Gene 528 (2013) 41–45

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Skeletal dysplasias with increased bone density: Evolution of molecular pathogenesisin the last century

Shagun Aggarwal ⁎Department of Medical Genetics, Nizam's Institute of Medical Sciences and Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500082, India

Abbreviations: TCIRG1, T-cell, immune regulator 1, ATPV0 subunit A3 [Homo sapiens]; SLC29A3, solute carrier fammember 3 [Homo sapiens]; SOST, sclerostin [Homo sapiensreceptor-related protein 5 [Homo sapiens]; RANKL, recekappa B ligand [Homo Sapiens]; CA2, carbonic anhydrase IIchannel, voltage-sensitive 7 [Homo sapiens]; OSTM1, ostebrane protein 1 [Homo sapiens]; PLEKHM1, pleckstrin homM (with RUN domain) member 1 [Homo sapiens]; FER3 [Homo sapiens]; RANK, receptor activator of NF-KB [Homessential modulator [Homo sapiens]; SNX10, sorting nexinlosis, progressive homolog (mouse) [Homo sapiens]; TGFbeta 1 [Homo sapiens]; WTX, Wilms tumor gene on thesapiens]; LEMD3, LEM domain containing 3 [Homo sapieAR, Autosomal recessive; SKD, Skeletal dysplasia.⁎ Tel.: +91 7702700980.

E-mail address: shagun.genetics@gmail.com.

0378-1119/$ – see front matter © 2013 Elsevier B.V. Allhttp://dx.doi.org/10.1016/j.gene.2013.04.069

a b s t r a c t

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Available online 5 May 2013

Keywords:OsteopetrosisIncreased bone densityGeneticsHistory

Skeletal dysplasias (SKD) with increased bone density form a discrete group of SKDs as per the Nosology andClassification of Genetic Skeletal Disorders, 2010 Revision. This group, with the prototype disorder beingosteopetrosis, has evolved over the last century, with new entities being described & their molecular basisbeing increasingly elucidated. Osteopetrosis, which remained an enigma in the early part of its description,is now known to be genetically heterogenous. Other disorders in this group, which were initially describedas variant forms of osteopetrosis, are now recognised to be distinct conditions. However, all these SKDs withincreased bone density share their molecular pathogenesis as majority arise due to mutations in the genesgoverning osteoclast formation and function.

© 2013 Elsevier B.V. All rights reserved.

1. Introduction

Skeletal dysplasias with increased bone density comprise a groupof 34 different conditions, characterised by excessive bone depositionof variable distribution and severity in the skeleton (Warman et al.,2011). The prototype of this group is osteopetrosis which was firstdescribed in 1904 by Albers Schonberg (Schonberg, 1904). This disor-der is characterised by a diffuse increase in bone mass and manifestsclinically with varying degree of severity, ranging from a neonatallethal form to an asymptomatic form presenting in adult life. In theearly part of its description, it was considered to be a disease involv-ing the parathyroid gland with secondary bone involvement. How-ever, the molecular bases were found after 1980s onwards and it wasrealised that the clinical heterogeneity could be attributed to the under-lying molecular heterogeneity (Stark and Savarirayan, 2009). A large

ase, H+ transporting, lysosomalily 29 (nucleoside transporters),]; LRP5, low density lipoproteinptor activator of nuclear factor[Homo sapiens]; CLCN7, chlorideopetrosis associated transmem-ology domain containing, familyMT3, fermitin family membero Sapiens]; NEMO, NF-kappa-B

10 [Homo sapiens]; ANKH, anky-B1, transforming growth factor,X chromosome protein [Homons]; AD, Autosomal dominant;

rights reserved.

number of other disorders which were initially described as variantforms of ostepetrosis are increasingly realised as being clinically aswell as genetically distinct (Horan and Beighton, 1978). The molecularpathogenesis of majority of conditions in this group is now knownand is intricately linked to each other. Insight into the molecular path-ways offers opportunity for developing novel treatment strategies inthe future. This group has indeed come a complete circle, starting as var-iants of osteopetrosis, segregation into distinct conditions and subse-quent recognition as functionally interconnected disorders. This articlepresents the evolution of this group from the recognition of osteopetrosisto the present day molecularly defined entities.

2. Osteopetrosis/Albers Schonberg disease/Marble bone disease

2.1. Early description and radiological features

This disorder was first described in1904 by Albers Schonberg aGerman radiologist (Schonberg, 1904). He reported the characteristicradiographic findings of increased bone density in a 26 year old mer-chant with history of recurrent fractures. In a review in 1960 of 40cases (Ellis, 1934), the radiographic findings of osteopetrosis weredescribed as “Symmetrically arranged areas of greatly increased den-sity are seen involving both the membrane and cartilage bones; thebase of the skull, the bodies of the vertebrae, and the long bones aregenerally most affected. The carpal bones often appear “ringed” with adark shadow. The dense, compact bone encroaches on the medullarycavity, which may ultimately become almost entirely obliterated. Theareas of sclerosis in some instances may be of uniform density through-out, or may show transverse lines of rarefaction. The contour of thebone in osteopetrosis is not altered by the sclerosis, although clubbingof the posterior clinoid process and of the ends of the long bones

42 S. Aggarwal / Gene 528 (2013) 41–45

(particularly of the lower ends of the femur and the radius) occurssufficiently often to be regarded as the rule rather than the exception”.Subsequently the disorder was reported by multiple observers and wascalled Albers Schonberg disease, a term which was later used for theadult onset variety. Other nomenclatures included “Marble Bone dis-ease” due to the increased density (Beighton et al., 1979; Johnstonet al., 1968) “Chalky Bones”, due to the increased brittleness (Pirie,1933), osteosclerosis and osteosclerosis fragilis generalisata (Nussey,1938). Karshner named it as “osteopetrosis”, which literally means“stony or petrified bones” in 1926 (Karshner, 1926). Initially, the dis-ease was reported to be sporadic & seldom familial with occasionalhistory of consanguinity in parents. Nussey was the first to suggestthat the “benign” form showed autosomal dominant inheritance and“malignant” form showed autosomal recessive inheritance (Nussey,1938). Many initial cases were the malignant type, with onset in earlyinfancy and with features of recurrent fractures, bony deformities,cranial nerve palsies, hydrocephalous, intractable infections, anemiaand early fatality (Dimson, 1948; Ellis, 1934; Lightwood and Williams,1940). Few adult cases were reported, and this form was recognisedto be a milder, sometimes asymptomatic condition presenting mostlyas unexplained fractures (Alexander, 1923; Ghormley, 1922; Pirie,1933). The radiographic findings in the adult cases were reported byvarious researchers as “The primary radiological change is in the diaph-yses. Sclerosis proceeds down the shaft; there is progressive narrowingof the medullary space, but in more severe cases the trabecular patternand the differentiation of cortex and medulla are lost. Transverse linesof increased density may occur and there may be vertical “cracks”near the bone ends. Sclerotic bands may also occur in the phalangesand ribs. The clubbing deformity of the long bones which consistentlyoccurs in the “malignant” osteopetrosis is not a feature, but there maybe some increase in diameter of the shafts of the long bones, particularlyin the distal half of femur. Similarly the iliac bones may show uniformconcentric shadows outlining their earliermargins. The vertebral bodieshave a “sandwich” appearance due to sclerosis at contiguous surfaces.The changes in the skull are primarily in the base, manifest in thick-ening of the clinoid processes and obliteration of air sinuses; some-times there is involvement of the facial bones” (Montgomery andStandard, 1960).

2.2. Pathological findings

The histopathological picture is of medullary obliteration by calci-fied bone tissue. Mccune and Bradley, 1934 reviewed the histopatho-logical findings and postulated the concept that the basic defect lies ina faulty differentiation of the primitive osteogenetic mesenchyme, theexcess of this foetal tissue interfering with endosteal and endochon-dral metabolism (Mccune et al., 1934). Zawisch reported that the ab-erration involves both an abnormal deposition as well as defectiveresorption, which occurs in intermittent bursts (Zawisch, 1947).The dominant picture is a progressive disappearance of osteoclasts.The gross pathology is a generalized accumulation of bone masspreventing the normal development of marrow cavities and the en-largement of osseous foramena (Beighton et al., 1979; Johnstonet al., 1968).

2.3. Etiology — early views and genetic insights

The etiologywas initially believed to be a hyperfunctioning parathy-roid gland, and various biochemical studies involving parathormone,calcium & phosphorous estimation were performed (Dent et al., 1965;Ellis, 1934). Other possible etiologies suggested were polyglandulardyscrasia, poisoning with phosphorus or fluorine and chronic boneinfection (Nussey, 1938).

Many cases with unusual clinical & radiographic findings werealso reported. In 1972, two different papers reported a distinct formof osteopetrosis with renal tubular acidosis & intracranial calcification

(Guibaud et al., 1972; Vainsel et al., 1972). During this time variousmouse models of osteopetrosis had concluded that the basic mecha-nism of increased bone density was decreased bone resorption due toheterogenous molecular defects (Gowen et al., 1999; Li et al., 1999;Marks, 1982; Marks and Lane, 1976; Wang et al., 1992; Wiktor-Jedrzejczak et al., 1986). Themolecular basis of the type of osteopetrosiswith renal tubular acidosis in humans was found to be a defect incarbonic anhydrase type II isozyme (Sly et al., 1983; Venta et al.,1991). Subsequently, dominant and recessive forms of osteopetrosisin humans were mapped to various chromosomal locations (Heaneyet al., 1998; Van Hul et al., 1997). In the year 2000, the gene for malig-nant osteopetrosis was identified as TCIRG by two different researchgroups (Frattini et al., 2000; Kornak et al., 2000). This encodes for aH+ATPase that leads to transport of protons into the resorption lacunaeformed by osteoclasts, thereby helping in acidification and bone disso-lution. This gene is now known to account for >50% cases of malignanttype of osteopetrosis (Sobacchi et al., 2001). Other genes of autosomaldominant & recessive types were discovered over the last 10 yearsonly (Aker et al., 2012; Bénichou et al., 2001; Campos-Xavier et al.,2003; Cleiren et al., 2001; Guerrini et al., 2008; Kilic and Etzioni, 2009;Mory et al., 2008; Pangrazio et al., 2011; Ramírez et al., 2004; Robertset al., 2010; Sobacchi et al., 2007; Van Wesenbeeck et al., 2007). Pres-ently 12 different genes are known to cause osteopetrosis, howeverthey too account for 70% of the cases (Aker et al., 2012; Pangrazioet al., 2011; Stark and Savarirayan, 2009;Warman et al., 2011). Anotherdistinction which was possible after the molecular studies was themolecular basis of the osteoclast poor and osteoclast rich type ofosteopetrosis. The osteoclast poor types are due to mutations in geneswhich govern osteoclast differentiation from the macrophage lineage.These disorders are associated with immune dysfunction. The osteo-clast rich ones are due to defects in osteoclast functioning (Stark andSavarirayan, 2009; Warman et al., 2011). Recently, an autosomal reces-sive osteopetrosis with structural brain abnormality has been describedas a distinct entity of unknown genetics (Stark et al., 2013). Also, thefirst TCIRG1 mutation in autosomal dominant osteopetrosis has beendescribed (Wada et al., 2013). Table 1 depicts the time frame of thediscovery of the various osteopetrosis genes along with their rolein disease pathogenesis.

3. Other disorders with increased bone density

These were initially reported as variant forms of osteopetrosiswith distinctive features. Many early attempts at classification &nomenclature were made by Gorlin et al. (1969) and McKusick andScoTr (1971). Beighton et al. (1977) classified them into four groups:Group 1 called “Osteosclerosis” characterised by disorders with dif-fuse increase in bone density and minimal bony configuration abnor-malities, comprised of Osteopetrosis and Pycnodysostosis. Group 2called “Craniotubular disorders” consisted of disorders with long boneundermodelling & cranial sclerosis. It comprised of craniometaphysealdysplasia, craniodiaphyseal dysplasia, metaphyseal dysplasia, fronto-metaphyseal dysplasia, dysosteosclerosis, oculo-dental-osseous dys-plasia, tubular stenosis (Kenny-Caffey) and osteodysplasty (MelnickNeedles). Group 3 named Craniotubular hyperostoses included dis-orders with bony overgrowth like Van Buchem disease, Sclerosteosis,Infantile cortical hyperostosis (Caffey disease), diaphyseal dysplasiaand Osteoectasia with hyperphosphatasia. Group 4 comprised of mis-cellaneous conditions like Osteopathica striata, Osteopoikilosis, Melorhe-ostosis, Pachydermoperioteitis and Osteitis deformans(Paget disease).Table 2 depicts the historical course of events pertaining to some of thecommon types of these disorders. A review of medical records of thefamous impressionist painter Toulouse-Lautrec showed that he was inmost likelihood suffering from pycnodystostosis (Maroteaux and Lamy,1965). A tenth century Viking Egill Skallagrímsson is now believed tobe suffering from Stride (2011).

Table 1Genes causing osteopetrosis — Discovery, molecular pathogenesis & phenotype.

S no. Gene Year identified Function Clinical phenotype Inheritance

1. CA2 Venta et al. (1991) Carbonic anhydrase for generation of H+ in osteoclasts Mild-moderate with renal tubular acidosis& intracranial calcification

AR

2. ATP6i/TCIRG1 Frattini et al. (2000) H+ K+ ATPase for transport of H+ into resorption lacuna Severe infantile ARAD

3. CLCN7 Cleiren et al. (2001);Campos-Xavier et al.(2003)

Chloride channel for transport of Cl− into lacuna Adult mildChildhood intermediateInfantile severe with neurodegeneration

ADAR

4. OSTM1 Ramírez et al. (2004) Associated with CLCN7 Severe infantile typeNeurodegeneration

AR

5. RANKL Sobacchi et al. (2007) Induces NF kappa B through RANK leading to osteoclastdifferentiation

Severe infantile AR

6. PLEKHM1 Van Wesenbeeck et al.(2007)

Important for vesicular trafficking & acidification machinery Mild-moderate AR

7. Kindlin-3/FERMT3 Mory et al. (2008) Mediates integrin activation and cellular differentiation Severe infantileImmune deficiency

AR

8. RANK Guerrini et al. (2008) Transmembrane receptor for RANKL Immune deficiency AR9. CalDAG-GEF1 Kilic and Etzioni (2009) Activates RAS pathway and stimulates differentiation of

osteoclastsSevere infantileImmune deficiency

AR

10. NEMO Roberts et al. (2010) Inhibits NF Kappa B signalling Anhidrotic ectodermal dysplasiaLymphedemaImmunodeficiency

AR

11. LRP5 Pangrazio et al. (2011) Increases bone formation by wnt pathway Mild–moderate AD12. SNX10 Aker et al. (2012) Responsible for the vesicular sorting of V-ATPase from Golgi

or for its targeting to the ruffled borderSevere infantileVariable

AR

AR: Autosomal recessive, AD: Autosomal dominant.

43S. Aggarwal / Gene 528 (2013) 41–45

The present day classification is as defined by the Nosology and Clas-sification of Genetic Skeletal Disorders, 2010 Revision (Warman et al.,2011). As per this classification, there are three broad type of disorderswith increased bone density, neonatal osteosclerotic dysplasias, increasedbone density group (without modification of bone shape) and increasedbone density group with metaphyseal and/or diaphyseal involvement.There are a total of 34 disorders with increased bone density.

Table 2Other disorders with increased bone density — History, molecular pathogenesis & phenoty

Disorder Year first reported Year when gene identified

Pycnodysostosis Maroteaux andLamy (1962)

Cathepsin,Johnson et al. (1996)

Metaphyseal dysplasia Pyle (1931) Not known

Craniometaphysealdysplasia

Spranger et al. (1965) AD: ANKH,Nürnberg et al. (2001)AR: mapped to 6q21-22,Iughetti et al. (2000)

Van Buchem disease/endosteal hyperosteosis

Van Buchem, Haddersand Ubbens (1955)

SOST,Balemans et al. (2002)LRP5, Van Wesenbeecket al. (2003)

Sclerosteosis Truswell (1958) SOSTBalemans et al. (2001)LRP5, Van Wesenbeecket al. (2003)

Craniodiaphyseal dysplasia Macpherson, 1974 SOSTKim et al. (2011)

Diaphyseal dysplasia/Camurati Engelmandisease

Camurati (1922) TGF betaJanssens et al. (2000)

Osteopathia striata withcranial sclerosis

Voorhoeve (1924) WTXJenkins et al. (2009)

Melorheosteosis Fairbank (1948) LEMD3Hellemans et al. (2004)

Osteopoikilosis/Buschke–Ollendorff syndrome

Buschke andOllendorff-Curth (1928)

LEMD3Hellemans et al. (2004)

AR: Autosomal recessive, AD: Autosomal dominant.

4. Past, present and future — Implications for molecular diagnosisand therapy

With the development of novel diagnostic strategies for Mendeliandisorders, the molecular testing for SKDs has also gained momentum.The molecular defect remains unknown in as many as 30% of patientswith osteopetrosis. Also, many other SKDs with increased bone density

pe.

Gene function Salient features Inheritancepattern

Collagenase secreted byosteoclasts — degradesorganic bone matrix

Open fontanelleAcrosteolysisClavicular dysplasiaFractures

AR

Not known Erlenmeyer flask deformityGenu valgum, Asymptomatic

AR

Decreases matrix formation& mineralisation

Paranasal wideningFacial and jaw distortionErlenmeyer flask deformity

ADAR

Decreases bone formationby inhibiting wnt signalling

Overgrowth & distortion of mandible,brow, cranial nerve palsiesSclerosis in mandible,calvarium & base

AR

Decreases bone formationby inhibiting wnt signalling

SyndactylySimilar to Van BuchemUndermodelling of long bones

AR

Decreases bone formationby inhibiting wnt signalling

“leontiasis ossea”Grotesque facies

AD

Decreases RANKL and inhibitsNF kappa B pathway

Myopathy, leg pains AD

Bone formation by wntsignalling

Male lethalityMacrocephaly,Longitudinal striations onlong bones, pelvis, scapula

X linkeddominant

Affects TGF beta and BMPsignalling

Dripping/flowing waxappearance of cortexAsymmetry

AD

Affects TGF beta and BMPsignalling

“Spotted bones” — osteosclerotic fociSkin lesions

AD

44 S. Aggarwal / Gene 528 (2013) 41–45

remain uncharacterised at the molecular level. Recently, using exomesequencing, the gene for dysosteosclerosis was identified as SLC29A3,a nucleoside transporter (Campeau et al., 2012). In addition, there existsmarked genetic heterogeneity in patients with osteopetrosis whichleads to difficulty in molecular testing by conventional techniques likeSanger sequencing. Recently, a next generation sequencing panel of 34genes has shown promising result in identification of causative muta-tions in patients with osteopetrosis, osteogenesis imperfecta & Ehlers–Danlos syndrome (Sule et al., 2013). Hence, next generation sequencingplatforms can be used for identification of novel genes aswell as provid-ing rapid molecular diagnosis in clinically overlapping disorders withunderlying genetic heterogeneity, as is exemplified by the SKDs withincreased bone density.

The increasing elucidation of the molecular pathogenesis of thedisorders of increased bone density has provided us insights into thepathways involved in the regulation of bone density. As these pathwaysare being recognised, efforts are being made to utilise this informationfor therapeutic purpose. There are preclinical studies reporting theeffects of antibodies and small molecules targeting sclerostin for im-proving bone density. This molecule acts through LRP5 receptors andinhibits wnt signalling which leads to decrease bone formation. In-activating mutations of SOST (gene encoding sclerostin) and LRP5cause Van Buchem disease, sclerostosis and osteopetrosis. Antibodiesand small molecules targeting sclerostin & LRP5 are being investigatedfor their effects on improving bone density (Lewiecki, 2011; Rey andEllies, 2010). This also has therapeutic implications for managementof common conditions with decrease bone density like osteoporosis. Arankl knockout mouse model has shown promising response to RANKLadministration. This raises hopes for improved therapy of the osteoclastpoor osteopetrosis, which have traditionally been resistant to treatment(Lo Iacono et al., 2012).

5. Conclusion

Disorders with increased bone density have been recognised sincelast hundred years. Over time, the clinical picture, classification andmolecular pathogenesis has evolvedwith increasing clarity. The molec-ular defects found in this group of disorders provide insight into thepathways regulating bone density. This information can be used in thefuture for developing novel therapies formonogenic aswell asmultifac-torial disorders affecting bone density.

Conflict of interest statement

None.

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