA Sequencing
PCR products were separated from reaction precursors by isopropanol precipitation and checked by agarose gel electrophoresis and ethidium bromide staining. Sequence was determined by using BigDye Terminator 1.1 (Applied Biosystems, Foster City, CA) to generate products that were separated and read on an ABI 310 or ABI 3130 genetic analyzer (Foster City, CA). All of the sequences were determined in the forward and reverse directions to confirm the base calling.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The Pdx1 structural genes were obtained by PCR-amplification of DNA isolated from the 4 patients’ blood using primers indicated in Table 2. The same primers were used in DNA sequencing. Patient sequences were compared with the prototype Pdx1 in a GenBank (accession Nos. AF03529 and AF035260) sequence and revealed no differences either in the coding sequence or the intron-exon splice sites. The discovery that pancreatic agenesis can be caused by a short half-life variant of Pdx17 suggests pancreatic development is sensitive to the level of PDX1 expression. Thus, a promoter sequence upstream of the Pdx1 gene was also sequenced. This revealed a sequence difference at position –176 (relative to the transcription start site) within the middle 1 of the 3 E-boxes. The database prototype sequence (GenBank accession No. AF192496) at this position is a G; patient 2 was homozygous A, and patients 1, 3, and 4 were heterozygous G/A. All of the 6 unaffected relatives of patients 1 and 2 were also tested: 2 were A/A and 4 were A/G, indicating that the sequence difference was not disease associated but was a polymorphism that has not been reported previously.

Alignment of Sox9, Sox17, and Ptf1a from all of the patients to the human genome prototype sequences (GenBank accession Nos. NM_000346, NC_000008, and BK000272, respectively) showed complete identity in coding regions, as well as splice sites. Hnf6 sequences encode proteins that are identical to the database. The only difference was a silent change in the proline codon at position 94 (CCC -> CCG) in patients 1 and 2, and this seems to be a polymorphism without disease relevance.

The transcription factor HlxB9 sequences in patients were identical to the Genbank sequence AF107452, except for a polyalanine stretch encoded in exon 1. The database prototype has a total of 14 alanines, of which 11 are encoded by the triplet GCC. Patients 1 and 4 have 16 alanines with 11 encoded by GCC repeats, and patient 3 has 14 alanines, of which 9 are encoded by GCC repeats. The parents of patients 1 and 2 were also sequenced and revealed the mother to be homozygous for 16 alanines, with 11 encoded by GCC repeats in the polyalanine tract, which is the same as patient 1. The father is heterozygous, 1 allele with 11 alanine codons containing 6 GCC repeat, the other 16 alanines, 11 encoded GCC, which is the same as patient 2. All of the polyalanine tract lengths that occur in affected individuals also appear in unaffected relatives, so they are presumed to be polymorphisms with no relevance to disease. In an analysis of HlxB9 alleles by Ross et al,21 no pathogenic association was made with the length of the polyalanine tract.


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
In this study, we report 3 cases of pancreatic agenesis and 1 case of pancreatic hypoplasia. The 3 patients with pancreatic agenesis presented with permanent neonatal diabetes mellitus, whereas the child with pancreatic hypoplasia presented with diabetes mellitus at the age of 1.5 years. All of the patients presented with evidence of pancreatic exocrine insufficiency. Two of the patients with pancreatic agenesis, patients 1 and 2, are siblings from an affected pedigree that had ≥1 other undiagnosed case. Patient 4 also lacked a pancreas, as judged by a CT scan. Information on the pedigree is limited but gives no indications of diabetes mellitus elsewhere in the family. The patient with pancreatic hypoplasia, patient 3, showed incomplete pancreas development, composing a tiny bud on a CT scan. It is notable that, in all of the patients we report here, the parents of the probands are first cousins. These pedigrees strongly suggest a genetic cause with unaffected carriers having a single copy of an ancestral mutation that has a severe phenotype when both copies are inherited.

A small number of patients with neonatal diabetes mellitus caused by the failure of pancreatic development have been reported in the literature. We know of just 19 previous subjects, and most of these died shortly after birth and suffered from other congenital malformations. Sellick et al,9 for example, reported 4 cases of neonatal pancreatic agenesis in 2 consanguineous Pakistani families. The children also had cerebellar agenesis, and none survived infancy. In these patients, the disease was traced to mutations in the transcription factor Ptf1a. The affected patients had inherited 2 copies of the mutant gene, the parents being carriers for the same ancestral mutation. Of the 19 previously reported patients, 6 were analyzed for Pdx1 mutations. Two patients have been ascribed to Pdx1 mutations; 4 patients had no abnormalities in coding sequences and splicing sequences of the Pdx1 gene. A summary of the cases of pancreatic agenesis, including the 4 reported here, is in Table 3.


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  		TABLE 3 Summary of Reported Cases of Pancreas Agenesis/Hypoplasia

 
In the patients we report on here, the neonates showed diabetes mellitus with pancreatic exocrine insufficiency but had no other detectable congenital abnormalities on CT scan or clinical examination other than the failure of pancreas development. In addition, the 3 patients with no detectable pancreas showed IUGR. To find the underlying cause, we chose to adopt a "candidate gene" approach. First, information from previously published studies of gene deletion in mice or of mutations in humans was used to identify genes of which the dysfunction is associated with a failure in pancreas development. This long list of candidate genes was then reduced by focusing on those causing pancreas-specific defects, because the patients reported in this study had no detectable developmental abnormalities other than failure of pancreas development. We initially investigated the Pdx1 gene, because this has a pivotal and specific role in pancreas development. Human embryonic data are lacking, but in the developing mouse, its expression is first detected at e8.5 in endodermal cells. A day later, the Pdx1 gene is expressed both in the dorsal and ventral pancreatic buds, and during pancreas development its expression is detected throughout the developing pancreatic epithelium. Patients similar to ours, described by Stoffers et al6 and Schwitzgebel et al,7 had been shown to have mutant Pdx1. In the case reported by Stoffers et al,6 the mutation led to the synthesis of a truncated protein that lacked the homeodomain and failed to bind its target sequence on DNA. A compound heterozygous mutation in Pdx1 was found in the case described by Schwitzgebel et al7 to yield protein with a reduced half-life. Both patients with defective Pdx1 developed normally after treatment with insulin and pancreatic enzymes.

To study our patients, genomic DNA was isolated, and both exons of Pdx1 were amplified by PCR. Primers for PCR were designed to lie in a flanking intronic sequence to allow propagation of the coding sequence, as well as the splice sites, because mutations in splice sites have been implicated in some 20% of genetic diseases.22 Sequencing of the amplified DNAs did not reveal any difference from the prototype Pdx1 sequence. To establish whether Pdx1 expression may have been abnormal in the fetal development of our patients, promoter sequences were determined. Integrity of the E-box sequences in the promoter upstream of the gene has been shown to be critical for Pdx1 expression in culture.23 The consensus for E-box sequences is 5'-CANNTG, and there are 3 that lie 95 to 195 base pairs (bp) upstream of the Pdx1 transcription start site. The second of the 2 Ns is a G in the database entry (Genbank accession No. AF192496). Patient 2 was homozygous A, and patients 1, 3, and 4 were heterozygous G/A. All of the 6 unaffected relatives of patients 1 and 2 were also tested: 2 were A/A, and 4 were A/G, suggesting that the sequence difference was a polymorphism without obvious disease association.

This work adds to that of other groups that have found the structural gene for Pdx1 to be present but unmutated10–12 in apancreatic children. Furthermore, we have ruled out coding and splicing mutations in a series of other transcription factors (Sox17, Sox9, Hlxb9, Ptf1a, and Hnf6) that are expressed early in pancreas development, that are close to Pdx1 in the transcriptional cascade that regulates pancreatic development, and in which mutations and deletions have been associated with the failure of pancreas development. These candidate genes are less pancreas specific than Pdx1 and encode products used in different cells or with signaling functions on multiple targets. It would, therefore, be unlikely that these genes would be found to have been deleted, because pleiotropic effects would result. Rather, we would predict a point mutation that causes a single amino acid substitution that alters the protein to affect its activity in a subset of cells. For example, Hlxb9 deletion in mice causes a failure of dorsal pancreas development,18 whereas Hlxb9 mutations in humans are associated with Currarino syndrome, which covers a broad spectrum of phenotypes but not pancreatic agenesis.24,25 This gene was included in our candidate list because it seemed possible that an as-yet-unreported HLXB9 mutation may be responsible for the phenotype of our patients. However, despite some polymorphisms in these candidate genes, none of our probands contained sequences that were not also present in unaffected relatives.

The findings reported here allow us to eliminate the coding and splicing sequences of Pdx1, Sox17, Sox9, Hlxb9, Ptf1a, and Hnf6. Our data do not address whether expression of any of these genes was at the correct level or at the correct time in development. It may be possible to deduce such information from patients’ DNA alone by promoter analysis. We have analyzed the E-boxes upstream of Pdx1 that have been shown to be critical for Pdx1 expression in cell-based reporter assays.23 This uncovered a single-base polymorphism in the gene-proximal E-box, but because this occurs both in probands and unaffected relatives, it is unlikely to be pathologic.

The candidate gene approach, by definition, is not all inclusive, and several genes known to be involved in pancreas development were excluded from our investigation because of their involvement in the development of other organs. For example, deletion of Hnf1β in mice causes pancreatic agenesis,26 although the Hnf1β–/– phenotype is embryologically lethal because of defective visceral endoderm formation.27 In humans, mutations in Hnf1β are associated with the maturity onset diabetes of the young type 5 phenotype, severe forms of which are sometimes associated with pancreatic hypoplasia.28 However, these mutations are also associated with abnormal urogenital development and with severe kidney defects, which are diagnostic for fetal termination. These phenotypes were inconsistent with those of our patients, so Hnf1β was excluded from our list of candidate genes. Pbx1 is another homeodomain transcription factor of which the inactivation is associated with failure of pancreas development,29 but which also has pleiotropic effects in other organs,30 leading to its exclusion from the current study.


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The precise molecular events that lead to pancreas development in humans await elucidation. Unraveling the molecular mechanisms of pancreatic developmental will be vital to developing stem cell approaches to treating diabetes mellitus. Our approach to tracing the mutations responsible for the failure to form a pancreas in our patients has been to analyze the major candidate genes. These candidates have been selected on knowledge derived from mouse models, in particular, gene ablation studies, and some human studies. Although this approach is focused and allows rapid screening of known genes, it cannot discover new genes that may be crucial for the development of the human, but not rodent, pancreas. Additional studies are required to define the autozygous regions of the genome that are common to affected individuals in which the mutation localizes.


   ACKNOWLEDGMENTS
 
This work was supported by Diabetes United Kingdom grant BDA:RD05/0003163.


   FOOTNOTES
 
Accepted Dec 13, 2007.

Address correspondence to Phil Marsh, PhD, King's College London, Hodgkin Building, Guy's Campus, London SE1 9UL, United Kingdom. E-mail: phil.marsh{at}kcl.ac.uk or Khalid Hussain, Great Ormond Street Children's Hospital NHS Trust and Institute of Child Health, London WC1N1EH, United Kingdom. E-mail: k.hussain{at}ich.ucl.ac.uk

The authors have indicated they have no financial relationships relevant to this article to disclose.

Drs Chen and Hussain contributed equally to this work.


What's Known on This Subject

Few cases of diabetes mellitus caused by pancreas-development failure have been reported. Knowledge of the underlying etiology is scant, but mutations in the structural gene of Pdx1 lead to pancreatic agenesis in both humans and mice.

 

What This Study Adds

We present 4 more cases of permanent diabetes mellitus caused by pancreas-development failure. All of the patients were from consanguineous kinships, and none presented with other developmental abnormalities. Pdx1 and other known genes that trigger pancreas development were normal.

 


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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