Pregnancy in women with autosomal recessive Alport syndrome caused by novel compound heterozygous mutations of COL4A3 gene: Two cases reports

Medicine · 5 authors, 2 centres

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This case report describes two pregnant women with autosomal recessive Alport syndrome (ARAS) caused by novel compound heterozygous mutations in the COL4A3 gene, presenting with progressive proteinuria during pregnancy. Despite severe proteinuria and fetal growth restriction, both pregnancies resulted in favorable neonatal outcomes after multidisciplinary management and cesarean delivery at 36-37 weeks. Postpartum treatment with Losartan reduced proteinuria to pre-pregnancy levels, highlighting the importance of genetic testing and coordinated care for ARAS in pregnancy.

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**Background:** Autosomal recessive Alport syndrome (ARAS) is a rare hereditary kidney disease caused by mutations in COL4A3 or COL4A4 genes, characterized by hematuria, proteinuria, and progressive renal dysfunction. Pregnancy in women with ARAS carries increased risks of worsening kidney function and preeclampsia. This report presents two cases of ARAS diagnosed during pregnancy due to novel compound heterozygous COL4A3 mutations.

**Methods:** Two pregnant women (21-year-old primigravida and 28-year-old secundigravida) presented with progressive proteinuria. Case 1 had 24-hour proteinuria rising from 2.03 g at 13 weeks to 11.72 g at 35 weeks; Case 2 from 2.10 g at 8 weeks to 9.32 g at 36 weeks. Both received multidisciplinary care including albumin infusions, compounded amino acids, calcium, vitamin D, and low molecular weight heparin (4000 IU every other day). Sanger sequencing of COL4A3 and COL4A4 genes was performed, and renal biopsies confirmed ARAS. Pregnancy was terminated by cesarean section at 36-37 weeks. Postpartum, both patients received Losartan for one year.

**Key Results:** Sanger sequencing revealed novel compound heterozygous mutations [c.1315 G>T (p.G439C) and c.4847 G>A (p.C1616Y)] in COL4A3 in both cases. Bioinformatics tools (SIFT, MutationTaster, PolyPhen-2) predicted both mutations as damaging. Renal biopsy showed characteristic basement membrane changes (diffuse stratified dense layer, basket-like structure). Neonatal outcomes were good: Case 1 delivered a boy (2400 g, Apgar 9-10-10); Case 2 delivered a girl (2370 g, Apgar 9-10-10). Postpartum, proteinuria persisted (Case 1: 2.67-5.31 g/day; Case 2: 3.26-6.84 g/day) but decreased to pre-pregnancy levels after one year of Losartan therapy. Case 1 developed high-frequency sensorineural hearing loss; Case 2 had no ocular or hearing involvement.

**Clinical Implications:** ARAS should be considered in pregnant women with unexplained progressive proteinuria, especially when family history is negative. Genetic testing (Sanger sequencing) is valuable for diagnosis. Multidisciplinary management (nephrology and obstetrics) can achieve favorable pregnancy outcomes despite severe proteinuria. Postpartum angiotensin receptor blocker therapy (Losartan) effectively reduces proteinuria. These cases expand the mutation spectrum of COL4A3 and underscore the need for awareness of ARAS in pregnancy.

STUDY TYPE

case_report

SPECIALTY

nephrology

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ORIGINAL PAPER

PMC10659596

Pregnancy in women with autosomal recessive Alport syndrome caused by novel compound heterozygous mutations of COL4A3 gene: Two cases reports

Medicine

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ABSTRACT

Rationale: Autosomal recessive Alport syndrome (ARAS) is an hereditary heterogeneous disease that poses a serious risk to pregnant women. Patient concerns: We reported 2 cases of pregnancy with progressive proteinuria. The case 1 was a 21-year-old woman with 24-h proteinuria increased from 2.03 to 11.72 g at 13 to 35 weeks of gestation, and the case 2 was a 28-year-old woman with 24-h proteinuria increased from 2.10 to 9.32 g at 8 to 36 weeks of gestation. In advanced stage of pregnancy, the fetal development was smaller than the gestational age. Diagnoses: Sanger sequencing showed that novel compound heterozygous mutations [c.1315 G>T (p.G439C) and c.4847 G>A (p.C1616Y)] of the collagen type IV alpha 3 chain ( COL4A3 ) gene were found in the 2 cases. Renal puncture pathology confirmed the diagnosis of ARAS. Interventions: The 2 cases were treated with albumin, compounded amino acids, calcium, vitamin D, and low molecular weight heparin in addition to conventional treatment during pregnancy. Pregnancy was terminated by cesarean section at 36 to 37 weeks of gestation. After delivery, the patients were treated with Losartan for anti-proteinuric therapy for 1 year. Outcomes: The neonatal weights and Apgar scores were normal. The patients recovered well and 24-h proteinuria decreased to pre-pregnancy level. Lessons: When pregnant women present with a persistent increasing proteinuria, ARAS needs to be considered. Sanger sequencing is useful to assist in the diagnosis of ARAS. Multidisciplinary treatments from nephrologists and gynecologists are needed to ensure the safety of pregnancy and the fetus.

CITATION EXPORT

Xiaoli Gao, Meilu Li, Kan Wang et al.. Pregnancy in women with autosomal recessive Alport syndrome caused by novel compound heterozygous mutations of COL4A3 gene: Two cases reports. Medicine. (2023). https://doi.org/10.1097/MD.0000000000036057

AUTHORS

5 · 2 CENTRES

Xiaoli Gao, Meilu Li, Kan Wang, Zengyan Li, Cha Han

a Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China
b Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China.