Neonatal diabetes mellitus (NDM) occurs within the first six months of life. Depending on clinical outcomes, it is classified into Transient Neonatal Diabetes Mellitus (TNDM) and Permanent Neonatal Diabetes Mellitus (PNDM) [
More than 20 pathogenic genes have been identified in PNDM, of which the most common are
We summarized the clinical features, molecular typing, treatment, and 1- to 13-year follow-up of 25 cases of NDM in order to better understand the clinical treatment and prognosis.
The present study included 25 patients diagnosed with NDM including 18 PNDM and 7 TNDM from Beijing Children’s Hospital, Zhengzhou Children’s Hospital, and Shanxi Children’s Hospital, from 2001 to 2013. Diagnostic criteria for NDM [
The symptoms at onset and laboratory reports were obtained from medical records. The family history of diabetes mellitus, especially glucose metabolism in parents, was recorded for every patient. Clinical follow-up started with diagnosis at 3- to 6-month intervals, subsequently. Height and weight were measured using normal growth chart of Chinese children. The self-reported frequency of severe hypoglycemia was recorded, and HbA1c was measured at every visit. All the data between years 2012 and 2013 were analyzed.
Patients aged below 18 months, showing normal blood glucose (fasting glucose < 5.6 mmol/L, postprandial glucose < 7.8 mmol/L) and HbA1c (<6.0%) without the need for insulin or oral hypoglycemic treatment, were defined as TNDM. Patients aged more than 18 months and requiring insulin or oral hypoglycemic agents to maintain normal glucose were defined as PNDM [
This study was approved by the Ethics Committee of Beijing Children’s Hospital of Capital Medical University and all parents have signed the informed consent.
Upon NDM diagnosis, 2 mL of blood samples was collected in ethylenediaminetetraacetic acid (EDTA) tubes from 25 patients and stored at −20°C. DNA was extracted from peripheral blood leukocytes using kits (QIAGEN, Valencia, CA).
Samples were tested for
Microarray comparative genomic hybridization was performed in 5 TNDM patients, in whom
We recalled KATP-PNDM patients to switch from insulin injection to oral glyburide, usually within 18 months of diagnosis. The transfer was carried out using a protocol that was similar to that described previously [
Type 1 diabetic patients with age of onset between 6 months and 2 years were matched one-to-one with those of PNDM (15 patients with recorded HbA1c). T1DM patients hospitalized during the same period as PNDM group with positive autoimmune antibody (ICA, GAD, or IAA) and comparable age, sex, duration of illness, and time of sample/data collection were selected as the control group. The HbA1c between the two groups was compared. The HbA1c of the PNDM group was tested at least 6 months after glyburide treatment.
Statistical analysis was performed using chi-square test and Student’s
Table
Clinical characteristics of NDM patients.
NDM | PNDM | TNDM | |
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Cases | 25 | 18 | 7 |
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Male (female) | 14 (11) | 11 (7) | 3 (4)# |
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Birth weight |
2.6 ± 0.5 | 2.7 ± 0.5 | 2.4 ± 0.6# |
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Age at diagnosis |
74.4 ± 41.4 | 81.3 ± 42.7 | 56.7 ± 34.6# |
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DK/DKA (%) | 68.0% | 77.8% | 42.9%# |
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Symptoms |
Infection (6) |
Infection (4) | |
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Physical development on follow-up (cases) | Physical and mental retardation (4), others are normal | Intellectual and physical development is normal | |
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Genetic testing (cases) |
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Therapy (cases) | Glyburide (3) |
Remission in 2 weeks to 1 year after insulin therapy (6) | |
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Average HbA1c at the last follow-up (cases had recorded results) | 7.2% (15) | 5.5% (5) |
#No significant differences compared with PNDM (
Clinical profile and gene analysis of NDM.
Subtype | Number | Gender | Term or preterm | HbA1c at diagnosis (%) | Age at last visit (yr) | HbA1c (%) at last visit | Height (cm) (percentile) | Weight (kg) (percentile) | Mutant gene | Inherited from |
|
Specific clinical features | Mutation | Zygosity | Insulin/glyburide therapy (age at transfer) | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Father | Mother | |||||||||||||||
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1 | M | Term | 13.7 | 4.1 | 6.1% | 107.0 |
17.0 |
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p.R201H | Congenital cataract | c.602G>A; p.R201H | HET | Insulin/interruption because of side effects (1 yr) | ||
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2 | F | Term | 4.0 | 2.0 | 6.0% | 88.0 |
12.5 |
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p.R201H | c.602G>A; p.R201H | HET | Glyburide response | |||
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3 | M | Term | 9.6 | 1.5 | 6.5% | 81.0 |
11.0 |
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p.G53S | c.157C>T; p.G53S | HET | Glyburide response | |||
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4 | M | Term | 8.1 | 2.5 | 7.5% | 85.0 |
11.0 |
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p.V59M | iDEND | c.175G>A; p.V59M | HET | Glyburide response | ||
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5 | M | Term |
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p.E229K | c.685G>A; p.E229K | HET | Insulin/no transition | ||||||||
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6 | F | Term | 9.6 | 5.1 | 8.0% | 105.0 |
15.0 |
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p.R825W | c.2473C>T; p.R825W | HET | Insulin/no response | |||
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7 | F | Term | 9.8 | 1.5 | 7.0% | 83.0 |
11.5 |
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c.293C>A; p.S98I | HET | Insulin | ||||
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8 | F | Term | 14.2 | 1.5 |
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No sample | No sample | Died of liver and kidney failure at 1.5 years of age | c.2570T>A; p.F857Y | HET | Insulin | ||||
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9 | M | Term | 10.4 | 5.0 | 7.9% | 110.0 |
17.5 |
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No sample | No sample | Moderate normocytic anemia | c.1213A>G; p.T405A | HET | Insulin | |
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10 | M | Term | 9.5 | 13.9 | 7.0% | 140.0 |
30.0 |
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p.C532STOP | WRS | c.1798A>T; p.C532STOP | HET | Insulin | ||
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11 | F | Term | 11.2 | 1.5 | 7.5% | 74.3 |
8.0 |
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p.leu182leufsX19 | p.Arg588Ter | WRS | c.1762C>T, p.Arg588Ter; |
HET | Insulin | |
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12 | F | Term | 9.8 | 4.5 | 7.5% | 106.0 |
15.0 |
Insulin (0.8 IU/kg/d) | |||||||
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13 | M | Term | 15.8 | 2.0 | 7.9% | 89.5 |
13.0 |
Insulin (based on glucose, injection once every other day) | |||||||
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14 | M | Term | 4.38 | 0.6 | 62.0 |
4.0 |
Died of DKA at 7 months of age |
Insulin | |||||||
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15 | M | Term | 5.2 | 6.0 | 8.2% | 115.0 |
18.5 |
Insulin | |||||||
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16 | M | Term | 5.0 | 7.4% | 113.0 |
20 |
Insulin | ||||||||
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17 | M | Term | 5.9 | 3.0 | 7.3% | 98.0 |
17.0 |
Insulin | |||||||
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18 | F | Term | 4.0 | 7.6% | 105.0 |
16.0 |
Insulin | ||||||||
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19 | F | Term | 7.1 | 1.8 |
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p.G296R | c.886G>A; p.G296R | HET | |||||||
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20 | M | Term | 10.2 | 1.8 | 5.6% | 83.6 |
11.2 |
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p.D212E | c.636G>T; p.D212E | HET | ||||
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21 | F | Term | 9.6 | 5.8 | 5.7% | 110.5 |
20.0 |
UPD6 | |||||||
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22 | F | Term | 7.4 | 4.8 | 5.6% | 110.0 |
19.0 |
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23 | M | Term | 5.5 | 5.6% | 112.5 |
18.0 |
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24 | M | Term | 9.9 | 3.7 | 5.2% | 102.3 |
16.5 |
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25 | F | Term | 4.0 |
In PNDM cases, twelve mutations were identified. Direct sequencing identified the most frequent mutations involving KATP channel (
All patients were treated with insulin initially. Following stable glucose control with insulin, transition from insulin to oral sulfonylureas was attempted in five of six KATP-PNDM cases. Finally, three cases (60%) were successfully placed on glyburide; one switched back to insulin as there was no response to glyburide; one stopped oral glyburide because of serious gastrointestinal reactions; and in another case glyburide was not tried because of loss of follow-up. The mean HbA1c of PNDM during the last visit was
Comparison of HbA1c between PNDM and infantile onset T1DM groups.
PNDM | T1DM |
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---|---|---|---|
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15 | 15 | |
M (F) | 10 (5) | 10 (5) | 1.00 |
Onset of age (years) | 0.2 ± 0.1 | 1.3 ± 0.5 | 0.00 |
Age at follow-up (years) | 4.0 ± 2.9 | 4.4 ± 2.1 | 0.70 |
Duration of illness (years) | 3.8 ± 2.9 | 3.1 ± 1.9 | 0.44 |
HbA1c at follow-up (%) | 7.2 ± 0.8 | 7.4 ± 0.9 | 0.41 |
Except in 4 PNDM cases, the height and development were found to be normal on follow-up. The patients who presented with convulsion at the onset showed no further convulsions.
Among patients with positive mutations, case
PNDM was associated with special syndromes. Case
There were three deaths (Cases
Remission among TNDM cases in our cohort was ascertained from 2 weeks to 1 year after diagnosis. None of these patients showed any congenital abnormalities such as macroglossia, umbilical hernia, dysmorphic facial features, hematopoietic dysfunction or abnormal hearing, and heart, liver, or kidney function. The development and height were normal. None of them had acanthosis nigricans. The oldest patient was 5 years old, with no recurrence of diabetes. No specific features were observed in patient carrying
The NDM patients generally presented with infection or decreased responsiveness at the onset, without the typical symptoms such as polyuria, polydipsia, polyphagia, and weight loss. In the present study, approximately 30% were TNDM patients, which is similar to the previous reports [
We identified six mutations in KATP channel that were previously reported and six non-KATP mutations in PNDM cases, five of which were not identified until now, and found two KATP mutations in TNDM cases. Three cases were placed on glyburide therapy and 15 cases were on insulin therapy, with good glycemic control in most cases.
In this study, we evaluated the gene mutations and clinical manifestations of PNDM cases. We identified two cases of p.R201H mutations, which were the most common
The second mutation of
The third mutation was
The fourth mutation was
Another case we identified with
The success rate of glyburide transition among cases with KATP mutations of 60.0% in the present study is lower than that reported from other countries. One reason for the low success rate could be the side effects of glyburide such as nausea and vomiting that affected its clinical application in infants in the present study. Diarrhea is the common reported side effects of glyburide but has not been seen in our patients. The failed transitions due to side effects were not reported in other studies, suggesting that Chinese children respond differently to glyburide compared with other ethnic groups. The small sample size may be another reason for such a response. We also found a novel
Other NDM mutations were associated with specific manifestations. Case
The genetic etiology of NDM suggests polygenic inheritance. The classification of TNDM and PNDM should be reconsidered. A diagnosis of diabetes in parents who carried the mutations cannot be excluded. We need additional and longer follow-up of cases to establish a TNDM diagnosis or PNDM remission.
Diarrhea is one of the manifestations of IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome), which is caused by
The mutations in KATP channel accounted for 33.3% of PNDM, including 27.8% in
PNDM children on insulin and glyburide therapy were found to have good glycemic control (mean HbA1c 7.2%) during follow-up, which is similar to infantile onset T1DM group. It was probably associated with younger age at onset, need for a lower insulin dose, and better residual pancreatic
TNDM is associated with chromosome 6q24 imprinting abnormalities in 70% of cases. The syndrome is associated with giant tongue, umbilical hernia, facial deformity, kidney abnormalities, congenital heart disease, hypothyroidism, and intrauterine growth retardation (>95%). Array-CGH could be used to detect UPD6 and duplication simultaneously, so it may be a cost-effective genetic analysis method for TNDM cases. In our study, all the TNDM cases did not exhibit the specific manifestations mentioned above. Recurrence of TNDM resulting from
In the present study, PNDM accounted for 72%; the onset symptoms are not typical. Seizure may be seen initially in NDM cases making it remain misdiagnosed. About one-third of PNDM and TNDM patients had KATP mutations. Only one TNDM case had paternal uniparental disomy of chromosome 6q24. The genetic etiology could not be determined in 50% of PNDM and 57% of TNDM cases. However, no maternal hypomethylation at Chr6q24 was detected, which may have affected the mutational analysis of the TNDM cohort. Glyburide was effective in most KATP-PNDM patients. Most NDM patients achieved good glycemic control (HbA1c < 7.5%) and there was no significant difference when compared to infantile onset T1DM.
The authors declare no conflict of interests.
A portion of this work was supported by the Open Research Project of Shanghai Key Laboratory of Diabetes Mellitus (SHKLD-KF-1304). The authors thank the patients and their relatives for providing the study samples. They also thank the referring hospitals and clinicians.