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Ophthalmic Surgery, Lasers & Imaging... Nov 2020Pierson syndrome is a rare genetic disease defined by congenital nephrotic syndrome in association with microcoria. The authors aim to describe the posterior segment and...
BACKGROUND AND OBJECTIVE
Pierson syndrome is a rare genetic disease defined by congenital nephrotic syndrome in association with microcoria. The authors aim to describe the posterior segment and retinal features in Pierson syndrome.
PATIENTS AND METHODS
A retrospective chart review of nine patients diagnosed with Pierson syndrome was ascertained. Details of ophthalmic history, ocular examination, retinal imaging, and surgical interventions were obtained during a median duration of 17 months of follow-up (range: 6 to 60 months). Retinal interventions included scatter laser photocoagulation and surgical retinal repair.
RESULTS
Sixteen eyes of nine patients were included. The axial length of five eyes with flat retina was 26.59 mm ± 0.99 mm. Highly myopic features including tessellated fundus with accompanying optic disc pallor, unidentifiable cup, and abnormal retinal vascular emanation from the disc were observed in all eyes (100%), whereas 12 eyes (75%) had parapapillary chorioretinal atrophy. Features of abnormal retinal vascularization included avascular peripheral retina on fluorescein angiography, aberrant course of the temporal arcades in 13 eyes (81.3%), and straightened nasal retinal blood vessels in 12 eyes (75%). Tortuous retinal blood vessels were observed in three eyes (18.75%). Surgical repair was performed in five out of seven eyes with rhegmatogenous retinal detachment (RRD). Recurrence was observed in all eyes, which required two to three procedures to achieve final reattachment.
CONCLUSIONS
Combined features of high axial myopia with incomplete peripheral vascular maturation characterize the posterior segment in Pierson syndrome. Careful posterior segment examination is essential to detect RRD or retinal neovascularization. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:618-627.].
Topics: Child; Humans; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders; Retinal Detachment; Retrospective Studies; Visual Acuity
PubMed: 33231694
DOI: 10.3928/23258160-20201104-03 -
Nature Reviews. Nephrology Feb 2021The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. The major components of the GBM... (Review)
Review
The glomerular basement membrane (GBM) is a key component of the glomerular capillary wall and is essential for kidney filtration. The major components of the GBM include laminins, type IV collagen, nidogens and heparan sulfate proteoglycans. In addition, the GBM harbours a number of other structural and regulatory components and provides a reservoir for growth factors. New technologies have improved our ability to study the composition and assembly of basement membranes. We now know that the GBM is a complex macromolecular structure that undergoes key transitions during glomerular development. Defects in GBM components are associated with a range of hereditary human diseases such as Alport syndrome, which is caused by defects in the genes COL4A3, COL4A4 and COL4A5, and Pierson syndrome, which is caused by variants in LAMB2. In addition, the GBM is affected by acquired autoimmune disorders and metabolic diseases such as diabetes mellitus. Current treatments for diseases associated with GBM involvement aim to reduce intraglomerular pressure and to treat the underlying cause where possible. As our understanding about the maintenance and turnover of the GBM improves, therapies to replace GBM components or to stimulate GBM repair could translate into new therapies for patients with GBM-associated disease.
Topics: Anti-Glomerular Basement Membrane Disease; Diabetic Nephropathies; Glomerular Basement Membrane; Humans; Myasthenic Syndromes, Congenital; Nephritis, Hereditary; Nephrotic Syndrome; Pupil Disorders
PubMed: 32839582
DOI: 10.1038/s41581-020-0329-y -
BMC Nephrology Aug 2020Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) cause substantial morbidity and mortality. In Japan, there is a lack of knowledge regarding... (Observational Study)
Observational Study
BACKGROUND
Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) cause substantial morbidity and mortality. In Japan, there is a lack of knowledge regarding the characteristics of CNS and INS. This study aimed to clarify the characteristics of CNS and INS in Japan.
METHODS
This cross-sectional nationwide survey obtained data from 44 institutions in Japan managing 92 patients with CNS or INS, by means of two survey questionnaires sent by postal mail. Patients aged < 16 years by 1 April 2015, with a diagnosis of CNS or INS, were included in this study. The primary outcome was end-stage kidney disease.
RESULTS
A total of 83 patients with CNS or INS were analyzed. The most frequent disease type was non-Finnish (60.2%); 33 patients (39.8%) had Finnish type. Among those with non-Finnish-type disease, 26 had no syndrome and 24 had a syndrome, of which the most frequent was Denys-Drash syndrome (70.8%). Patients with non-Finnish-type disease with syndrome showed the earliest progression to end-stage kidney disease compared with the other two groups, whereas patients with non-Finnish-type disease without syndrome progressed more slowly compared with the other two groups. In the Finnish-type group, the disease was diagnosed the earliest; a large placenta was reported more frequently; genetic testing was more frequently performed (93.8%); mental retardation was the most frequent extra-renal symptom (21.2%); and thrombosis and infection were more frequent compared with the other groups. Patients with non-Finnish-type disease with syndrome had a higher frequency of positive extra-renal symptoms (79.2%), the most common being urogenital symptoms (54.2%). Treatment with steroids and immunosuppressants was more frequent among patients with non-Finnish-type disease without syndrome. Two patients with non-Finnish-type disease without syndrome achieved complete remission. In all groups, unilateral nephrectomy was performed more often than bilateral nephrectomy and peritoneal dialysis was the most common renal replacement therapy.
CONCLUSIONS
The present epidemiological survey sheds light on the characteristics of children with CNS and INS in Japan. A high proportion of patients underwent genetic examination, and patient management was in accord with current treatment recommendations and practices.
TRIAL REGISTRATION
Not applicable.
Topics: Adolescent; Child; Child, Preschool; Denys-Drash Syndrome; Disease Progression; Female; Genetic Testing; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Intellectual Disability; Japan; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Myasthenic Syndromes, Congenital; Nephrectomy; Nephrotic Syndrome; Organ Size; Placenta; Pregnancy; Pupil Disorders; Renal Replacement Therapy; Surveys and Questionnaires; Syndrome
PubMed: 32838745
DOI: 10.1186/s12882-020-02010-5 -
BMJ Case Reports Jul 2020
Topics: Fatal Outcome; Humans; Infant, Newborn; Kidney Diseases, Cystic; Male; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Pupil Disorders
PubMed: 32616536
DOI: 10.1136/bcr-2020-236517 -
Archivos Argentinos de Pediatria Jun 2020Pierson syndrome is characterized by congenital nephrotic syndrome and bilateral microcoria. Genetically, mutations in the LAMB2 gene, which encodes the laminin β2...
Pierson syndrome is characterized by congenital nephrotic syndrome and bilateral microcoria. Genetically, mutations in the LAMB2 gene, which encodes the laminin β2 chain, lead to this disorder. To date, 98 cases and 50 different mutations have been reported in literature. There are no specific therapies for Pierson syndrome and treatment is supportive. The prognosis is poor because of progressive impairment of renal function and complications of renal failure. We report a novel homozygous mutation (c.1890G>T, p.Q630H) in the LAMB2 gene in a patient with Pierson syndrome who had atypical phenotypic feature such as epidermolysis bullosa.
Topics: Female; Genetic Markers; Homozygote; Humans; Infant; Laminin; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Phenotype; Pupil Disorders
PubMed: 32470267
DOI: 10.5546/aap.2020.eng.e288 -
Kidney International Jul 2020The importance of the glomerular basement membrane (GBM) in glomerular filtration is underscored by the manifestations of Alport and Pierson syndromes, caused by defects...
The importance of the glomerular basement membrane (GBM) in glomerular filtration is underscored by the manifestations of Alport and Pierson syndromes, caused by defects in type IV collagen α3α4α5 and the laminin β2 chain, respectively. Lamb2 null mice, which model the most severe form of Pierson syndrome, exhibit proteinuria prior to podocyte foot process effacement and are therefore useful for studying GBM permselectivity. We hypothesize that some LAMB2 missense mutations that cause mild forms of Pierson syndrome induce GBM destabilization with delayed effects on podocytes. While generating a CRISPR/Cas9-mediated analogue of a human LAMB2 missense mutation in mice, we identified a 44-amino acid deletion (LAMB2-Del44) within the laminin N-terminal domain, a domain mediating laminin polymerization. Laminin heterotrimers containing LAMB2-Del44 exhibited a 90% reduction in polymerization in vitro that was partially rescued by type IV collagen and nidogen. Del44 mice showed albuminuria at 1.8-6.0 g/g creatinine (ACR) at one to two months, plateauing at an average 200 g/g ACR at 3.7 months, when GBM thickening and hallmarks of nephrotic syndrome were first observed. Despite the massive albuminuria, some Del44 mice survived for up to 15 months. Blood urea nitrogen was modestly elevated at seven-nine months. Eight to nine-month-old Del44 mice exhibited glomerulosclerosis and interstitial fibrosis. Similar to Lamb2 mice, proteinuria preceded foot process effacement. Foot processes were widened but not effaced at one-two months despite the high ACRs. At three months some individual foot processes were still observed amid widespread effacement. Thus, our chronic model of nephrotic syndrome may prove useful to study filtration mechanisms, long-term proteinuria with preserved kidney function, and to test therapeutics.
Topics: Animals; Laminin; Mice; Mice, Knockout; Nephrotic Syndrome; Pupil Disorders
PubMed: 32456966
DOI: 10.1016/j.kint.2020.01.033 -
BMC Medical Genetics Apr 2020Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have...
BACKGROUND
Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have extended the lifespan of patients, whereas the full clinical spectrum of PS in infancy and beyond remains elusive.
CASE PRESENTATION
We present the case of a 12-month-old boy with PS, manifesting as the bilateral microcoria and congenital nephrotic syndrome. He was born without asphyxia, and was neurologically intact from birth through the neonatal period. Generalized muscle weakness and hypotonia were recognized from 3 months of age. The infant showed recurrent vomiting at age 5 months of age, and was diagnosed with gastroesophageal reflux and intestinal malrotation. Despite the successful surgical treatment, vomiting persisted and led to severely impaired growth. Tulobuterol treatment was effective in reducing the frequency of vomiting. Targeted sequencing confirmed that he had a compound heterozygous mutation in LAMB2 (NM_002292.3: p.Arg550X and p.Glu1507X). A search of the relevant literature identified 19 patients with severe neuro-muscular phenotypes. Among these, only 8 survived the first 12 months of life, and one had feeding difficulty with similar gastrointestinal problems.
CONCLUSIONS
This report demonstrated that severe neurological deficits and gastrointestinal dysfunction may emerge in PS patients after the first few months of life.
Topics: Abnormalities, Multiple; Gastrointestinal Tract; Humans; Infant; Laminin; Male; Mutation; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Phenotype; Pupil Disorders
PubMed: 32295525
DOI: 10.1186/s12881-020-01019-9 -
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 -
Journal of Human Genetics Apr 2020Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete...
Null variants in LAMB2 cause Pierson syndrome (PS), a severe congenital nephrotic syndrome with ocular and neurological defects. Patients' kidney specimens show complete negativity for laminin β2 expression on glomerular basement membrane (GBM). In contrast, missense variants outside the laminin N-terminal (LN) domain in LAMB2 lead to milder phenotypes. However, we experienced cases not showing these typical genotype-phenotype correlations. In this paper, we report six PS patients: four with mild phenotypes and two with severe phenotypes. We conducted molecular studies including protein expression and transcript analyses. The results revealed that three of the four cases with milder phenotypes had missense variants located outside the LN domain and one of the two severe PS cases had a homozygous missense variant located in the LN domain; these variant positions could explain their phenotypes. However, one mild case possessed a splicing site variant (c.3797 + 5G>A) that should be associated with a severe phenotype. Upon transcript analysis, this variant generated some differently sized transcripts, including completely normal transcript, which could have conferred the milder phenotype. In one severe case, we detected the single-nucleotide substitution of c.4616G>A located outside the LN domain, which should be associated with a milder phenotype. However, we detected aberrant splicing caused by the creation of a novel splice site by this single-base substitution. These are novel mechanisms leading to an atypical genotype-phenotype correlation. In addition, all four cases with milder phenotypes showed laminin β2 expression on GBM. We identified novel mechanisms leading to atypical genotype-phenotype correlation in PS.
Topics: Amino Acid Substitution; Child; Child, Preschool; Female; Glomerular Basement Membrane; Humans; Infant; Laminin; Male; Mutation, Missense; Myasthenic Syndromes, Congenital; Nephrotic Syndrome; Protein Domains; Pupil Disorders; RNA Splicing
PubMed: 31959872
DOI: 10.1038/s10038-019-0715-0 -
The Journal of Clinical Endocrinology... Mar 2020Mutations in LAMB2, encoding the basement membrane protein, laminin β2, are associated with an autosomal recessive disorder characterized by congenital nephrotic...
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.
Topics: Albuminuria; Child; Humans; Hypopituitarism; Laminin; Male; Mutation; Optic Nerve Hypoplasia; Phenotype
PubMed: 31769495
DOI: 10.1210/clinem/dgz216