Case report: A novel R246L mutation in the LMX1B homeodomain causes isolated nephropathy in a large Chinese family.

BACKGROUND: Genetic factors contribute to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Advances in genetic testing have enabled the identification of hereditary kidney diseases, including those caused by LMX1B mutations. LMX1B mutations can lead to nail-patella syndrome (NPS) or nail-patella-like renal disease (NPLRD) with only renal manifestations. CASE PRESENTATION: The proband was a 13-year-old female who was diagnosed with nephrotic syndrome at the age of 6. Then she began intermittent hormone and drug therapy. When she was 13 years old, she was admitted to our hospital due to sudden chest tightness, which progressed to end-stage kidney disease (ESRD), requiring kidney replacement therapy. Whole-Exome Sequencing (WES) results suggest the presence of LMX1B gene mutation, c.737G > T, p.Arg246Leu. Tracing her family history, we found that her father, grandmother, uncle and 2 cousins all had hematuria, or proteinuria. In addition to the grandmother, a total of 9 members of the family performed WES. The members with kidney involved all carry the mutated gene. Healthy members did not have the mutated gene. It is characterized by co-segregation of genotype and phenotype. We followed the family for 9 year, the father developed ESRD at the age of 50 and started hemodialysis treatment. The rest patients had normal renal function. No extra-renal manifestations associated with NPS were found in any member of the family. CONCLUSIONS: This study has successfully identified missense mutation, c.737G > T (p.Arg246Leu) in the homeodomain, which appears to be responsible for isolated nephropathy in the studied family. The arginine to leucine change at codon 246 likely disrupts the DNA-binding homeodomain of LMX1B. Previous research has documented 2 types of mutations at codon R246, namely R246Q and R246P, which are known to cause NPLRD. The newly discovered mutation, R246L, is likely to be another novel mutation associated with NPLRD, thus expanding the range of mutations at the crucial renal-critical codon 246 that contribute to the development of NPLRD. Furthermore, our findings suggest that any missense mutation occurring at the 246th amino acid position within the homeodomain of the LMX1B gene has the potential to lead to NPLRD.

The first presentation of a case of nail-patella syndrome newly diagnosed at the onset of rheumatoid arthritis: a case report.

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA). CASE PRESENTATION: A 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission. CONCLUSIONS: We have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations.

Identification of a novel LMX1B nonsense variant associated with congenital talipes equinovarus by prenatal exome sequencing: A case report.

BACKGROUND: Congenital talipes equinovarus (CTEV) is a rotational foot deformity that affects muscles, bones, connective tissue, and vascular or neurological tissues. The etiology of CTEV is complex and unclear, involving genetic and environmental factors. Nail-patella syndrome is an autosomal dominant disorder caused by variants of the LIM homeobox transcription factor 1 beta gene (LMX1B, OMIM:602575). LMX1B plays a key role in the development of dorsal limb structures, the kidneys, and the eyes, and variants in this gene may manifest as hypoplastic or absent patella, dystrophic nails, and elbow and iliac horn dysplasia; glomerulopathy; and adult-onset glaucoma, respectively. This study aimed to identify pathogenic variants in a fetus with isolated talipes equinovarus diagnosed by ultrasound in the second trimester, whose father exhibited dysplastic nails and congenital absence of bilateral patella. METHODS: Prenatal whole-exome sequencing (WES) of the fetus and parents was performed to identify the genetic variant responsible for the fetal ultrasound abnormality, followed by validation using Sanger sequencing. RESULTS: A novel heterozygous nonsense variant in exon 6 of LMX1B (c.844C>T, p.Gln282*) was identified in the fetus and the affected father but was not detected in any unaffected family members. This nonsense variant resulted in a premature termination codon at position 282, which may be responsible for the clinical phenotype through the loss of function of the gene product. CONCLUSIONS: Our study indicating that a fetus carrying a novel nonsense variant of LMX1B (c.844C>T, p.Gln282*) can exhibit isolated talipes equinovarus, which expands the LMX1B genotypic spectrum and is advantageous for genetic counseling.

Total Knee Arthroplasty Using Computer-Assisted Navigation in a Patient with Nail-Patella Syndrome: A Case Report.

CASE: Nail-patella syndrome (NPS) is a genetic disorder causing anatomical abnormalities about the knee, including significant patellar hypoplasia. We present a case of a patient with NPS and severe knee osteoarthritis undergoing computer-assisted total knee arthroplasty (TKA). Several intraoperative anatomical challenges were appreciated. Postoperatively, the patient developed arthrofibrosis requiring manipulation; however, his final outcome was favorable. CONCLUSION: Computer assistance may improve precision in patients with NPS undergoing TKA, but surgeons must be aware of the associated anatomic abnormalities and potentially increased risk of arthrofibrosis. Patellar resurfacing is often not feasible because of lack of bone stock.

Simultaneous kidney and pancreas transplantation in a patient with nail-patella syndrome and insulin-dependent diabetes.

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder caused by a mutation in LIM-homeodomain transcription factor 1-beta (LMX1B) and characterized by nail dystrophy, skeletal changes, glaucoma, and kidney disease with up to 30% of patients progressing to kidney failure. Autoimmune diseases, including thyroid disease, have been reported previously in patients with NPS. CASE-DIAGNOSIS/TREATMENT: We report the case of a pediatric patient with NPS with kidney failure, hypothyroidism, and type 1 diabetes mellitus. The patient's pedigree and identification of a kidney specific mutation in LMX1B was a result of whole exome sequencing. Clinical data was obtained from retrospective chart review and included the 1-year post-transplant follow-up period. At 15 years of age, our patient received a simultaneous kidney-pancreas transplantation, from a 3 HLA antigen mismatched deceased donor. The donor was CMV + , EBV - and our patient was CMV - , EBV - at time of transplant. Our patient maintained normal kidney function and euglycemia without insulin therapy at 1 year post-transplant. CONCLUSIONS: The patient's hypothyroidism, diabetes mellitus, and kidney failure may all be related to LMX1B mutation. Further study is needed to clarify the genetic link between these processes. Simultaneous kidney-pancreas transplantation can be used to successfully treat diabetes mellitus and kidney failure in a pediatric patient.

Case Report: Inversion of LMX1B - A Novel Cause of Nail-Patella Syndrome in a Swedish Family and a Longtime Follow-Up.

Nail-patella syndrome (NPS, OMIM #161200) is a rare autosomal dominant disorder with symptoms from many different parts of the body, including nails, knees, elbows, pelvis, kidneys and eyes. It is caused by truncating variants in the LMX1B gene, which encodes a transcription factor with important roles during embryonic development, including dorsoventral patterning of the limbs. To our knowledge, inversions disrupting the LMX1B gene have not been reported. Here, we report a family with an inversion disrupting the LMX1B gene in five affected family members with mild but variable clinical features of NPS. Our finding demonstrates that genomic rearrangements must be considered a possible cause of NPS.

Total Shoulder Arthroplasty in a Patient with Nail-Patella Syndrome: A Case Report.

CASE: A 62-year-old woman with a medical history of nail-patella syndrome (NPS) presented with chronic right shoulder pain. Physical examination revealed that her right shoulder had a restricted range of motion. Radiograph of the shoulder revealed arthritic changes with glenohumeral joint space narrowing, inferior humeral head osteophytes, and posterior glenoid wear. The patient was successfully treated with total shoulder arthroplasty (TSA). The patient had an uneventful postoperative course and was satisfied with her quality of life at the 30-month follow-up. CONCLUSION: TSA may be successfully performed with careful reaming of the hypoplastic glenoid fossa in patients with NPS.

A Novel LMX1B Variant Identified in a Patient Presenting with Severe Renal Involvement and Thin Glomerular Basement Membrane.

We report a case of nail-patella syndrome (NPS) with unusual thinning of the glomerular basement membrane (GBM) associated with a novel heterozygous variant in the LMX1B gene. A 43-year-old female patient with a previous diagnosis of NPS, referred to our hospital for persistent proteinuria, underwent a renal biopsy, which revealed minor glomerular abnormalities. She underwent a second renal biopsy at the age of 56 owing to the presence of persistent proteinuria and decline in serum albumin, meeting the diagnostic criteria for nephrotic syndrome. Light microscopy demonstrated glomerulosclerosis and cystic dilatation of the renal tubules. Notably, electron microscopy revealed unusual thinning of the GBM, which is quite different from typical biopsy findings observed in patients with NPS, characterized by thick GBM with fibrillary material and electron-lucent structures. Comprehensive genetic screening for 168 known genes responsible for inherited kidney diseases using a next-generation sequencing panel identified a novel heterozygous in-frame deletion-insertion (c.723_729delinsCAAC: p.[Ser242_Lys243delinsAsn]) in exon 4 of the LMX1B gene, which may account for the disrupted GBM structure. Further studies are warranted to elucidate the complex genotype-phenotype relationship between LMX1B and proper GBM morphogenesis.

Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity.

LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis.

Peters Anomaly in Nail-Patella Syndrome: A Case Report and Clinico-Genetic Correlation.

PURPOSE: The purpose of this study was to report the clinicopathological features of Peters anomaly in a child with nail-patella syndrome. METHODS: Nail-patella syndrome (NPS) is a rare autosomal dominant connective tissue disorder characterized by several anomalies of the extremities, joints and nails, glomerulopathy, and rarely ocular involvement. NPS is caused by heterozygous loss-of-functional mutations in the LMX1B gene that encodes the LIM homeodomain proteins. RESULTS: This case reports a new association of Peters anomaly in a child with NPS that also had classic skeletal/nail anomalies and protein losing nephropathy. Furthermore, DNA sequence analysis identified a novel missense heterozygous mutation in the LMX1B gene (Transcript ID: NM_001174146) resulting in the replacement of tryptophan by serine in codon 266, suggesting that the mutation (p.Trp.266Ser) affects LMX1B function by disturbing its interactions with other proteins. To the best of our knowledge, this association of Peters anomaly is novel and has not been reported earlier in the ophthalmic and systemic literature on NPS. CONCLUSION: The corneal findings in our case with NPS are similar to those seen in congenital corneal opacification because of Peters anomaly. This novel association of Peters anomaly with NPS may be related to the effects of the LMX1B mutation on corneal development.

A Novel Mutation in LMX1B (p.Pro219Ala) Causes Focal Segmental Glomerulosclerosis with Alport Syndrome-like Phenotype.

A 69-year-old woman presented with mild renal dysfunction, proteinuria, and sensorineural hearing loss. A renal biopsy showed focal segmental glomerulosclerosis with thinning of the glomerular basement membrane. There was a positive family history of end-stage kidney disease and hearing loss. Although Alport syndrome was suspected from these features, a genetic test using next-generation sequencer identified a novel missense mutation in LMX1B, c.655C>G: p. (Pro219Ala). In silico analyses predicted the pathogenicity of the mutation. Thus, the present case was diagnosed as LMX1B-associated nephropathy presenting with Alport syndrome-like phenotype, expanding the disease spectrum of LMX1B nephropathy.

Diagnosing nail-patella syndrome: can it be so simple?

We describe here an interesting case of a 7-day-old male infant brought with parental concerns of inability to extend both knees. Clinical evaluation revealed dysplastic fingernails, bilateral abnormal patellae, triangular lunules in conjunction with pathognomic iliac horns on pelvic radiographs suggesting the possibility of nail-patella syndrome (NPS). Other competing diagnoses with similar phenotypic features were considered and sequentially excluded. A definitive diagnosis was established by the identification of the principal mutation at the LMX1B gene locus of chromosome 9. NPS is seldom diagnosed in neonates due to the heterogeneity of clinical presentations as well as the subtlety of clinical clues in this population. NPS is a dominantly inherited disorder that is predominantly familial in origin and thus carries important implications for the prenatal diagnosis of future pregnancies as well as pre-emptive surveillance of nephropathy in the index child.

A rare disorder causing chronic joint pain in an adolescent.

ABSTRACT: This article describes a patient with chronic knee pain and deformities of her hands and feet that led to a diagnosis of nail-patella syndrome, a rare autosomal dominant disorder.

[Prenatal diagnosis and pedigree analysis of a case of Nail-patella syndrome].

OBJECTIVE: To carried out prenatal diagnosis and genetic analysis for a case with Nail-patella syndrome. METHODS: Based on the clinical phenotype and prenatal imaging, genetic testing and prenatal diagnosis were carried out through whole exome sequencing (WES) and Sanger sequencing. RESULTS: Analysis of amniotic fluid showed that the fetus has carried a heterozygous c.139+1G>T splicing site variant [Chr9(GRCh37): g.129376868G>T] of the LMX1B gene, which was verified by Sanger sequencing. The same heterozygous variant was found in the pregnant woman, her daughter and her mother but not in her husband. Searching of HGMD database showed that the c.139+1G>T was previously unreported. CONCLUSION: Nail-patella syndrome is an autosomal dominant genetic disorder with various clinical manifestations. WES is helpful for its genetic and prenatal diagnosis.

Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene.

BACKGROUND: In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction. OBJECTIVE: To demonstrate linkage and to identify the underlying genetic cause of disease. METHODS: Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed. RESULTS: Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant in LMX1B present in all affected individuals, logarithm of the odds (LOD) score of z = 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants in LMX1B encoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS. CONCLUSIONS: Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. © 2020 International Parkinson and Movement Disorder Society.