Here, we present a female patient with MHC II deficiency due to a new mutation in the RFXANK gene. She was from a consanguineous family in southwest China and was their first child. There had been no similar illnesses in the family before this (Fig. 1). She was hospitalized for aspiration pneumonia after birth. One month ago, at the age of three months, she developed cough and wheezing, which led her to the local hospital, and the symptoms improved after three days of hospitalization. Twenty days ago, she was again admitted to a local hospital with a chief complaint of diarrhoea and intermittent fever, where she was treated with mechanical ventilation, antibiotics, and gammaglobulin, but her respiratory symptoms continued to worsen. She was urgently transferred to our hospital for further treatment.

Family tree diagram of the patient

At the time of admission, the child's transcutaneous oxygen saturation was 77%. The symptoms of respiratory distress included pale lips, cyanosis, nodding respiration, nasal agitation, and inspiratory triple concavity. The Initial chest CT (Fig. 2A) showed decreased transmittance and diffuse patchy hyperdensity in both lungs, confirming acute respiratory distress, and the child was placed on a constant-frequency ventilator to assist with the treatment. The initial ultrasound evaluation showed diffuse B-line predominance (Fig. 3A) and a markedly enlarged liver approximately 3–4 cm below the ribs. Hepatomegaly is initially considered to be due to severe infections As the child had been on antibiotics and a mechanical ventilator for a prolonged period, considering drug-resistant organisms and some opportunistic pathogens, anti-infective therapy with meropenem, sulfamethoxazole, and metagenomics next generation sequencing (mNGS) were performed. The child experienced severe hypoxemia (PaO2 49 mmHg) and hypercapnia (PaCO2 77.4 mmHg) within 7 h of admission and was switched to a high-frequency ventilator for assisted respiration. The next day, sputum sequencing revealed that the patient had a mixed infection with multiple bacteria, fungi, and viruses, including Stenotrophomonas maltophilia, Candida parapsilosis, Clavispora lusitaniae, Human betaherpesvirus 5, Human respiratory syncytial virus A, and Rhinovirus A. Based on the sequencing results, the decision was made to discontinue meropenem and switch to cefoperazone sulbactam sodium combined with sulfamethoxazole for intravenous infusion against infections and voriconazole for oral antifungal. In the following days, the patient’s symptoms stabilized, but by the sixth day, the neutrophil count dropped sharply (0.18 × 109/L, normal range 0.6–7.5 × 109/L). It was decided to discontinue cefoperazone sodium sulbactam and replace it with piperacillin-tazobactam to be alert for hematologic abnormalities and adverse drug reactions. By day 7, the child’s respiratory distress is better than before; with hypercapnia relieved (PaCO2 42.2 mmHg), the mode was switched back to constant-frequency ventilation. From day 9 to day 14, the child again showed a change in condition, with intermittent fever occurring every day, and routine blood results showed marked elevation of ultrasensitive C-reactive protein (50.5 mg/L, normal range 0–10 mg/L) and interleukin 6 (265.8 pg/ml, normal range ≦ 7 pg/ml). On day 10, ultrasonography of the lungs (Fig. 3B) revealed extensive blurring of the pleural lines. Compared with the ultrasound examination on admission (Fig. 3A), there was an increase in the number of B-lines (Fig. 3B-1), signs of fragmentation (Fig. 3B-2), and substantial changes Fig (Fig. 3B-3), which are typical of inflammation in the lungs. On day 12, the child was successfully taken off the ventilator and switched to humidified high-flow nasal cannula oxygen therapy. Serum cytomegalovirus DNA was 2.14 × 105 copies/ml (normal range < 5.00 × 102 copies/ml), so ganciclovir anticytomegalovirus therapy was added on day 13. Hemophagocytic syndrome was suspected due to the child’s recurrent severe infections, pancytopenia (WBC 1.8 × 109/L, normal range 4.3–14.2 × 109/L; RBC 2.94 × 1012/L, normal range 3.3–5.2 × 109/L; PLT 92 × 109/L, normal range 183–614 × 109/L), persistent fever, ferritin more significant than 500 (FER > 1650.0ng/mL), elevated triglyceride levels (TG 5.59 mmol/L, normal range 0–2.30 mmol/L), and plasma fibrinogen < 1.5g/L (FIB 1.22 g/L), and bone marrow smear on the 14th day showed hemophagocytes in the bone marrow, which finally confirmed hemophagocytic syndrome. Dexamethasone was soon infused, but etoposide was not, considering she receiving a powerful antiviral treatment and extreme weakness. By day 20, the child’s oxygen saturation was gradually stabilized (transcutaneous carbon dioxide pressure monitoring TCPCO2 38 mmHg, transcutaneous oxygen pressure monitoring TCPO2 59 mmHg), and humidified high-flow nasal cannula was stopped instead of a nasal cannula. On the four weeks of treatment, the child was reexamined with a chest CT, and the CT showed (Fig. 2B) that the patient’s lung lesion area much reduced from the time of admission (Fig. 2A), suggesting that much of the inflammation had been resorbed, but that the substantial interstitial changes had increased from before. After 30 days of treatment, she was successfully discharged from the hospital; however, continuous oxygen inhalation via nasal cannula is still required. Cytomegalovirus amplification continues to rise in children after discharge from hospital, ineffective second-line treatment, enlarged and progressively ruptured left axillary lymph nodes (Fig. 4), and a positive blood test for tuberculosis and ultimately died 3 months after discharge from our hospital.

The images shown in (A-1), (A-2), (A-3), and (A-4) are the chest CT on the day of admission showed diffuse flaky, patchy hyperdense shadows in both lungs, with scattered small patches of air retention and areas of ground glass density within them. The images shown in (B-1), (B-2), (B-3), and (B-4) are the chest CT after 4 weeks of treatment showed extensive ground-glass density shadows in both lungs with some solid lesions, which were more resorbed than before

The images shown in (A-1), (A-2), and (A-3) are ultrasound images of the lungs at the time of admission, showing a diffuse B-line distribution in the anterior (A-1), middle (A-2), and posterior (A-3) of the lungs. The images shown in (B-1), (B-2), and (B-3) are ultrasound images of lungs on day 10, showing thickening and blurring of pleural lines, extensive B-lines (star) (B-1), localized fragmentation signs in the anterior lungs (black triangle) (B-2), and large solid lesions are seen in the posterior lungs (right arrow) (B-3)

A distinctive red mass is visible in the child’s left axilla

Due to the recurrent multiple pathogen infections, the tortuous nature of antibiotic therapy, and the young age and severity of the child’s condition, we suspected that this young patient had a primary immunodeficiency disease. Laboratory findings (Table 1) showed pancytopenia; weakened immunity, mainly in the form of decreased IgA and IgM; and using flow cytometry to assess the cellular immunodeficiency of the child, a decrease in CD4 and CD3 ratio, an increase in CD8 ratio, and a reversal of CD4/CD8 observed, which further confirmed the presence of an immunodeficiency. In order to clarify the diagnosis, peripheral blood whole exome testing was completed with the consent of the family.

Whole exome sequencing data revealed that the patient’s RFXANK gene underwent a mutation in the pure c.516 (exon7) dup (Fig. 5), resulting in MHC II deficiency. This mutation occurs at exon 7 of the RFXANK gene and results in a duplication of nucleotides at position 516 in the sequence of the gene. This further triggers a protein frameshift mutation starting at amino acid 173, which causes the 173rd amino acid encoded by the gene to shift from valine to cysteine and prematurely terminates the translation process of the protein after a subsequent extension of 8 amino acids. This mutation is a novel site that has not been documented to date.

A novel, pure-heterozygous mutation was identified in the RFXANK gene (NM_003721; exon 7; c.516(exon7)dup), which results in a frameshift mutation that leads to protein dysfunction. Sanger sequencing confirmed that the patient was pure heterozygous and that both parents (father and mother) were heterozygous carriers of the mutation. (In the illustration, the black line symbolizes guanine, the blue line represents cytosine, the red line represents thymine, and the green line is a symbol for adenine)