Materiały źródłowe

• #1 Nail-Patella Syndrome | Consultant360

  https://www.consultant360.com/articles/nail-patella-syndrome-0

  NPS (hereditary onycho-osteodysplasia, iliac horn syndrome, Turner-Keiser syndrome) is an autosomal dominant disorder that affects mainly the fingernails, bone joints, and kidney and occasionally the eyes and skin. It is rarely associated with colon cancer. The prevalence is 1 in 50,000 births. Boys and girls of all ethnic groups are affected equally. When a parent has NPS, each child has a 50% chance of inheriting the disease-causing mutations. New mutations can occur with no family history of the syndrome. […] The fingernails, most commonly of the thumb and index fingers, may be small, discolored, and concave with pitting, ridges, and splits. One or both patellas may be absent or dislocated and have a square appearance. Supporting structures (ligaments, tendons) may be malformed. Some patients have bone spurs mainly on the posterior iliac crest and clubfoot. Subluxation of the elbows is not uncommon. Patients require regular screening for scoliosis and lordosis. Proteinuria is a common finding. Associated ophthalmic conditions include open-angle glaucoma (caused by blockage of the outflow of aqueous humor) and iris pigmentary changes (Lester sign). […] Kidney biopsy, radiographs, and ophthalmological evaluation can aid diagnosis. Molecular genetic testing of LMX1B, the only gene known to be associated with NPS, is available on a clinical basis.

• #2 Nail-Patella Syndrome (Hereditary osteo-onychodysplasia (HOOD), Fong disease, Turner-Kieser syndrome, Osterreicher-Turner Syndrome) – Dermatology Advisor

  https://www.dermatologyadvisor.com/home/decision-support-in-medicine/dermatology/nail-patella-syndrome-hereditary-osteo-onychodysplasia-hood-fong-disease-turner-kieser-syndrome-osterreicher-turner-syndrome/

  The LMX1B gene is mutated in nail patella syndrome. This gene encodes the transcription factor LMX1B, which is involved in the normal development of the limb as well as the early formation of the glomerular basement membrane. It serves a fundamental role in pattern formation during vertebrate limb development and development of the kidney. […] The most serious issue that can be lethal in nail patella syndrome is renal failure. The pathophysiology for this issue involves a defect in the glomerular basement membrane. The first sign of renal involvement is most commonly proteinuria, which can also occur with hematuria. The proteinuria can be present at birth, or later, and can also be intermittent. Pregnancy can cause the onset or worsening of renal dysfunction, and can be associated with pre-eclampsia. […] In the study of 123 patients with the syndrome, the mean age that renal involvement was detected was 21.7 years, and renal failure occurred in 3% of patients. The course of renal dysfunction is variable, but it can progress to nephrotic syndrome, nephritis, and renal failure.

• #3 Nail-Patella Syndrome – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1132/

  Nail-patella syndrome is caused by pathogenic loss-of-function variants in LMX1B, encoding a transcription factor which directs dorso-ventral patterning of limb development and the formation of the anterior eye and the podocytes of the kidneys. This explains the phenotypic features of knee and elbow manifestations (early embryologic state of lower extremities positioned dorsally), glaucoma, and kidney disease associated with proteinuria. […] The majority (~80%) of pathogenic variants in LMX1B are found in the LIM domains, with the rest in the homeodomain. There is variability in the phenotype between and within families, even with the same LMX1B pathogenic variant. For this reason, it is difficult to predict the disease severity based on the genotype. However, there appear to be more pathogenic variants in the homeodomain in individuals who have been described with kidney disease (see Genotype-Phenotype Correlations).

• #4 Nail-Patella Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK559190/

  Nail-patella syndrome is an autosomal dominant disorder due to a heterozygous loss of function mutation of the LMXB1 gene on chromosome 9q34.1. LMXB1 encodes a transcription factor involved in multiple important embryological developments to include limb dorsal-ventral patterning, differentiation of dopaminergic and serotonergic neurons, skull patterning, periocular mesenchyme development, and renal podocyte development. At least 142 LMXB1 mutations have been identified as well as evidence of somatic mosaicism, which is known to occur in unaffected parents of patients affected by autosomal dominant disorders. NPS is highly penetrant, but there is inter- and intrafamilial variability contributing to the conditions variable clinical manifestations. Another factor contributing to the conditions various manifestations may include interactions between the LMXB1 homeodomain with other genes. The PAX2 transcription factor has been studied for its interaction with LMXB1 as both proteins are involved in renal and eye development. Mutations of the LMXB1 gene homeodomain have been shown to affect interactions with PAX2 raising the question of the latters role in the NPS phenotypic variability, although more research would be needed to test this possibility.

• #5 Nail-Patella Syndrome – MD Searchlight

  https://mdsearchlight.com/genetic-disorders/nail-patella-syndrome/

  Nail-patella syndrome is an inherited disorder that is passed from parents to children. It is caused by a mutation in a specific gene called LMXB1, which resides on a particular section of chromosome 9. The LMXB1 gene is responsible for creating a protein that plays a critical role in the development of numerous body parts during embryonic stages, including certain parts of limbs, types of brain cells, skull structure, development around the eyes, and specific kidney cells. […] It is known that at least 142 types of changes or mutations in the LMXB1 gene can cause this syndrome. There is also evidence of what is known as somatic mosaicism, a condition where some cells have the genetic mutation causing the syndrome, while others do not. This often happens in parents who do not have the syndrome, but have a child who does.

• #6 Nail-patella syndrome. A case with a de novo mutation in the LMX1B gene not previously described | Nefrología

  https://revistanefrologia.com/en-nail-patella-syndrome-a-case-with-articulo-X2013251413052799

  The nail-patella syndrome is an uncommon hereditary disease caused by mutations that result in a loss of function of the transcription factor LMX1B. Prevalence is estimated at 1/50,000 new-born babies. It is transmitted with an autosomal dominant inheritance pattern with complete penetrance. The pleiotropic gene LMX1B, a member of the homeogene family involved in development, participates in the normal configuration of the dorsal-ventral axis and the glomerular basement membrane during embryonic development. […] The transcription factor LMX1B is expressed in the podocyte in postnatal life, which suggests that its role is to regulate various genes in this cell, such as NPHS2 and CD2AP. […] Since LMX1B gene mutations have only been associated with the nail-patella syndrome, we assume that it is responsible for the patients clinical profile.

• #7 Nail-patella syndrome – UpToDate

  https://www.uptodate.com/contents/nail-patella-syndrome

  NPS is an autosomal dominant disorder with full gene penetrance but variability of expression even within families. […] Approximately 85 percent of families with NPS present with mutations of the LMX1B gene located at the distal end of the long arm of chromosome 9. LMX1B is a transcription factor of the LIM-homeodomain type that plays an important role for limb and kidney development in vertebrates; however, it is expressed lifelong within the podocyte and it is essential for the maintenance the structured actin cytoskeleton in podocytes. […] The identification of entire LMX1B deletions confirms that haploinsufficiency is the principal pathogenetic mechanism of NPS. […] Studies in homozygous knock-out mice and in vitro assays demonstrated that LMX1B protein expressed in glomerular podocytes helps control the transcription of multiple genes integral for proper glomerular basement membrane (GBM) formation, and/or glomerular podocyte differentiation and function during the early stages of kidney development.

• #8 Identification of entire LMX1B gene deletions in nail patella syndrome: evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance in man | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg200883

  Heterozygous mutations in the LMX1B gene cause nail patella syndrome (NPS) that is associated with nail and skeletal malformations, nephropathy, and glaucoma. […] The identification of entire LMX1B deletions strongly confirms that haploinsufficiency is the principal pathogenetic mechanism of NPS and suggests a difference in dosage sensitivity for this gene between mice and man. […] The hypothesis that haploinsufficiency is the main pathogenic mechanism underlying dominant inheritance in human NPS is based on the fact that the same phenotypic variability is observed in individuals with LMX1B missense, nonsense, frameshift or splice-site mutations and that the range and severity of symptoms varies both within and between NPS families. […] The present finding of entire gene deletions in families with classic NPS confirms beyond any doubt that a reduced dosage of the LMX1B protein causes NPS and emphasizes that loss-of-function is the predominant mechanism underlying NPS pathogenesis. […] This finding provides strong evidence for haploinsufficiency as the main pathogenic mechanism underlying dominant inheritance of NPS in man.

• #9 Nail–Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg201577

  NailPatella Syndrome (NPS) is due to variants affecting function in LMX1B, which encodes a LIM-homeodomain protein critical for limb, kidney and eye development. […] The main pathogenic mechanism underlying autosomal dominant NPS in humans is haploinsufficiency. […] The majority of patients carry either LMX1B variants or complete or partial deletions responsible for haploinsufficiency through the nonsense-mediated mRNA decay pathway. […] Nevertheless, although no clear genotype-phenotype correlation was apparent for extra-renal manifestations, Bongers and co-workers observed that individuals with variants located in the HD had significantly higher renal involvement raising the possibility of dominant-negative and/or gain-of-function effects. […] In the present study, we describe the phenotype and molecular data of 55 index patients and their 39 relatives affected with NPS.

• #10 Nail-Patella Syndrome – GeneReviews® – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK1132/

  Pathogenic missense variants within the homeodomain reduce or eliminate DNA binding. Pathogenic missense variants within the LIM domains are believed to affect the secondary structure of the zinc fingers. […] NPS is the result of heterozygous loss-of-function pathogenic variants within the gene encoding the transcription factor. Bongers et al [2005] suggested a potential mechanism of disease of dominant-negative effect on the normal gene product, but this has not been replicated in subsequent studies.

• #11 Nail-patella syndrome. A case with a de novo mutation in the LMX1B gene not previously described | Nefrología

  https://revistanefrologia.com/en-nail-patella-syndrome-a-case-with-articulo-X2013251413052799

  In this disease, more than 130 different mutations have been described, mainly consisting of changes in just one nucleotide. They are predominantly distributed between exons 2 and 6. A more common series of mutations has been described which together represent 30% of the total. 12% of mutations are de novo. […] The confirmation of a mutation in the LMX1B gene avoids the need to perform a renal biopsy to confirm diagnosis.

• #12 Nail–Patella Syndrome: clinical and molecular data in 55 families raising the hypothesis of a genetic heterogeneity | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg201577

  In 9% of the families tested, no alteration was found in LMX1B by the routine screening. […] These patients were not clinically different from the patients harbouring an LMX1B alteration. […] To our knowledge, the hypothesis of a genetic heterogeneity has never been studied in NPS. […] Given the large number of genes involved in the WNT signaling pathway, potential candidate genes are numerous. […] LMX1B deregulation due to a genomic alteration in another locus could also be a hypothesis.

• #13 Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity

  https://search.lib.asu.edu/discovery/fulldisplay?docid=cdi_doaj_primary_oai_doaj_org_article_c839defb640841778feac8543d2361dc&context=PC&vid=01ASU_INST:01ASU&lang=en&adaptor=Primo%20Central&tab=Everything&query=null%2C%2C420%2CAND&mode=advanced&offset=30

  LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. […] Herein, we report on two conserved L mx1b – a ssociated cis – r egulatory m odules ( 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. […] 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. […] Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.

• #14 Nail-Patella Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK559190/

  The pathophysiology of nail-patella syndrome centers around the LMX1B protein role in embryological development. LMX1B is involved in dorsal-ventral limb patterning and has a normal gradient of expression from distal to proximal and from anterior to posterior. This expression pattern likely explains nail and patellar (an epiphyseal equivalent) involvement with decreasing severity of findings going from anterior to posterior as well as going from distal to proximal. It has also been shown that motor axonal migration from the lateral motor columns becomes random with mutations in the LMX1B. […] In another example, the anterior structures of the eye to include the cornea, trabecular meshwork, and anterior chamber depth, are each influenced by LMX1B during development. It is an abnormal anterior chamber depth in patients with NPS that is most likely responsible for primary open-angle glaucoma, the most potentially serious and most frequent ocular complication of NPS.

• #15 Nail–patella syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Nail%E2%80%93patella_syndrome

  Nailpatella syndrome is inherited via autosomal dominancy linked to aberrancy on human chromosome 9’s q arm (the longer arm), 9q34. This autosomal dominancy means that only a single copy, instead of both, is sufficient for the disorder to be expressed in the offspring, meaning the chance of getting the disorder from an affected heterozygous parent is 50%. The disorder is linked to the ABO blood group locus. […] It is associated with random mutations in the LMX1B gene. Studies have been conducted and 83 mutations of this gene have been identified. […] The lack of development or complete absence of fingernails results from the loss of function mutations in the LMX1B gene. This mutation may cause a reduction in dorsalising signals, which then results in the failure to normally develop dorsal specific structures such as nails and patellae.

• #16 Nail-patella-syndrome in a young patient followed up over 10 years: relevance of the sagittal trochlear septum for patellofemoral pathology | SICOT-JMendeley

  https://www.sicot-j.org/articles/sicotj/full_html/2016/01/sicotj150179/sicotj150179.html

  In patients with NPS, hypoplastic and laterally subluxated or dislocated patellae and anterior knee pain are common. In those patients a thick septum in the femoral trochlea was described earlier. In the literature, the etiology and relevance of this septum are not absolutely clear. The LMX1B transcription factor, which is affected in NPS patients, plays an important role in early mesenchymal development. The persistent septum may be a flaw of apoptotic processes necessary for appropriate formation of the anterior knee joint cavity. […] According to our findings in children and adults diagnosed with NPS presenting typical knee pathologies, we think that the thick sagittally oriented septum in the femoral trochlea leads to pathognomonic anatomic developments during growth: (1) the trochlea femoris becomes deep and scalloping; (2) the patella remains on the lateral side of the septum and cannot center into the trochlea. During growth the septum remains centrally within the trochlea groove and thereby displaces the patella laterally. This leads to elongation of the passive medial stabilizers like the medial patellofemoral ligament (MPFL). Simultaneously the lateral soft tissues like the lateral retinaculum stay shortened. The older the patient the more complex the soft tissue pathologies are. This is due to adaptation of the passive stabilizers to the severely lateralized patella during skeletal development. Altered patellofemoral biomechanics with a lateralized patella may lead to early symptomatic patellofemoral arthritis.

• #17 Nail-Patella Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK559190/

  LMX1B plays an important role in embryological renal development, particularly with the podocytes and glomeruli. The podocyte foot processes may be effaced and exhibit abnormal slit diaphragms, causing splitting of the glomerular basement membrane as well as decreased endothelial fenestrations. These microscopic changes explain why patients with NPS can present with proteinuria with or without hematuria.

• #18 SciELO Brazil – Do you know this syndrome? Nail patela syndrome: a pathognomonic dermatologic finding* Do you know this syndrome? Nail patela syndrome: a pathognomonic dermatologic finding*

  https://www.scielo.br/j/abd/a/vHQNkSMVTD49WxBJ86vJR4G/

  Nail patella syndrome (NPS) is a disease of autosomal dominant inheritance, occurring in 1 to 50,000 individuals. […] Its diagnosis is purely clinical, with the possibility of genetic testing for LMX1B mutation. It presents two pathognomonic findings: triangular lunula (80%) and bilateral iliac horns on pelvic radiography (70-80%). […] Studies describe that the LMX1B mutation impairs the development and functioning of podocytes and glomerular filtration slits, being strongly associated with the mechanism of renal damage. […] Another consequence of the disease possibly associated with the LMX1B mutation is glaucoma. […] Analyzes of the LMX1B mutation reveal a role of this gene in the development of dopaminergic and mesencephalic serotoninergic neurons.

• #19

  https://99nicu.org/forums/topic/305-nail-patella-syndrome/

  The NailPatella Syndrome (Fong Syndrome) is inherited as autosomal dominant (AD). Is caused by a defect in the LMX1B gene that is characterized by hypoplastic patella, nail dystrophy with triangular lunula, posterior iliac horns, pigmentation of the margin of the pupils (Lester iris), and glomerulonephropathy. Triangular nail lunulae is the pathognomonic sign of this syndrome. […] In addition to ocular and renal involvement, recently neurological and gastrointestinal symptoms have also been described including depression and anxiety symptoms, epilepsy, peripheral neurological symptoms, irritable bowel syndrome and constipation. […] Nail dysplasia (bilateral and symmetrical) is usually present at birth, but it has been noted to appear after birth. […] You will find in this article that the diagnosis of NPS though possible at birth is often missed at this time, and discovered later on if at all discovered.

• #20 Genetics of Nail-Patella Syndrome: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/947391-overview

  Nail-patella syndrome (NPS) is an autosomal dominant condition characterized by the classical clinical tetrad of nail dysplasia, patellar aplasia-hypoplasia, elbow arthrodysplasia, and iliac horns. The third documented chromosomal linkage identified in humans was between the nail-patella syndrome locus and the ABO blood group on chromosome 9. LMX1B, located at 9q34.1, is an LIM-homeodomain transcription factor required for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Heterozygous loss-of-function mutations in LMX1B cause nail-patella syndrome. […] Although the joint anomalies in nail-patella syndrome may limit range of motion (ROM), the associated glaucoma and nephropathy may be the most serious complication. Mutations in the homeodomain of LMX1B versus LIM-A or LIM-B may be associated with proteinuria. However, further investigation of a larger population of patients with nail-patella syndrome (ideally sporadic) is needed to determine if this genotype-phenotype correlation is valid outside large pedigrees of nail-patella syndrome, which may be simultaneously segregating nephropathy-related genes.

• #21

  https://link.springer.com/article/10.1007/s00467-002-0911-5

  Nail-patella syndrome (NPS) is a rare autosomal dominant pleiotropic disorder characterized by dysplasia of the nails, patellar aplasia or hypoplasia, iliac horns, dysplasia of the elbows, and frequently glaucoma and progressive nephropathy. […] The recent identification of the causative gene for this syndrome has initiated further studies of the phenotype and molecular pathogenesis of kidney disease in NPS. […] The gene underlying NPS, LMX1B, is a LIM-homeodomain transcription factor involved in normal patterning of the dorsoventral axis of the limb during development and early morphogenesis of the glomerular basement membrane. […] Molecular studies of Lmx1b, combined with genetic and immunohistochemical investigation of different alpha chains of type IV collagen in the Lmx1b null mice kidney, a mouse model for NPS, have provided evidence that Lmx1b is involved in the pathogenesis of NPS glomerulopathy. […] At present evidence for a correlation between the presence and severity of the renal and extrarenal anomalies and LMX1B genotype is lacking.

• #22 Nail-Patella Syndrome – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/connective-tissue-disorders-in-children/nail-patella-syndrome

  Nail-patella syndrome is an autosomal dominant disorder caused by a mutation in the gene for the transcription factor LMX1B, which plays an important role in vertebrate limb and kidney development. […] Renal dysfunction occurs in up to 50% of patients due to focal segmental glomerular deposits of IgM and C3. Proteinuria, hypertension, and hematuria are the most common manifestations, but about 30% of patients with renal involvement slowly progress to renal failure. […] Diagnosis of nail-patella syndrome is suggested clinically; sometimes renal biopsy and bone x-rays are indicated, which are diagnostic. […] LMX1B mutation analysis is possible, including for prenatal diagnosis, but the type of mutation does not usually predict clinical severity.

• #23 Orphanet: Nail-patella syndrome

  https://www.orpha.net/en/disease/detail/2614

  NPS is an autosomal-dominant disorder and the majority of the cases are caused by LMX1B mutations (9q33.3) leading to loss of function of the LMX1B protein. About 10% are caused by a de novo pathogenic variant. […] The diagnosis is based on clinical findings. Molecular test can identified the LMX1B gene mutations in around 95% of the cases, thus helping to confirm the clinical diagnosis or cases where clinical signs and symptoms are not clear. […] NPS is inherited in an autosomal dominant manner. Each child of an NPS affected individual has a 50% chance of inheriting the LMX1B pathogenic variant of the disease. The penetrance of the disease is complete, but the clinical expression is variable even in individuals of the same family. About 90% of NPS patients have an affected parent. In NPS, somatic and germline mosaicism has been reported in unaffected parents.

• #24 33 Fong’s Disease/Nail Patella Syndrome | Radiology Key

  https://radiologykey.com/33-fongs-diseasenail-patella-syndrome/

  NPS has been recognized as a hereditary condition, with an autosomal dominant inheritance in the ABO blood group. The risk of transmission is 50% per pregnancy, irrespective of gender, females being affected ~10% more often than males. About 20% of cases are sporadic, as a result of a new mutation. The incidence is ~1 in 50,000, and the condition occurs in all ethnic groups. […] The gene for NPS, recently discovered and named LMX1B, is located on chromosome 9q34. The pathophysiology underlying NPS is not yet known, but it is clear that the musculoskeletal abnormalities arise from a disorder of collagen synthesis, assembly, or degradation.

• #25 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Nail-Patella-Syndrome-Genetics.aspx

  Nail patella syndrome or NPS, is a genetic disorder passed down to children from their parents. […] NPS is an autosomal dominant trait. […] Most genetic diseases tend to get passed on only when both parents have the defective gene. However, with an autosomal dominant trait, the diseased gene is strong enough to dominate the healthy gene from the other parent. […] Apparently in cases where neither parent has NPS, the child may still develop the syndrome due to random mutations affecting the perpetuating gene. Conditions for the mutation of the gene are still being studied by genetic scientists. […] The defective gene that causes NPS is called LMX1B and it is mapped to chromosome 9q34. […] The mutation of this gene is what causes the abnormal development of nails, kneecaps, elbows, and other skeletal defects in the embryo.

• #26 Nail-Patella Syndrome: Symptoms & Causes

  https://my.clevelandclinic.org/health/diseases/nail-patella-syndrome

  Gene variants cause the LMX1B protein to work differently than expected. As a result, various parts of your child’s body don’t form in typical ways, leading to the features of nail-patella syndrome. […] Some people have the signs and symptoms of nail-patella syndrome without changes to their LMX1B gene. But this is rare. Researchers believe other genes might play a role, and they continue to look for more clues.

• #27

  https://www.omim.org/entry/161200

  A number sign (#) is used with this entry because of evidence that nail-patella syndrome (NPS) is caused by heterozygous mutation in the LIM-homeodomain protein LMX1B (602575) on chromosome 9q33. […] Nail-patella syndrome (NPS) is an autosomal dominant disorder characterized by developmental defects of dorsal limb structures, the kidney, and the eye, manifested by nail dysplasia, patellar abnormalities, elbow dysplasia, iliac horns, nephropathy, and glaucoma, respectively (summary by Bongers et al., 2005). […] The heterozygous mutations in the LMX1B gene that were identified in patients with NPS by Dreyer et al. (1998) occurred de novo. […] The transmission pattern of NPS in the families reported by Vollrath et al. (1998) was consistent with autosomal dominant inheritance. […] Ghiggeri et al. (1993) suggested that mutations in the COL5A1 gene may be involved in the pathogenesis of the nail-patella syndrome.

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