Mutations in LAMB2 Are Associated With Albuminuria and Optic Nerve Hypoplasia With Hypopituitarism

Abstract

Context Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic syndrome, ocular abnormalities, and neurodevelopmental delay (Pierson syndrome). Case description This report describes a 12-year-old boy with short stature, visual impairment, and developmental delay who presented with macroscopic hematuria and albuminuria. He had isolated growth hormone deficiency, optic nerve hypoplasia, and a small anterior pituitary with corpus callosum dysgenesis on his cranial magnetic resonance imaging, thereby supporting a diagnosis of optic nerve hypoplasia syndrome. Renal histopathology revealed focal segmental glomerulosclerosis. Using next-generation sequencing on a targeted gene panel for steroid-resistant nephrotic syndrome, compound heterozygous missense mutations were identified in LAMB2 (c.737G>A p.Arg246Gln, c.3982G>C p.Gly1328Arg). Immunohistochemical analysis revealed reduced glomerular laminin β2 expression compared to control kidney and a thin basement membrane on electron microscopy. Laminin β2 is expressed during pituitary development and Lamb2–/– mice exhibit stunted growth, abnormal neural retinae, and here we show, abnormal parenchyma of the anterior pituitary gland. Conclusion We propose that patients with genetically undefined optic nerve hypoplasia syndrome should be screened for albuminuria and, if present, screened for mutations in LAMB2.

Five-Year Follow-Up and Successful Kidney Transplantation in a Girl with a Severe Phenotype of Pierson Syndrome

“…Although hypothyroidism may be a consequence of the urinary loss of thyroid binding globulin as a part of nephrotic proteinuria, it occurred in our patient only after the second nephrectomy. As secondary reasons were excluded, it could be hypothetically related to the primary disease as laminin isoforms are expressed throughout the pituitary development and may lead to hypopituitarism with growth hormone deficiency [9]. We also suspected an impact of PIERSS on disturbed erythropoiesis in our patient who presented with unexplained erythropoietin-resistant anemia either after KTx.…”

“…The most representative and relatively constant ocular anomaly in PIERSS is congenital microcoria caused by hypoplasia or aplasia of the dilator muscles of the iris [20]. It is a part of the wide spectrum of other ophthalmological features in PIERSS, including lens anomalies (cataract, abnormal lens shape, and posterior lenticonus), nystagmus, optic nerve hypoplasia, posterior embryotoxon, megalocornea, and retinal defects [3,9,18,20]. They are related to the failed LMβ2 expression in ocular structures during eye organogenesis [20].…”

“…Additionally, severe neurodevelopmental deficits, including hypotonia and intellectual disability are present. In contrast, in some cases caused by missense variants of the LAMB2 gene, much milder phenotypes are observed [6][7][8][9][10]. Unfortunately, the majority of the affected children with typical form of PIERSS die during infancy, mainly due to consequences of the renal disease [3,11].…”

LAMB2 novel variant c.2885‐9 C>A affects RNA splicing in a minigene assay

“…Several reports showed that patients with biallelic putative LAMB2 truncating variants exhibited a complete lack of renal laminin beta‐2 expression, whereas those with presumed non‐truncating LAMB2 variants on at least one allele showed residual or even normal glomerular expression of laminin beta‐2 (Maselli et al, 2009 ; Tahoun et al, 2020 ; Zenker et al, 2004 ). A similar phenomenon was observed in our patient with biallelic LAMB2 truncating variants.…”

Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing

“…LAMB2 variants cause congenital nephrosis with mesangial sclerosis and optical abnormalities ( 35 ). In 2020, compound heterozygous missense mutations identified in LAMB2 (c.737G>A [p.Arg246Gln] and c.3982G>C [p.Gly1328Arg]) were detected in a patient with isolated GH deficiency and global developmental delay, hypoplastic anterior pituitary, optic nerve hypoplasia, and corpus callosum dysgenesis ( 8 ). The details have not been investigated, but the pituitary glands of Lamb2 –/– mice were found to have abnormal cellular clusters.…”