Abstract
Pancreas agenesis is a rare condition underlying a variant of permanent neonatal diabetes mellitus. Neonates with this condition are born small for gestational age, but less is known about which components of growth are impacted, the timing of the growth restriction and potential sex differences. Our objective was to assess in which periods in gestation complete pancreas agenesis restricts fetal growth and possible sex differences in susceptibility. Published cases (n = 49) with pancreas agenesis providing relevant data (gestational age, fetal sex, birth weight, birth length, head circumference, placental weight) were identified by MEDLINE and secondary literature search covering the years 1950–January 2023. Semiquantitative analysis of these case reports used centiles based on Intergrowth-21 reference charts. Neonates with pancreas agenesis were severely growth restricted; however, median centiles for birth weight, birth length, and head circumference of those born before week 36 were significantly higher compared to those born from 36 weeks. Similar results were found when data were separated by before and from 38 weeks. Head circumference was less affected than birth weight or birth length. No sex differences were found. In conclusion, pancreas agenesis severely restricts fetal length and head circumference in addition to weight growth, with stronger effects evident from 36 weeks of gestation. In addition to the well-known effects of insulin on growth of fetal fat mass, the pronounced effect on birth length and head circumference indicates effects of insulin on fetal lean body growth as well. Lack of power may account for failure to find sex differences.
Significance statement
Neonates with complete pancreas agenesis are born small, but the details of their growth deviation, timing, and potential sex differences remain uncertain. All neonates with pancreas agenesis in our study had reduced birth weight, length, and head circumference, with milder effects in those born before 36 weeks compared to after 36 weeks. This trend persisted when data were separated into before and after 38 weeks, with no discernible sex differences. The absence of the pancreas, and therefore insulin, significantly reduces fetal growth, especially after 36 weeks of gestation. In addition to insulin’s known role in fetal fat mass, our findings suggest it has a substantial influence on birth length and head circumference, underscoring its impact on fetal lean body growth.
Introduction
Pancreas agenesis (PA) is a very rare condition that causes permanent neonatal diabetes mellitus (PNDM) and pancreatic exocrine insufficiency. It presents most commonly with neonatal hyperglycemia in small for gestational age babies. PA can be (i) partial, commonly with absence of the dorsal pancreas, or (ii) complete, with both dorsal and ventral pancreas missing. PA is caused by genetic abnormalities with an increasing number of transcription factor mutations having been identified, including in GATA6, PDX1, and PTF1A (1, 2, 3).
In cases of complete PA, insulin, a major fetal growth regulator, and C-peptide concentrations are usually below the limit of detection in cord blood. The importance of insulin and other pancreatic hormones for fetal growth through the embryonic and fetal stages of development until delivery is not well understood. Thus, studying the consequences of absence of the pancreas may allow important insights in fetal growth regulation by pancreatic hormones.
So far, mainly case reports or qualitative reviews of the literature on PA have been published. Recently, effects of fetal insulin absence on fetal growth in neonates known to have either recessive absence of the INS1 gene or genes mutation known to cause PA has been reported (4). In this article we report a semiquantitative analysis of literature data of PA cases, with inclusion only of cases with confirmed complete PA. The aim was to answer the following two research questions:
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From which gestational age is fetal growth compromised by PA? We hypothesized that the impact of a lack of insulin would be greatest during the last weeks of pregnancy, when in normal pregnancies fetal insulin concentrations increase as reflected by increasing cord blood C-peptide concentrations (5).
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Are there sex differences in the effect of PA on fetal growth? Both sexes follow different growth trajectories and fetal insulin is associated with length and weight in a sex-specific manner (6, 7).
Methods
Data acquisition
A MEDLINE search was performed in early January 2023 using the keywords ‘pancreas’ or ‘pancreatic’ combined with the keywords ‘agenesis’ or ‘aplasia’. Furthermore, bibliographies of retrieved articles were reviewed for additional citations. We only selected cases with confirmed complete PA (no pancreas detected on ultrasound or postmortem). In total 38 reports were found, describing 49 cases of complete PA, including reports from 1969 until 2022. Outcomes of interest were the following parameters: sex, birth weight, birth length, and head circumference. When placental weight and/or a genetic diagnosis were reported, they were also recorded. When data were missing in the case report, authors were contacted and asked to provide missing information. Of the 26 authors contacted, 8 replied, and 4 of them were able to provide additional data.
Data analysis
To standardize for gestational age at birth and to harmonize the data, birth weight, birth length, and head circumference were transformed into centiles for each week of gestation using Intergrowth-21 reference charts (8). Since the charts are for gestational age of 24 weeks or more, cases born before 24 weeks were excluded (n = 3). When fetal sex was unknown, the average of the centiles for males and females was used. When no specific gestational age was reported, only ‘near term’ or ‘at term’ a gestational age of 40 weeks was assumed. To calculate the centiles of placental weight, a published centile chart was used, which began at 24 weeks of gestation (9). The differences between the centiles listed for each gestational age in this table was presumed linear, which enabled us to calculate the specific centile by linear interpolation (8).
The cases were separated into subgroups based on gestational age at birth (<36 weeks, ≥36 weeks and <38 weeks, ≥38 weeks), neonatal sex or genetic diagnosis. Differences between subgroups were tested using the Mann–Whitney U test with P < 0.05 as significance level.
Results
Of the 49 case reports of complete pancreas agenesis (2, 3, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46), 43 reported neonatal sex (20 female, 23 male). The pregnancies were all singleton. Of four cases, no data on birth weight, birth length, head circumference, or placenta weight were available, and of three cases, gestational age at birth was unknown, and no centiles could be calculated. The median duration of pregnancy was 37 weeks (range 15–41 weeks). Fifteen neonates were born before 36 weeks of gestation, 10 in week 36 or 37, and 21 offspring from 38 weeks of gestation.
Anthropometric characteristics of the neonates are described in Table 1. Median centiles of birth weight, birth length, and head circumference were 0.5, 0.7, and 13.4, respectively. More detailed information, including method of PA diagnosis and genetic analysis findings of each case, are shown in Table 2.
Anthropometric characteristics of the neonates (n = 49).
| Neonatal characteristic | n | Median (IQR) or n (%) | n | Median centile (IQR) |
|---|---|---|---|---|
| Gestational age at birth, weeks | 46 | 37 (34–39) | − | − |
| Female sex | 43 | 20 (42%) | − | − |
| Birth weight, kg | 45 | 1.62 (1.34–1.97) | 41 | 0.5 (0.02–2.6) |
| Birth length, cm | 19 | 41.0 (40.0–44.0) | 19 | 0.7 (0.0–11.9) |
| Head circumference, cm | 15 | 31.0 (30.0–32.0) | 15 | 13.4 (0.5–22.3) |
IQR, interquartile range.
Characteristics of the cases found for the analysis.
| Author | Reference | Sex | Gestational age (week) | Live birth | Birth weight (g, %) | Birth length (cm, %) | Head circumference (cm, %) | Diagnosis of pancreas agenesis | Genetic mutation | NDM | Syndrome reported |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Al-Shammari et al.a | (33) | M | 36 | Yes (4 m) | – | – | – | US | Mutation in PTF1A | Yes | Cerebellar agenesis, optic atrophy |
| Ashraf et al. | (2) | F | 40 | Yes | 1610 (0.01) | 41 (0) | 31 (0.68) | CT and surgical exploration | No mutation in Pdx1 or IPF1 | Yes | Atrial and ventricular septal defects, absent gallbladder |
| Barbarini et al. | (25) | F | 34 | Yes | 1570 (5.58) | 41 (2.88) | 31.6 (65.73) | MRI | No mutation found in chromosome 6, KCNJ11, ABCC8, IPF1, PTF1A, HNF1beta | Yes | Diaphragmatic hernia |
| Baumeister et al. | (20) | F | 32 | Yes | 1010 (0.58) | 36 (1.11) | 28 (22.26) | Repeated US | NA | No | Absent gallbladder, double outlet right ventricle |
| Body-Bechou et al. | (29) | M | 30 | No | 1530 (71.33) | – | – | PM | Mutation in TCF2 | NA | Bilateral multicystic renal dysplasia, bilateral clubfoot |
| Body-Bechou et al. | (29) | M | 22 | No | 511 (NA) | – | – | PM | Mutation in TCF2 | NA | Bilateral multicystic renal dysplasia |
| Bruce and Coutts | (40) | M | 37 | Yes (2 days) | 2340 (8.14) | 47 (31.99) | 32.2 (24.96) | PM | NA | NA | Agenesis of midgut and superior mesenteric artery |
| Chao et al.a | (39) | M | Term | Yes | – | – | – | CT | Mutation in GATA6 | Yes | Atrial septal defect, Patent Ductus Arteriosus |
| Chao et al.a | (39) | M | Term | Yes | – | – | – | Endoscopic retrograde cholangio-pancreatography | Mutation in GATA6 | Yes | Cystic duct, gallbladder absent, mitral valve stenosis and patent ductus arteriosus |
| Chen et al. | (21) | M | 39 | Yes | 2800 (13.16) | – | – | CT | No mutation in PDX1, SOX17, HLXB9, PTF1A, and HNF6 | Yes | No |
| Chen et al. | (21) | F | 39 | Yes | 2400 (2.62) | – | – | CT | No mutation in PDX1, SOX17, HLXB9, PTF1A, and HNF6 | Yes | No |
| Chen et al. | (21) | M | 38 | Yes | 2300 (2.68) | – | – | US and CT | No mutation in PDX1, SOX17, HLXB9, PTF1A, and HNF6 | Yes | No |
| Cospain et al.a | (43, 44) | F | 15 | No | 71 (NA) | – | – | PM | Mutation in CNOT1 | NA | Dysmorphic features, cleft lip, semi lobar holoprosencephaly, absent corpus callosum |
| De Franco et al. | (44) | F | 38 | Yes | 1340 (0.01) | 41 (0.02) | 30 (0.52) | US and MRI | Mutation in CNOT1 | Yes | Absent gallbladder, lobular holoprosencephaly with dysplastic frontal horns of the lateral ventricles, missing septum pellucidum, broadly joined cella media of the lateral ventricles, and hypoplasia of the corpus callosum |
| De Franco et al. | (44) | M | 39 | Yes | 1900 (0.10) | – | – | US | Mutation in CNOT1 | Yes | Mild dysmorphic features |
| Demirbilek et al. | (3) | -- | 31 | Yes | 1500 (49.50) | -- | -- | Pancreatic imaging | Mutation in PTF1A | Yes | Developmental delay |
| Demirbilek et al. | (3) | – | 39 | Yes | 2400 (2.25) | – | – | Pancreatic imaging | Mutation in PTF1A | Yes | No |
| Demirbilek et al. | (3) | – | 32 | Yes | 1200 (3.92) | – | – | Pancreatic imaging | Mutation in PTF1A | Yes | Neonatal cholestatis |
| Dodge et al. | (13) | M | 39 | Yes (3 days) | 2130 (0.4) | 50 (66.64) | 33 (21.68) | PM (no pancreatic islets present in histological examination) | NA | Yes | NA |
| Dourov et al. | (10) | F | 33 | Yes (19 days) | 1800 (44.55) | 42 (22.28) | 31 (65.55) | PM | NA | No | Absent gallbladder |
| Evliyaoglu et al. | (37) | F | 37 | Yes | 1900 (0.81) | – | – | US | Mutation in PTF1A | Yes | No |
| Evliyaoglu et al. | (37) | F | 37 | Yes | 1520 (0.06) | – | – | US and MRI | Mutation in PTF1A | Yes | Foramen ovale, pulmomary stenosis |
| Gabbay et al. | (32) | M | 37 | Yes | 1935 (1.00) | 43 (0.65) | 32 (20.03) | US | Mutation in PTF1 No mutation in KCNJ11, ABCC8, INS, EIF2AK3, FOXP3, GATA4, GATA6, GCK, GLIS3, HNF1B, IER3IP1, PDX1, PTF1A, NEUROD1, NEUROG3, NKX2-2, RFX6, SLC2A2, SLC19A2, STAT3, WFS1, and ZFP57. | Yes | No |
| Hilbrands et al. (also described in De Franco et al. 2019) | (30, 44) | F | 38 | Yes (12 weeks) | 1100 (0) | – | – | PM | Mutation in CNOT1 No mutations in IPF1, PTF1A, GATA6, GATA4, HNF1B, and HNF6. | Yes | Missing corpus callosum, immature brain development (semilobar holoprosencephaly), absent gallbladder |
| Houghton et al. | (42) | M | 38 | Yes | 1980 (0.44) | – | – | US | Mutation in PTF1A | Yes | Patent ductus arteriosus and a small atrial septal defect |
| Houghton et al. | (42) | F | 37 | Yes | 2000 (1.54) | – | – | US | Mutation in PTF1A | Yes | No |
| Howard et al. | (15) | M | Term | Yes | 1950 (0.06) | 48 (11.86) | – | C (absence or a generalized secretory defect of pancreatic islets) | NA | Yes | No |
| Ito et al. | (31) | M | 30 | No | 600 (0) | – | – | PM | Mutation in GL13 | NA | Absent gallbladder, thyroidal atrophy, adrenal atrophy, malrotation of intestine, atresia of anus, bilateral hypoplasia of kidney, hypoplasia of tentalia, hypospadia, polysyndactyly, polysplenia |
| Johnson et al. | (41) | M | 19 | No | 221 (NA) | – | – | PM | NA | NA | Caudal regression syndrome, ventricular septal defect |
| Lemons et al. | (14) | – | 41 | No | 1350 (0) | 40.3 (0) | 30.5 (0.06) | PM | NA | NA | NA |
| Mehes et al. | (12) | F | Near term | Yes (11 days) | 1750 (0.02) | – | – | PM | NA | Yes | Absent gallbladder |
| Nakao et al. / Suzuki et al. | (27, 28) | F | 37 | Yes | 1353 (0.02) | 39.5 (0.01) | 30 (1.43) | MRI/CT | Mutation in GATA6 | Yes | Diaphragmatic hernia, ventricular septal defect, ductus arteriosus |
| Raghuram et al. | (46) | M | 34 | Yes | 1310 (1.37) | 38 (0.12) | 30 (13.41) | US and MRI | Mutation in GATA6 | Yes | Absent gallbladder, unilateral thyroid lobe agenesis, truncus arteriosus |
| Salina et al. | (26) | M | 35 | Yes | 1620 (1.91) | 45 (29.45) | – | CT and MRI | No mutation in KCNJ11, SUR1, GCK, PDX1, PTF1A, SOX9, SOX17, HNF6, HLXB9, HNF4a, NEUROD1, HNF1α and HNF1β | Yes | Atrial septal defect |
| Samaee et al. | (23) | M | 40 | Yes | 1800 (0.02) | 41 (0) | 30 (0.03) | US and CT | NA | Yes | No |
| Schwitzgebel et al. | (19) | F | 40 | Yes | 2140 (0.23) | 44 (0.16) | – | US and CT | Mutation in PDX1 | Yes | No |
| Shaw-Smith et al. | (36) | – | 34 | Yes (4 days) | 1240 (0.81) | – | – | PM | Mutation in GATA4 | NA | Abnormal white matter development |
| Sherwood et al. | (11) | – | At term | Yes (6 weeks) | 1280 (0) | 37 (0) | 29 (0.01) | PM | NA | NA | NA |
| Stanescu et al. | (35) | F | 39 | Yes (3 months) | 1760 (0.04) | – | – | CT | Mutation in GATA6 No mutation in IPF1. | Yes | Cardiac malformation, hydronephrosis hydroureter, absent gallbladder |
| Taha et al. | (22) | M | 35 | Yes (11 months) | 1700 (2.92) | – | – | US and CT | No mutation in PTF1A and PDX1, KCNJ11 and ABCC8 or chromosome 6 | Yes | Dysmorphic features, and recurrent bacterial infections |
| Thomas et al. | (24) | M | 37 | Yes | 1560 (0.11) | – | – | US and CT: small amount of tissue that could represent pancreas or small bowel, small hypoechoic structure in area of pancreatic head. Stool elastase <50 µg/g | Homozygous mutation in the IPF1 No mutation in KCNJ11 or GCK | Yes | No |
| Verwest et al. | (18) | M | At term | Yes | 1500 (0) | – | 32.5 (5.62) | US, CT, and laparotomy | No mutation in PDX1 | Yes | Absent gallbladder, choledochal duct stenosis |
| Voldsgaard et al. | (17) | F | 37 | Yes (48 h) | 1400 (0.03) | 43.5 (1.62) | 31.5 (16.78) | PM | NA | Yes | No |
| Weedon et al. | (38) | F | 39 | Yes | 2800 (18.92) | – | – | CT | Mutation in PTF1A | Yes | No |
| Weedon et al. | (38) | M | 39 | Yes | 2400 (1.88) | – | – | CT | Mutation in PTF1A | Yes | No |
| Weedon et al. a | (38) | F | – | Yes | – | – | – | MRI | Mutation in PTF1A | Yes | No |
| Wright et al./ Stoffers et al. | (16, 55) | F | 41 | Yes | 1700 (0.01) | 44 (0.07) | – | US | Mutation in IPF1 No mutation in ΔF508 | Yes | No |
| Yau et al. | (34) | M | 37 | Yes | 1740 (0.32) | – | – | During surgery at 8 months | Mutation in GATA6 | Yes | Congenital diaphragmatic hernia, absent gallbladder |
| Zanfardino et al. | (45) | F | 34 | Yes | 1180 (0.46) | 40 (0.90) | – | C | NA | Yes | No |
aGestational age below 22 weeks and thus not included in Fig. 1.
C, clinical; NA, not assessed; NDM, neonatal diabetes mellitus; PM, postmortem; US, ultrasound;
Gestational age differences
In Fig. 1, the median centile for birth weight, birth length, and head circumference of neonates born before week 36 of gestation and those born from 36 weeks are presented. Median centiles for birth weight and head circumference were significantly higher in the neonates born before 36 weeks compared to those born from 36 weeks (2.4 vs 0.1 (P = 0.006), 2.0 vs 0.1 (P = 0.13), 43.9 vs 1.4 (P = 0.03) for birth weight, birth length, and head circumference, respectively). When considering those born before and from 38 weeks gestation, differences in centiles between groups were smaller, but significantly higher in those born earlier for all growth parameters (1.0 versus 0.1 (P = 0.03), 1.4 vs 0.01 (P = 0.04), 21.2 vs 0.5 (P = 0.006) for birth weight, birth length, and head circumference, respectively).
Centiles of birth weight, birth length, and head circumference for neonates born <36 weeks (white circles) and those born ≥ 36 weeks of gestation (gray circles). Red lines indicate median centiles, based on the Intergrowth-21 reference charts (8). The dashed line represents the 50th centile. Red numbers indicate reference where cases/mutation analyses were reported.
Citation: Endocrine Connections 13, 3; 10.1530/EC-23-0500
Sex-specific differences
In the total cohort, no significant sex differences were found in the median centiles for birth weight, birth length, and head circumference (all P > 0.15).
Genetic diagnosis
Genetic analysis data were reported in 37 of 49 cases. For 5 and 11 cases, pancreas agenesis was due to a genetic mutation in the GATA6 and PTF1A gene, respectively, with mutations also being reported inTCF2, PDX1, CNOT1, GLI3, GATA4, and IPF1. No differences with the whole collective were found for birth weight, length, or head circumference. One case with GATA6 and only two with a PTF1A mutation were born before 36 weeks of gestation. Hence, the potential influence of specific genetic causes of PA on fetal growth according to gestational age, i.e. before or at and after week 35, could not be assessed. CNOT1 mutations were consistently associated with dysmorphic head and brain features.
Outlier birth weights
For the five cases with birth weight above the tenth percentile, we checked the diagnosis of pancreas agenesis and genetic analysis findings, and for all cases, the pancreas could not be identified at autopsy or CT/MRI scans (3, 10, 21, 29, 38). Two of the five had a PTF1A mutation (3, 37), one a TCF2 mutation (28), whereas one had no mutation detected and one did not report genetic analysis (9).
Placental weight
Placental weight was provided in only three cases, all with low placental weight. In the first of these, the placenta weighed 55 g at week 17 (not able to calculate centile), which corresponded to placental weight at week 13 (43). In two other cases, it was 385 g at week 34 (eighth centile) (25) and 480 g at week 37 (12th centile) (17), respectively.
Discussion
This semiquantitative analysis has assessed the effect of complete PA on growth of human fetuses. The aim was to get more insight into which period of pregnancy the fetus is most dependent on a developing pancreas for growth of the skeleton, the head and overall birth weight, and if there are sex-specific differences. Answering these questions is impossible by qualitatively reviewing reported cases. To make individual data comparable, we have used centiles based on well-established and widely used growth charts.
Our analysis confirms the association of complete PA with severe fetal growth restriction and is consistent with the report of cases with fetal insulin absence determined on the basis of genetic diagnosis (4). While severe growth restriction was evident in the majority of neonates born before 36 weeks gestation, the findings show that fetal growth is exceedingly dependent on the pancreas in the last weeks of pregnancy. Furthermore, the effect of PA is more pronounced on fetal length (i.e. skeleton) and weight growth than on head growth, although head growth is severely impacted in late pregnancy. Sex differences in birth weight, birth length, and head circumference percentiles, which are adjusted for sex using the Intergrowth-21 reference charts, were not detected, which may reflect lack of power and variation in the data, which in turn precluded detecting a difference.
Among the four hormones of the endocrine pancreas, i.e. insulin, glucagon, pancreatic polypeptide hormone and somatostatin, insulin is the key regulator of growth as it acts as a potent mitogen and is anabolic. Growth regulating functions of pancreatic polypeptide hormone and somatostatin have not been found to date. Glucagon may be inhibitory to fetal growth (47). Its absence, therefore, should favor increased fetal size. Thus, growth restriction found in neonates with PA is most likely attributable to the absence of insulin. In infants with Donohue syndrome, a rare genetic disorder characterized by absence of insulin receptors, fetuses are also undergrown (48). The essential role of the pancreas for fetal growth is also shown by experimental pancreatectomy in sheep (49).
Insulin acts on lean body growth either directly, or indirectly by inducing hepatic IGF-1 production and secretion and fat mass accrual through direct action. In normal human pregnancies, cord blood C-peptide, and by inference insulin, levels are relatively low before week 34 of gestation and rise thereafter (5). This might also explain why the effects of PA are more pronounced in fetuses born from 36 weeks of gestation.
The fetal growth restriction in PA is either symmetric, with reductions in fetal length, weight, and head circumference, or asymmetric, with head (i.e. brain) sparing more evident in neonates born before 36 weeks. These findings indicate that insulin is important to both fetal lean (including skeletal) and fat mass growth. The few data on head circumference before 36 weeks suggest asymmetric growth restriction in some of these neonates, which may have long term implications such as increased risk for metabolic syndrome and noncommunicable diseases later in life (50). The association of the CNOT1 mutation with abnormal head and brain development warrants further study. Head circumference in cases of CNOT1 mutation was only reported once and was severely reduced, i.e. at 0.5th centile, suggesting smaller brain volume with the risk for neurodevelopmental delay (51).
There were few placenta weights available for analysis; however, the findings would be consistent with a role of fetal insulin in determining final placenta size. This notion is supported by recent genetic data (52, 53) and animal experiments (54).
While severe growth restriction was evident in the majority of the neonates reported to have PA, there were a small number of outliers. As this may have been a consequence of inaccurate diagnosis of PA, we determined the method used to determine PA and assessed the genetic diagnosis information. The methods were robust, and mutations were found in three of the five cases (TCF2 in one and PTF1A in two). Pancreatic hypoplasia as opposed to PA cannot be completely excluded in these cases as an explanation.
So far, fetal insulin has received attention in pregnancies characterized by maternal diabetes or obesity as major contributor to excessive fat accretion. The collective evidence presented here demonstrates the key role of insulin for fetal growth also in pregnancies of women without metabolic disturbances.
We acknowledge that this semiquantitative analysis has limitations due to the paucity of data. We are hoping that future case reports will include information on serial ultrasound assessments of fetal growth, gestational age at birth, birth weight, birth length, head circumference, placental weight, as well as genetic diagnosis. We also encourage all clinicians who have already reported on PA to screen their records for availability of the data used here and share them with us for a future new and better powered analysis of fetal growth in this very rare genetic disorder.
Declaration of interest
The authors have no conflict of interest related to this work.
Funding
The study was conducted without funding. The open access was funded by the University of Graz.
Data availability statement
Data will be available from the corresponding author upon reasonable request.
Acknowledgements
The authors are grateful to Dr Melanie Klancnik for researching part of the data. We thank Dr Daniela Seick-Barbarini, Dr Ming Chen, Dr Inas Thomas as well as Dr Regina Moisés for providing additional data.
References
- 1↑
Allen HL, Flanagan SE, Shaw-Smith C, De Franco E, Akerman I, Caswell R, International Pancreatic Agenesis C, Ferrer J, Hattersley AT, & Ellard S. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nature Genetics 2011 44 20–22. (https://doi.org/10.1038/ng.1035)
- 2↑
Ashraf A, Abdullatif H, Hardin W, & Moates JM. Unusual case of neonatal diabetes mellitus due to congenital pancreas agenesis. Pediatric Diabetes 2005 6 239–243. (https://doi.org/10.1111/j.1399-543X.2005.00114.x)
- 3↑
Demirbilek H, Arya VB, Ozbek MN, Houghton JA, Baran RT, Akar M, Tekes S, Tuzun H, Mackay DJ, Flanagan SE, et al.Clinical characteristics and molecular genetic analysis of 22 patients with neonatal diabetes from the South-Eastern region of Turkey: predominance of non-KATP channel mutations. European Journal of Endocrinology 2015 172 697–705. (https://doi.org/10.1530/EJE-14-0852)
- 4↑
Hughes AE, De Franco E, Freathy RM, Flanagan SE, & Hattersley AT. Monogenic disease analysis establishes that fetal insulin accounts for half of human fetal growth. Journal of Clinical Investigation 2023 133. (https://doi.org/10.1172/JCI165402)
- 5↑
Sosenko IR, Kitzmiller JL, Loo SW, Blix P, Rubenstein AH, & Gabbay KH. The infant of the diabetic mother: correlation of increased cord C-peptide levels with macrosomia and hypoglycemia. New England Journal of Medicine 1979 301 859–862. (https://doi.org/10.1056/NEJM197910183011603)
- 6↑
Eder M, Csapo B, Wadsack C, Haas J, Catalano PM, Desoye G, & van Poppel MN. Sex differences in the association of cord blood insulin with subcutaneous adipose tissue in neonates. International Journal of Obesity 2016 40 538–542. (https://doi.org/10.1038/ijo.2015.185)
- 7↑
Lampl M, & Jeanty P. Timing is everything: a reconsideration of fetal growth velocity patterns identifies the importance of individual and sex differences. American Journal of Human Biology 2003 15 667–680. (https://doi.org/10.1002/ajhb.10204)
- 8↑
Villar J, Cheikh Ismail L, Victora CG, Ohuma EO, Bertino E, Altman DG, Lambert A, Papageorghiou AT, Carvalho M, Jaffer YA, et al.International standards for newborn weight, length, and head circumference by gestational age and sex: the Newborn Cross-Sectional Study of the INTERGROWTH-21st project. Lancet 2014 384 857–868. (https://doi.org/10.1016/S0140-6736(1460932-6)
- 9↑
Almog B, Shehata F, Aljabri S, Levin I, Shalom-Paz E, & Shrim A. Placenta weight percentile curves for singleton and twins deliveries. Placenta 2011 32 58–62. (https://doi.org/10.1016/j.placenta.2010.10.008)
- 10↑
Dourov N, & Buyl-Strouvens ML. Agenesia of the pancreas. Anatomo-clinical observations of a case of diabetes mellitus, with steatorrhea and hypotrophy, in a newborn infant. Archives Francaises de Pediatrie 1969 26 641–650.
- 11↑
Sherwood WG, Chance GW, & Hill DE. A new syndrome of familial pancreatic agenesis: the role of insulin and glucagon in somatic and cell growth. Pediatric Research 1974 8 360.
- 12↑
Mehes K, Vamos K, & Goda M. Agenesis of pancreas and gall-bladder in an infant of incest. Acta Paediatrica Academiae Scientiarum Hungaricae 1976 17 175–176.
- 13↑
Dodge JA, & Laurence KM. Congenital absence of islets of Langerhans. Archives of Disease in Childhood 1977 52 411–413. (https://doi.org/10.1136/adc.52.5.411)
- 14↑
Lemons JA, Ridenour R, & Orsini EN. Congenital absence of the pancreas and intrauterine growth retardation. Pediatrics 1979 64 255–257. (https://doi.org/10.1542/peds.64.2.255)
- 15↑
Howard CP, Go VL, Infante AJ, Perrault J, Gerich JE, & Haymond MW. Long-term survival in a case of functional pancreatic agenesis. Journal of Pediatrics 1980 97 786–789. (https://doi.org/10.1016/s0022-3476(8080270-8)
- 16↑
Wright NM, Metzger DL, Borowitz SM, & Clarke WL. Permanent neonatal diabetes mellitus and pancreatic exocrine insufficiency resulting from congenital pancreatic agenesis. American Journal of Diseases of Children 1993 147 607–609. (https://doi.org/10.1001/archpedi.1993.02160300013005)
- 17↑
Voldsgaard P, Kryger-Baggesen N, & Lisse I. Agenesis of pancreas. Acta Paediatrica 1994 83 791–793. (https://doi.org/10.1111/j.1651-2227.1994.tb13144.x)
- 18↑
Verwest AM, Poelman M, Dinjens WN, Batstra MR, Oostra BA, Lequin MH, Larsson LI, Aanstoot HJ, Bruining GJ, & de Krijger RR. Absence of a PDX-1 mutation and normal gastroduodenal immunohistology in a child with pancreatic agenesis. Virchows Archiv 2000 437 680–684. (https://doi.org/10.1007/s004280000305)
- 19↑
Schwitzgebel VM, Mamin A, Brun T, Ritz-Laser B, Zaiko M, Maret A, Jornayvaz FR, Theintz GE, Michielin O, Melloul D, et al.Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. Journal of Clinical Endocrinology and Metabolism 2003 88 4398–4406. (https://doi.org/10.1210/jc.2003-030046)
- 20↑
Baumeister FA, Engelsberger I, & Schulze A. Pancreatic agenesis as cause for neonatal diabetes mellitus. Klinische Padiatrie 2005 217 76–81. (https://doi.org/10.1055/s-2004-822657)
- 21↑
Chen R, Hussain K, Al-Ali M, Dattani MT, Hindmarsh P, Jones PM, & Marsh P. Neonatal and late-onset diabetes mellitus caused by failure of pancreatic development: report of 4 more cases and a review of the literature. Pediatrics 2008 121 e1541–e1547. (https://doi.org/10.1542/peds.2007-3543)
- 22↑
Taha D, Bardise J, Hegab A, Bonnefond A, Marchand M, Drunat S, Vaxillaire M, & Polak M. Neonatal diabetes mellitus because of pancreatic agenesis with dysmorphic features and recurrent bacterial infections. Pediatric Diabetes 2008 9 240–244. (https://doi.org/10.1111/j.1399-5448.2007.00365.x)
- 23↑
Samaee H, Sadeghi-Moghadam P, Arab-Hosseini A, Aramesh MR, & Marzban A. Neonatal diabetes mellitus due to pancreatic agenesis. Archives of Iranian Medicine 2008 11 335–336.
- 24↑
Thomas IH, Saini NK, Adhikari A, Lee JM, Kasa-Vubu JZ, Vazquez DM, Menon RK, Chen M, & Fajans SS. Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous Ipf-1 Pro63fsX60 mutation. Pediatric Diabetes 2009 10 492–496. (https://doi.org/10.1111/j.1399-5448.2009.00526.x)
- 25↑
Barbarini DS, Haslinger V, Schmidt K, Patch AM, Muller G, & Simma B. Neonatal diabetes mellitus due to pancreas agenesis: a new case report and review of the literature. Pediatric Diabetes 2009 10 487–491. (https://doi.org/10.1111/j.1399-5448.2009.00523.x)
- 26↑
Salina A, Pasquali L, Aloi C, Lugani F, d'Annunzio G, & Lorini R. Neonatal diabetes caused by pancreatic agenesia: which other genes should be used for diagnosis? Diabetes Care 2010 33 e112. (https://doi.org/10.2337/dc10-0876)
- 27↑
Nakao A, Takeda T, Hisaeda Y, Hirota A, Amagata S, Sakurai Y, & Kawakami T. Pancreatic agenesis with congenital diaphragmatic hernia and congenital heart disease: a case report. AJP Reports 2013 3 119–122. (https://doi.org/10.1055/s-0033-1353388)
- 28↑
Suzuki S, Nakao A, Sarhat AR, Furuya A, Matsuo K, Tanahashi Y, Kajino H, & Azuma H. A case of pancreatic agenesis and congenital heart defects with a novel GATA6 nonsense mutation: evidence of haploinsufficiency due to nonsense-mediated mRNA decay. American Journal of Medical Genetics 2014 164A 476–479. (https://doi.org/10.1002/ajmg.a.36275)
- 29↑
Body-Bechou D, Loget P, D'Herve D, Le Fiblec B, Grebille AG, Le Guern H, Labarthe C, Redpath M, Cabaret-Dufour AS, Sylvie O, et al.TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia. Prenatal Diagnosis 2014 34 90–93. (https://doi.org/10.1002/pd.4264)
- 30↑
Hilbrands R, Keymolen K, Michotte A, Marichal M, Cools F, Goossens A, Veld PI, De Schepper J, Hattersley A, & Heimberg H. Pancreas and gallbladder agenesis in a newborn with semilobar holoprosencephaly, a case report. BMC Medical Genetics 2017 18 57. (https://doi.org/10.1186/s12881-017-0419-2)
- 31↑
Ito S, Kitazawa R, Haraguchi R, Kondo T, Ouchi A, Ueda Y, & Kitazawa S. Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas. Diagnostic Pathology 2018 13 1. (https://doi.org/10.1186/s13000-017-0682-8)
- 32↑
Gabbay M, Ellard S, De Franco E, & Moises RS. Pancreatic agenesis due to compound heterozygosity for a novel enhancer and truncating mutation in the PTF1A gene. Journal of Clinical Research in Pediatric Endocrinology 2017 9 274–277. (https://doi.org/10.4274/jcrpe.4494)
- 33↑
Al-Shammari M, Al-Husain M, Al-Kharfy T, & Alkuraya FS. A novel PTF1A mutation in a patient with severe pancreatic and cerebellar involvement. Clinical Genetics 2011 80 196–198. (https://doi.org/10.1111/j.1399-0004.2010.01613.x)
- 34↑
Yau D, De Franco E, Flanagan SE, Ellard S, Blumenkrantz M, & Mitchell JJ. Case report: maternal mosaicism resulting in inheritance of a novel GATA6 mutation causing pancreatic agenesis and neonatal diabetes mellitus. Diagnostic Pathology 2017 12 1. (https://doi.org/10.1186/s13000-016-0592-1)
- 35↑
Stanescu DE, Hughes N, Patel P, & De Leon DD. A novel mutation in GATA6 causes pancreatic agenesis. Pediatric Diabetes 2015 16 67–70. (https://doi.org/10.1111/pedi.12111)
- 36↑
Shaw-Smith C, De Franco E, Lango Allen H, Batlle M, Flanagan SE, Borowiec M, Taplin CE, van Alfen-van der Velden J, Cruz-Rojo J, Perez de Nanclares G, et al.GATA4 mutations are a cause of neonatal and childhood-onset diabetes. Diabetes 2014 63 2888–2894. (https://doi.org/10.2337/db14-0061)
- 37↑
Evliyaoglu O, Ercan O, Ataoglu E, Zubarioglu Ü, Ozcabi B, Dagdeviren A, Erdogan H, De Franco E, & Ellard S. Neonatal diabetes: two cases with isolated pancreas agenesis due to homozygous PTF1A enhancer mutations and one with developmental delay, epilepsy, and neonatal diabetes syndrome due to KCNJ11 mutation. Journal of Clinical Research in Pediatric Endocrinology 2018 10 168–174. (https://doi.org/10.4274/jcrpe.5162)
- 38↑
Weedon MN, Cebola I, Patch AM, Flanagan SE, De Franco E, Caswell R, Rodriguez-Segui SA, Shaw-Smith C, Cho CH, Allen HL, et al.Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nature Genetics 2014 46 61–64. (https://doi.org/10.1038/ng.2826)
- 39↑
Chao CS, McKnight KD, Cox KL, Chang AL, Kim SK, & Feldman BJ. Novel GATA6 mutations in patients with pancreatic agenesis and congenital heart malformations. PLoS One 2015 10 e0118449. (https://doi.org/10.1371/journal.pone.0118449)
- 40↑
Bruce MB, & Coutts JP. Complete agenesis of the mid-gut: a case report. Australian and New Zealand Journal of Surgery 1982 52 313–315. (https://doi.org/10.1111/j.1445-2197.1982.tb05408.x)
- 41↑
Johnson P, Seller MJ, Morrish N, Neales K, & Maxwell D. Pancreatic and sacral agenesis in association with maternal diabetes mellitus: case report. Prenatal Diagnosis 1991 11 329–331. (https://doi.org/10.1002/pd.1970110509)
- 42↑
Houghton JA, Swift GH, Shaw-Smith C, Flanagan SE, de Franco E, Caswell R, Hussain K, Mohamed S, Abdulrasoul M, Hattersley AT, et al.Isolated pancreatic aplasia due to a hypomorphic PTF1A mutation. Diabetes 2016 65 2810–2815. (https://doi.org/10.2337/db15-1666)
- 43↑
Cospain A, Faoucher M, Cauchois A, Carre W, Quelin C, & Dubourg C. Fetal description of the pancreatic agenesis and holoprosencephaly syndrome associated to a specific CNOT1 variant. Pediatric and Developmental Pathology 2022 25 548–552. (https://doi.org/10.1177/10935266221095305)
- 44↑
De Franco E, Watson RA, Weninger WJ, Wong CC, Flanagan SE, Caswell R, Green A, Tudor C, Lelliott CJ, Geyer SH, et al.A specific CNOT1 mutation results in a novel syndrome of pancreatic agenesis and holoprosencephaly through impaired pancreatic and neurological development. American Journal of Human Genetics 2019 104 985–989. (https://doi.org/10.1016/j.ajhg.2019.03.018)
- 45↑
Zanfardino A, Piscopo A, Curto S, Schiaffini R, Rollato AS, Testa V, Miraglia Del Giudice E, Barbetti F, & Iafusco D. Very low birth weight newborn with diabetes mellitus due to pancreas agenesis managed with insulin pump reservoir filled with undiluted insulin: 16-month follow-up. Diabetes and Metabolic Syndrome 2022 16 102561. (https://doi.org/10.1016/j.dsx.2022.102561)
- 46↑
Raghuram N, Marwaha A, Greer MC, Gauda E, & Chitayat D. Congenital hypothyroidism, cardiac defects, and pancreatic agenesis in an infant with GATA6 mutation. American Journal of Medical Genetics 2020 182 1496–1499. (https://doi.org/10.1002/ajmg.a.61569)
- 47↑
Cilvik SN, Wesolowski SR, Anthony RV, Brown LD, & Rozance PJ. Late gestation fetal hyperglucagonaemia impairs placental function and results in diminished fetal protein accretion and decreased fetal growth. Journal of Physiology 2021 599 3403–3427. (https://doi.org/10.1113/JP281288)
- 48↑
Perge K, Massoud M, Gauthier-Moulinier H, Lascols O, Pangaud N, Villanueva C, & Pons L. Intrauterine growth restriction and hypertrophic cardiomyopathy as prenatal ultrasound findings in a case of leprechaunism. Molecular Syndromology 2020 11 223–227. (https://doi.org/10.1159/000509837)
- 49↑
Fowden AL, & Comline RS. The effects of pancreatectomy on the sheep fetus in utero. Quarterly Journal of Experimental Physiology 1984 69 319–330. (https://doi.org/10.1113/expphysiol.1984.sp002808)
- 50↑
Barouki R, Gluckman PD, Grandjean P, Hanson M, & Heindel JJ. Developmental origins of non-communicable disease: implications for research and public health. Environmental Health 2012 11 42. (https://doi.org/10.1186/1476-069X-11-42)
- 51↑
Vissers LELM, Kalvakuri S, de Boer E, Geuer S, Oud M, van Outersterp I, Kwint M, Witmond M, Kersten S, Polla DL, et al.De novo variants in CNOT1, a central component of the CCR4-NOT complex involved in gene expression and RNA and protein stability, cause neurodevelopmental delay. American Journal of Human Genetics 2020 107 164–172. (https://doi.org/10.1016/j.ajhg.2020.05.017)
- 52↑
Beaumont RN, Flatley C, Vaudel M, Wu X, Chen J, Moen GH, Skotte L, Helgeland O, Sole-Navais P, Banasik K, et al.Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth. Nature Genetics 2023 55 1 807–1 819. (https://doi.org/10.1038/s41588-023-01520-w)
- 53↑
Shields BM, Spyer G, Slingerland AS, Knight BA, Ellard S, Clark PM, Hauguel-de Mouzon S, & Hattersley AT. Mutations in the glucokinase gene of the fetus result in reduced placental weight. Diabetes Care 2008 31 753–757. (https://doi.org/10.2337/dc07-1750)
- 54↑
Susa JB, Gruppuso PA, Widness JA, Domenech M, Clemons GK, Sehgal P, & Schwartz R. Chronic hyperinsulinemia in the fetal rhesus monkey: effects of physiologic hyperinsulinemia on fetal substrates, hormones, and hepatic enzymes. American Journal of Obstetrics and Gynecology 1984 150 415–420. (https://doi.org/10.1016/s0002-9378(8480150-7)
- 55↑
Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, & Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nature Genetics 1997 15 106–110. (https://doi.org/10.1038/ng0197-106)
