January 1, 2005
Diagnosis and Symptoms, Other
Question from Bulgaria:
I am writing to you, because I think that my baby, who was born on July 1, 2004, has Transient Neonatal Diabetes Mellitus (TNDM). I would like your opinion.
When my daughter was 10 weeks old, she entered the hospital and she was diagnosed with type 1 diabetes. She weighed 2720 grams (six pounds), was 49 centimeters (19.3 inches) in height, and had a head measurement of 34 centimeters 13.4 inches. She suckled until the moment of hospitalization. She had no immunizations/vaccinations. My daughter has a half-brother, age 12, who was diagnosed with type 1 at the age of six months. Her half-sister is 28 and healthy. My daughter had been in good health. She had gained adequate weight since birth being breast fed. About two days before entering the hospital, she started to drink more water. On the evening of September 7, she had become very unrestful, had cried repeatedly with squeals, and had drawn her legs to her abdomen. By the next morning, her condition worsened. Although she had seemingly calmed down, she had become very languid, inert, with hurried and labored breathing. She had stopped taking liquids through her mouth. Because of the above stated reasons, the child was brought to and entered the Child Intensive Resuscitation as an emergency case.
Objective condition: suckling in an extremely poor general condition, languid, inert; she cries weakly; she reacts towards provocations in an inert way. Skin and visible mucosa – pale with highly decreased turgor and elasticity. Entered with weight 3750 grams (8.3 pounds), hypodermic fatty tissue – highly reduced, visible mucosa – dry mucosa. Head – with regular configuration. Big fontanel 40/40 mm, considerably under the level of the skull bones. Circled eyes. With perioral cyanosis. Strong acetone breath from the mouth. Lymph nodes – not increased. Neck – movable, without struma. Respiratory system – symmetrical chest, both pectoral halves have equal part in breathing, which is tachypnoic, acidotic, respiratory frequency 80/min, total circulation, intense, vesicular, without rales. Cardiovascular system – rhythmical, atrial flutter cardiac activity, cardiac frequency 130/min., clear tones. Abdomen – soft, not painful with umbilical hernia, without organomegalia. Limbs – movable, symmetric, without tumefaction. Throat – pink, dry mucosa. NS – no data for MRD. Paraclinics: At the moment of entering: Hb – 124g/l, Ht – 0.38, leukocytes – 25×109/l, thrombocytes – 929. Blood sugar – 36.7, other biochemical indices – no aberration. Acid – alkaline state – pH-6.84, standard HCO3 -3.9, BE (-31.6), sodium – 150, potassium – 5.7, chlorine – 115, calcium – 3.02. The resuscitation, started after record for treatment of diabetic ketoacidosis including the intravenous injection of insulin at a rate of 0.1E/kg per hour, correction of high degree metabolic acidosis and infusion of water-salt and glucose solutions. Blood-sugar profile: followed at every hour – read smooth reduction of blood-sugar values to euglycemic levels for the first five hours after taking and kept within 7.9 to 23.4 mmol/L [142 to 421 mg/dl] for the next 24 hours, while the indices of acid – alkaline state were slowly and gradually normalized. The final and full elimination of ketoacidosis was achieved in the afternoon of September 9. Hypodermic injection of Actrapid with pen, half doses four times a day (every 6 hours) were started on September 10 when her blood sugar was 7.6 mmol/L [137 mg/dl].
During the following days with normal indices of acid – alkaline state, blood sugar values were registered mostly within the 14 to 22 mmol/L [252 to 396 mg/dl] range. Venous infusions were discontinued. The child continued taking mixed feeding. Insulin doses were increased to two doses of one unit each, two doses of 0.5 units each and then, to one units four times a day. On 17 September, the child was moved to a Second Child Clinic. A slow tendency in the reduction of blood sugar values was registered until she was discharged.
Additional paraclinic examinations: Check up of nose-throat secretion – throat enterobacter in small quantities. From nose – residential microflora. DSK – negative. Blood group – 0(+). Biochemistry: urea-6.2, creatinine-75, general albumin-70, general bilirubin – 14, ALAT- 28, ASAT- 31, PKK – followed up four times: no aberration from the norms for this age. Speed precipitation of erythrocites 18/10 mm. Riography of pectoral cell – no infiltration changes. Echography of abdomen organs: Liver – not enlarged, homogenous structure. Spleen and kidneys – no peculiarities. Treatment: Antibiotic treatment with piperacilin, Enterol, AC zimes, Creon, vitamin C, Humanalbumin.
On the second day of hospitalization, together with the normalization of blood sugar and the acid – alkaline state indices, an improvement of the child’s general condition was gradually observed and, later, it was permanently afebrile with stable bowel movement, good nutrition tolerance and adequate diuresis until she was discharged. The child took mother’s milk in the whole period of hospitalization with a fivefold regimen of feeding about the following hours: 6 a.m., 10:30 a.m., 1:30 p.m., 6 p.m., 11:30 p.m. – 12 a.m. At the moment of discharge, her weight was 4650 grams (10.2 pounds).
When she was four months old, the following examinations took place:
No Indices,
Results
Referential Values
C-Peptide
49.4 pmol/l
174-960
IA-2 Antibodies
0.23 U/ml
<0.9
GAD 65 Antibodies
8.8 ng/ml
<32
Insulin Antibodies
1.0 U/ml
<10
At the moment, my daughter is 5 months old and her health condition is very good. She is growing, which is normal for her age. Her weight is 7.7 kg (17 pounds) and she is 66 centimeters 926 inches) in height. She gets an injection of 1.5 units of Mixtard 40/60 at 6 a.m. and 1 p.m., with an injection of 1.5 units of Mixtard 70/30 at 8 p.m.
Given her history, I don't agree with the diagnosis of type 1 diabetes because there is no autoimmune process. She has no other typical symptoms, such as readings below 4 mmol/L [72 mg/dl] and above 20 mmol/L [360 mg/dl]. Is there any chance my daughter has TNDM and can be cured? How can she be diagnosed correctly? What insulin do you recommend? How do we get a second opinion?
Answer:
It sounds like very early type 1 diabetes, but only time will tell if this is really transient. I think that the GAD 65 antibodies are positive by the assay levels that we use, but the values you use in reference do not seem to confirm this. There was no islet cell antibody although, in very small babies, this is often negative. In fact, most antibodies are negative in the blood even with small babies who continue to have type 1 autoimmune diabetes. If HLA testing is available on the half-brother and this baby, this might be confirmatory but not 100% conclusive.
Most pediatric diabetologists would use Lantus once or twice a day (breakfast and bedtime) as basal insulin coupled with boluses of Humalog or NovoLog to cover meals. Frequent blood glucose monitoring would be needed to decide actual doses. It is usually very difficult to decide, even if only breast milk provided. C-peptide levels would give some idea of how much endogenous insulin is available. A1c levels would suggest how easy or difficult management would be and thus, indirectly, let one know about insulin reserves and overall control.
The pediatric endocrine group in Varna is excellent, very knowledgeable and very skilled. Dr. Violeta Iotova should be consulted if she is not already involved with care. The pediatric endocrine group in Sofia Children’s Hospital, Maja Konstantinova, is also excellent.
SB
Additional comments from Dr. Andrea Scaramuzza:
Neonatal diabetes, transient or permanent, is a peculiar type of diabetes, characterized by hyperglycemia, not always due to insulin deficiency, and has a genetic basis. Recently, a Multicenter Italian study has supported these statements.
Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase, an enzyme involved in glucose metabolism, can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. So, it is not uncommon in this type of diabetes to have a negative autoimmune testing.
In transient neonatal diabetes (TNDM), the beta cell is preserved and able to secrete insulin through the stimulatory G protein pathway while exhibiting a specific defect of insulin secretion after glucose stimulation. This form of diabetes can be managed with insulin or diet, although new therapeutic agents (glucagon-like synthetic analogs) may prove useful in the future. A lack of treatment leads to long-lasting hyperglycemia without the risk of ketoacidosis, but associated with microangiopathy in adult life.
However transient and permanent neonatal diabetes mellitus are rare conditions occurring in one in 400,000 to 500,000 live births. In transient neonatal diabetes, growth-retarded infants develop diabetes in the first few weeks of life only to go into remission in a few months with later relapse as permanent type 2 diabetes, often around the time of adolescence. Pancreatic dysfunction in this condition is maintained throughout life with relapse initiated at times of metabolic stress such as puberty or pregnancy. The mechanisms involved in this rare condition may inform on fetal pancreatic development, islet cell physiology and predisposition to type 2 diabetes. In permanent neonatal diabetes, insulin secretory failure occurs in the early postnatal period. A number of conditions are associated with PNDM, some of which have been elucidated at the molecular level. Insulin therapy is difficult to manage in the neonatal period, and in experienced hands, the insulin pump may provide a valuable tool to administer insulin.
AS
