Francesca Marini Maria Luisa Brandi
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
Address for correspondence: Maria Luisa Brandi
Department of Surgery and Translational Medicine University of Florence
Florence, Italy
E-mail: marialuisa.brandi@unifi.it Summary
Hypophosphatasia (HPP) is a congenital, rare and het-erogeneous bone disorder, characterized by a deficit of calcified tissue mineralization, leading to skeletal defor-mities and osteomalacia in adults, rickets in infants and children, and fragility fractures and premature loss of dentition in children and adults. The disease is caused by a reduced or absent expression and activity of the tissue non-specific alkaline phosphatase (TNSALP) en-zyme, derived from inactivating mutations of the alkaline phosphatase (ALPL) gene.
Six different clinical variants have been reported, fined by the onset age and characterized by different de-grees of severity.
The adult form of HPP presents a wide range of clinical manifestations, many of which are non-specific, mild, and often overlapping with other metabolic bone dis-eases. Consequently, many cases of adult HPP are, com-monly, undiagnosed or misdiagnosed, and, subsequent-ly, wrongly or non-treated with severe consequences for patients and a very negative impact on their quality of life and life expectancy, as well as with costs due to the administration of wrong therapies and treatments of their side effects.
The occurrence of a fragility atypical femur fracture in the adulthood can be suspected as a clinical indication of an undiagnosed adult mild form of HPP; and the pres-ence of at least one of this kind of fracture can help in the diagnosis of adult HPP, together with conventional HPP biochemical signs.
KEY WORDS: adult hypophosphatasia; fragility atypical femur fractures; differential diagnosis; amino-bisphosphonates; side effect.
Introduction
Hypophosphatasia (HPP) is a rare congenital heterogeneous
bone disorder (OMIM #241500, #241510, #146300) charac-terized by a deficit in the mineralization of calcified tissues. This disorder was described for the first time in 1948 by Rathbun, who diversified this novel disease from osteogene-sis imperfecta and chondrodysplasia, because of the pres-ence of specific clinical signs, like a very low serum level of alkaline phosphatase (ALP) and the occurrence of convul-sions.
The incidence of lethal and severe forms of HPP varies from about 1/100,000 in Canada, 1/300,000 in Europe to 1/900,000 in Japan, while the incidence of mild and adult forms cannot be correctly estimated since they are undiag-nosed, or, commonly, misdiagnosed for other metabolic bone diseases which overlap some clinical signs and symp-toms.
HPP is caused by inactivating mutations of the alkaline phosphatase (ALPL; MIM 1717160) gene encoding the tis-sue-nonspecific alkaline phosphatase (TNAP) enzyme, that accounts about 95% of the total serum ALP activity (1).
ALPL mutations can be homozygote, heterozygote or
com-posed homozygote, with an autosomal dominant or reces-sive pattern of inheritance. Over 270 different mutations (in-cluding missense, nonsense, frameshift and splicing-site variations) have been described, to date, affecting the entire coding region and intron-exon junctions of the gene. Differ-ent mutations are responsible for HPP differDiffer-ent clinical pre-sentations, age of onset and disease severity. Lethal and se-vere forms of HPP are associated with ALPL mutations that affect crucial domains of TNAP enzyme leading to a mutated protein that is rapidly degraded with a subsequent highly re-duced or absent enzymatic activity and a severe hypominer-alization. Conversely, mild and adult forms of HPP are associ-ated with ALPL mutations that affect non-essential amino acid of TNAP enzyme, granting residual enzymatic activity and min-eralization. It is also probable that some mild and adult forms can be due to the presence of one or more functional polymor-phism of the ALPL gene, polymorpolymor-phisms which demonstrated to be positively associated with variations in serum ALP con-centration and bone mineral density (BMD) (2, 3).
Main clinical manifestations of HPP are rickets in children and osteomalacia in adults, associated with bone deformi-ties, early bone mass loss, and fragility fractures. Clinical expression is highly variable and six different forms of the disease have been classified, mainly according to the age of onset and the severity of the disease: 1) perinatal (lethal), 2) benign prenatal, 3) neonatal (lethal in 50% of cases), 4) childhood (infantile), 5) adulthood and 6) odonto-hypophosphatasia (a mild form affecting only teeth but not bones). A very rare variant, named pseudohypophosphata-sia, has been also described and it is clinically indistin-guishable from infantile variant but with a normal range of serum ALP.
An earlier age of onset is always associated with a more severe pathology and a worse prognosis. Main clinical characteristic of the six HPP forms are depicted in Table 1.
Atypical femur fractures: a distinctive tract of adult
T a b le 1 M a in c h a ra c te ri s ti c s o f th e d if fe re n t c lin ic a l fo rm s o f h y p o p h o s p h a ta s ia . C li n ic a l fo rm O M IM In h e ri ta b il it y A g e o f d ia g n o s is B o n e m a n if e s ta ti o n s D e n ta l m a n if e s ta ti o n s O th e r a s s o c ia te d s ig n s a n d s y m p to m s C li n ic a l d ia g n o s is P e ri n a ta l (l e th a l) # 2 4 1 5 0 0 A R B e fo re b ir th S e v e re h y p o m in e ra liz a ti o n . D if fu s e o s te o c h o n d ra l e x -o s to s e s . R e d u c e d l e n g th o f lo n g b o n e s . N o n v a lu a b le S e v e re b re a th in g c o m p lic a ti o n s d u e t o r ic k e ts o f ri b c a g e a n d h y p o -p la s ti c l u n g s . E p ile p ti c c ri s is a n d s e iz u re s . R a d io g ra p h y a n d /o r p re n a ta l u lt ra s o n o g ra -p h y. D o s a g e o f s e ru m A L P f ro m u m b ili c a l c o rd . B e n ig n p re n a ta l # 2 4 1 5 1 0 A D B e fo re b ir th R e d u c e d l e n g th a n d b o w in g o f lo n g b o n e s . B o n e d e fo rm it ie s a n d re d u c e d m in e ra liz a ti o n im p ro v e d u ri n g t h e t h ir d t ri -m e s te r o f p re g n a n c y. A s p o n ta n e o u s i m p ro v e -m e n t o f b o n e d e fe c ts i m m e -d ia te ly a ft e r b ir th N o n v a lu a b le N o n e P re n a ta l u lt ra s o n o g -ra p h y. D o s a g e o f s e ru m A L P fr o m u m b ili c a l c o rd . N e o n a ta l (l e th a l in 5 0 % o f c a s e s ) # 2 4 1 5 0 0 A R C h ild re n a p p e a r n o rm a l a t b ir th . S ig n a n d s y m p to m s a p p e a r d u ri n g t h e fi rs t s ix m o n th s o f lif e P re m a tu re c ra n io s y n o s to s is a s s o c ia te d w it h i n c re a s e d in tr a c ra n ia l p re s s u re . D if fu s e h y p o m in e ra liz a ti o n . R ic k e ts . F ra g ili ty f ra c tu re s (i .e . ri b c a g e ) P re m a tu re l o s s o f d e c id u o u s t e e th . B re a th in g c o m p lic a ti o n s d u e t o ri c k e ts o f ri b c a g e . H y p e rc a lc e m ia . Ir ri ta b ili ty . A n o re x ia , v o m it in g , h y p o to n ia , p o ly u ri a , p o ly d ip s ia , d e h y d ra ta ti o n a n d c o n s ti p a ti o n , a s s o c ia te d w it h re d u c e d n u tr it io n a n d i n s u ffi c ie n t w e ig h t g ro w th . H y p e rc a lc iu ri a a n d p o s s ib le n e p h -ro c a lc in o s is . E p ile p s y n o n r e s p o n s iv e t o t h e v it a m in B 6 a d m in is tr a ti o n . R a d io g ra p h y. B o n e s c in ti g ra p h y. M e d ic a l e x a m in a ti o n . S e ru m d o s a g e o f A L P , P E A a n d P L P . C h ild h o o d # 2 4 1 5 1 0 A R ( fr e q u e n t) A D ( ra re ) S ig n s a n d s y m p to m s a p p e a r d u ri n g t h e e a rl y c h ild h o o d (u s u a lly a ft e r th e fi rs t s ix m o n th s a n d b e fo re t h e fi rs t 5 y e a rs o f lif e ) D if fu s e b o n e d e fo rm it ie s . R ic k e ts . L o w h e ig h t. D o lic h o c e p h a ly . A rt ic u la r w e a k n e s s . P o s s ib le a rt ic u la r p a in (m o s tl y A T HE e x tr e m it ie s ). F ra g ili ty f ra c tu re s . P re m a tu re l o s s o f d e c id u o u s t e e th (b e fo re 5 y e a rs o f a g e ) A ta x ic g a it ( d u c k g a it ). D e la y i n g ro w th a n d w a lk in g . M u s c le h y p o to n ia . In tr a -c ra n ia l h y p e rt e n s io n . R a d io g ra p h y. B o n e s c in ti g ra p h y. M e d ic a l e x a m in a ti o n . S e ru m d o s a g e o f A L P , P E A a n d P L P . B M D e v a lu a ti o n ( D X A ) to b e c o n ti n u e d
A d u lt h o o d # 1 4 6 3 0 0 A R o r A D S ig n s a n d s y m p to m s a p p e a r d u ri n g t h e a d u lt h o o d e v e n i f a l o w p e rc e n ta g e o f p a ti e n ts r e fe r a m ild r ic k e ts d u ri n g c h ild h o o d , a h is to ry o f d e la y i n f ra c tu re h e a lin g , p re m a tu re lo s s o f d e c id u o u s te e th , a ll o f th e m fo llo w e d b y a g o o d h e a lt h s ta tu s . S e v e re o s te o a rt h ro p a th y. O s te o m a la c ia . O s te o p o ro s is . O s te o a rt h it is . C h o n d ro c a lc in o s is a n d a rt ic u la r p a in d u e t o d e p o -s it io n o f c a lc iu m p y ro p h o s -p h a te d e h y d ra te s a lt s . M e ta ta rs u s a n d t ib ia s tr e s s fr a c tu re s o ft e n a s s o c ia te d w it h r e d u c e d a n d d e la y e d fr a c tu re h e a lin g . F e m u r a ty p ic a l fr a g ili ty f ra c -tu re s (p s e u d o -f ra c tu re s ). R e c u rr e n t d e n ta l p a -th o lo g ie s . P re m a tu re e x fo lia ti o n o f d e c id u o u s t e e th , a n d , m o re r a re ly , o f p e rm a n e n t te e th . P o s s ib le p re m a tu re lo s s o f p e rm a n e n t te e th a t 4 0 -6 0 y e a rs . M y o p a th y a n d m u s c u la r p a in . F a ti g u e . N e p h ro c a lc in o s is . In s o m n ia . D e p re s s io n . A n x ie ty . R a d io g ra p h y. M e d ic a l e x a m in a ti o n . S e ru m d o s a g e o f A L P , P E A a n d P L P . B M D e v a lu a ti o n ( D X A ) O d o n to h y -p o p h o -s p h a ta s ia # 1 4 6 3 0 0 A R o r A D C h ild h o o d N o n e P re m a tu re e x fo lia ti o n o f d e c id u o u s t e e th (p a rt ic u la rl y i n c is o r te e th ). R e c u rr e n t a n d s e v e re d e n ta l c a ri e s . R e d u c e d d e n ti n t h ic k -n e s s a n d e n la rg e m e n t o f c a v it ie s c o n ta in in g th e d e n ta l p u lp . 0 re m a tu re l o s s o f d e c id u o u s a n d p e rm a -n e n t te e th . N o n e M e d ic a l a n d d e n ti s tr y e x a m in a ti o n . S e ru m d o s a g e o f A L P , P E A a n d P L P . F o o tn o te s : A R = a u to s o m a l d o m in a n t; A D = a u to s o m a l re c e s s iv e ; A L P = a lk a li n e p h o s p h a ta s e ; P E A = p h o s p h o ry le th a n o la m in e ; P L P = p y ri d o x a l p h o s p h a te ; B M D = b o n e m in e ra l d e n s it y ; D X A = D u a l-e n e rg y X -r a y a b s o rp ti o m e tr y. Co nt in ue fr om T ab le 1
Diagnosis of HPP
A correct diagnosis of HPP and a differential diagnosis with respect to other bone disorders, mostly for mild and adult forms which are often undiagnosed or misdiagnosed for os-teomalacia, osteopenia and/or early osteoporosis, are funda-mental for the correct treatment of this disease to be started as soon as possible (an enzyme replacement therapy is now available).
In perinatal HPP, the diagnosis is made prevalently by skele-tal radiographs and it allows to distinguish HPP from osteo-genesis imperfecta and rare forms of congenital dwarfism. Intrauterine diagnosis is performed during the second trimester of pregnancy by the finding of bone anomalies, polydramnios, diffuse skeletal hypomineralization (particular-ly skull and spine), reduced bone length, dwarfism, bowed bones. Perinatal form (lethal), whose intrauterine diagnosis is almost always associated with a decision for a voluntary pregnancy interruption, has to be distinguished, through an accurate radiographic and ultrasound analysis, from the be-nign prenatal form whose signs and symptoms usually nor-malize during the third trimester of pregnancy or immediately after birth.
For all the other forms of HPP, the diagnosis is the result of an association between biochemical tests, instrumental eval-uation of the skeleton and a specific medical examination to-gether with the mutation screening of the ALPL gene. Biochemical evidences for HPP include: 1) reduced serum level of ALP (reduction level is directly proportional to dis-ease severity); 2) high plasma level of pyridoxal phosphate (PLP; also known as the active form of vitamin B6); 3) in-creased level of TNAP specific substrates [urinary phospho-rylethanolamine (PEA) and urinary inorganic pyrophosphate (PPi)]. The single finding of low serum level of ALP alone is not sufficient to diagnose the HPP. Indeed, low circulating level of ALP can be ascribed also to other clinical conditions like severe anemia (pernicious and profound forms), hy-pothyroidism, celiac disease, malnutrition, vitamin C, folic acid or vitamin B12 insufficiency, vitamin D intoxication, hy-pomagnesemia, hypoparathyroidism, Wilson’s disease, clei-docranial dysplasia, Cushing’s syndrome, multiple myeloma, osteogenesis imperfectatype II or Zn2+ deficiency. In case of equivocal situations, biochemical measurements of plasma PLP and urinary PEA could be useful. In few cases of mild and adult HPP levels of PEA and PPi can be within the nor-mal range, but PLP is always an indicative marker, since, unless an excessive dietary intake of active vitamin B6, the plasma level of PLP is not expected to be elevated in patho-logical conditions other than HPP.
Instrumental diagnostic screening is principally made by ra-diographs of the skeleton; in childhood and adulthood forms a Dual-energy X-ray absorptiometry (DXA) is performed for the evaluation of BMD.
Mutation test of the ALPL gene is principally useful to con-firm the biochemical diagnosis or it can help in a diagnosis when biochemical and clinical data are not completely clear. However, a negative ALPL genetic test in patients with low serum level of ALP ad reduced bone mass should not make them to be excluded as mild forms of HPP.
In childhood and adulthood HPP forms, in association with biochemical and instrumental screenings, a specific and complete medical examination is important for a clear diag-nosis, through the investigation for the presence of HPP-as-sociated manifestations, including both the common ones
and the rare and asymptomatic ones. Indeed, especially for adult forms of HPP many manifestations are mild and often overlap with other metabolic bone disorders, often resulting in a wrong or no diagnosis. In most cases, the diagnosis of adult HPP is made after a low serum level of ALP is casually detected during routine blood screening, or when tested after a direct family member was diagnosed with the condition. However, today a percentage of adult HPP with low BMD and bone fragility is still misdiagnosed for early-onset osteo-porosis or other metabolic bone disorders, with the risk of administration of a wrong pharmacological therapy that is not only ineffective but it can also get worse the mineralization status, resulting in a great reduction of quality of life and an increase of side effect hospitalization costs. In this light, the correct and early diagnosis of mild and adult forms of HPP is very important. Serum ALP level, and other HPP-related bio-chemical markers, should be routinely checked as possible cause of low BMD and bone fragility, even in individuals over 50 years, to distinguish HPP from osteoporosis and avoid administration of anti-resorptive drugs.
Fragility atypical femur fractures in HPP
Clinical manifestations and disease severity are variable be-tween patients in adult form of HPP, even in presence of the same ALPL mutation; many of the knowledge of clinical psentation of this HPP form has been derived from case re-ports and pedigree studies (4). Some patients can be asymptomatic with only low serum level of ALP and a re-duced bone mass; therefore, the disease can remain undiag-nosed for years. Symptoms of adult HPP usually appear af-ter 40-50 years of age (even if a careful inaf-terrogation of clini-cal history often reveals signs also during childhood or even infancy), and they consist principally of diffuse osteomalacia and osteoarthritis. Many patients refer a history of joint pain and of foot and leg pain caused, respectively, by chondral deposition of calcium pyrophosphate dehydrate and by metatarsal stress fractures associated with poor and slow healing and frequent fracture non-union. Also premature ex-foliation and structural alterations of deciduous teeth, and, more rarely, of permanent teeth, as well as an increased oc-currence of severe dental caries can characterize adult HPP. Low bone mass and fragility fractures represent distinctive signs of adult HPP, and, in patients over 50-55 years, they can lead to a wrong diagnosis of osteoporosis.
It’s well known that fragility atypical femur fractures are a hallmark of adult form of HPP, and they represent an impor-tant marker for the diagnosis (5). Atypical femur fractures (subtrochanteric, diaphyseal or femoral shaft fractures) rep-resent a small fraction (10-30%) of all hip/femur fractures; usually, many of them (about 75%) are associated with ma-jor traumas, while only 25% of them consist of spontaneous or low-trauma fragility fractures. In particular, fragility atypi-cal femur fractures account for about 3% of all femur frac-tures in the elderly. Atypical femur fracfrac-tures can occur also in other bone disorders such as X-linked hypophosphatemia, osteopetrosis, pycnodysostosis, and in a percentage of os-teoporosis patients long-term treated with amino-bisphos-phonates (NBPs) or denosumab. However, if the occurrence of these fractures is associated with low level of ALP, this is a strong suspect of an adult form of HPP.
Fragility atypical femur fractures in HPP present distinctive features that should be considered as helpful for the
differen-tial diagnosis. Adult HPP typically presents bilateral femoral pseudo-fractures (Looser’s zones) that are chronic and pro-dromically painful, and they, usually, occur in the lateral cor-tex of the subtrochanteric diaphysis; conversely, more com-mon forms of osteomalacia and X-linked hypophosphatemia manifest their typical pseudo-fractures principally within the medial cortex of the femoral neck (6). Moreover, atypical fe-mur fractures in HPP show, at the radiograph examination, a transverse or short oblique orientation, in contrast to the typi-cal spiral aspect of fragility femur fractures in osteoporosis; and when the HPP fracture is complete it usually shows the presence of medial spikes and lack of comminution. There-fore, the radiological localization of the fracture within the fe-mur and the radiological evaluation of fracture edge and ori-entation are important parameters for HPP diagnosis. Moreover, fragility atypical femur fractures in HPP are often associated with prodromal pain which manifests even weeks and months before the occurrence of the real fracture event. These fractures origin as stress micro pseudo-fractures that can remain asymptomatic, and untreated, for years, progres-sively advancing till their occurrence (usually by low or no trauma). The presence of prodromal pain (both dull or aching) at hip, groin or thighs, especially in case of bilateral symptoms, could be an indication of presence of stress mi-cro pseudo-fractures and should be consider at the time of medical examination, and followed by a bilateral radiograph-ic evaluation of both femurs. If plain radiographs do not evi-dence micro-fractures or images are controversial, MRI or radionuclide scintigraphy should be performed. MRI is able to detect cortical stress fractures associated with bone and marrow edema or with hyperemia.
Besides to be a useful diagnostic marker for adult HPP (7), fragility atypical femur fractures are also a possible side ef-fect of long-term NBP treatment. An increased risk of this kind of fracture in NBP-treated osteoporosis patients has been evidenced (8-10). This risk has been also reported in HPP. One study of Sutton et al. (11) described a case of a 55-year-old Caucasian woman manifesting a fragility atypical subtrochanteric femur fracture, occurred after 4 year-therapy with alendronate and zoledronate for suspected osteoporo-sis; targeted analyses revealed the patient to be an adult HPP form. NBPs are synthetic molecules that mimic the chemical structure of PPi, a natural substrate of TNAP and a potent inhibitor of mineralization. Thanks to their structure these drugs, besides to inhibit mevalonate pathway and os-teoclast differentiation, act also as agonist of PPi, inhibiting the activity of TNAP. The administration of NBPs in HPP pa-tients induces a PPi-like inactivation of TNAP, in subjects with an already existing genetic-derived reduced ALP activi-ty, and further reduces mineralization. It has been speculat-ed that in HPP patients NPBs may intensify the inhibition of mineralization process and be responsible for an increased
risk and a higher prevalence of NBP-associated atypical sub-trochanteric femur fractures. Consequently, HPP patients misdiagnosed with osteoporosis, but with a low level of serum ALP and the presence of genetic variants of the ALPL gene responsible for reduction of the normal expression and activity of TNAP, treated with NBPs drugs, are prone to de-velop atypical femoral fractures (even bilateral and recurrent) from these treatments. Thus, the correct diagnosis of HPP is fundamental to avoid the wrong therapy with NBPs or other anti-resorptive drugs, which are ineffective and detrimental in these patients. On the other hand, the presence of one or more atypical femur fractures after a treatment with NBPs should be consider an indication to suspect an adult HPP form (11), and biochemical dosage of ALP and other HPP-related biomarkers is strongly suggested to set up the right diagnosis and prevent further NBP-related atypical fractures. References
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