A case report: Alport syndrome and growth hormone deficiency associated with a new COL4A4 mutation

Abstract

Background: Alport syndrome (AS) is a rare progressive hereditary kidney disease that is clinically principally associated with hematuria, proteinuria, and progressive renal dysfunction. This condition not only impairs renal function but also potentially affects auditory and ocular health, significantly impacting the patient's quality of life.

Case description: This article reports a young girl with AS, combined with dwarfism attributable to growth hormone (GH) deficiency, diagnosed at Wenzhou People's Hospital in 2019. The clinical data and diagnostic steps were retrospectively analyzed. Genetic testing showed that she carried a new mutation in the COL4A4 gene, c.2317_2318delAG (p.R773Gfs*14), classified as "pathogenic" under the criteria of the American College of Medical Genetics and Genomics (ACMG), confirming her AS diagnosis. Significantly, the patient's height was more than two standard deviations (SDs) below the average for children of her race, sex, and age. The peak GH level post-stimulation was below 5 ng/mL, coupled with a growth rate of less than 5 cm/year, leading to the diagnosis of GH deficiency. Consequently, recombinant human GH (rhGH) therapy was initiated.

Conclusions: After a year of rhGH treatment, we observed a notable increase in her height, without any adverse effects like elevated intracranial pressure, hypothyroidism, or worsening kidney function.

Keywords: Alport syndrome (AS); case report; growth hormone deficiency (GH deficiency); recombinant human growth hormone (rhGH); short stature.

Figure 1

Family pedigree chart of the patient.

Figure 2

Renal pathology of the proband. (A) Immunofluorescence a3: ×400. Glomerular and renal tubular basement membrane expression levels were normal. (B) Immunofluorescence a5: ×400. Glomerular basement membrane, Bowman capsule, and renal tubular basement membranes exhibited segmental weakening. (C) EM: ×6,000. The red arrow indicates diffuse thinning of the basement membrane to <180 nm and segmental fusion of podocyte foot processes. (D) PAS staining: ×400. Shows mild glomerular lesions. EM, electron microscopy; PAS, periodic acid-Schiff.

Figure 3

The heterozygous frameshift mutation in the COL4A4 gene of the proband, leading to a change from arginine to glycine and a premature stop at position 786. (A) Mutational information. (B) COL4A4 sequencing of the proband and the parents. NM, nuclear mRNA; Het, heterozygous; AD, autosomal dominant; LP, likely pathogenic.

Figure 4

Three-dimensional structures of COL4A4 proteins. (A) Wild-type; (B) the mutant. As mutations that change amino acids 773 to 786 are not known. Only amino acid 773 is shown.