Results
Clinical data: The proband was male, aged 19 months. He was admitted to the hospital on 20th December 2018, due to excessive drinking, polyuria for overhalf a month and wheezing for 3 days. The medical history showed that the child was given birth by a G1P1 woman with a caesarean section in the 39thgestational week. Birth weight and length were 3.35 kg and 51 cm, respectively. The health status during the neonatal period as well as the child’s mental and physical development was normal More than half a month before admission, the patient had polydipsia and polyuria without known inducement, and his daily water intake significantly increased compared to before. 2 days before admission, the child presented with a severe wheezing accompanied by Kussmaul respiration and a poor general condition. He was sent to the local hospital and was admitted to the intensive care unit (ICU) for treatment. After admission, his random blood glucose levels were 40mmol/L, urine ketone body was positive, and the preliminary given diagnosis was ”diabetes, diabetic ketoacidosis”. Due to an unsatisfactory therapeutic effect, the child was transferred to the Beijing Children hospital for further diagnosis and treatment. On arrival at the emergency unit, the intravenous blood glucose level was 20.74mmol/L, and blood gas analysis resulted in pH 7.07, PCO2 17.5mmHg, BE - 23.5mmol/L, afterwards the patient was admitted to the endocrinology department for further treatment. The patient had no family history, and the blood glucose levels of both parents were normal.
Physical examination on admission : Patient’s temperature was 37℃, respiration rate was 37 times/min, pulse was 150 times/min, blood pressure was 116/62mmHg. The patient’s weight was 12 kg with a normal physical development. He was in a poor general condition, with decreased level of consciousness, no tears when crying, an anaemic appearance, Kussmaul respiration and a fruity breath odor. His lips and skin were dry with slightly low skin elasticity. The right upper lung presented with moist carackles. The upper extremities were cool to the elbows, while the lower extremities were cool to the knees, with a dilated blood vessel pattern on the limbs and a CRT of 3 seconds.
Laboratory and imaging results: The blood sugar was 21.69mmol/L (Normal range: 3.9 - 6.1mmol/L), glycosylated haemoglobin was 11.1% (Reference value: 4 - 6%), insulin level was 0.56 μIU/ml at the 0th min (6.0 - 27.0μIU/ml), C-peptide level was 0.09ng/ml at minute 0 (1.1-5.0ng/ml). Anti-islet cell (ICA) and anti-glutamate decarboxylase antibodies (GADA) were negative. Blood gas analysis was repeated: pH was 7.06, the carbon dioxide partial pressure was 15mmHg, the oxygen partial pressure was 74mmHg, the actual and standard hydrogen carbonates were 4.2mmol/L and 5.8mmol/L, respectively, the total carbon dioxide was 4.7mmol/L, the extracellular fluid base storage 26.1mmol/L, and whole blood base storage was 24.2mmol/L. Blood biochemistry showed that potassium was 3.24mmol/L, sodium was 136mmol/L, chlorine was 109.9mmol/L, while the osmotic pressure was 296mOsm/kg. The urea was 2.35mmol/L, creatinine was 30umol/L, total calcium was 2.53mmol/L, lipase was 9.2u/L, amylase was 50U/L and D-3 hydroxybutyric acid was 10.18mmol/L. Concentrations of insulin-like growth factor were < 25.0ng/ml, while the insulin-like growth factor binding globulin was 0.56 g/ml. Urine routine analyses showed that the glucose was 4+, ketone was 3+, the protein was 1+, while the urobilinogen and nitrite were negative, occult blood trace was negative and centrifugation microscopy showed no erythrocyte/HPF. The serum cortisol at 8 AM was >50.0μg/dl, and adrenocorticotrophic hormone at 8 AM was 68.8pg/ml. Thyroid analysis showed that the total serum levels of T3 and T4 were 19.77ng/dl and 2.04ug/dl, respectively. The serum thyroid-stimulating hormone had a blood concentration of 0.391mIU/L, serum-free T3 and T4 were 3.52pmol/L and 5.51pmol/L. Chest X-ray showed slightly more texture and fuzziness in the lungs with patchy shadow on the right upper lung. Abdominal ultrasound showed no abnormalities.
After admission, the patient was diagnosed with Type 1 diabetes, diabetes ketoacidosis and pneumonia. After fluid infusion, ketone correction, insulin and anti-infection treatment the patient gradually recovered.After 17 days of hospitalization, the blood glucose level was stable and the patient was discharged. The total amount of insulin dosage at discharge was 7.5IU, equivalent to 0.625IU/kg/d.
Gene sequencing results: The genetic sequencing results revealed that the patient carried a rare c.487C>T heterozygous mutation in the 7th exon region of the PAX4 gene. This mutation led to a R163W variation in the amino acid sequence. The patient‘s father carried the same heterozygous mutation while the mother presented with a normal genotype, suggesting that the mutation could be autosomal dominant. The estimated frequency of the mutation in the normal population database was 0.00010, which is a low-frequency mutation. There were no related reports of this mutation in the HGMD database. SIFT, PolyPhen_2, Mutation Taster, GERP++ and REVEL respectively predicted this mutation as harmful, harmful, benign, harmful and benign. According to the ACMG guideline, the mutation was preliminarily determined to be of unknown clinical significance.
Gene sequencing results of the proband and his parents are shown in Figures 1, 2 and 3.