Osteogenesis Imperfecta: Current and Prospective Therapies.

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI.

Osteogénesis Imperfecta / Osteogenesis Imperfecta

La osteogenesis imperfecta (OI) es un grupo de trastornos del tejido conectivo que genera anomalías esqueléticas caracterizadas por fragilidad y deformidades óseas. Las características genéticas son variables y se han descrito nuevos subgrupos los últimos años agregando información a las clasificaciones tradicionales. Su incidencia es de 1/10.000 a 20.000 RN vivos. Existe un amplio espectro de manifestaciones clínicas, que van desde una leve fragilidad ósea, en niños asintomáticos, hasta versiones que son letales al momento de nacer. El diagnóstico es principalmente clínico y debe diferenciarse de otras anomalías del esqueleto que producen fragilidad y de lesiones por maltrato infantil. El tratamiento es multidisciplinario y está orientado a mejorar la calidad de vida de los pacientes. Para lo que se debe mejorar la densidad ósea, a través de medicamentos, buena musculatura y cargas fisiológicas. Las fracturas se tratan con períodos cortos de inmovilización y carga precoz, o con cirugías que limiten el tiempo de inmovilización. Por otro lado, las deformidades esqueléticas deben tratarse en forma quirúrgica utilizando osteosíntesis que sean extensibles y mantengan la corrección a medida que el niño crece. El manejo coordinado de los distintos profesionales involucrados es de gran importancia para lograr los mejores resultados en esta enfermedad crónica que involucra al niño y todo su entorno

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders involved in skeletal abnormalities characterized by bone fragility and deformities. Genetic abnormalities are variable and new subgroups have been described recently, adding information to traditional classifications. There is a wide spectrum of clinical manifestations, ranging from mild bone fragility, in otherwise asymptomatic children, to versions that are lethal at birth. Its incidence is 1/10.000-20.000 newborns. The diagnosis is mainly clinical and must be distinguished from other skeletal abnormalities and child abuse. The treatment is multidisciplinary, and it is aimed to improve the quality of life of patients. For which the bone density must be improved, through medications, strong musculature, and physiological loads. Fractures are treated by immobilizing for short periods, trying to load at soon as possible, or by surgeries that limit immobilization time. On the other hand, skeletal deformities should be treated surgically using dynamic rods that are extensible and maintain correction as the child grows. The coordinated management of the different professionals involved is of the utmost importance to achieve the best results in this chronic disease that involves the child and his entire environment

Pseudo-Protrusio Acetabular Deformity in Osteogenesis Imperfecta Patients.

BACKGROUND: Osteogenesis imperfecta (OI) can develop a protrusio acetabuli deformity. However, the authors observed a pseudo-protrusio-type acetabular deformity (PPAD) on 3-dimensional computed tomography (3D-CT). Hence, we systematically reviewed 3D-CT and pelvis radiographs of OI patients and report the incidence and patterns of acetabular deformity in OI patients and the associated radiographic signs. METHODS: The study included 590 hips of 295 OI patients, who were older than 5 years, and did not have a pelvic fracture. The incidence of a deformed acetabulum (center-edge angle >40 degrees) and its correlation with disease severity were investigated. In 40 hips for which 3D-CT was available, 3-dimensional morphology of the acetabular deformity was analyzed to delineate PPAD. On plain radiographs, PPAD-related signs were determined, focusing on the contour of ilioischial line, iliopectineal line, acetabular line, and their relationship. These radiographic signs were also evaluated in the remaining hips with deformed acetabula that did not have 3D-CT. RESULTS: One hundred twenty-three hips of 590 hips (21%) showed deformed acetabula. The incidence of deformed acetabula was significantly associated with disease severity (P<0.001). Three-dimensional analysis showed that 10 hips had protrusio acetabuli, whereas 17 had PPAD, which showed that the hemipelvis was crumpled, the acetabular roof was rotated upwardly and medially, and the hip center migrated superiorly, uncovering the anterior femoral head. Among the PPAD-related signs, superomedial bulging of the iliopectineal line was the most predictive radiographic sign (73% sensitivity and 100% specificity). This sign was also observed in almost one third of deformed acetabula of those investigated only with plain radiographs. CONCLUSIONS: This study showed that acetabular deformity is common in OI patients and is associated with disease severity. A substantial number of hips showed PPAD, which may not cause femoroacetabular impingement but result in anterior uncovering of the hip joint. Superomedial bulging of the iliopectineal line suggests this pattern of acetabular deformity. LEVEL OF EVIDENCE: Lever IV-prognostic studies.

The evolution of the nosology of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a relatively common genetic skeletal disorder with an estimated frequency of 1 in 20 000 worldwide. The manifestations are diverse and although individually rare, the several different forms contribute to the production of a significant number of affected individuals with considerable morbidity and mortality. During the last decade, there have been extensive molecular investigations into the etiology of OI and these advances have direct relevance to the medical management of the disorder, and the purpose of this review is to document the history and evolution of the nosology of OI. The current nosology, based on molecular concepts, which are crucial in the identification of genotype-phenotype correlations in persons with OI, is also outlined. The successive revisions of the nosology and classification of OI have highlighted the importance of the nomenclature of the condition in order for it to be recognized by clinicians, scientists and patient advocacy groups. In this way, improved counseling of patients and individualized, tailored therapeutic approaches based on the underlying pathophysiology of the individual's type of OI have been facilitated.

Osteogenesis imperfecta: Novel genetic variants and clinical observations from a clinical exome study of 54 Indian patients.

Osteogenesis imperfecta (OI) is a group of inherited disorders with increased bone fragility and wide genetic heterogeneity. We report the outcome of clinical exome sequencing validated by Sanger sequencing in clinically diagnosed 54 OI patients in Indian population. In 52 patients, we report 20 new variants involving both dominant and recessive OI-specific genes and correlate these with phenotypes. COL1A1 and COL1A2 gene variants were identified in 44.23%, of which 28.84% were glycine substitution abnormalities. Two novel compound heterozygous variants in the FKBP10 gene were seen in two unrelated probands. A novel heterogeneous duplication of chromosomal region chr17: 48268168-48278884 from exons 1-33 of the COL1A1 gene was found in one proband. In five probands, there were additional variants in association with OI. These were ANO5 in association with CRTAP in two probands of the same family causing gnathodiaphyseal dysplasia, COL5A2 with LEPRE1 causing Ehlers Danlos syndrome, COL11A1 in addition to COL1A1 causing Stickler syndrome, and a previously unreported combination of SLC34A1 gene variant with FKBP10 leading to Fanconi renal tubular syndrome type II. Our findings demonstrate the efficacy of clinical exome sequencing in screening OI patients, classifying its subtypes, and identifying associated disorders in consanguineous populations.

[Genotypes and phenotypes of nine Uygur children with osteogenesis imperfecta in Xinjiang].

Objective: To explore the genotypes and phenotypes of osteogenesis imperfecta (OI) in Xinjiang Uygur children. Methods: The history of nine Uygur children with OI who were hospitalized in First Affiliated Hospital of Xinjiang Medical University from January 2013 to December 2017 were retrospectively reviewed. They were classified into 4 types according to the classical Sillence classification. The genes associated with OI were detected, and the pathogenic variation was assessed by InterVar and Alamut software according to the American College of Medical Genetics and Genomics (ACMG) recommendations. The phenotypes of children with different genotypes were further analyzed. Results: Nine cases aged 3 years and 6 monthes to 15 years were all clinically diagnosed as OI, the clinical manifes tations were repeated fractures, skeletal deformities,short stature, blue sclera, abnormol hearing, hypoplasia of dentin, and relaxation of Joint ligaments, among whom 6 was type Ⅲ OI, 3 were type Ⅳ OI. Nine mutations in 3 genes (COL1A1, COL1A2, and SERPINF1) were detected, and 5 of them were first reported and were all pathogenic variations. Conclusions: The cinical phenotypes of osteogenesis imperfecta in Xinjiang Uygur are complex and varied, but all of them have fractures and skeletal deformities. Genotype is different from that reported at China and abroad, and the SERPINF1 gene may have a higher incidence in Uyghur population. The genetic heterogeneity and unique gene variation pedigree of Uyghur osteogenesis imperfecta defects further provide a basis for the correlation between genotype and phenotype of osteogenesis defects.

COL1-related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers-Danlos syndrome overlap.

The 2017 classification of Ehlers-Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re-define this OI/EDS overlap as a missing EDS type. Twenty-one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS-related features. OI-related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N-proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.

Hearing impairment and osteogenesis imperfecta: Literature review.

The goal is to clarify the epidemiology of hearing loss in patients with osteogenesis imperfecta (OI), so as to improve management. A literature review analyzed data from 15 patient series. Hearing loss prevalence in OI varied widely, from 2% to 94.1%. Typically, hearing loss was conductive in young patients and sensorineural in older patients. Prevalence increased with age, but after 50 years the increase was slight, and seldom became total. Hearing loss was usually bilateral, but not necessarily symmetrical. There were no correlations between type of mutation (COL1A1 or COL1A2), prevalence, type or severity of hearing loss, or age of symptom onset; there was intra-familial variability. There was also no correlation between mutated gene, type of mutation and auditory phenotype. Frequency, type and severity of hearing loss were unrelated to other clinical parameters. Hearing loss prevalence depended on type of OI: higher in type I and lower in type IV. Incidence of otitis media was higher in children with OI, related to the associated craniofacial dysmorphia. Hearing screening before 5 years of age with long-term follow-up are recommended.

Functional Outcome of Humeral Rodding in Children With Osteogenesis Imperfecta.

BACKGROUND: The impact of humeral rodding on functional ability in children with osteogenesis imperfecta (OI) has not previously been reported. This article investigates this issue. METHODS: A retrospective chart review was conducted on 35 children with OI who underwent humeral rodding at our institution between 1995 and 2013. Fassier-Duval rods were inserted in 19 cases, K-wires in 13 cases, and Rush rods in 3 cases. Functional ability was assessed preoperatively and every year postoperatively using the self-care and mobility domains of the Pediatric Evaluation of Disability Inventory (PEDI). RESULTS: The mean PEDI self-care score increased by 5.7 (P=0.028) and the mean PEDI mobility score increased by 3.6 (P=0.008) at 1-year postsurgery. Improved function was maintained in the majority of cases at a mean of 7.0 years postcorrection. CONCLUSIONS: Humeral rodding in children with OI leads to significant improvement in functional ability. LEVEL OF EVIDENCE: Level IV.

Extremely low level of serum pigment epithelium-derived factor is a special biomarker of Chinese osteogenesis imperfecta patients with SERPINF1 mutations.

BACKGROUNDS: SERPINF1 mutations caused deficiency of pigment epithelium-derived factor (PEDF) and would lead to osteogenesis imperfecta (OI) type VI. However, serum PEDF levels were unclear in Chinese OI patients who had clear molecular diagnosis. OBJECTIVE: To assess PEDF levels in different genotypes of OI, to evaluate the influencing factors of PEDF in Chinese OI patients with clear molecular diagnosis. METHODS: Known candidate genes of OI were examined by a targeted next generation sequence. Serum PEDF levels were measured by ELISA in 6 OI patients with SERPINF1 mutations, 6 carriers of one copy of the SERPINF1 mutation, 88 OI patients with COL1A1, CLO1A2, IFITM5 and other pathogenic mutations of OI and 24 healthy controls. We compared the differences in serum PEDF levels among different OI patients and normal controls. RESULTS: Serum PEDF levels were extremely low in OI patients with SERPINF1 mutations (0.66±1.60µg/ml) than in OI patients with other pathogenic mutations (4.88±1.43-7.07±2.43µg/ml), carriers of one copy of SERPINF1 mutation (4.94±2.35µg/ml), and normal controls (7.29±2.31µg/m) (P<0.001). No significant differences in serum PEDF concentrations were found among patients with OI type I, III or IV, and between patients with or without bisphosphonate treatment. Serum PEDF level was positively correlated with Z-score of weight (r=0.310, P=0.004), BMI (r=0.253, P=0.020) and alanine aminotransferase (r=0.291, P=0.007). CONCLUSIONS: Extremely low level of PEDF was demonstrated as a specific, convenient, and inexpensive diagnostic biomarker for OI patients with SERPINF1 mutations, but it could not provide information regarding the clinical severity of OI and the efficacy of bisphosphonates treatment.

Conducta obstétrica en la osteogénesis imperfecta. A propósito de un caso / Obstetric behavior in osteogenesis imperfect. About a clinical case

La osteogénesis imperfecta (OI) se produce por un trastorno del tejido conectivo que afecta a la producción de colágeno. Los embarazos asociados a la OI están relacionados con una mayor morbilidad. La incidencia de fracturas no se incrementa durante el embarazo, pero sí las deformidades pélvicas, con una mayor incidencia de desproporciones cefalopélvicas y anomalías comunes en la presentación fetal. Resulta imprescindible la valoración preanestésica, pero la inducción al trabajo de parto está contraindicada. La vía del parto debe ser consensuada e individualizada con la gestante, valorando el estado materno y fetal en todo momento. Una actuación correcta, y sobre todo un buen asesoramiento preconcepcional por parte de la matrona, contribuye a disminuir las complicaciones desencadenadas por esta patología

Osteogenesis imperfecta (OI) is produced by a connective tissue disorder that affects the production of collagen. Pregnancies associated with OI are related to increased morbidity, the incidence of fractures does not increase during pregnancy, but pelvic deformities with a higher incidence of cephalopelvic disproportions and common abnormalities in fetal presentation. Preanesthetic assessment is essential and induction of labor is contraindicated. The way of delivery should be agreed and individualized with the woman assessing the maternal and fetal status at all times. A correct performance, and above all a good preconceptional counseling by the midwife, contributes to decrease the complications triggered by this pathology

Developmental charts for children with osteogenesis imperfecta, type I (body height, body weight and BMI).

Osteogenesis imperfecta (OI) is a rare genetic disorder of type I collagen. Type I is the most common, which is called a non-deforming type of OI, as in this condition, there are no major bone deformities. This type is characterised by blue sclera and vertebral fractures, leading to mild scoliosis. The body height of these patients is regarded as normal, or only slightly reduced, but there are no data proving this in the literature. The aim of this study is the preparation of the developmental charts of children with OI type I. The anthropometric data of 117 patients with osteogenesis imperfecta were used in this study (61 boys and 56 girls). All measurements were pooled together into one database (823 measurements in total). To overcome the problem of the limited number of data being available in certain age classes and gender groups, the method called reverse transformation was used. The body height of the youngest children, aged 2 and 3 years, is less than that of their healthy peers. Children between 4 and 7 years old catch up slightly, but at later ages, development slows down, and in adults, the median body height shows an SDS of -2.7. CONCLUSION: These results show that children with type I OI are smaller from the beginning than their healthy counterparts, their development slows down from 8 years old, and, ultimately, their body height is impaired. What is Known: • The body height of patients with osteogenesis imperfecta type I is regarded as normal, or only slightly reduced, but in the known literature, there is no measurement data supporting this opinion. What is New: • Children with type I osteogenesis imperfecta are smaller from the beginning than their healthy counterparts, their development slows down from 8 years old and, ultimately, their final body height is impaired. • The developmental charts for the body height, body weight and BMI of children with type I osteogenesis imperfecta are shown.

Orthopaedic Considerations for the Adult With Osteogenesis Imperfecta.

Osteogenesis imperfecta is a heritable group of collagen-related disorders that affects up to 50,000 people in the United States. Although the disease is most symptomatic in childhood, adults with osteogenesis imperfecta also are affected by the sequelae of the disease. Orthopaedic manifestations include posttraumatic and accelerated degenerative joint disease, kyphoscoliosis, and spondylolisthesis. Other manifestations of abnormal collagen include brittle dentition, hearing loss, cardiac valve abnormalities, and basilar invagination. In general, nonsurgical treatment is preferred for management of acute fractures. High rates of malunion, nonunion, and subsequent deformity have been reported with both closed and open treatment. When surgery is necessary, surgeons should opt for load-sharing intramedullary devices that span the entire length of the bone; locking plates and excessively rigid fixation generally should be avoided. Arthroplasty may be considered for active patients, but the procedure frequently is associated with complications in this patient population. Underlying deformities, such as malunion, bowing, rotational malalignment, coxa vara, and acetabular protrusio, pose specific surgical challenges and underscore the importance of preoperative planning.

Dental panoramic indices and fractal dimension measurements in osteogenesis imperfecta children under pamidronate treatment.

OBJECTIVES: To verify radiomorphometric indices and fractal dimension (FD) in dental panoramic radiographs (DPRs) of children with different types of osteogenesis imperfecta (OI) and also to verify the effect of pamidronate (PAM) treatment in such panoramic analyses. METHODS: In this retrospective study, 197 DPRs of 62 children with OI Types I, III and IV who were in treatment with a comparable dosage of intravenous PAM were selected. The mandibular cortical width (MCW), mandibular cortical index, visual estimation of the cortical width and FD of three standardized trabecular and cortical mandibular regions of interest were obtained from the radiographs. Factorial analysis of variance and Fisher test were used to compare FD and MCW measurements in children with different types of OI for different PAM cycles. RESULTS: Children with all types of OI have thinner and more porous mandibular cortices at the beginning of treatment. There were significant differences between MCW and FD of the cortical bone, regarding different types of OI and number of PAM cycles (p = 0.037 and p = 0.044, respectively). FD measurements of the trabecular bone were not statistically different among OI types nor were PAM cycles (p > 0.05). CONCLUSIONS: Children with OI presented cortical bone alterations after PAM treatment. Both MCW and the FD of the cortical bone were higher in children with OI after PAM treatment. It is argued that cortical bone should be considered for analyzing patients with OI, as well as to monitor the progress of PAM treatment.

Health outcomes of neonates with osteogenesis imperfecta: a cross-sectional study.

OBJECTIVE: To assess at-birth health outcomes of neonates with osteogenesis imperfecta (OI). STUDY DESIGN: A total of 53 women who self-reported having had at least one child with OI completed the survey. We evaluated pregnancy length, neonatal intensive care unit (NICU) usage, at-birth complications, and the child's clinical information including OI type, height and weight. RESULTS: Information was gathered on a total of 77 children (60 type I, 4 type III and 13 type IV). Health conditions reported at birth included breech presentation (24%), prematurity (27%), fracture (18%), bone deformity (18%) and respiratory problems (22%). Approximately 31% (n = 24) received NICU care. There was a significant association between younger maternal age, preterm delivery and NICU admission. CONCLUSION: Our findings suggest that newborns with OI appear to be at high risk of skeletal disorders, preterm delivery and breech presentation. Younger maternal age and preterm delivery seem to be strong predictors of the need for NICU care. Our data suggest that pregnant women with OI younger than 20 years of age may benefit from added clinical supervision in anticipation of adverse effects on their child.

Advances in the Classification and Treatment of Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a rare disorder of type 1 collagen with 13 currently identified types attributable to inherited abnormalities in type 1 collagen amount, structure, or processing. The disease is characterized by an increased susceptibility to bony fracture. In addition to the skeletal phenotype, common additional extraskeletal manifestations include blue sclerae, dentinogenesis imperfecta, vascular fragility, and hearing loss. Medical management is focused on minimizing the morbidity of fractures, pain, and bone deformities by maximizing bone health. Along with optimizing Vitamin D status and calcium intake and physical/occupational therapy, individualized surgical treatment may be indicated. Pharmacological therapy with bisphosphonate medications is now routinely utilized for moderate to severe forms and appears to have a good safety profile and bone health benefits. New therapies with other anti-resorptives as well as anabolic agents and transforming growth factor (TGF)ß antibodies are in development. Other potential treatment modalities could include gene therapy or mesenchymal cell transplant. In the future, treatment choices will be further individualized in order to reduce disease morbidity and mortality.

Pregnancy outcomes in women with osteogenesis imperfecta.

OBJECTIVE: To assess the relationship between osteogenesis imperfecta (OI) type, mode of delivery and outcomes as self-reported by women in the International Osteogenesis Imperfecta (OI) Registry. METHODS: A cross-sectional study using data from 274 women with OI who reported their experience with pregnancy practices, including mode of delivery, number of children, genetic counseling, assisted conception techniques, mean ages at menarche and at menopause, and pregnancy complications. Chi-square analyses were performed to compare pregnancy outcomes, number of children and OI type. Prevalence ratios and 95% confidence intervals were obtained to quantify exposure-outcome relationships. RESULTS: The most common mode of delivery was the sole use of cesarean section (C-section) reported by 55% of the participants. Approximately two-thirds had at least two children. Twenty-nine percent (n = 80) reported pregnancy complications. There was a significant relationship between the mode of delivery and OI type (p < 0.001), genetic counseling (p = 0.010), and number of children (p < 0.0001). There was neither evidence of an association between pregnancy complications and number of children (p = 0.16), OI type (p = 0.27), nor mode of delivery (p = 0.11). CONCLUSIONS: These findings suggested that clinical OI type, pre-natal genetic counseling, and number of children were strong predictors for choosing the mode of delivery. Severity of OI, multiparity, and vaginal delivery were not associated with increased pregnancy complications in this cohort of women with OI.

Primary Osteoporosis.

Primary osteoporosis in childhood encompasses a range of bone fragility conditions that typically have a genetic origin. Understanding of the pathophysiology and genetics of primary osteoporosis has increased dramatically over the past 10 years. The clinical manifestations and consequences of the disease range from mild to severe, with the degree of growth retardation and bony deformity reflecting the severity and the underlying pathology. In children, primary osteoporosis is most commonly caused by one of the forms of osteogenesis imperfecta, which comprises a group of disorders characterised by abnormalities in type I collagen synthesis or processing. Diagnosis of any primary osteoporotic condition depends on the clinical history and examination but may be supported by other investigations, including various imaging techniques, histology and genetic analyses. Good management requires a multidisciplinary approach involving paediatricians, surgeons and allied health professionals, amongst others. Bisphosphonate therapy has revolutionised the approach to management and has positively modified outcomes for many children and their families. Physiotherapy and occupational therapy are the keys to optimising independence in mobility and daily living. Surgery is required in many severe cases to straighten limbs or stabilise the spine. Bisphosphonates remain the mainstay of medical treatment, but there are a number of alternative therapeutic agents under investigation that may further improve management of primary osteoporosis in children over the coming years.

Genetics of Osteoporosis in Children.

In the pathogenesis of paediatric osteoporosis, genetic causes may play an important role. The most prevalent monogenic cause of paediatric osteoporosis is osteogenesis imperfecta, a disorder characterised primarily by liability to fractures. With regard to diagnosis or exclusion of a monogenic cause of paediatric osteoporosis, clinical practice has changed rapidly in recent years. This is largely due to the discovery of many new genetic causes in patients with a clear clinical diagnosis of osteogenesis imperfecta but also due to the identification of genetic causes in patients with isolated or non-syndromal osteoporosis with fractures. In this chapter, known monogenic causes of syndromal and non-syndromal osteoporosis in children will be described. Furthermore, we will discuss when to refer for clinical genetic evaluation as well as the current and future merits of genetic evaluation of children with osteoporosis.

Classification of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is an extremely heterogeneous group of heritable connective tissue disorders. Most of the affected patients carry autosomal dominant mutations in the genes encoding for collagen type I, the most abundant protein of the bone extracellular matrix. The resulting phenotypes are extremely broad and have been classified by Sillence and colleagues into four groups according to clinical, radiological and genetic criteria.More recently, proteins have been described that interact directly or indirectly with collagen biosynthesis and their deficiency result in rare forms of mostly autosomal recessive OI sharing phenotypic features of 'classical' types but lacking primary defects in type I collagen. Consequently the Sillence classification has been gradually expanded to include novel forms based on the underlying mutations. The goal of this article is to revisit the actual OI classification and to outline current approaches in categorizing the disorder.