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Bisphosphonate Treatment in a Patient Affected by MPS IVA with Osteoporotic Phenotype

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Morquio A syndrome (Mucopolysaccharidosis type IVA) (MPS IVA) is a rare inherited metabolic disorder characterized by the defective degradation of keratan sulfate and chondroitin-6-sulfate. Classically, MPS IVA patients present with severe
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  Hindawi Publishing CorporationCase Reports in MedicineVolume 󰀲󰀰󰀱󰀳, Article ID 󰀸󰀹󰀱󰀵󰀹󰀶,  pageshttp://dx.doi.org/󰀱󰀰.󰀱󰀱󰀵󰀵/󰀲󰀰󰀱󰀳/󰀸󰀹󰀱󰀵󰀹󰀶 Case Report  Bisphosphonate Treatment in a Patient Affected by MPS IVA with Osteoporotic Phenotype  AlbinaTummolo, 1 OrazioGabrielli, 2  AlbertoGaeta, 3 MaristellaMasciopinto, 1 LuciaZampini, 2 LuigiMichelePavone, 4 PaolaDiNatale, 4 andFrancescoPapadia  1 󰀱  Metabolic Diseases and Clinical Genetics Unit, Children’s Hospital Giovanni XXIII, Via Amendola 󰀲󰀰󰀷, 󰀷󰀰󰀱󰀲󰀶 Bari, Italy  󰀲 Department of Clinical Sciences, Polytechnic University of Marche, Azienda Ospedali Riuniti, Via Conca 󰀷󰀱, 󰀶󰀰󰀱󰀲󰀶 Ancona, Italy  󰀳 Radiology Unit, Children’s Hospital Giovanni XXIII, Via Amendola 󰀲󰀰󰀷, 󰀷󰀰󰀱󰀲󰀶 Bari, Italy  󰀴 Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Zona Ospedaliera,Via Pansini 󰀵, 󰀰󰀱󰀳󰀱 Naples, Italy  Correspondence should be addressed to Albina Tummolo; albinatummolo@yahoo.itReceived 󰀱󰀳 June 󰀲󰀰󰀱󰀳; Accepted 󰀸 October 󰀲󰀰󰀱󰀳Academic Editor: Indraneel BhattacharyyaCopyright © 󰀲󰀰󰀱󰀳 Albina Tummolo et al. is is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the srcinal work is properly cited.Morquio A syndrome (Mucopolysaccharidosis type IVA) (MPS IVA) is a rare inherited metabolic disorder characterized by thedefectivedegradationofkeratansulfateandchondroitin-󰀶-sulfate.Classically,MPSIVApatientspresentwithseveremultisystemicinvolvement and have a short life expectancy. Attenuated forms with clinical features limited to minor skeletal abnormalitiesand short stature have also been described, sometimes associated to an early-onset osteoporotic phenotype. No treatment withallogenic bone marrow transplantation or gene therapy is currently available for Morquio A syndrome, and enzyme replacementtherapy is under evaluation. We report a case of MPS IVA, who manifested tardily attenuated phenotype and significant bone massreduction, which was treated with a bisphosphonate (BPN), resulting in an improvement of X-ray skeletal aspects and functionalbone performance. We suggest that the use of bisphosphonates may be an interesting supportive therapeutic option for Morquio Apatients with osteoporotic phenotype, but further studies involving more patients are necessary to confirm our findings. 1. Introduction Morquio A syndrome (Mucopolysaccharidosis type IVA)(MPS IVA) is a rare inherited metabolic disorder charac-terized by the defective degradation of keratan sulfate andchondroitin-󰀶-sulfate, due to the abnormal or absent activity of N-acetylgalactosamine-󰀶-sulfatase (GALNS gene) [󰀱].Classically, Morquio A patients do not present mentalretardation, but usually manifest significant skeletal abnor-malities such as pectus carinatum, rib flaring, genua valga,and dysostosis multiplex. Spine involvement is one of the most recognizable skeletal aspects with platyspondyly,kyphosis, gibbus, and hypoplasia or the absence of odon-toid process, leading to atlantoaxial instability and cervicalmyelopathy. Joint ligament laxity is also detectable and isassociated with frequent dislocations (hips and knees) and joint abnormalities. Corneal opacities and deafness are alsofeatures of the syndrome [󰀲].Different phenotypes of MPS IVA have been recognized.e most severe phenotypes are characterized by severepulmonary involvement, quadriparesis, and death, usually between the second and third decade of life. In attenuatedforms, a longer life expectancy has been observed [󰀳], andclinical features may be limited to minor skeletal abnormali-tiesandshortstature[].Insomecases,thediagnosismaybedelayedastheurinaryglycosaminoglycans(GAGs)maybeinthe normal range.No treatment with allogenic bone marrow transplanta-tionorgenetherapyiscurrentlyavailableforMorquioAsyn-drome,andenzymereplacementtherapyisunderevaluation.Palliativemeasuresincludesurgeryforskeletalabnormalitiesand multispecialist support for systemic involvement.  󰀲 Case Reports in MedicineIn the last few years, MPS IVA has been reported to beassociated to an early-onset osteoporotic phenotype, whichcanaffecttheclinicalcourseofthiscondition.eaccumula-tion of keratan sulfate disturbing bone mass acquisition andperturbing the regular microarchitecture of bone tissue hasbeen reported to reflect on bone mass density (BMD) in thiscondition [󰀵].We report a case of MPS IVA, who presented withattenuatedphenotypeandsignificantbonedensityreduction,which was treated with a bisphosphonate (BPN), resultingin the improvement of X-ray skeletal aspects and functionalbone performance. 2. Case Report e patient is the second son of nonconsanguineous Italianparents. He was born with full-term uneventful delivery.Growth rate and psychomotor development were normalduring the neonatal period and early childhood.e patient was referred to our hospital at the age of 󰀱󰀱 because of pain in the lower limbs and concomitantfunctional limitation.On examination, he showed short stature, although com-patible with the parents’ height, mild facial dysmorphismwith normal psychomotor development, and normal visualand hearing ability.e radiological evaluation showed accentuated dorsalkyphosis and lumbar lordosis, dysplastic appearance of bothfemoral heads, and irregular upper contour of the acetabularroof (Figure 󰀱(a)). e abnormal aspect of dorsolumbarmetamers was also detected, but there no dysplastic appear-ance of the odontoid process.Pelvic Computed Tomography (CT) scan highlighted ahypoplasic aspect of femoral cephalic nuclei growth and anirregular delineation of the acetabular articular surfaces andcephalicpolarprofiles.eradiologicalfindingof“coxavara”led to the radiological diagnosis of bilateral Perthes’ disease.Nonsteroidal anti-inflammatory drugs (NSAIDs) werethereforecommenced.However,a󰀀erathree-weektreatmentprotocol, no significant improvement was observed. Onthe contrary, the patient manifested a gradual and steady deteriorationof the initialconditions,resultingin a completefunctional limitation of the lower limbs.e study of the bone metabolism showed normal bonealkaline phosphatase, 󰀸.󰀵  g/L (n.v. 󰀲–󰀸󰀹), and osteocalcin󰀵.ng/mL (n.v. 󰀲–󰀱󰀲󰀳), and abnormal serum biomarkers,(vitamin D: 󰀶ng/mL (n.v. 󰀱󰀳–󰀶󰀷)). However, dual-energy X-rayabsorptiometry(DXA)showedaseverereductioninbonemineral content, in the range of severe osteoporosis: totalBMD of 󰀰.󰀵󰀶g/cm 2 , 󰀵󰀶%,  Z  -score − 󰀳.󰀶󰀵.esystemicosteoarthropathyandmildfacialcoarseningprompted further investigation for lysosomal storage dis-eases.Quantitative evaluation of urinary mucopolysaccharides[󰀶] was normal (󰀱󰀲  g/mg creatinine, normal range 󰀱󰀰–󰀶󰀳),but electrophoresis of urinary mucopolysaccharides revealeda band corresponding to keratan sulfate. e enzymaticassay [󰀷] revealed a decreased activity of galactose-󰀶-sulfate (a)(b) F󰁩󰁧󰁵󰁲󰁥 󰀱: (a) First pelvic X-ray: dysplastic appearance of bothfemoral heads and irregular upper contour of the acetabular roof with mild coxa vara. (b) Last pelvic CT scan (three-dimensional volume-rendered reformatted picture): almost total reconstructionof anatomic structures. sulfatase: 󰀰.󰀹nmol/󰀱󰀷h/mg protein (normal values 󰀸.󰀸+/ − 󰀱󰀷.󰀰, range 󰀱󰀹.󰀵–󰀷󰀷.󰀲).e diagnosis of MPS type IVA was confirmed by molec-ular analysis of the GALNS gene, which detected a com-pound heterozygosity of genotype p.H󰀱󰀵Q/p.G󰀲󰀹󰀰S (basechange c.󰀵󰀱󰀸C > A/c.󰀹󰀲G > A), consistent with the diagnosisofMorquioAsyndrome.eknownpolymorphismp.G󰀲󰀹󰀰Swas also found.Inviewofthereducedmobilityandthesignificantreduc-tion in the bone mineral content, we decided to commence atherapeutic protocol with a BPN namely, neridronate, givenatadoseof󰀲mg/kg,infusedintravenouslyintwohoursevery 󰀳 months [󰀸].e patient was followed up for the duration of therapy with clinical, radiological, and biochemical monitoring, dur-ingwhichweobservedagradualimprovementinpostureandmobility as well as a gradual and steady reduction in jointpain.A󰀀er two years of therapy, the bone turnover indexeswere all found to be in the normal range (vitamin D:󰀱󰀸.󰀱ng/mL,bonealkalinephosphatase:󰀳󰀸  g/L,andosteocal-cine: 󰀸󰀰.󰀵ng/mL) and the mean lumbar spine (L󰀱–L) BMDwas 󰀰.󰀸󰀵g/cm 2 ,  Z  -score: +󰀰.󰀱󰀷.  Case Reports in Medicine 󰀳CT scan showed an almost total reconstruction of anatomic structures. In particular, the acetabular roof pre-sented greater regularity,althougha few smallgeodic cavitiescould be detected at the proximal femoral epiphysis, whichstill appeared slightly flattened (Figure 󰀱(b)).At ten months from the end of the treatment with theBPN, no adverse effects have been detected. e patient canwalk normally, his height percentile has improved, and he isable to perform sports activity. 3. Discussion Morquio A syndrome is a rare condition, and in Italy its esti-mated incidence is about 󰀱:󰀱󰀲󰀵󰀰󰀰󰀰󰀰 live births [󰀹], althoughthe ongoing newborn screening strategies will probably alterthese data in the near future. is condition is characterizedby different degrees of severity of the clinical picture, whichmay result in a delayed diagnosis.ediagnosisisusuallymadebetweentheagesof󰀲and󰀶,when skeletal abnormalities become more evident and causenot only retarded and altered ambulation but also severegrowth retardation.Our patient manifested in late childhood mild boneabnormalitiesandosteoporosisbutnootherpeculiarfeaturesof MPS IVA.Hecht et al. [󰀱󰀰] reported a case of a 󰀱-year-old boy withan attenuated form of Morquio syndrome who presented ashavingseverebilateralPerthes’disease.Othercaseshavebeendescribed [, 󰀱󰀱, 󰀱󰀲], thus suggesting that the attenuated form ofMPSIVAmaynotbesorareaswasthoughtanditsfeaturesmay be misdiagnosed.In our patient, the residual enzyme activity was 󰀱.󰀸%of the wild-type activity. DNA analysis resulted in the het-erozygous phenotype p.H󰀱󰀵Q/p.G󰀲󰀹󰀰S. Mutation p.G󰀲󰀹󰀰Swas first described in a British patient with a severe form[󰀱󰀳]andwassubsequentlyobservedinotherseverecases.eother mutation, p.H󰀱󰀵Q, has not been reported previously;it was not found in 󰀱󰀰󰀰 normal alleles, thus suggesting that itmay be a novel mutation. Since this alteration occurred in anonconserved amino acid of the GALNS protein, it probably explains the 󰀱.󰀸% residual enzyme activity and probably accounts for the attenuated phenotype in our patient. eeffect of attenuated mutations in MPS IVA patients wasreported by Monta˜no et al. [󰀱]: mutants found in the severe phenotypes had less than 󰀱% of normal activity, while mostmutants found in the attenuated phenotype had a higherresidual activity (󰀲.󰀲–󰀳󰀶% of the wild-type activity).e radiological study, particularly with the integrationof traditional radiology and CT scan, prompted us to suspectthe clinical diagnosis and was also important for the follow up.e main differential diagnosis of MPS IV remains bilat-eral Legg-Perthes’ disease due to avascular injury of thefemoral head. is condition, however, is usually unilateraland shows significant improvement a󰀀er a few weeks of treatment with NSAIDS.MPS IVA has already been associated to early-onsetosteoporosis[󰀱󰀵].Otherstudiesfoundanassociationbetweenother forms of MPS and the development of early osteo-porosis [󰀱󰀶, 󰀱󰀷]. Several possible causes have been suggested, among which were the lack of adequate nutrients (calciumand vitamins) and the lack of exposure to sunlight. Aninteresting possible explanation may come from studies by Li et al. [󰀱󰀸], who first highlighted how the accumula-tion of keratan and chondroitin-󰀶-sulfate, differently fromotherglycosaminoglycans(GAGs),determinesexcessive col-lagenolytic activity of a protease highly expressed in osteo-clasts and involved in bone reabsorption: cathepsin K. epromotion of the collagenolytic activity of this degradingprotease in MPS IVA may be involved in the pathogenesis of the osteoporotic phenotype recognizable in some patients.To our knowledge, this is the first case of Morquio Asyndrome treated with a BPN.BPNs are widely prescribed for osteoporosis, both inadultsandinchildren,showingsignificantefficacyinincreas-ing bone mass and preventing fractures in several random-ized controlled trials [󰀱󰀹]. Once incorporated into newly formed bone, BPNs can persist there for years throughmultiple cycles of bone reabsorption and deposition [󰀲󰀰].ey inhibit bone resorption by impairing several osteoclastactivitiesnecessaryforitandbypromotingosteoclastapopto-sis [󰀲󰀱]. e main indication in childhood is for osteogenesisimperfecta, but they are also used in other forms of primary andsecondarychildhoodosteoporosis.emostserioussideeffects of BPN use, such as uveitis, thrombocytopenia, andavascular necrosis of the jaw, have rarely been reported inchildren and adolescents [󰀲󰀲].In our experience, neridronate given intravenously topediatric patients was not associated to significant adverseevents.In conclusion, mild skeletal abnormalities may be theonly initial signs of attenuated forms of MPS IVA. Bone massdensity deficiency may be detectable and can greatly worsenthe clinical course of these patients.e use of BPNs may result in morphological as wellas functional improvements in the bone and may be aninteresting supportive therapy for Morquio A patients withosteoporotic phenotype, but further studies involving morepatients are needed to confirm our findings.  Abbreviations MPSIVA: Mucopolysaccharidosis type IVAGALNS: N-Acetylgalactosamine-󰀶-sulfataseGAGs: GlycosaminoglycansBPN: BisphosphonateCT: Computed tomography BMD: Bone mass density NSAIDs: Nonsteroidal anti-inflammatory drugsDXA: Dual-Energy X-ray absorptiometry. Conflict of Interests e authors declare that there is no conflict of interest.   Case Reports in Medicine References [󰀱] E. F. Neufeld and J. Muenzer, “e mucopolysaccharidoses,” in e Metabolic and Molecular Bases of Inherited Disease , C. R.Scriver, A. L. Beaudet, D. Valle, and W. S. 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