A 7-day-old male was transferred to our hospital due to “refusal of milk with poor response for 4 days”. The patient's mother (gravida 2, parity 2), gave birth by cesarean section. The newborn had a birth weight of 3,000 g, a length of 50 cm, and had no history of asphyxia. On the third day after birth, the infant presented with milk refusal, poor mental response, yellow staining of the skin and mucosa of the whole body, and fever (38.4 ℃), but no convulsions. The local hospital diagnosed “neonatal septicemia and jaundice”. After management of symptoms for 4 days, his body temperature returned to normal, but he still had poor mental response, and was transferred to the Department of Neonatology of our hospital. At admission to our department, his blood glucose level was 2.02 mmol/L, and he was discharged after 12 days of supportive treatment. On the 28th day after birth, the jaundiced skin and mucosa recurred, although we did not measure the blood glucose level. At this time, the results from whole exome sequencing (WES) were available, and he was readmitted for 7 days, and received regular follow-up in the outpatient clinic.

The father was in good health with blood type A, the mother had blood type B, and the marriage was non-consanguineous. The mother had a history of hypothyroidism during pregnancy for which she received levothyroxine sodium tablets. Their first child was a girl who unfortunately passed away during the neonatal period from unknown causes.

When the neonate was first admitted to our department (age of 7 days), his body temperature was 36.8 ℃, pulse rate was 160 beats per minute, respiration rate was 40 breaths per minute, and blood pressure was 85/51 mmHg (11/6.8 kPa). At that time, his length was 50 cm and his weight was 3,150 g. The patient had a relatively sluggish response to stimulation and emitted a weak cry. No seizures or signs of impaired consciousness were observed. The skin had a yellowish hue throughout, with an absence of pigmentation. The scleral areas were also yellowish, and the pupil diameter was 2 mm, with responsive light reflexes. Furthermore, both lungs displayed coarse breath sounds upon auscultation, palpation of the liver approximately 1 cm below the subcostal margin indicated no splenomegaly, and there was also no umbilical hernia. However, there was varus deformity of the left foot and weak muscle tone in all extremities. Primitive reflexes were elicitable.

Laboratory tests performed at the same time indicated a blood glucose level of 2.02 mmol/L, serum sodium level of 130.6 mmol/L, total bilirubin level of 194.5 µmol/L, direct bilirubin level of 24.3 µmol/L, indirect bilirubin level of 170.2 µmol/L, γ-glutamyl transpeptidase (GGT) level of 235 U/L, and bile acid level of 134.7 µmol/L. The procalcitonin (PCT) level was 0.105 ng/ml, but a blood culture and sputum culture were both negative for infection. Following supportive treatment, the PCT level returned to normal and the mental response improved, although milk refusal, hypoglycemia, and jaundice persisted without explanation, perhaps suggesting neonatal sepsis. Further endocrine examination showed low levels of cortisol (<0.1 µg/dl) and adrenocorticotropic hormone (ACTH, 2.l pg/ml), but the levels of growth hormone (GH), luteinizing hormone, and thyroid stimulating hormone were within normal limits (Table 1). The low score on the Neonatal Behavioral Neurological Assessment (NBNA) indicated impaired behavioral responses. The NBNA evaluates newborn behavioral capabilities, passive and active muscle tone, primitive reflexes, and general condition. The scale includes 20 items, scored out of a total of 40 points. A score below 35 is considered abnormal, the subject in question attained a score of 24.

On day 31 after birth, cranial magnetic resonance imaging (MRI), pituitary MRI, and adrenal CT all yielded normal results. However, an electroencephalogram (EEG) was abnormal, with a slow background rhythm. We analyzed the WES results to search for variants that may be associated with the clinical phenotype, and also performed genetic analysis of the parents. The patient had compound heterozygous variants, c240-246del(p.leu81Profs*54, NM_005149.3) and c377C>T(p.Pro126leu, NM_005149.3), that were in exon 1 of the TBX19 gene, and these variants were inherited from the father and mother (Figure 1). According to the guidelines of the American College of Medical Genetics, p.Leu81profs*54 is a suspected pathogenic variant, although the clinical significance of p.Pro126leu is unknown. We initiated hydrocortisone (HC) replacement therapy when the infant was 31-days-old, after which the levels of bilirubin and bile acid gradually decreased, and the levels of ACTH and cortisol gradually increased (Table 1).

During the whole hospitalization, the parents of the child obtained informed consent and actively cooperated with the treatment. When the child was admitted to the hospital for the first time, we considered neonatal hypoglycemia, neonatal hyperbilirubinemia and neonatal sepsis based on symptoms, physical signs and auxiliary examinations. We thought the possible cause of neonatal hypoglycemia might be endocrine disorders. A normal head MRI excluded endocrine dysfunctions caused by the pituitary gland and hypothalamus. We took appropriate temporary treatment measures. We maintained stable blood sugar by intravenous infusion of 10% glucose, conducted intermittent phototherapy and used ursodeoxycholic acid capsules for liver protection and choleresis. At the same time, we used piperacillin sodium and tazobactam sodium for injection to treat neonatal sepsis for seven days. After treatment, the child's clinical symptoms disappeared and there was no recurrence of hypoglycemia. The child was discharged after improvement.

The second time, the child had hypoglycemia and jaundice symptoms again. At this time, as we had previously suspected neonatal endocrine diseases and had the report of whole exome sequencing (WES), the child was clearly diagnosed with neonatal IAD (age of 31 days). We immediately administered HC (10 mg/m²/day) for replacement therapy. After the condition stabilized, the child was discharged. We instructed the child to take medicine on time and regularly monitor blood sugar, adrenal cortical hormones, cortisol, etc. at the outpatient clinic to adjust the dosage.

We initiated the HC treatment (20 mg/m²/day) immediately after receiving the WES results. During the follow-up, we also administered two cycles of intermittent phototherapy, and this led to a relief from jaundice, and decreases in the levels of total bile acids and bilirubin (Figure 2). Additionally, the blood glucose levels increased to the normal range, and there was no evidence of liver disease, leading to patient discharge.

During the 100-day follow-up period, we gradually decreased the HC dosage to 10 mg/m²/day. At the last follow-up (135 days after birth), the patient's height was 68 cm (>P97), weight was 8.7 kg (>P97), head circumference was 42.7 cm (P90–P97), and he appeared to have normal mental development (Figure 3). The ACTH and cortisol levels gradually increased, but did not fully return to normal, although the bilirubin level showed gradual recovery (Table 1). On day 100 of the HC treatment, the bilirubin level returned to normal range (Table 1; Figure 2). Moreover, the child's blood glucose remained stable, he had no clinical symptoms or adrenal crisis, and his liver function remained within normal limits.

For a literature search, we used the terms “newborn”, “child”, “congenital isolated adrenocorticotropic hormone deficiency”, and “TBX19” to retrieve relevant studies until December 2023 from the following databases: China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Medical Journal Full-text Database, VIP database, Sinomed, PubMed, Embase, and Web of Science. This search of case reports of IAD in any language led to identification of 35 cases, including the current infant. Twelve studies were in the English language (3–14) and 4 studies were in the Chinese language (15–18) (Supplementary Material).

There were 24 boys (69%) and 11 girls (31%). There were 24 newborns (69%), 7 cases (20%) between 1-month and 3-years-old, and 4 cases (11%) over 3-years-old (Supplementary Material). Further analysis of the age at which IAD treatment began showed that 16 cases (46%) were between 0 and 3-months-old, 3 cases (8%) were between 3-months-old and 1-year-old, 7 cases (20%) were between 1-year-old and 3-years-old, and 9 cases (26%) were more than 3-years-old. The most common clinical symptoms were hypoglycemia (n = 33), jaundice (n = 21), and epilepsy and convulsion (n = 18). The other notable symptoms were feeding difficulties and poor mental response (n = 7), recurrent respiratory tract infection (n = 2), abdominal pain and vomiting (n = 6), and hypothermia (n = 2). The laboratory data showed that all 35 patients had low levels of ACTH and cortisol; 33 cases had blood glucose levels lower than 2.8 mmol/L and 2 cases had unknown blood glucose levels without hypoglycemia symptoms; 17 cases had increased total bilirubin levels, 1 case had a normal level, and 17 cases had unknown levels; 14 cases had hyponatremia, 11 cases had normal serum sodium levels, and 10 cases had unknown levels. The MRI results showed that 29 cases had normal pituitary results, 3 cases had varying degrees of pituitary changes, and 3 cases had unknown results; the brain MRI results showed bilateral subdural hematoma, hypoglycemic encephalopathy, and left cerebral hemisphere diffuse atrophy (1 case each). Among all 35 children, 7 were from consanguineous marriages, and 16 children were from families that had other children who had a disease or died of unknown causes.

Whole genome sequencing was performed in all 35 children. Twenty-four children had TBX19 gene mutations (with mutations at 19 different sites), 9 had no TBX19 mutations, and the results of the other 2 cases were not reported.

Thirty-five patients received long-term HC replacement therapy after the diagnosis of IAD. After HC treatment, the clinical symptoms completely resolved in 30 patients, the clinical symptoms of 3 patients were significantly resolved, except for refractory seizures that were treated with antiepileptic therapy, and the effects of treatment in 2 patients were not reported.

After treatment, 18 cases had no neurological development delay, 15 cases had different degrees of neurological development delays, and follow-up data of 2 cases were not reported. Among the 15 cases with complications, 13 cases began treatment after the age of 1 year, and 1 case did not receive regular HC treatment (Supplementary Material).