Congenital Metabolic Bone Disorders as a Cause of Bone Fragility

Bone fragility is a pathological condition caused by altered homeostasis of the mineralized bone mass with deterioration of the microarchitecture of the bone tissue, which results in a reduction of bone strength and an increased risk of fracture, even in the absence of high-impact trauma. The most common cause of bone fragility is primary osteoporosis in the elderly. However, bone fragility can manifest at any age, within the context of a wide spectrum of congenital rare bone metabolic diseases in which the inherited genetic defect alters correct bone modeling and remodeling at different points and aspects of bone synthesis and/or bone resorption, leading to defective bone tissue highly prone to long bone bowing, stress fractures and pseudofractures, and/or fragility fractures. To date, over 100 different Mendelian-inherited metabolic bone disorders have been identified and included in the OMIM database, associated with germinal heterozygote, compound heterozygote, or homozygote mutations, affecting over 80 different genes involved in the regulation of bone and mineral metabolism. This manuscript reviews clinical bone phenotypes, and the associated bone fragility in rare congenital metabolic bone disorders, following a disease taxonomic classification based on deranged bone metabolic activity.


Introduction
Bone is a mineralized connective tissue (hard tissue), which exerts important biological functions, such as locomotion, support, and protection of soft tissues and organs, as well as being the storage of calcium and phosphate [1].
Despite its inert appearance, bone is a highly active tissue, continuously undergoing a remodeling process, by which the old tissue is replaced by new bone, granting the skeleton the ability to adapt to mechanical use, correct calcium and phosphate homeostasis, and to heal fractures. The correct equilibrium between bone resorption and new bone formation is necessary for skeletal health. An imbalance between these two phases results in bone fragility, a pathological condition in which the correct bone microarchitecture is altered, the strength of bone tissue is reduced, and the skeleton is prone to deformities and fractures, even in the presence of low-impact traumas or with no trauma [2].
Skeletal development and life-long bone turnover are two finely and complexly regulated processes, in which numerous local and systemic factors participate (chemokines, cytokines, hormones, intracellular signals, and biomechanical stimulation) [3,4]. A variety of genes and epigenetic factors concur for the correct modeling and remodeling of the skeleton. As a consequence, a defect of expression and/or activity in one of these key factors can alter normal bone turnover and be responsible for bone fragility.
At the cellular level, bone fragility can be caused by excessive osteoclast-driven bone resorption that is not balanced by a corresponding amount of bone formation, which

Bone Fragility in Rare Congenital Metabolic Bone Disorders
The most recent taxonomic classification of human rare congenital skeletal metabolic diseases, prepared by the Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation, and based on the genetic defect and the deranged bone metabolic activity causing the disease, reported a total of 116 Mendelian-inherited clinical phenotypes, and 86 mutated causative genes, involved in the regulation of bone and mineral metabolism homeostasis [8]. According to this taxonomy, congenital metabolic bone diseases can be divided into four major groups, based on their primary pathogenic molecular mechanisms: (1) disorders due to altered activity of bone cells (osteoclasts, osteoblasts, or osteocytes); (2) disorders due to altered bone extracellular matrix proteins; (3) disorders due to altered bone microenvironmental regulators; and (4) disorders due to altered activity of calciotropic and phosphotropic hormones/regulators.
Inheritance is variable among diseases; it can be autosomal dominant, autosomal recessive, or in rare cases, follows X-linked modes. Mutations are usually inherited from one or both parents; however, more rarely, they may occur de novo at the embryo level [9]. They can be inactivating mutations, leading to a loss-of-function of the encoded protein, or activating mutations, resulting in a gain-of-function of the encoded protein.

Bone Fragility in Bone Disorders Due to Altered Activity of Bone Cells
Bone turnover is a multiphase process that, to develop correctly, requires the coordinated actions of bone cells (osteoblasts, osteoclasts, osteocytes, and bone lining cells). Osteoblasts are the active bone-forming cells that differentiate, under the induction of specific systemic and local signals, from the mesenchymal stem cells of the bone marrow. They are responsible for the secretion of bone extracellular matrix proteins and the promotion of matrix mineralization during the bone structuring and restructuring pro-cesses [10]. Osteoclasts are the sole bone-resorbing cells, designed to remove old bone tissue in order to initiate normal bone remodeling and to reabsorb dead bone ends at the fracture site during bone healing. They are multinucleate cells deriving from circulating precursors of the monocyte/macrophage lineage upon stimulation of two essential factors: the monocyte/macrophage colony-stimulating factor (M-CSF) and the receptor activation of NF-κB ligand (RANKL) [11]. Osteocytes, the most abundant bone cell type, are mature osteoblasts embedded within calcified bone matrix, which act as mechano-sensors and orchestrators of the bone remodeling process [12]. The function of bone lining cells is not clear, but they seem to play a key role in coupling bone resorption to bone formation [13]. Bone remodeling consists of three sequential phases: (1) an osteoclast-driven initiation of bone resorption, (2) a transition period from resorption to new bone formation, and (3) an osteoblast-driven new bone formation [14].
Alterations in number, differentiation, and/or activity of bone cells are causes of abnormal bone tissue homeostasis. Disorders caused by genetic defects altering the correct functions of bone-forming and bone-reabsorbing cells consist of numerous different rare phenotypes (Table 1), which can be further divided into four subgroups: (1) diseases characterized by low bone resorption ( Diseases characterized by low bone resorption are caused by a reduced osteoclast number and/or a decreased osteoclast function, due to germinal mutations in genes regulating either osteoclast differentiation (TNFRSF11A, TNFSF11) or osteoclast activity (CA2, CLCN7, and CTSK) [8]. This subgroup includes various phenotypes that, despite their different causative gene defects, share common skeletal characteristics, such as a generalized high bone mass, an increased bone density, and hardening of bone tissue, consisting of thickening of trabecular bone (osteosclerosis) and widening of cortical bone (hyperostosis), which can manifest as solitary sclerotic bone lesions or as diffuse bony sclerosis. As a consequence, these diseases show a high fragility fracture rate, prevalently manifesting in the severe recessive forms.
Conversely, diseases characterized by high bone resorption are caused by a pathologically enhanced osteoclast function. The increased resorptive activity of osteoclasts, not balanced by sufficient formation of new bone tissue, leads to osteoporosis and osteolytic lesions, skeletal deformities and functional impairment, bowed long bones, and a high tendency of pathological fractures [8].
The cause of diseases characterized by high bone mass formation is enhanced activity of osteoblasts resulting in increased mineralized bone mass deposition and increased bone density. This class of diseases includes various clinical phenotypes, mainly caused by mutations in genes regulating osteoblast differentiation from their mesenchymal precursors (RUNX2, LRP5, AMER1, and LEMD3) or modulating the activity of mature osteoblasts (SOST). Some diseases of this subgroup manifest skeletal overgrowth and deformities, and disease-specific localized bone defects, and, in rare cases, ectopic exostosis. Fragility fractures are rarely reported [8].
Diseases characterized by low bone formation include clinical phenotypes, caused by genetic defects responsible for reduced function of osteoblasts (inactivating mutations in genes necessary for the correct osteoblast differentiation, such as LRP5, RUNX2, SP7, NOTCH2, and genes regulating the osteoblast-driven mineralization, such as IFITM5 and PLS3). This subgroup also includes five clinical phenotypes of Osteogenesis imperfecta (types V, VI, XII, XV, and XX), not molecularly affecting the structure of collagen type 1 directly, but showing a defective osteoblast activity and/or bone matrix mineralization, resulting in short stature, hypomineralized skeleton, bone deformities, and pathological fractures. Generalized bone mass and osteosclerosis; bone fragility (stress fractures of the tibia and femur, spondylolysis); short stature; deformity of the skull (including wide sutures); maxilla and mandible (obtuse angle of mandible) and phalanges (acro-osteolysis and short terminal phalanges); clavicular dysplasia

1b. Diseases Characterized by High Bone Resorption (Increased Osteoclast Function)
Diffuse cystic angiomatosis of bone 123880 Unknown Not applicable Not applicable.
Early-onset progressive osteolysis caused by excessive bone resorption (monostotic or polyostotic occurrence), leading to skeletal deformities, functional impairment, and fragility fractures; localized bone pain Focal abnormalities of bone segments (monostotic or polyostotic), mainly in the axial skeleton; skeletal pain and bony deformities of the lower limbs, such as bone enlargement and bowing of the long bones; skull can be affected by swelling and deformity of the jaw associated with loosening and loss of teeth, and progressive hearing loss; molecular evidence of increased osteoclastic bone resorption and disorganized bone structure at the lesions

AR
This gene encodes an endoplasmic reticulum-located chaperone protein, which is necessary for the receptors LRP5 and LRP6 of the canonical Wnt signaling and osteoblastogenesis [18].
Severe progressive form of OI.; many patients die due to respiratory failure in infancy, childhood or adolescence; progressive deforming bone dysplasia; severe osteopenia, skeletal deformities, and both healed and new multiple fractures on radiography (prenatal occurrence of fractures has been reported)

1d. Diseases Characterized by High Bone Formation (Increased Osteoblast Function and/or Matrix Mineralization)
Metaphyseal dysplasia with maxillary hypoplasia with or without brachidactyly (MDMHB) Generalized osteosclerosis, most pronounced in the cranial vault; bone pain and hearing loss manifest in some cases; the only osteopetrosis disease that appears not to be associated with increased fracture rate Hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses; sclerosis of the skull, leading to asymmetry of the mandible and cranial nerve compression with hearing loss and facial palsy This gene encodes the TGFβ1 protein that enhances osteoblast proliferation and production of matrix proteins during the early stages of osteoblast differentiation, blocks osteoblast apoptosis, and recruits osteoblastic precursors to the bone site through chemotactic attraction [20].
Cortical thickening of the diaphyses of the long bones; hyperostosis is bilateral and symmetrical and usually starts during childhood, at the diaphyses of the femora and tibiae, expanding to fibulae, humeri, ulnae, and radii; limb pain and sclerotic changes at the skull base may be present OMIM, Online Mendelian Inheritance in Man ® ; "#" before the OMIM number indicates a confirmed Mendelian clinical phenotype with identified causative gene(s); no symbol before the OMIM number indicates a clinical phenotype for which the Mendelian basis, although suspected, has not been clearly established; AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant; XLR, X-linked recessive; RANK, receptor activator of nuclear factor κB; RANKL, receptor activator of nuclear factor κB ligand; OPG, osteoprotegerin; OI, osteogenesis imperfecta.
In 1999, Dinolus et al. [21] described a unique inherited bone condition in a threegeneration family, presenting expansile bone striatal bilateral lesions of the distal radius and ulna, cortical thickening of the proximal long bones, metaphyseal cupping of the metacarpals and phalanges, and pathologic fractures. The clinical phenotype is currently reported in the OMIM database as "expansile bone lesions" (MIM number 603439), but the genetic cause is still unknown. Cortical thickness, shown in the affected members, and bone phenotype partially overlapping with familial expansile osteolysis suggest that this disease may be caused by an altered activity of bone cells. Inheritance appears to be autosomal dominant.

Bone Fragility in Bone Disorders Due to Altered Extracellular Matrix Proteins
Bone extracellular matrix is composed of inorganic elements (minerals and water) and an organic component (collagen, non-collagenous proteins, and lipids). The correct composition of the matrix is fundamental for the microarchitecture of bone tissue, bone strength and function, and concurs with the regulation of proper matrix mineralization. Collagen type 1 is the most abundant protein (over 90% of the organic matrix) of bone extracellular matrix, and one of the major constituents implicated in its correct mineralization [22]. Therefore, disruption of the correct quantitative and qualitative collagen synthesis and assembly is responsible not only for altered composition of the organic component of bone matrix, but also for defective mineralization, both leading to bone fragility.
Collagen type 1 consists of three post-translationally modified chains, which form a triple helical fibril of two identical α1 chains, and one, structurally similar but genetically different, α2 chain, encoded by the COL1A1 and COL1A2 genes, respectively. About 85-90% of patients with inherited diseases caused by alteration of collagen type 1 quantity or structure have an inactivating mutation in one of these two genes [23].
Currently, all the known inherited diseases of the bone matrix affect collagen type 1. These can be divided into the following subgroups: (1) disease caused by genetic defects affecting the collagen type 1 synthesis and structure ( Table 2, Subgroup 2a), (2) disease caused by gene mutations altering the post-translational collagen modification (Table 2, Subgroup 2b), and (3) diseases caused by gene mutations involved in the processing and crosslink of collagen ( Table 2, Subgroup 2c). All together, these diseases include 16 genetically heterogeneous clinical forms of Osteogenesis imperfecta, Bruck syndromes type 1 and type 2 (caused by loss-of-function mutations in two genes encoding proteins involved in the regulation of folding and crosslinking of procollagen type 1), and two Osteogenesis imperfecta-like syndromes (Cole-Carpenter syndromes type 1 and type 2) [8]. Despite these clinical forms distinguished by their clinical severity, bone characteristic features commonly overlap. People with these conditions have fragile bones, prone to deformities, that fracture easily, often from a mild trauma or with no apparent cause. Additional pathognomonic bone features may include short stature, curvature of the spine (scoliosis), joint deformities (contractures), and dentinogenesis imperfecta. The severe forms show marked growth deficiency and multiple fractures that may occur even before birth. Conversely, patients with milder forms are usually of normal or near normal height, and show only a few fractures during their lifetime, manifesting prevalently during childhood and adolescence as the result of minor trauma.

AD
This gene encodes the α1 chains of collagen type 1.
Mildest form of OI, due to a 50% reduction of the amount of collagen type 1; multiple bone fractures, usually resulting from minimal trauma, rare in the neonatal period and a constant onset starting from childhood to puberty, fracture rate decreases in the adulthood and often increases following menopause in women and after the sixth decade in men; general growth deficiency, but no remarkable craniofacial deformity; hearing loss occurs in about 50% of families; the subtype IA also presents dentinogenesis imperfecta, while the subtype IB has normal dentinogenesis Osteogenesis imperfecta type II (OI2) #166210 COL1A1 (heterozygote, loss-of-function) or COL1A2 (heterozygote, loss-of-function) AD COL1A1 gene encodes the α1 chains of collagen type 1, while COL1A2 gene encodes the α2 chain of collagen type 1.
Most severe form of OI.; perinatally lethal, due to rib cab deformity and respiratory insufficiency, following a premature birth; intrauterine fractures and abnormal skeletal modeling; severe hypomineralization of the skull bones (wide-open anterior and posterior fontanels); multiple neonatal fractures, severe bowing of long bones, severe undermineralization Osteogenesis imperfecta type III (OI3) #259420 COL1A1 (heterozygote, loss-of-function) or COL1A2 (heterozygote, loss-of-function) AD COL1A1 gene encodes the α1 chains of collagen type 1, while COL1A2 gene encodes the α2 chain of collagen type 1.
Severe form of OI, progressively deforming with age; pronounced growth impairment and craniofacial deformities, due to bending of head bones; dentinogenesis imperfecta; severe osteoporosis with multiple fractures starting from the infancy; progressive deformities of long bones and spine

AR
This gene encodes a protein located in the endoplasmic reticulum that concurs to the cis-trans isomerization of proline residues for proper folding of collagen fibrils.
Most severe form of OI.; early severe osteoporosis; severe bone undermineralization; multiple fractures at birth and in the infancy; severe deformities of long bones; molecular analysis of bone biopsies show an overhydroxylation of collagen type 1 components, over the entire length of the collagen and procollagen triple helix
Moderate-severe form of OI.; generalized osteopenia; prenatal fractures; severe short stature in adulthood; variable scoliosis and pectal deformity; marked anterior angulation of the tibia

Bone Fragility in Bone Disorders Due to Altered Bone Microenvironmental Regulators
The regulation of bone remodeling is both systemic and local. Local regulation of bone homeostasis includes cytokines and growth factors that modulate bone cell functions, or enzymes involved in the control of bone and mineral metabolism, such as alkaline phosphatase (ALP).
According to the genetic defects affecting the bone microenvironmental regulators, these disorders can primarily be divided into the following subgroups: (1) diseases due to altered ALP activity (Table 3, Subgroup 3a), and (2) diseases due to alterations in bone-regulating cytokines and growth factors [8]. The latter can be further divided into: (1) diseases due to alterations of the RANK/RANKL/OPG system (Table 3, Subgroup 3b), (2) diseases due to alterations of the glycosylphosphatidylinositol (GPI) biosynthesis pathway ( Table 3, Subgroup 3c), (3) diseases due to alterations of LRP5-Wnt signaling ( Table 3, Subgroup 3d), and (4) diseases due to alteration of the bone morphogenetic protein receptor (BMPR) ( Table 3, Subgroup 3e).
ALPs are membrane-bound enzymes that hydrolyze monophosphate esters in the presence of an alkaline microenvironment (pH 8-10), releasing inorganic phosphate molecules, necessary for the formation of hydroxyapatite crystals and bone matrix mineralization, and, at the same time, hydrolyzing the inorganic pyrophosphate, one of the main biological inhibitors of bone mineralization [31]. There are four different ALP enzymes in humans, encoded by four different genes: tissue-nonspecific ALP (TNSALP), intestinal, placenta, and germ cell specific isoforms [32]. TNSALP, encoded by the ALPL gene, is prevalently expressed in liver, bone, and kidneys, and it accounts for approximately 95% of total serum ALP activity. Disorders of ALP activity are caused by a reduced/absent ALP function (hypophosphatasia, HPP), due to inactivating mutations of the ALPL gene, and are characterized by hypomineralization of hard tissues. HPP includes six different clinical forms, i.e., perinatal lethal, prenatal benign, infantile, childhood, adult, and odonto-HPP, following a classification prevalently based on the age of diagnosis and associated with a progressively decreasing degree of severity, ranging from a perinatal lethal form, with absolutely no skeletal mineralization and severe bone deformities, multiple pathological fractures and craniosynostosis, to mild forms, with late adult onset, in which bone fragility manifests principally as early-onset nontraumatic fractures, a delay in fracture healing, recurrent and/or slow-to-heal metatarsal or tibial stress fractures, and unilateral or bilateral subtrochanteric or diaphyseal femoral pseudofractures (atypical femur fractures, AFFs).
RANKL, expressed on the membrane of osteoblast-lineage cells, is the master inductor of differentiation of mature osteoclasts from their hematopoietic precursors [33] through its direct bond with the RANK receptor expressed, in response to M-CSF, on the surface of osteoclast precursor cells. RANKL-RANK signaling is negatively regulated by osteoprotegerin (OPG), which is a soluble decoy receptor for RANKL that prevents the RANKL binding to RANK and inhibits osteoclastogenesis [34]. The five diseases caused by gene mutations altering the RANK/RANKL/OPG system (  Subgroup 1b).
GPI is a cell surface glycolipid that anchors over 150 proteins (enzymes, receptors, and adhesion molecules) to the cell membrane, concurring to signal transduction [35]. Twenty-two phosphatidyl inositol glycan (PIG) genes are involved in the synthesis of GPI within the endoplasmic reticulum, and four post-GPI attachment to protein (PGAP) genes modify GPI in the endoplasmic reticulum and Golgi [36]. Germinal biallelic mutations in some of these genes have been associated with congenital GPI deficiencies and with a class of diseases known as hyperphosphatasia with mental retardation syndrome (HPMRS), characterized by cognitive delay, intellectual disability, epilepsy, and markedly elevated serum activity of total ALP, leading to typical skeletal abnormalities.  Severe osteoclast-poor osteopetrosis; extensive trabecular structures, with retention of large areas of cartilage  Hyperphosphatasia; moderately to severely delayed psychomotor development; facial dysmorphism; brachytelephalangy  Hyperphosphatasia; global developmental delay; dysmorphic features (bitemporal narrowing, depressed nasal bridge with upturned nares, short neck); in some cases, brachytelephalangy, proximal limb shortening, hip dysplasia, and osteopenia have been reported

3d. Diseases due to Alterations of the LRP5-Wnt Signaling
Osteogenesis imperfecta type XV (OI15) #615220 WNT1 (homozygote or compound heterozygote, loss-of-function) AR This gene encodes a ligand of the canonical Wnt pathway, involved in the regulation of osteoblastogenesis.
Severe form of OI.; early-onset recurrent fractures; bone deformities; significant reduction of bone density; short stature; tooth development and hearing are normal Osteogenesis imperfecta type XX (OI20) #618644 MESD (homozygote, loss-of-function) AR This gene encodes an endoplasmic reticulum-located chaperone protein, necessary for the receptors LRP5 and LRP6 of the canonical Wnt signaling and osteoblastogenesis [18].
Severe progressive form of OI.; several patients die due to respiratory failure in infancy, childhood, or adolescence; progressive deforming bone dysplasia; severe osteopenia; skeletal deformities; and both healed and new multiple fractures on radiography (prenatal occurrence of fractures has been reported) The low-density lipoprotein-related receptor 5 (LRP5) participates in the stabilization and activation of β-catenin, positively regulating the Wnt signaling, which regulates nearly all aspects of osteoblast function, from initial osteogenic lineage commitment to the control of osteoblast differentiation [37]. Genetic alterations of LRP5-Wnt signaling disrupt the correct osteoblastogenesis; inactivating mutations lead to diseases characterized by low bone mass, while activating mutations cause diseases with high bone mass. The five diseases caused by gene mutations altering the LRP5-Wnt signaling ( Table 3, Subgroup 3d) are also included in diseases caused by an altered activity of osteoblasts, three diseases are caused by reduced osteoblast function (Table 1, Subgroup 1c) and two diseases are caused by increased osteoblast function (Table 1, Subgroup 1d).
Bone morphogenetic proteins (BMPs) are multifunctional growth factors that play an important role in postnatal bone formation, acting via their bond to serine/threonine kinase transmembrane receptors [38]. To date, only one clinical phenotype has been associated with a heterozygote germinal activating mutation in the Activin A receptor type 1 (ACVR1) gene, a component of the BMP receptor (BMPR), which is responsible for fibrodysplasia ossificans progressiva (FOP), an extremely severe and incurable, spontaneously arisen, progressive heterotopic ossification of soft tissues, mainly muscles and tendons.

Bone Fragility in Bone Disorders Due to Altered Activity of Calciotropic and Phosphotropic Hormones/Regulators
Calcium ion and phosphate are the two components of hydroxyapatite crystals of bone mineralized matrix. The appropriate regulation of calcium ion and phosphate homeostasis and their correct availability are fundamental aspects for the mineralization process to properly take place. Calciotropic and phosphotropic hormones are the endocrine effectors regulating the systemic homeostasis of calcium and phosphate, respectively. Calciotropic hormones include the parathyroid hormone (PTH) and the active form of vitamin D (1,25dihydroxyvitamin D), while the only phosphotropic hormone is the fibroblast growth factor 23 (FGF23).
Diseases affecting the correct regulation of calcium and/or phosphate homeostasis, and, subsequently, bone mineralization, can be classified into: (1) disorders due to an excess or a deficiency of PTH secretion by the parathyroid glands (named hyperparathyroidism and hypoparathyroidism, respectively); (2) disorders caused by abnormal PTH receptor signaling (pseudohypoparathyroidism); (3) disorders due to altered vitamin D metabolism and activity (Table 4); and (4) congenital disorders of the phosphate homeostasis (Table 5).
Inherited forms of primary hyperparathyroidism, due to hyperfunction, hyperplasia, adenoma, or, in extremely rare cases, carcinoma of parathyroid gland(s), which cause an excessive secretion of PTH and persistent hypercalcemia, can occur as isolated diseases (familial isolated primary hyperparathyroidism, familial hypocalciuric hypercalcemia disorders, and neonatal severe hyperparathyroidism), or in the context of congenital endocrine syndromes (multiple endocrine neoplasia syndromes type 1, 2a, and 4, and hyperparathyroidism jaw-tumor syndrome). Persistently elevated PTH induces constant bone resorption, leading to early-onset osteopenia/osteoporosis, both at trabecular and cortical bones, with respect to the reference population of the same age and sex, conferring an increased risk of osteoporotic fragility fractures.
Conversely, congenital forms of primary hypoparathyroidism are a varied group of genetically distinct endocrine disorders, caused by reduced function of the parathyroid glands, characterized by low levels of PTH and hypocalcemia, leading to specific bone signs, such as an increase in trabecular bone volume and cortical bone thickness [39]. Although people with hypoparathyroidism experience an increase in bone mass and are expected to have a reduced rate of fractures, a study by Chawla et al. showed a greater prevalence of vertebral fractures in patients with hypoparathyroidism, especially in postmenopausal women [40]. In addition, a recent study by Starr et al. [41] showed, via a micro-indentation analysis, that individuals with hypoparathyroidism had significantly lower scores of bone material strength index than control subjects, concluding that, despite a "thicker" bone, bone matrix properties are abnormal in hypoparathyroidism, being suggestive of a reduced bone turnover and an increased risk of fractures.
Diseases caused by a deregulated function of PTH develop, in the presence of a normal activity of parathyroids and a correct regulation of PTH synthesis and secretion, as a consequence of genetic defects affecting PTH receptor signaling. They comprise extremely rare forms of congenital pseudohypoparathyroidism caused by tissue resistance to PTH, collectively named "inactivating PTH/PTHrP signaling disorder" (iPPSD), all of which manifest skeletal alterations, ranging from hyperostosis, osteosclerosis, osteodystrophy, and heterotopic ossifications of soft tissues [42].
Genetic disorders that alter correct vitamin D metabolism and function cause defects of growth plates and generally reduced bone mineralization, leading to rickets in children and osteomalacia in adults, both associated with long bone deformities and an increased rate of fragility fractures (Table 4).
Pathological uncontrolled deficiency or excess of serum phosphate concentration are responsible for severe pathologies, secondarily affecting skeleton mineralization. Diseases of the phosphate homeostasis include hypophosphatemic disorders (Table 5, Subgroup 5a) and hyperphosphatemic disorders ( Table 5, Subgroup 5b), and are caused by mutations in genes encoding a class of proteins, named phosphatonins, which are responsible for the regulation of phosphate homeostasis [43], such as the FGF23 hormone, the regulators of active FGF23 levels (GALNT3 and PHEX) and activity (KLOTHO), the FGF23 receptor (FGFR1), and kidney sodium/phosphate cotransporters (NPTIIa and NPTIIc). Hypophosphatemic disorders are characterized by low serum levels of phosphate, hyperphosphaturia (excessive urinary excretion of phosphate), and high serum levels of bone ALP, causing poor bone mineralization (rickets/osteomalacia). Total calcium and calcium ion are normal. Conversely, hyperphosphatemic disorders present high serum levels of phosphate, hypophosphaturia, and elevated serum levels of active vitamin D, causing altered skeletal mineralization and low/normal bone mass, as well as ectopic calcification of soft tissues.

AR
This gene encodes an enzyme of the Golgi (ppGaNTase-T3) that is responsible for glycosylation and prevention of glycolysis of FGF23 protein, granting the activation of FGF23.
Progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues (ectopic multiple calcifications), and sometimes bone; in some cases, the disorder is characterized by involvement of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis ("hyperostosis-hyperphosphatemia syndrome") Progressive deposition of basic calcium phosphate crystals in periarticular spaces, soft tissues (ectopic multiple calcifications), and sometimes bone; in some cases, the disorder is characterized by involvement of the long bones associated with the radiographic findings of periosteal reaction and cortical hyperostosis ("hyperostosis-hyperphosphatemia syndrome") Hyperphosphatemic familial tumoral calcinosis type 3 (HFTC3) #617994 KLOTHO (homozygote, loss-of-function) AR This gene encodes a co-receptor protein (KL) that increases the affinity of FGF23 for its receptors, favoring the FGF23 signaling.
Progressive ectopic calcifications; osteopenia; patchy sclerosis in the hands, feet, long bones, and calvaria; intracranial calcifications OMIM, Online Mendelian Inheritance in Man ® ; "#" before the OMIM number indicates a confirmed Mendelian clinical phenotype with identified causative gene(s); "%" before the OMIM number indicates a confirmed Mendelian phenotype for which the underlying genetic basis is still unknown. AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant; XLR, X-linked recessive.

Conclusions
Although osteoporosis represents the most common cause of pathological fractures, bone fragility is also a common hallmark of a large spectrum of rare congenital metabolic bone disorders, caused by germinal mutations in genes involved in various aspects of regulation of cellular and molecular homeostasis of bone tissue.
To date, over 100 different congenital metabolic bone disorders involving abnormalities of cartilage and bone have been reported, with skeletal phenotypes often overlapping among these rare conditions. As a consequence, a differential diagnosis may require a thorough medical evaluation, including personal and family medical histories, anthropometric evaluation, radiological imaging, biochemical measurements, and genetic counseling, carried out by specialists with specific expertise. The identification of the precise causative genetic variant is of key importance for the diagnosis and clinical management of the patient, since knowing the deregulated pathway(s) responsible for disease development may help personalize clinical care, to choose a specific medical treatment, if available, and to determine the eligibility of the patient to participate in clinical trials underway for novel target therapies.
Multigenic panel testing using next-generation sequencing technique, which allows the simultaneous screening of genes responsible for congenital metabolic bone disorders, including the high-resolution analysis of copy number variants, can provide rapid and comprehensive diagnostic and therapeutic benefits to clinicians and patients, and therefore should become part of the medical work-up for patients.