In December 2019, a 6-month-old boy was admitted to our hospital due to edema for 1 week and fever for 1 day. The child was the first child of a non-consanguineous marriage and with full term of 39W+2, was delivered by cesarean section, had a birth weight of 3,900 g, and had no remarkable details regarding medical or personal history. At admission, there was prominent edema on the whole body and pitting edema on the anterior tibial area. We diagnosed the patient with NS based on nephrotic-range proteinuria (263 mg/kg/day), obvious hypoalbuminemia (12.2 g/L). There were also several other abnormal laboratory results (Table 1). In particular, the coagulation function was altered with decreased antithrombins (AT) and slightly increased level of D-dimer and activated partial thromboplastin time (APTT). However, the prothrombin time (PT), fibrinogen degradation products (FDP), and fibrinogen (Fib) were in normal ranges (Table 1).
The ultrasound showed enlarged kidneys (the left and right kidney were 8.5 x 4.9 x 4.0 cm and 8.6 x 4.9 x 3.7 cm, respectively) with hyperechogenicity of renal parenchyma, blurred cortical and medullary boundaries. The depth of pelvic and abdominal cavity effusion was 3.4 cm. A chest computerized tomography (CT) showed multiple bilateral pulmonary foci, partial pulmonary consolidation, bilateral pleural effusion, and poorly inflated adjacent pulmonary alveoli. His heart function was normal and the nervous system had no abnormalities. The routine urine test results of both parents were normal.
We prescribed ceftriaxone for anti-infective treatment and other adjuvant therapies, such as infusion of plasma and albumin, to increase the colloidal osmotic pressure and manage the diuresis. He received the administration of intravenous enoxaparin sodium 0.06 ml/day (50 AxaIU/kg/day) for anticoagulant therapy at admission because of severe hypoalbuminemia and complicated fluid management. We also administered intravenous immunoglobulin intermittently to provide immune support. The levels of free triiodothyronine (FT3) and free thyroxine (FT4) were significantly reduced, and the level of thyroid-stimulating hormone (TSH) was significantly increased, but there were no evident abnormalities in ultrasound. The diagnosis of hypothyroidism was considered, and we administered oral levothyroxine sodium (12.5 mug/day).
The child developed an intestinal infection caused by norovirus after hospitalization. Due to his young age and this infection, after excluding tuberculosis, we administered intravenous methylprednisolone (1.6 mg/kg/day) on the 4th day in the hospital. After 25 days of hospitalization, the child's general condition improved significantly, the edema subsided, the 24-h urine protein had decreased significantly (0.43 g/day), and the plasma albumin increased to 20.5 g/L. Analysis of coagulation showed that AT, D-dimer, APTT, PT, FDP, and Fib returned to their normal ranges. The child was discharged and continued to take adequate oral prednisone (2 mg/kg/day) for 2 weeks with a gradually reducing dosage (2 and 0.5 mg/kg/day alternatively in the morning) for 1 month. After that 2 mg/kg/day on an alternate day for 2 weeks, then reduce 2.5 mg every 2 weeks.
Because of the young age at disease onset, we considered the child might have had congenital NS. Therefore, we performed trio whole-exome and mitochondrial genetic sequencing on the 5th day in the hospital. Briefly, 3 mL of peripheral blood was collected from the patient and his parents, and genomic DNA was extracted using a blood genome extraction kit (Tiangen). Capture sequencing was performed using the human total exome capture probe of JOY Orient. The capture probe covered the coding region of 19,396 genes in the human genome, and the capture target interval was 39 MB. A total of 429,826+ capture probes were designed and synthesized, and the capture probe covered 51 M. Sequencing was performed using the Novase Q6000 instrument. After obtaining the original sequenced reads, fine filtering of raw reads was required. Clean reads obtained in this way were compared with HG19/GRCH37 (reference genome). Software (GATK) was used for detection and analysis of single nucleotide polymorphisms and InDels. The coverage of the target area was 99.90%, and the average depth was 109-fold. The results indicated a novel hemizygous potentially pathogenic variant, c.2717A>G (p.His906Arg), in exon 17 of the TBC1D8B gene. This potentially pathogenic variant was derived from the mother (who had no history of symptoms and no proteinuria) and the father's gene was normal (Figure 1). The amino acid sequences for this site (His906) showed that it was identical in Homo sapiens, Pan troglodytes, Macaca mulatta, Canis lupus familiaris, Mus musculus, Rattus norvegicus, Gallus gallus, and Danio rerio (Figure 1). The minor allele frequency (MAF) of this site in the gnomAD database was 0.0005 (East Asia). Protein structure and function prediction software indicated the variant was probably damaging (Polyphen) or deleterious (SIFT).
The child was followed up for 1 year (Table 2) and treated with oral prednisone, vitamin D, and calcium supplementation. During this follow-up period, the boy experienced 2 relapses of NS when alternate-day morning prednisone was reduced to 17.5 mg (March 2020), and the second recurrence was accompanied by a fever (June 2020) which indicated steroid-dependent NS. Adequate oral prednisone (20 mg/day) was given to achieve remission, followed by dose reduction. As of November 2020, the dose of alternate-day prednisone was 5 mg. The urine test results were normal (protein negative, 2.12 RBCs/HPF), and the 24-h urine protein was 0.12 g/day. The child's serum albumin returned to normal (42.6 g/L), as did his renal function (blood urea nitrogen, 2.87 mmol/L; serum creatinine: 17.5 mumol/L). And the patient didn't show any signs of steroid toxicity. We reduced the oral levothyroxine sodium dose to 6.25 mug/day, and measurements of thyroid function were in the normal ranges (FT3 5.71 pmol/L; FT4, 12.4 pmol/L; TSH, 0.7323 muIU/mL).