A 35-day-old male baby was admitted to the outpatient clinic of Tianjin Children’s Hospital (Tianjin, China) at 14:00 in February. The patient had been found with laryngeal stridor for 2 days and feeding intolerance for 1 day. The family members stated that the child had been crying less and moving less, and he had lost 0.6 kg of weight after birth. The baby was born via full-term vaginal delivery, G1P1 and had no other evidence of major medical or birth defects. The mother of the baby was naturally pregnant and had fever on the 2nd day after giving birth. The blood culture in the hospital showed Escherichia coli and enterococcus infection. She was suspectedly diagnosed with sepsis in the local hospital and discharged after 15 days of anti-infection with meropenem. The parents were not engaged in toxic or harmful work and had no history of diabetes, epilepsy, neurological deafness, other family genetic illness and inbreeding. The following results were obtained by physical examination after admission: anal temperature, 37.2 °C; pulse, 130/min; respiration, 21/min; blood pressure, 80/50 mmHg (1 mmHg = 0.133 kPa); body weight, 3.4 kg; head circumference, 34 cm; body length, 53 cm; clear consciousness; poor response; irregular respiration rate; and moist rales in both lungs. Muscle tone was low, crying was absent and movement was minimal. On admission, the white blood cell count was 20.22 × 109/L, neutrophil was 56.2%, monocyte was 10.1%, platelet was 216 × 109/L, haemoglobin was 149 g/L and c-reactive protein (CRP) was 25.3 mg/L. Arterial blood gas was normal. Chest film showed bronchopneumonia. The child was admitted with a diagnosis of bronchopneumonia.
Given the severity of the illness in the child, he was admitted to the intensive care unit, where given oxygen atomisation and empirical application of 60mg/kg/day cephalosporin was conducted for anti-infection treatment.But at 2h after admission, the patient suddenly stopped breathing, and his blood oxygen saturation level was only 78%. Timely rescue support was provided via tracheal intubation and mechanical ventilation of symptoms. The child had a rectal temperature of 35.7 ℃, breathing rate of 20 times/min, irregular breathing rhythm, pulse of 95 bpm, transcutaneous oxygen saturation of 90%, oxygen flow of 4 L/min, bad spirit and exhibited lethargy and cool peripheral limbs. As a result of the child’s poor general condition on admission, the neonatal behavioural assessment scale (NABA, a test in China that can help determine newborns’ ability to behave and detect minor brain injuries early, allowing for early intervention to prevent and treat disability) was not appropriate.
On the basis of the significant increase in the inflammatory index after admission, such as peripheral blood white blood cells (mainly neutral), CRP, primitive calcitonin and the mother’s postpartum history of suspected sepsis, the possibility of drug-resistant bacterial infection should be considered, so the antibiotic meropenem combined with linezolid anti-infection treatment was adjusted. After oxygen inhalation, physical heating, atomisation, anti-infection and other corresponding treatment measures, the blood oxygen saturation on the 3rd day after admission was better than before and rose to 99% without oxygen inhalation, but the child still demonstrated irregular breathing. On the 5th day after admission, we performed lumbar puncture examination, and the cerebrospinal fluid biochemistry was generally normal. At this time, the blood routine examination showed that the inflammatory indexes decreased, and linezolid was discontinued. The re-examination of arterial blood gas showed pH 7.40, partial pressure of carbon dioxide of 52.4 mmHg, partial pressure of oxygen of 110 mmHg, residual alkali of 6.4 mmol/L and actual bicarbonate of 32.5 mmol/L. These findings indicated compensatory respiratory acidosis combined with metabolic alkalosis, and subsequent observation was necessary. On the 7th day of admission from the machine, the child’s oxygen saturation reached 98%, but the rectal temperature was sustained at 35.7 ℃–37.3 ℃ and the breathing rate was 20–30 times/min. Moreover, the child demonstrated poor sucking ability and low limb muscle tension. At 21 days in the hospital, the child’s systemic symptoms showed an improvement; the milk feeding rate was 60 mL/s, Q3H and daily calorie intake was about 76.2 kcal/kg/day. The NABA was performed on the child at discharge (Table 1).
Table 1. Neonatal 20-item Behavioural Neurological assessment (NABA) at discharge from the hospital in this case
During admission, the head MRI of the child showed patchiness and slightly longer T1 and T2 signal shadow in the bilateral frontal and parietal ventricles, a small amount of haemorrhage in the subarachnoid space, widened extracerebral space, soft tissue swelling in the left frontal scalp and unorganised adjacent cranial plate (see Figure 1). Electroencephalogram (EEG) showed low to medium activity with amplitude of 1.5–2.5 Hzδ in awake state and a few low-amplitude fast waves. The voltage of each conduction part was less than 20 μV. There was no epileptic discharge or abnormal EEG in awake state, and the voltage of each conduction part was low.
Upon discharge, the family members were informed that ‘pneumonia sepsis’ could not fully explain the current clinical manifestations and physical examination of the child. After reviewing the literature, the child was suspected to be suffering from congenital or genetic diseases. After seeking the consent of the child’s family members, the peripheral blood of the child and his parents was obtained for whole-exome sequencing (WES). The results of genetic testing showed that the child had variations in PURA gene C. 154dupG (p.L54Afs*147), while the blood samples of his parents showed no variation in this locus. The disease associated with this locus was autosomal dominant mental deficiency type 31 associated with the PURA gene.
Gene detects: WES found a heterozygous mutation at the dupG site of Pura gene c.154, which changed leucine 54 into alanine, causing premature termination at 147 and frameshift mutation (Figure 2). At present, there are no studies about whether the variants disrupted the alleles of all protein translation, or mutations of codon translation if proteins are pathogenic. However, according to the American College of Medical Genetics and Genomics (ACMG) guidelines(1), it was determined to be pathogenic: ①PVS1 (very strong): this mutation is a frameshift mutation, which may lead to the loss of gene function; ②PM2 (medium): the frequency in the normal population database is -, which is a low frequency variation; and ③PM6 (medium): a new variant that has not been verified by parental samples. According to the pathogenic mutation classification criteria: PVS1 (very strong) +PM2 (moderate) +PM6 (moderate), the mutation was determined to be pathogenic.
After the discharge of the child, at 1 month after the call to reply, the milk volume of the child was increased to 100 mL/q4h. The child’s cry was louder than before, general movement increased and drowsiness was significantly better than before, but he still showed slow response to sound and demonstrated feeding difficulties, such as coughing when feeding and poor sucking. Subsequently, he received irregular follow-up in the outpatient department of genetics and metabolism and rehabilitation department of our hospital. One year later, the child’s weight was 10.5 kg. He was about 80 cm long; had strabismus and poor muscle strength; could not turn over; sat alone for not more than 1 min; displayed irritability, slow sound response and poor speech development; could only recognise the mother; and did not know the rest of the family. The family did not complain of the child having irregular breathing patterns. The child’s current diet comprised vegetables and meat.