Arch Metab. Endocrinol 2019;63/1 and moderate hypophosphatasia ofsevere prevalence al one from inwhichthegeneproduct negative effect, of anautosomaldominant mutation withadominant transmission or because autosomal recessive through both alleles of the gene. This could be mutations affect hypophosphatasia, the dominant inheritance. In severe of onethecopiesgene,leadingtoautosomal isfunctionalloss (1). Inmildhypophosphatasia,there loss, ricketsorosteomalacia,andcalcificarthropathies complicationsfeaturingtooth osseous andarthritic an inhibitorofmineralization,explainsthedento- ALP substrates,includinginorganic pyrophosphate, In hypophosphatasia,extracellularaccumulationof the tissue-nonspecific isoenzymeof ALP ( mutationswithinthegenethatencodes lossoffunction (ALP) activity(hypophosphatasaemia)dueto alkaline phosphatase characterized bylowserum H INTRODUCTION 2019;63(1):89-93 review the literature on the adult form of the disease and its genetic mechanism. hypophosphatasia witharare onset hypophosphatasia. We presentacaseof41-year-old malediagnosedwithadultformof targeted enzyme-replacementtherapy(asfotasealfa)was approved in2015 totreatpediatric- best supportive treatmentandtopreventtheuseofanti-resorptiondrugsinthesepatients.Bone- reveal minor formsof the disease in adults. It is important to recognize the diseasetoprovide the Fractures, jointcomplicationsofchondrocalcinosis, calcifyingpolyarthritis andmultiplepainsmay presentations. The clinicalpresentationoftheadult-onsethypophosphatasia ishighlyvariable. of hypophosphatasia areextremelyvariable,rangingfromlifethreateningtoasymptomaticclinical orduetoadominantnegativeeffect.cases areeitherautosomalrecessive Clinicalmanifestations calcific arthopathies. Mild hypophosphatasia usuallyhasautosomaldominantinheritance,severe leads todento-osseousandarthritic complicationsfeaturingtoothloss,rickets orosteomalacia,and phosphatase (TNSALP).isoenzyme of alkaline Extracellular accumulation of TNSALP substrates duetoloss-of-functionmutationsinthegeneencodingtissue-nonspecific phosphatase activity Hypophosphatasia isarareinbornerror ofmetabolismcharacterized bylowserumalkaline SUMMARY Francisco Galeano-Valle and review oftheliterature a casereport ofadultform A rare mutation inhypophosphatasia: lele interferes with homo-dimerization(2).The lele interferes 241510) is a rare inborn error ofmetabolism error inborn 241510) isarare ypophosphatasia (OMIM146300,241500, 1 ALPL ,Jaime Vengoechea mutationthathasbeenpreviouslydescribedonlyonceand ALPL 2 , Rodolfo J. Galindo ). has been previously described only once and review described onlyonceandreview has beenpreviously hypophosphatasia witharare case ofa41-year-old of malediagnosedwithadultform bone fragility in adult hypophosphatasia. We a present ofthe availableforthe correction established treatment onset hypophosphatasia.Currently, isnowell- there pediatric- in2015totreat asfotase alfawasapproved therapywith Bone-targeted enzyme-replacement inthesepatients(1,4-6). osteoporosis to primary tobonefragility, related the fractures andattributed for prescribed frequently drugs, of anti-resorption use theinappropriate toprevent important extremely Moreover, it’s and associated with pseudarthrosis. complicated frequently which are fractures, to prevent thebesttreatment, thediseasetoprovide to recognize ofthediseaseinadults.Itisimportant minor forms andmultiplepainsmayreveal calcifying polyarthritis jointcomplicationsofchondrocalcinosis, Fractures, identified. are clinical forms major seven and variable extremely manifestations ofhypophosphatasiaare (3). Clinical respectively patients in Europe, estimatedat1/300,000and1/6,370 were forms Arch EndocrinolMetab. 3 ALPL 69 Jesse HillJr. Dr., Diabetes andMetabolism Division ofEndocrinology, UniversitySchoolEmory ofMedicine, Rodolfo J. Galindo Correspondence to: GA,Atlanta, USA Endocrinology Section, of Medicine,Diabetesand 3 Medicine, GA,Atlanta, USA of HumanGeneticsand of Medicine,Departments 2 Gregorio Marañón,Madrid,Spain Instituto deinvestigación Sanitaria Gregorio Marañón,Madrid,Spain; GeneralUniversitario Hospital 1 DOI: 10.20945/2359-3997000000108 Accepted onDec/11/2018 Receivedon Aug/26/2018 [email protected] 30303 – GA,Atlanta, USA Glenn Bld,Suite202 Emory UniversitySchoolEmory UniversitySchoolEmory Department ofInternalMedicine, genemutationthat case report
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Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 90 Figure 1. kidneys.Aftergeneticcounseling, showed normal Kidneysultrasound abnormalities. the ribsdidnotreveal normal. A, B1,B2,B3,B5andB12were range20-125nmol/L).Vitamin 328.7 nmol/L(normal B6was rangeinmales6.5-20.1μg/L).Vitamin (normal 45-115 U/L).Bone-specificALPwas4.8μg/L range for atleast2years,ranging18-20U/L(normal ALP decreased revealed Historicaltestresults normal. D (25(OH)D) were albumin and 25-hydroxyvitamin kidneyfunction, hormone, andparathyroid thyroid in teeth. Plasmatic calcium, phosphate, magnesium, slightlack ofenamel Physical examinationrevealed 1). andpoordentition(Figure adulthood, fractures plasmaticALPduring decreased with long-term Inaddition,thepatienthadonesister and fractures. to bisphosphonates, members, with poor response inseveralfamily osteoporosis ofpremenopausal history disability orvitaminsupplementation.Hehadafamily teethloss,cavities,musclepain,intellectual fractures, of ribs painforseveralmonths.Hedeniedanyhistory Additionally, hehadrightlower thepatient related mood. of asthenia, constipation and depressed endocrinology clinicwithalongstandinghistory A 41-year-old tothe Caucasianmalepresented CASE REPORT genetic mechanism. ofthediseaseandits ontheadultform the literature Adult-onset hypophosphatasia HTN Pedigree ofthepatient’s family. HTN: hypertension; ALP: alkaline phosphatase; T2DM: type2diabetesmellitus. HTN Depression uicide 8 Asymptomatic Depression rnonths Di erticulitis 20 6 83 Asymptomatic Asymptomatic 3
Radiograph of ractures poor decreased ALP Poor dentition Long standing dentition T2DM 62 39 steoporosis
62 DISCUSSION team includingadentist. byamultidisciplinary supervision range andregular and focusedonmaintaining25(OH)Dwithinnormal is basicallysymptomatic(analgesics,antidepressants), treatment therapy(ERT)replacement andthecurrent was made.Thepatientnotenabletouseenzyme autosomal dominanthypophosphatasia(adultform) the 2015ACMG/AMPguidelines.Thediagnosisof to according was establishedbytheclinicallaboratory Theclassificationaspathogenic (p.Ala492Profs*29). termination protein inaframeshiftandpremature result to pathogenic variant,c.1474del,whichispredicted fora This showedthatthepatientwasheterozygous Wisconsin, USA). Genetics,Marshfield, (Prevention molecular diagnosticlab ataCLIA-certified performed ALPL of TNSALP monomers is required forcatalytic of TNSALPmonomersisrequired by post-translationalmodifications.Homodimerization thatdiffer teeth. TNSALPisactuallyafamilyofisoforms abundant intheskeleton,liver, kidneyanddeveloping gene, the fourth ALP,specific intestinal,placentalandgerm-cell whereas genes accountforALP. genesencodethetissue- Three in1988(8).Inhumans,four mutation wasreported 1948 byJ.C.Rathbun(7)andthefirstidentified in reported The firstcaseofhypophosphatasiawas asthenia constipation depressed mood ostal pain steoporosis gene (NM_000478.5) Sanger sequencing was 1 Multiple medical problerns steoporosis 90 ALPL nee in uryat 0 , encodesTNSALP, whichis cuff in ury steoporosis otator Arch Metab. Endocrinol 2019;63/1 91 cuff in ury otator replacernent nee 0 ALPL
Arch Metab. Endocrinol 2019;63/1 common. Astudy showedthattheonset ofsymptoms Delayeddiagnose is very form. most underdiagnosed the thisisprobably oftheadultform, clinical features (5,6,12-15). frequent are psychiatric symptoms(insomnia, anxiety, depression) headachesand joint pain,andmusclepain.Recurring fracturing, skeletal and debilitating due to recurrent canbecome Thisform maybepresent. nephrocalcinosis ossificationofligamentsand Calcific periarthritis, tooth loss. loose teeth and premature disorders, includeenamel (5,12-14). Dentalabnormalities femoralregion inthesubtrochanteric proximally laterallyand affect (orpseudofractures) fractures Theothercharacteristic may leadtopseudarthrosis. usuallyshow a delayedconsolidationand recurrent, are involvethemetatarsals.Thesefractures fractures arthropathy, includingpseudogout. The most frequent duetoosteomalacia andPPi caused byfractures during middleage(13).Themainsymptomispain (2,11,12). early lifepresentation any skeletal complications, generally being worse with Itsoutcomeisconditionedprincipallyby clinical forms. hypophosphatasia hasbeenclassifiedintosevenmajor isacontinuum, Although itsclinicalspectrum withoutbonediseaseinadulthood. calcific periarthritis unmineralized skeleton to dental complications or death of severitythatspansfrom adults(4,6). insomeaffected arthropathies a widerangeofothersymptomsincludingcalcific andadults, inchildren osteomalacia, respectively rickets and producing thereby and growth, formation crystal ofhydroxyapatite leads totheimpairment inhibitor of mineralization and its superabundance (1).PPiisapotent includingneurotransmitters reactions of vitaminB6andacofactorforseveralenzymatic 5’-phosphate (PLP)inplasmawhichistheactive (PPi)inurineandbloodpyridoxal pyrophosphate both phosphoethanolamine(PEA)andinorganic inhypophosphatasia: accumulate extracellulary population(3). intheEuropean respectively estimatedat1/300,000and1/6,370 were forms and moderate hypophosphatasia ofsevere prevalence inhypophosphatasia(9).The of allTNSALPisoforms isdeficiency bytheliver(10).There cleared that are assolublehomodimers activity (9).ALPscirculate Due to the extraordinary rangeofvariabilitythe Due totheextraordinary Adult-onset hypophosphatasiatypicallypresents range Hypophosphatasia showsanextraordinary TNSALP phosphocompoundsubstrates Three in utero with an
form form adult patients and it is rarely investigated further (16). investigated further adult patients and it is rarely intheclinicalsetting inhospitalized usually recognized ofhypophosphatasia,itisnot diagnosis ofallforms persistent hypophosphatasaemiaisthehallmarkfor all patients with hypophosphatasia (2). Although ALPL PLP (1,7). sensitivity and specificity by elevatedserum excess inhypophosphatasiaismarkedwithgreatest severity of hypophosphatasia (1,6). TNSALP substrate the TNSALP substrate accumulation generally reflects of hypophosphatasemia and diagnosis. Thedegree studies, andradiographicfindingsconsistentwiththe history, laboratory physicalexamination,routine when persistent hypophosphatasemiamatches a medical asymptomatic (12). ofpatientsappeared onethird time ofpresentation, and themedianageatdiagnosiswas atamedianageof in adulthoodoccurred and are reported inthe reported and are and fiftyonemutationshavebeenidentified hundred one ortwomutationsinvolving substrates. Allpatientswith hypophosphatasiacarry levelsofits TNSALPactivityandincreased decreased ALPL anymutationinthe Hypophosphatasia derivesfrom forunderstandinginheritance. iscrucial information diagnosed without testing(20). laboratory onroutine normal inmostadults(1,14).Weakreduced musclesappear onlyslightly assessedbyDXAare (14,18,19). Z-scores andcalcificperiarthritis arthropathy pyrophosphate pseudofractures, fractures, healing metatarsalstress adult hypophosphatasiaincludeosteopenia,poorly- laboratories(1).Radiologicalfindingsof in research (17). in mild hypophosphatasia can be unremarkable diagnosis ofhypophosphatasia.However, PEAexcretion a of anelevatedPEAlevelinbloodorurinesupports bone TNSALPactivity (1,6). Documentation suppress causes ofhypophosphatasaemiaseemtoparticularly low, bone,are notjustfrom isoforms, andtheother hypophosphatasia astheactivitiesofallTNSALP an elevatedlevelmightbeexpectedexclusivelyin an explanation otherthan hypophosphatasia, because helpfulwhenhypophosphatasaemiahas is particularly PLP andconditions (17). Assaying serum drugs certain useof from Hypophosphatasaemia canalsoresult Hypophosphatasia hasbeendiagnosedtraditionally Although hypophosphatasiacantypicallybe gene analysis is expected to reveal adefectin geneanalysisisexpectedtoreveal gene located on chromosome 1p36.1thatcauses gene locatedonchromosome Currently, outonly carried assaysforPPiare ALPL ALPL mutation analysis, this genemutation database Adult-onset hypophosphatasia ALPL
49 years.Atthe (6). Three (6). Three
44 years 91
Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 92 with perinatallethal however the fetus wasaffected nomissensemutationhadever beendescribed, where aregion the last 30 amino acids of the protein, affected case,themutationonly In thatreported proteins. andmRNAdecayorsignificantlyshorter termination inaframeshiftwithearly deletions result the reported All broadinstitute.org/variant/1-21904036-CG-C). (http://gnomad. a publicdatabase,indicatingitisrare in1of236,966alleles variant hasbeenonlyobserved perinatal lethalhypophosphatasia(24).Inaddition,this the variantisdescribedasc.1471del)inapatientwith transcript so reference uses a non-current (the report andcols. byBrun-Heath variant, hasbeenreported was made.Thisvariant,alongwithanother autosomal dominanthypophosphatasia(adultform) thediagnosis of and therefore (p.Ala492Profs*29) termination protein in aframeshiftandpremature result to defined asc.1474del,whichispredicted inexon12ofthe heterozygous Thispatientwas relatives. possibleaffected to inform genetic testing.Geneticcounselingwasperformed by suspicion ofhypophosphatasia,thatwasconfirmed leadtothe ofboneandjointproblems family history symptoms, persistentlylowALPlevelsandthestrong family (2,15). ofthediseasemayeven occur withina presentations phenotypic hypophosphatasia. Significantlydifferent accounting forcasesofautosomaldominantperinatal inadominant negative effect, considerably andresult enzymatic function of theTNASLPdimercandecrease with the formation Missense mutations that interfere hypophosphatasia, respectively.mild versussevere transmission of these defects generally explain recessive TNSALP activity. Autosomaldominantandautosomal on of missensemutationsandtheirvariableeffect of inheritance and depends on the large number pattern tothe clinical variabilityofthediseaseiscorrelated major transcriptioninitiationsite(17,22-24).Thehigh the mutations, andanucleotidesubstitutionaffecting splicing mutations, nonsense composed of microlesions, being missensepointmutationswiththeremainder are genotypes (21).Themajorityoftheknownmutations numberofcompoundheterozygous and inagreat inhighlyvariableclinicalexpression of mutationsresults in the disease. This variety allelic heterogeneity strong patients,indicatingavery Japanese, andEuropean American, 24,2018)inNorth accessed onMarch (http://www.sesep.uvsq.fr/03_hypo_mutations.php, Adult-onset hypophosphatasia Despite ourpatienthavingmildandunspecific ALPL geneforavariant ALPL
contributor tothepatient’sphenotype. inthegenome couldbea modifier variantelsewhere ofthe analysis molecular ofthe gene (24). Weproduct performed ofhypophosphatasia,duetotheaberrant forms severe forthemore responsible inframeshiftare resulting indeletionsandinsertions the mutationsresulting Finally, oftheprotein. (26), part reported aspreviously ofthecarboxy-terminal theimportance and confirmed membrane anchoringisessentialforTNSALPfunction forthatpatientsuggested phenotype observed but notforenzymaticactivity(25).Thelethal formembraneanchoring wasnecessary and thisregion in thelastexonofgene,itescapedmRNAdecay, activity. Thisindicatesthat,becausethedeletionoccurs enzymatic anormal butretained was notexcreted the protein showed that in the absence of this region, withadeletionofthelast30aminoacids using aprotein hypophosphatasia. Funding: this work was not supported byanygrant. Funding: thiswork wasnotsupported only onceinmedicalliterature. described The mutationc1474delhas beenpreviously asymptomatic. otherwise butwhoare abnormalities those with biochemical subclinical manifestations from to distinguishhypophosphatasiapatientswith clinical examination mutation findings bythorough theneedtomanage used inclinicalpractice,confirming treatments. withadelayeddiagnosisandinappropriate recognized tobe anditisoftendifficult form and theleastsevere accountsforthemostcommon Adultform features. ofmetabolismwithawiderange ofclinical error (5). recommendations limited tomakestrong adults withhypophosphatasia.However, thedataisstill functionaloutcomesinsomeadolescents and improved Inaclinicaltrial, asfotasealfa and ithadpositiveresults. Recombinant PTHwastriedonvariousclinicalcases (6,28). managementistypicallysupportive adult form pediatric-onsethypophosphatasia. However,treat the targeted ERT in2015to (asfotasealfa)wasapproved of thebonefragilityinadulthypophosphatasia.Bone- availablefor thecorrection is noestablishedtreatment worsen underlyingosteomalacia(27).Currently, there as they may not recommended, therapies are resorptive (5).Anti- painandmooddisorders in additiontochronic must includeassessmentofboneandjointcomplications, In conclusion, Hypophosphatasia is a rare inborn inborn In conclusion,Hypophosphatasiaisarare Management ofadultpatientswithhypophosphatasia ALPL ALPL mutation testing is being increasingly mutation testingisbeingincreasingly In vitro geneonly, itispossiblethata Arch Metab. Endocrinol 2019;63/1 experiments performed experimentsperformed Arch Metab. Endocrinol 2019;63/1 13. 12. 11. 10. 9. 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES was reported. relevant tothisarticle nopotentialconflictofinterest Disclosure:
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