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European Journal of Pediatrics Apr 2017This report describes a novel mutation of LAMB2, the gene associated with Pierson syndrome (microcoria-congenital nephrosis syndrome), in two female siblings. The...
UNLABELLED
This report describes a novel mutation of LAMB2, the gene associated with Pierson syndrome (microcoria-congenital nephrosis syndrome), in two female siblings. The c.970T>C p.(Cys324Arg) mutation in the LAMB2 gene affects one of the eight highly conserved cysteine residues within the first EGF-like module of the laminin β2 protein. These residues form disulfide bonds in order to achieve a correct 3D structure of the protein. The reported phenotype is considered a relatively mild variant of Pierson syndrome and is associated with later-onset (18 months) therapy-resistant nephrotic syndrome leading to renal failure, and ocular abnormalities consisting of high myopia, microcoria, diverse retinal abnormalities, hence a low level of visual acuity. Importantly, the reported LAMB2 mutation was associated with normal neurological development in both siblings.
CONCLUSION
this report presents the variability of the renal, ocular and neurological phenotypes associated with LAMB2 mutations and underscores the importance of ophthalmologic examination in all children with unexplained renal insufficiency or nephrotic syndrome. What is known • LAMB2 mutations are associated with Pierson syndrome • Pierson syndrome is associated with congenital nephrotic syndrome, microcoria and neurological deficits What is new • A novel mutation in the LAMB2 gene in two female siblings • Genotype and clinical phenotype description of a novel LAMB2 mutation.
Topics: Abnormalities, Multiple; Child; Child, Preschool; Eye Abnormalities; Female; Humans; Kidney; Kidney Glomerulus; Laminin; Mutation; Myasthenic Syndromes, Congenital; Nephrectomy; Nephrotic Syndrome; Phenotype; Pupil Disorders; Renal Insufficiency; Retina; Siblings; Tomography, Optical
PubMed: 28188379
DOI: 10.1007/s00431-017-2871-6 -
Indian Journal of Pediatrics Dec 2014
Topics: Abnormalities, Multiple; Diagnosis, Differential; Eye Abnormalities; Humans; Infant, Newborn; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 24944146
DOI: 10.1007/s12098-014-1507-3 -
Ophthalmology. Retina Feb 2024To describe the ocular and renal features, as well as outcomes of retinal detachment repair, in patients with a novel, homozygous laminin β-2 (LAMB2) pathogenic variant.
PURPOSE
To describe the ocular and renal features, as well as outcomes of retinal detachment repair, in patients with a novel, homozygous laminin β-2 (LAMB2) pathogenic variant.
DESIGN
Single-center retrospective chart review of patients with a homozygous variant, c.619T>C p.(Ser207Pro), in the LAMB2 gene.
SUBJECTS
Eleven patients (22 eyes) from 4 families.
METHODS
Demographic data and ocular findings were recorded. Patients were recalled for a detailed renal evaluation.
MAIN OUTCOME MEASURES
Ocular features, renal features, and outcomes of retinal detachment repair.
RESULTS
The mean age at presentation was 6.0 (range, 1-26) years. None of the study eyes had microcoria, and none of the patients had nephrotic-range proteinuria. The mean refraction and axial length were -7.9 diopters (range, -4.0 to -12.0 diopters) and 25.3 (range, 22.7-27.7) mm, respectively. Eleven eyes (50%) had cataract at presentation. Fifteen eyes had a clear view to the fundus and all showed tessellated myopic fundus, avascular peripheral retina evident clinically or on fluorescein angiography, and rudimentary fovea. Optic disc pallor was observed in 10 eyes (66.7%). Straightened retinal vessels, abnormal vascular emanation (situs inversus) from the optic disc, supernumerary vascular branching at the optic disc, and vascular tortuosity were observed in 10 (66.7%), 2 (13.4%), 2 (13.4%), and 2 (13.4%) eyes, respectively. Discrete areas of punched-out chorioretinal atrophy were observed in 4 (26.7%) eyes. Spectral-domain OCT showed retinal and choroidal thinning in 13 eyes (86.7%), retinoschisis temporal to the fovea in 2 eyes (13.4%), and rudimentary fovea in 15 eyes (100%). Among the 22 eyes, 14 eyes (63.6%) developed rhegmatogenous retinal detachment (RRD), mostly during childhood, of which 5 patients had bilateral RRD. Eight eyes were operated on and 6 (75%) achieved retinal reattachment at the last follow-up. The mean preoperative visual acuity was 20/300 and the mean postoperative visual acuity at the last follow-up was 20/400.
CONCLUSIONS
This study describes a distinct phenotype of LAMB2-related disease with a novel, homozygous LAMB2 variant, and further expands the spectrum of ophthalmic and renal features, and the molecular genetic basis, of LAMB2-related disease. Because the typical microcoria and nephrotic-range proteinuria might be absent, the retinal features can guide the diagnosis.
FINANCIAL DISCLOSURE(S)
The authors have no proprietary or commercial interest in any materials discussed in this article.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Young Adult; Eye Abnormalities; Myopia; Proteinuria; Retina; Retinal Detachment; Retrospective Studies
PubMed: 37678612
DOI: 10.1016/j.oret.2023.08.022 -
Molecular Genetics & Genomic Medicine Jul 2021Both Pierson syndrome (PS) and isolated nephrotic syndrome can be caused by LAMB2 biallelic pathogenic variants. Only 15 causative splicing variants in the LAMB2 gene...
BACKGROUND
Both Pierson syndrome (PS) and isolated nephrotic syndrome can be caused by LAMB2 biallelic pathogenic variants. Only 15 causative splicing variants in the LAMB2 gene have been reported. However, the pathogenicity of most of these variants has not been verified, which may lead to incorrect interpretation of the functional consequence of these variants.
METHODS
Using high-throughput DNA sequencing and Sanger sequencing, we detected variants in a female with clinically suspected PS. A minigene splicing assay was performed to assess the effect of LAMB2 intron 20 c.2885-9C>A on RNA splicing. We also performed the immunohistochemical analysis of laminin beta-2 in kidney tissues.
RESULTS
Two novel LAMB2 heteroallelic variants were found: a paternally inherited variant c.2885-9C>A in intron 20 and a maternally inherited variant c. 3658C>T (p. (Gln1220Ter)). In vitro minigene assay showed that the variant c.2885-9C>A caused erroneous integration of a 7 bp sequence into intron 20. Immunohistochemical analysis revealed the absence of glomerular expression of laminin beta-2, the protein encoded by LAMB2.
CONCLUSION
We demonstrated the impact of a novel LAMB2 intronic variant on RNA splicing using the minigene assay firstly. Our results extend the mutational spectrum of LAMB2.
Topics: Diagnosis, Differential; Female; Genetic Testing; HEK293 Cells; Humans; Infant; Laminin; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Point Mutation; Pupil Disorders; RNA Splicing
PubMed: 33982833
DOI: 10.1002/mgg3.1704 -
CEN Case Reports Aug 2021Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic...
Biallelic pathogenic variants in the laminin β2 (LAMB2) gene, which encodes laminin β2, are associated with Pierson syndrome characterized by a congenital nephrotic syndrome that rapidly progresses to end-stage renal disease, distinct ocular maldevelopment with bilateral microcoria, and neurodevelopmental deficits. However, the phenotypic spectrum of LAMB2-associated disorder is broader than expected, and cases with milder phenotypes such as isolated congenital or infantile nephrotic syndrome have also been reported. We report a patient with LAMB2-associated renal disorder showing an extremely mild phenotype. A 5-year-old girl presented with asymptomatic proteinuria and hematuria detected by urinalysis screening. She had been previously healthy without any additional renal symptoms. The serum albumin and creatinine levels were normal. Renal biopsy revealed minor glomerular abnormalities with occasional focal mesangial proliferation. Electron microscopy showed no structural changes in the glomerular basement membrane. Targeted sequencing of podocyte-related genes using next-generation sequencing was performed. As a result, previously reported biallelic pathogenic variants of the truncating variant (c.5073_5076dupCCAG) and a splice site variant (c.3797 + 5G > A) in the LAMB2 gene were detected, and the patient was diagnosed with LAMB2-associated renal disorder. Interestingly, a previously reported case with this splicing variant also showed an atypically mild phenotype. We suggest that clinicians should consider LAMB2-associated nephritis as an important differential diagnosis in children with asymptomatic proteinuria and microscopic hematuria if there is no structural change in the glomerular basement membrane. A comprehensive gene-screening system using next-generation sequencing is useful for diagnosing these atypical cases with isolated urine abnormalities.
Topics: Child; Female; High-Throughput Nucleotide Sequencing; Humans; Laminin; Nephritis
PubMed: 33476040
DOI: 10.1007/s13730-021-00574-1 -
Pediatric Hematology and Oncology 2023Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat patients with beta-thalassemia major, evidence showing whether this treatment...
Thalassemia patients in transfussion dependent period and after hematopoietic stem cell transplantation: how are the psychiatric status and life quality of these patients?
Although hematopoietic stem cell transplantation (HSCT) has been widely used to treat patients with beta-thalassemia major, evidence showing whether this treatment improves mental health, self esteem and health-related quality of life (HRQoL) is limited. We aimed to describe psychiatric problems, HRQoL and self-esteem scores of patients who have thalassemia and compared with patients who underwent HSCT in the current study. A total of 24 patients with thalassemia major and 13 patients who underwent HSCT at least 2 years ago aged between 7-37 years were included. We used The Children's Depression Inventory, The Spielberger State-Trait Anxiety Inventory, and Pediatric Quality of LifeTM (PedsQL™) for assesment of children and Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), World Health Organization Quality of Life Scale Brief Version (WHOQOL-BREF) for assessment of adults. We also used Piers Harris Self Concept Scale for children and adults. Psychopathologies are common in both groups (50% in Thalassemia group and 69.2% in HSCT group). Popularity scores in Piers Haris scale of patients in HSCT group were significantly higher compared to thalassemia group ( = 0.03). Additionally, HSCT group had higher scores in physical health subscales of HRQoL in both children and parents'( = 0.02, = 0.03 respectively). Our findings suggest improved HRQoL and self-esteem in thalassemia patients after HSCT. However, due to the high prevalence of mental disorders in both groups, we would like to emphasize that clinicians should examine not only the physical but also the psychological state of the patients with thalessemia during the their treatment and follow-up period after HSCT.
Topics: Adult; Humans; Child; Adolescent; Young Adult; Quality of Life; beta-Thalassemia; Thalassemia; Parents; Hematopoietic Stem Cell Transplantation
PubMed: 37519029
DOI: 10.1080/08880018.2023.2220733 -
BMC Pediatrics Mar 2016LAMB2 mutations cause Pierson syndrome (OMIM 609049), an autosomal recessive genetic disease typically characterized by congenital nephrotic syndrome (CNS) and early...
BACKGROUND
LAMB2 mutations cause Pierson syndrome (OMIM 609049), an autosomal recessive genetic disease typically characterized by congenital nephrotic syndrome (CNS) and early onset renal failure, as well as bilateral microcoria. NPHP1 mutations cause familial juvenile nephronophthisis type 1 (NPHP1, OMIM 256100), another autosomal recessive renal disease that usually occurs years after birth. Both Pierson syndrome and nephronophthisis cause end-stage renal disease and rare kidney diseases in children. We report an extremely rare case of concurrent mutations of LAMB2 and NPHP1 in a Chinese girl with isolated CNS and the association of the phenotype with novel non-truncating mutations of LAMB2.
CASE PRESENTATION
A-34-day-old girl presented with CNS but no eye abnormalities, and mild hyperechogenicity of kidneys. A novel c.1176_1178delTCT mutation caused deletion of a glycine in exon 9 of LAMB2, and another mutation c.4923 + 2 T > G led to a splicing error. In addition, compound heterozygous mutations of NPHP1 were identified in this child using next generation sequencing, and confirmed by Sanger sequencing.
CONCLUSION
Mutations of the LAMB2 and NPHP1 are present in infants with isolated CNS. Next generation sequencing enabled high-throughput screening for mutant genes promptly, with clinically significant outcomes. In addition, our results expand the phenotype spectrum of LAMB2 mutations as the only renal manifestation.
Topics: Adaptor Proteins, Signal Transducing; China; Cytoskeletal Proteins; Female; Genetic Markers; Heterozygote; Humans; Infant; Laminin; Membrane Proteins; Mutation; Nephrotic Syndrome; Phenotype
PubMed: 27004562
DOI: 10.1186/s12887-016-0583-0 -
European Journal of Medical Genetics May 2020Congenital microcoria (MCOR) is an eye anomaly characterized by a pupil with diameter below 2 mm, and is caused by underdevelopment or absence of the dilator muscle of...
Congenital microcoria (MCOR) is an eye anomaly characterized by a pupil with diameter below 2 mm, and is caused by underdevelopment or absence of the dilator muscle of the pupil. Two types have been described: a recessive, syndromic (Pierson syndrome OMIM 609049) and a dominant, isolated form (MCOR syndrome OMIM 156600). Fares-Taie and colleagues described inherited microdeletions in chromosome band 13q32.1 segregating with dominant microcoria in several families. The GPR180 gene is located within the smallest commonly deleted region and encodes a G protein-coupled receptor involved in smooth muscle cells growth. We here describe a patient with isolated, non-syndromic MCOR. The patient presented with a blue iris and small pupils, non-reactive to cycloplegic agents. Her mother had a milder ocular phenotype, namely a blue iris with hypoplastic crypts and mild myopia. We present a detailed clinical examination and follow up. DNA from the index patient was analyzed for the presence of chromosomal imbalances using molecular karyotyping. The genetic test revealed a small duplication of chromosome band 13q32.1. The duplication affected a 289 kb region, encompassing 11 genes including GPR180. Interestingly, the patient displays only MCOR in contrast to patients with the reciprocal deletion who present with MCOR and iridocorneal angle dysgenesis. This genetic anomaly was inherited from the mother who carries the duplication in mosaic form, which should be considered when offering genetic counselling. In summary, we describe the first 13q32.1 duplication encompassing GPR180 associated with MCOR.
Topics: Adult; Child, Preschool; Chromosome Duplication; Chromosomes, Human, Pair 13; Eye; Female; Humans; Mosaicism; Pedigree; Pupil Disorders; Receptors, G-Protein-Coupled
PubMed: 32200002
DOI: 10.1016/j.ejmg.2020.103918 -
BMC Nephrology Jul 2017Congenital nephrotic syndrome (CNS) is a rare disorder caused by various structural and developmental defects of glomeruli. It occurs typically as an isolated kidney...
BACKGROUND
Congenital nephrotic syndrome (CNS) is a rare disorder caused by various structural and developmental defects of glomeruli. It occurs typically as an isolated kidney disorder but associates sometimes with other systemic, extrarenal manifestations.
CASE PRESENTATIONS
An infant presented with severe CNS, which progressed rapidly to renal failure at age of 3 months and death at 27 months. The clinical phenotypes and genetic causes were studied, including the renal pathology at autopsy. Besides the CNS, the affected child had remarkable right-side predominant eye-ball hypoplasia with bilateral anterior chamber dysgenesis (microcoria). Brain MRI revealed grossly normal development in the cerebrum, cerebellum, and brain stem. Auditory brainstem responses were bilaterally blunted, suggesting a defective auditory system. At autopsy, both kidneys were mildly atrophied with persistent fetal lobulation. Microscopic examination showed a diffuse global sclerosis. However, despite of the smaller size of glomeruli, the nephron number remained similar to that of the age-matched control. Whole-exome sequencing revealed that the affected child was compound heterozygous for novel truncating LAMB2 mutations: a 4-bp insertion (p.Gly1693Alafs*8) and a splicing donor-site substitution (c.1225 + 1G > A), presumably deleting the coiled-coil domains that form the laminin 5-2-1 heterotrimer complex.
CONCLUSIONS
Our case represents a variation of Pierson syndrome that accompanies CNS with unilateral ocular hypoplasia. The average number but smaller glomeruli could reflect either mal-development or glomerulosclerosis. Heterogeneous clinical expression of LAMB2 defects may associate with the difference in fetal β1 subtype compensation among affected tissues. Further study is necessary to evaluate incidence and features of auditory defect under LAMB2 deficiency.
Topics: Fatal Outcome; Female; Humans; Infant; Laminin; Loss of Function Mutation; Nephrons; Nephrotic Syndrome; Pedigree
PubMed: 28683731
DOI: 10.1186/s12882-017-0632-4 -
Anales de Pediatria (Barcelona, Spain :... Dec 2016
Topics: Abnormalities, Multiple; Eye Abnormalities; Female; Humans; Infant, Newborn; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 26975222
DOI: 10.1016/j.anpedi.2016.01.025