Osteoporosis-pseudoglioma syndrome in four new patients: identification of two novel LRP5 variants and insights on patients' management using bisphosphonates therapy.

This study describes the clinical, radiological, and molecular data of four new patients with osteoporosis-pseudoglioma syndrome and assesses their response to bisphosphonate therapy. INTRODUCTION: Osteoporosis-pseudoglioma syndrome (OPPG) is a very rare disorder characterized mainly by severe juvenile osteoporosis and congenital blindness. OPPG is caused by biallelic mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5). METHODS: We present the clinical, radiological, and molecular findings of four new patients with OPPG from Egypt. We also assessed patients' response to oral and intravenous bisphosphonate therapy. RESULTS: All patients had reduced bone mineral density (BMD) with variable number of fractures per year, in addition to bone abnormalities and the characteristic eye phenotype associated with OPPG. Mutation analyses of LRP5 gene revealed three different homozygous variants including two novel ones, c.7delG (p.A3Qfs*80) and c.3280G > A (p.E1094K). The c.3280G > A (p.E1094K) was recurrent in two unrelated patients who shared a unique haplotype suggesting a possible founder effect. The use of bisphosphonate therapy was beneficial; however, intravenous bisphosphonate administration led to a more favorable response. CONCLUSION: Our study described the phenotypic and genetic features of four patients with OPPG and identified two new LRP5 variants, thus expanding the mutational spectrum of OPPG. In addition, our study reinforces the efficiency of using intravenous bisphosphonates in the management of patients with OPPG.

Evaluation of growth, puberty, osteoporosis, and the response to long-term bisphosphonate therapy in four patients with osteoporosis-pseudoglioma syndrome.

Osteoporosis-pseudoglioma syndrome (OPPG; MIM #259770) is a rare autosomal recessively inherited disease, characterized by early-onset osteoporosis and congenital blindness, caused by loss-of-function mutations in the LRP5 gene. Beneficial effects of bisphosphonate treatment in patients with OPPG are well known, while follow-up data on growth and pubertal parameters are limited. This article provides clinical follow-up data and long-term bisphosphonate treatment results in four OPPG patients from three unrelated families, ranging between 2.5 and 7 years of age at presentation. Clinical diagnosis was molecularly confirmed in all patients, with four different germline biallelic LRP5 mutations including a novel nonsense variant c.3517C>T (p.(Gln1173*)) in two siblings with marked phenotypic variability. Anthropometric and pubertal data and bone mineral density (BMD) measurements were evaluated retrospectively. Early puberty was observed in two patients. The bisphosphonate treatment duration of patients varied around 4-7 years and improvement in BMD z-scores with bisphosphonate treatment was demonstrated in all patients (z-score changes were +5.6, +4.0, +1.0, and +1.3). Although further research is needed to identify the possible association between early puberty and OPPG, all OPPG patients should be followed up with detailed endocrinological evaluation regarding pubertal status.

Clinical and biochemical response to neridronate treatment in a patient with osteoporosis-pseudoglioma syndrome (OPPG).

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive syndrome characterized by juvenile-onset osteoporosis and ocular abnormalities due to a low-density lipoprotein receptor-related protein 5 (LRP5) gene mutation. Treatment with bisphosphonates, particularly with pamidronate and risedronate, has been reported to be of some efficacy in this condition. We report on a patient with OPPG due to an LRP5 gene mutation, who showed an encouraging response after a 36-month period of neridronate therapy. We report a case of a patient treated with bisphosphonates. Bisphosphonates should be administered in OPPG patients as a first-line therapy during early childhood.

Novel Homozygous Nonsense Mutation in the LRP5 Gene in Two Siblings with Osteoporosis-pseudoglioma Syndrome

Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder characterized by severe osteoporosis and eye abnormalities that lead to vision loss. In this study, clinical findings and genetic study of two siblings with OPPG are presented. Whole exome sequencing of DNA enriched for exonic regions was performed with SureSelect 38Mbp all exon kit v. 7.0. The two siblings presented with different clinical manifestations of OPPG. The younger female sibling had blindness and severe osteoporosis with multiple fractures, while her older brother was also blind but with less severe osteoporosis and no fractures. On analysis, a novel homozygous nonsense mutation (c.351G>A) in exon 2 of LRP5 (NM_002335) was found, predicted to change a tryptophan at 117 to a stop codon (p. Trp117Ter). Thus, a variable phenotype was associated with an identical variant in these two siblings. The novel mutation reported herein expands the spectrum of the underlying genetic pathology of OPPG.

LRP5, Bone Mass Polymorphisms and Skeletal Disorders.

The formation and maintenance of the gross structure and microarchitecture of the human skeleton require the concerted functioning of a plethora of morphogenic signaling processes. Through recent discoveries in the field of genetics, numerous genotypic variants have been implicated in pathologic skeletal phenotypes and disorders arising from the disturbance of one or more of these processes. For example, total loss-of-function variants of LRP5 were found to be the cause of osteoporosis-pseudoglioma syndrome (OPPG). LRP5 encodes for the low-density lipoprotein receptor-related protein 5, a co-receptor in the canonical WNT-ß-catenin signaling pathway and a crucial protein involved in the formation and maintenance of homeostasis of the human skeleton. Beyond OPPG, other partial loss-of-function variants of LRP5 have been found to be associated with other low bone mass phenotypes and disorders, while LRP5 gain-of-function variants have been implicated in high bone mass phenotypes. This review introduces the roles that LRP5 plays in skeletal morphogenesis and discusses some of the structural consequences that result from abnormalities in LRP5. A greater understanding of how the LRP5 receptor functions in bone and other body tissues could provide insights into a variety of pathologies and their potential treatments, from osteoporosis and a variety of skeletal abnormalities to congenital disorders that can lead to lifelong disabilities.

Clinical Response to Treatment with Teriparatide in an Adolescent with Osteoporosis-Pseudoglioma Syndrome (OPPG): A Case Report.

Introduction: Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder characterized by severe osteoporosis and eye abnormalities that leads to vision loss. In this study, we report the outcome of a short period of treatment with teriparatide in one patient with OPPG. Case Presentation: The patient was a 17-year-old girl who suffered a bone fracture at the age of two and was diagnosed with OPPG at the age of three. Genetic testing was performed for the patient, and a novel homozygous nonsense mutation (c.351G>A) in exon 2 of the LRP5 gene was reported. She was treated with pamidronate, but the bone fracture increased, and the disability progressed. Therefore, at the age of 11 years and nine months, teriparatide was administered subcutaneously at a dose of 20 micrograms per day for four consecutive months. After the treatment with teriparatide, physical activity was achieved, and no further fractures were observed besides the gradual rise in bone mineral density (BMD) (from 0.532 to 0.711 gr/cm2 in lumbar spine and 0.372 to 0.635 gr/cm2 in femur neck). Conclusions: In children and adolescents diagnosed with OPPG who do not respond to other conventional therapies, short courses of teriparatide therapy may be helpful.

[Osteoporosis-pseudoglioma Syndrome: a pediatric case of primary osteoporosis]. / Síndrome de osteoporosis-pseudoglioma: a propósito de un caso pediátrico de osteoporosis primaria.

Osteoporosis should be considered in children with severe chronic diseases or in association with some genetic diseases that bear an increased risk of bone fragility. Primary osteoporosis is an entity in which emerging aetiologies are being recognized. Its association with congenital retinal folds should guide the diagnosis to the Osteoporosis-Pseudoglioma syndrome (OMIM 259770), a rare disease (prevalence of 1/2 000 000), caused by the loss of function of the protein LRP5 (low-density lipoprotein receptor-related protein 5) resulting in the alteration of the Wnt/ß-catenin signalling pathway. We report the case of a child with congenital retinal folds, progressive loss of vision and multiple fractures whose clinical, biochemical and genetic studies confirmed the diagnosis of primary osteoporosis due to a novel homozygous inactivating variant in LRP5.

La osteoporosis es un trastorno para tener en cuenta en niños con patologías crónicas graves o con algunas enfermedades genéticas que predisponen al incremento de la fragilidad ósea. La osteoporosis primaria es una entidad con etiologías emergentes y puede ocurrir en forma sindrómica. La asociación con pliegues retinianos congénitos debe orientar al diagnóstico de osteoporosis-pseudoglioma (OMIM 259770), síndrome poco frecuente (prevalencia de 1/2 000 000), que se origina por la pérdida de función de la proteína LRP5 (low-density lipoprotein receptor-related protein 5) y compromete la vía de señalización de Wnt/ß-catenina. Se presenta el caso de un niño con pliegues retinianos congénitos, ceguera progresiva y múltiples fracturas cuyo estudio clínico, bioquímico y genético confirmó el diagnóstico de osteoporosis primaria debido a una nueva variante inactivante en el gen LRP5 en homocigosis.

Application of anti-Sclerostin therapy in non-osteoporosis disease models.

Sclerostin, a known inhibitor of the low density lipoprotein related protein 5 and 6 (LRP5 and LRP6) cell surface signaling receptors, is integral in the maintenance of normal bone mass and strength. Patients with loss of function mutations in SOST or missense mutations in LRP5 that prevent Sclerostin from binding and inhibiting the receptor, have significantly increased bone mass. This observation leads to the development of Sclerostin neutralizing therapies to increase bone mass and strength. Anti-Sclerostin therapy has been shown to be effective at increasing bone density and strength in animal models and patients with osteoporosis. Loss of function of Sost or treatment with a Sclerostin neutralizing antibody improves bone properties in animal models of Osteoporosis Pseudoglioma syndrome (OPPG), likely due to action through the LRP6 receptor, which suggests patients may benefit from these therapies. Sclerostin antibody is effective at improving bone properties in mouse models of Osteogenesis Imperfecta, a genetic disorder of low bone mass and fragility due to type I collagen mutations, in as little as two weeks after initiation of therapy. However, these improvements are due to increases in bone quantity as the quality (brittleness) of bone remains unaffected. Similarly, Sclerostin antibody treatment improves bone density in animal models of other diseases. Sclerostin neutralizing therapies are likely to benefit many patients with genetic disorders of bone, as well as other forms of metabolic bone disease.

Osteoporosis-pseudoglioma syndrome: Report of two cases and a manifesting carrier.

BACKGROUND: Osteoporosis-pseudoglioma syndrome is a very rare disease mainly characterized by severe eye abnormalities and osteoporosis but also causing a broader range of clinical features. The syndrome is associated with homozygous or compound heterozygous variations in the LRP5 gene. In this report, we describe two children with a severe early-onset form of familial exudative vitreoretinopathy associated with skeletal abnormalities. MATERIALS AND METHODS: Two probands (4 and 7 years of age respectively) and their parents were assessed by genetic analysis and comprehensive ophthalmic examination. RESULTS: In both probands, the diagnosis of osteoporosis-pseudoglioma syndrome was confirmed by detection of three new pathogenic LRP5 variants: p.(Asp379Asn), found in the homozygous state in one proband, and p.(Asp203Ala) in the compound heterozygous state with p.(Cys612Valfs*25) in the other. The clinical and genetic study was extended to their parents, confirming that heterozygous carriers may also have incomplete clinical manifestation of this syndrome. CONCLUSIONS: To our knowledge, these are the first two cases of the syndrome described in Italy. Genetic testing proved to be fundamental for definition of the syndrome and confirms the importance of early detection of LRP5 variants for management of systemic features of the disease in patients and carrier relatives.

Novel Homozygous LRP5 Mutations in Mexican Patients with Osteoporosis-Pseudoglioma Syndrome.

AIMS: Osteoporosis-pseudoglioma syndrome (OPPG) is an uncommon autosomal recessive disorder characterized by the rare association of early-onset osteoporosis and severe ocular abnormalities such as persistent fetal vasculature and microphthalmia. Biallelic mutations in the low-density lipoprotein receptor-related protein-5 gene (LRP5) have been associated with OPPG. We present clinical and genetic data from three Mexican OPPG patients, a pair of sibs, and a sporadic case. MATERIALS AND METHODS: Three patients underwent clinical examination, including a complete ophthalmic evaluation. Based on the clinical diagnosis of OPPG, the entire coding sequence of LRP5 was polymerase chain reaction-amplified and directly Sanger-sequenced. Genetic testing was extended to the parents of the affected patients. RESULTS: Phenotypic variability was observed in the familial case and molecular analysis identified a novel homozygous c.1145C>T, p.(Pro382Leu) variant in both sibs. As expected, their parents were heterozygous carriers. The sporadic patient exhibited a severe osseous phenotype, microphthalmia, and neurological symptoms. In this patient, homozygosity for the c.442C>T, p.(Gln148*) variant was demonstrated, whereas her parents were heterozygous carriers. The p.(Pro382Leu) pathogenic mutation has been previously reported only in a compound heterozygous state in OPPG patients. CONCLUSIONS: Two novel homozygous missense and nonsense variants were demonstrated in three OPPG cases from Mexico. Our results expand the spectrum of disease-causing LRP5 mutations. This is the first report of OPPG in our population and our findings may potentially add to a genotype-phenotype correlation.

Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure.

Osteoporosis pseudoglioma syndrome (OPPG) is a rare autosomal recessive disorder of childhood osteoporosis and blindness due to inactivating mutations in LDL receptor-like protein 5 (LRP5). We and others have reported improvement in areal bone mineral density (aBMD) by DXA in OPPG on short term bisphosphonates. Long-term data on bisphosphonate use in OPPG and measures of volumetric BMD (vBMD) and cortical structure are not available. In addition, no long-term DXA data on untreated OPPG is available. The aims of this study were to: (1) record low trauma fractures and longitudinal aBMD by DXA in 5 OPPG patients on chronic bisphosphonate treatment, and in 4 OPPG patients never treated (2) to perform tibia peripheral quantitative CT (pQCT) to evaluate volumetric bone mineral density (vBMD), cortical structure and calf muscle area in 6 OPPG patients and 14 unaffected first degree family members. pQCT results were converted to sex-specific Z-scores for age and adjusted for tibia length based on data in >700 reference participants. We observed 4 fractures (3 femoral shafts) in 3 OPPG patients while on bisphosphonates, after each achieved significant improvement in aBMD. OPPG participants had significantly lower mean trabecular vBMD (-1.51 vs. 0.17, p = 0.002), cortical area (-2.36 vs. 0.37; p < 0.001) and periosteal circumference (-1.86 vs. -0.31, p = 0.001) Z-scores, compared with unaffected participants and had a trend toward lower muscle area Z-score (-0.69 vs. 0.47, p = 0.12). These data demonstrate substantial bone fragility despite improvements in aBMD. The pQCT data provide insight into the fragility with substantial deficits in trabecular vBMD and cortical dimensions, consistent with OPPG effects of bone formation. Treatment that improves bone quality is needed to reduce fractures in OPPG.

Congenital Bilateral Retinal Detachment in Two Siblings with Osteoporosis-Pseudoglioma Syndrome.

The birth of a bilaterally blind child is catastrophic for families and a challenging diagnostic and management problem for ophthalmologists. Early identification of the underlying cause and its genetic basis helps initiate possible treatment, delineate prognosis, and identify risks for future pregnancies. In some cases, an early diagnosis can also influence the treatment of other family members. We report two sisters with bilateral retinal detachment and retro-lental masses from birth with no detectable NDP or FZD4 mutations. They were born to parents without detectable retinal anomalies. At 1 year of age, the elder sister had low impact bone fractures, and further evaluation identified severe osteopenia and multiple spinal compression fractures. Molecular testing identified biallelic lipoprotein receptor-related protein 5 (LRP5) mutations (NM_002335.3:c. [889dupA]; [2827 + 1G > A]) confirming a diagnosis of osteoporosis-pseudoglioma (OPPG) syndrome. After this diagnosis, the father and mother were found to have low bone mass and the father started on therapy. We conclude that early detection of LRP5 mutations is important for initiation of treatment of reduced bone density in the patients and their carrier relatives.

Síndrome de osteoporosis-pseudoglioma: a propósito de un caso pediátrico de osteoporosis primaria / Osteoporosis-pseudoglioma Syndrome: a pediatric case of primary osteoporosis

La osteoporosis es un trastorno para tener en cuenta en niños con patologías crónicas graves o con algunas enfermedades genéticas que predisponen al incremento de la fragilidad ósea. La osteoporosis primaria es una entidad con etiologías emergentes y puede ocurrir en forma sindrómica. La asociación con pliegues retinianos congénitos debe orientar al diagnóstico de osteoporosis-pseudoglioma (OMIM 259770), síndrome poco frecuente (prevalencia de 1/2000000), que se origina por la pérdida de función de la proteína LRP5 (low-density lipoprotein receptor-related protein 5) y compromete la vía de señalización de Wnt/ß-catenina. Se presenta el caso de un niño con pliegues retinianos congénitos, ceguera progresiva y múltiples fracturas cuyo estudio clínico, bioquímico y genético confirmó el diagnóstico de osteoporosis primaria debido a una nueva variante inactivante en el gen LRP5 en homocigosis

Osteoporosis should be considered in children with severe chronic diseases or in association with some genetic diseases that bear an increased risk of bone fragility. Primary osteoporosis is an entity in which emerging aetiologies are being recognized. Its association with congenital retinal folds should guide the diagnosis to the Osteoporosis-Pseudoglioma syndrome (OMIM 259770), a rare disease (prevalence of 1/2000000), caused by the loss of function of the protein LRP5 (low-density lipoprotein receptor-related protein 5) resulting in the alteration of the Wnt/ß-catenin signalling pathway. We report the case of a child with congenital retinal folds, progressive loss of vision and multiple fractures whose clinical, biochemical and genetic studies confirmed the diagnosis of primary osteoporosis due to a novel homozygous inactivating variant in LRP5

Pregnancy-associated osteoporosis with a heterozygous deactivating LDL receptor-related protein 5 (LRP5) mutation and a homozygous methylenetetrahydrofolate reductase (MTHFR) polymorphism.

Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 months of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26-year-old primagravida with a neonatal history of unilateral blindness attributable to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼40 and 32 years, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not cosegregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or nongenetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this enigmatic disorder and identify some at-risk women.

Aberrant and alternative splicing in skeletal system disease.

The main function of skeletal system is to support the body and help movement. A variety of factors can lead to skeletal system disease, including age, exercise, and of course genetic makeup and expression. Pre-mRNA splicing plays a crucial role in gene expression, by creating multiple protein variants with different biological functions. The recent studies show that several skeletal system diseases are related to pre-mRNA splicing. This review focuses on the relationship between pre-mRNA splicing and skeletal system disease. On the one hand, splice site mutation that leads to aberrant splicing often causes genetic skeletal system disease, like COL1A1, SEDL and LRP5. On the other hand, alternative splicing without genomic mutation may generate some marker protein isoforms, for example, FN, VEGF and CD44. Therefore, understanding the relationship between pre-mRNA splicing and skeletal system disease will aid in uncovering the mechanism of disease and contribute to the future development of gene therapy.

Treatment and management of osteoporosis-pseudoglioma syndrome.

Osteoporosis-pseudoglioma syndrome (OPPG; MIM 259770) is a very rare genetic disorder with an autosomal recessive mode of inheritance, characterized by congenital or infancy-onset visual loss and skeletal fragility, diagnosed during childhood. This syndrome can lead to severe disability and chronic bone pain. Low-density lipoprotein receptor-related protein 5 (LRP5) is the gene mutated and inactivated in OPPG, and plays a pivotal role in bone accrual and skeletal remodeling by controlling bone formation through activators, such as Wnt proteins, or inhibitors, such as DKK1. OPPG should be differentiated from osteogenesis imperfecta and child abuse by clinicians. Eye examination, coupled to bone phenotype and research of LRP5 mutation, are key points to diagnose OPPG. Chronic pain should be managed correctly in this syndrome with severe functional disability. Bisphosphonates allows fracture prevention, the catch-up of bone mineral density and improvement in mobility in children with OPPG. New drugs favoring osteoblast function and osteoclast inhibition are potential candidates in the treatment of OPPG.