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Archives de pédiatrie
Volume 24, n° 5S2
pages 574-579 (mai 2017)
Doi : 10.1016/S0929-693X(18)30019-8
Hypophosphatasia: the contribution of imaging
Hypophosphatasie : apport de la radiologie
 

A. Linglart 1, J.-P. Salles 2, 3,
1 AP-HP, Centre de référence pour les maladies rares du calcium et du phosphate, Plateforme d’Expertise Maladies Rares Paris-Sud, filière OSCAR, INSERM U1169 and service d’endocrinologie pédiatrique, hôpital Bicêtre Paris-Sud, Le Kremlin-Bicêtre, France 
2 Centre de référence pour les maladies rares du métabolisme du calcium et du phosphore, filière OSCAR; unité d’endocrinologie, maladies osseuses, génétique et gynécologie, hôpital des enfants, CHU de Toulouse, TSA 70034, 31059 Toulouse Cedex 09, France 
3 Centre de physiopathologie de Toulouse-Purpan, CPTP, INSERM UMR 1043, université de Toulouse-Paul-Sabatier, 31059 Toulouse, France 

*Corresponding author.
Summary

Radiography and imaging are necessary for the diagnosis of hypophosphatasia (HPP) at all stages of life, from the antenatal period to the complications of adulthood, and in the forms of variable severity. The consequences of alkaline phosphatase activity deficiency, namely defective mineralization and bone fragility, may be detected by radiological tools and share features that distinguish them from other diseases responsible for mineralization defects. Radiography and imaging are also fundamental for the screening and diagnosis of the complications of HPP, some of which are related to the episodes of hypercalcemia and hyperphosphatemia (nephrocalcinosis). Radiologists should be aware of the particularities of HPP to efficiently orient the patients toward optimal medical care.

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Résumé

La radiographie et l’imagerie sont au cœur du diagnostic de l’hypophosphatasie (HPP) à tous les âges de la vie, de la période anténatale aux complications de l’âge adulte, et dans ses formes de gravité variable. Les manifestations occasionnées par le déficit d’activité de la phosphatase alcaline, déficit de minéralisation, fragilisation de l’os, sont détectables radiologiquement et possèdent des particularités que l’on peut distinguer d’autres pathologies hypominéralisantes. La radiographie et l’imagerie sont aussi fondamentales pour la détection et le diagnostic des complications de l’HPP, certaines liées aux perturbations du métabolisme phosphocalcique (craniosténose « fonctionnelle » de l’HPP, néphrocalcinose). Les radiologues doivent être avertis des particularités du diagnostic d’HPP afin d’orienter efficacement les patients vers une prise en charge optimale.

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Introduction

HPP is a pleomorphic disease in its clinical presentation. It is also pleomorphic in its radiological presentation. It may be diagnosed at any age using radiological methods in the context of symptoms that vary in terms of presentation, severity and extent.

Role of imaging in HPP management

Radiology is a major pillar in both diagnosis and managment of patients affected with HPP. The first symptoms such as lower limb deformities, fractures or rickets, usually trigger an imaging assessment that should lead to the final diagnosis of HPP. The difficulty resides in recognizing the variety of signs, sometimes not specific, that, associated to clinical and laboratory data, suggest the diagnosis of HPP. The difficulty of the radiological diagnosis is proportional to the the age of the patient.

Following diagnosis, the radiologist is closely involved in patient’s monitoring. Depending on the severity of the disease, certain organs require a regular follow-up, such as mineralization of the skeleton, shape of the long bones, growth of the skull, and development of ectopic calcifications – particularly renal calcifications. So far, there is no national or international recommendations regarding the use of imaging for the diagnosis and/or management of HPP.

Prenatal diagnosis

The first report of the antenatal signs of HPP was published in 1996 [1]. The earliest signs attributable to HPP were reported at 13 weeks of amenorrhea ([WA]) using ultrasound. They consisted of hydramnios and severe asymmetrical bone abnormalities [2]. Otherwise, the antenatal screening of HPP is done through repeated ultrasound, three-dimensional ultrasound, and/or fetal CT scan from 28-30 WA. Prenatal imaging allow investigation for specific signs of HPP: severe mineralization defect of of the diaphyseal extremities, growth retardation with short long bones, curved long bones, boney spines jutting from the long bones of the arms or legs and covered by skin, fractures, hypoplastic lungs, and severe mineralization defect of the roof of the skull and vertebrae (Figure 1) [3]. In many cases, the thoracic and abdominal circumferences are within the normal limits.



Figure 1


Figure 1. 

Antenatal imaging of hypophosphatasia.

1A. Fetal CT scan at 32 WA. Note the absence of mineralization of the roof of the skull (arrow 1), thin ribs, and metaphyseal peaks (arrow 2). The infant died of respiratory insufficiency 12 hours after birth.

1B. Fetal CT scan at 32 WA. Curved long bones (arrow 3). Main differential diagnosis: Osteogenesis Imperfecta.

1C. Ultrasound showing radial curving (arrow 4) and fractures (arrow 5) confirmed by postnatal radiography (arrow 6) (severely defective skeletal mineralization), images after [14].

Zoom

Sometimes the diagnosis is only considered in the third trimester of pregnancy, through ultrasound, when discovering isolated curved long bones, or short long bones or long bones at the lower limit of the normal range. The study by Wenkert et al. of 17 patients diagnosed in utero showed that the antenatal radiological signs, even when severe, were not necessarily predictive of the postnatal course. Indeed, 4 fetuses had signs of spontaneous pre- or post-natal improvement [2] [4]. The discovery of these skeletal abnormalities should trigger the discussion of certain differential diagnoses, including Osteogenesis Imperfecta, which is much more common than HPP (Table 1) [5].

Radiological diagnosis in infants and children

Some clinical features (Table 2) may trigger standard radiography of the skeleton (neonates) or of long bones (children). The image analysis should address the diagnosis of HPP in the presence of one or several of the signs listed below. Patients share a defective mineralization of both bone and teeth the degree of which varies depending on the severity of the disease.

Overall, the defective bone mineralization is correlated to the alkaline phosphatase (ALP) level. The lower ALP, the greater the bone mineralization defect. Thus, the disease affects the entire skeleton in severe neonatal forms (Figure 1C); certain bones such as the vertebrae, phalanges, and flat bones including the roof of the skull are sometimes completely absent [6]. The metaphyses are hollow, irregular and sometimes bifid. The diaphyses are very thin. The clavicles are generally visible and preserved. In less severe forms, in which residual ALP activity is present, hypomineralization predominates at the metaphyses and epiphyses in the form of ‘tongues’ entering into the diaphyses (Figure 2), and consisting in areas of non-mineralized osteomalacic bone. The metaphyses may also look like spurs (Figure 1A). This presentation is highly suggestive of HPP and distinguishes other causes of hypomineralization in children, in particular hypophosphatemic rickets and nutritional rickets. HPP should be clearly individualized from other types of rickets in that there is never any sign of bone resorption or hyperparathyroidism. The laboratory markers of bone resorption associated with HPP are rather low. In the absence of ALP, calcium does not bind to the bone matrix and, in infants and young children, hypercalcemia occurs suppressing the secretion of parathyroid hormone (PTH). On X-rays, these aspects may be confused with rickets since defective mineralization of the physis imparts a blurred appearance to the metaphyseal margins. The ALP measurement is therefore critical in confirming the final diagnosis and showing low ALP levels. At diaphyseal level, there may be hyperdense areas (called ‘osteosclerosis’) alternating with hypodense areas [7]. Since the signs predominate in metaphyses, they disappear at the end of growth. Subsequently, only limb deformation, demineralization and skeletal fragility persist after cartilage closure [8].



Figure 2


Figure 2. 

Radiological characteristics of hypophosphatasia (HPP) in children.

2A. Radiography of the left hand of a boy aged 6 years with recessive autosomal HPP (compound heterozygous mutations). Note the defective mineralization of the radial metaphysis (yellow arrow 1) and ulnar (2) with a ‘lick’ appearance.

2B. Standing weight bearing radiography of the same patient’s legs showing genu varum , the same hypomineralization lesions of the inferior femoral metaphyses (arrow 1) and muscle deficiency (3).

2C. Whole body MRI of a girl aged 12 years with dominant autosomal HPP. Bilateral lesions of the proximal metaphyseal and diaphyseal regions of the humerus evidenced by STIR hypersignal; bilateral lesions of the same type affecting the proximal metaphyseal and diaphyseal regions of both femurs, more marked at the knees (femoral and tibial epiphyseal regions) and ankles.

Zoom

Thus, in adults, the radiological diagnosis is based on signs that are not specific and likely becomes more difficult.

Other radiological features identified during childhood are slender bones, muscle insufficiency (Figure 2), delayed fracture consolidation and pseudarthrosis. In some patients, bone or joint pain may be the main manifestation of the disease. The mineralization defect may be mild leading to a long diagnostic errance. Such patients present with episodes of inflammation with swelling of wrist, knee and ankle joints. The patients complain of back pain and their quality of life is markedly impaired. The pain is generally alleviated by non-steroidal inflammatory drugs (NSAID). Whole body magnetic resonance imaging (MRI) may evidence images at the ends of the long bones and some flat bones (shoulder blades): zones in hyposignal T1 and in hypersignal STIR (Short-tau inversion recovery) (Figure 2) [9]. Those images are compatible with bone edema.

Radiological diagnosis in adults

Radiological diagnosis of HPP is a real challenge since there are no specific signs of the disease. Radiography constitutes a component of the clinical, radiological and laboratory picture that ultimately enables diagnosis of HPP. The signs visible on standard X rays are: recurrent metatarsal fractures (Figure 3A), vertebral crush fractures, femoral pseudo-fractures (Figure 3B), areas of osteolysis or osteonecrosis, foci of chondrocalcinosis, the sequelae of pediatric disease, and peri-articular calcifications [10, 11, 12, 13].



Figure 3


Figure 3. 

Radiological characteristics of hypophosphatasia in adults.

3A. Stress fracture of the fourth metatarsal (arrow 1).

3B. Pseudo-fracture of the lateral cortex undergoing consolidation. Images derived from [15].

Zoom

Contribution of imaging to follow-up
Cranial radiograph or brain CT scan

Infants and children with HPP aged less than 5-6 years undergo very close monitoring of brain growth since the risk of craniosynostosis is very high. If the increase in cranial circumference slows, ocular fundus examination is indicated to investigate for papillary edema. Preoperative cranial radiography or brain CT scan may be conducted at the surgeons request to review the closure status of the cranial sutures (Figure 4).



Figure 4


Figure 4. 

Imaging craniosynostosis

4A. Radiography of the skull showing the typical presentation of craniosynostosis with chronic intracranial hypertension and digitiform impressions.

4B. Preoperative brain CT scan and three-dimensional reconstruction; partial closure of the sutures; digitiform impressions visible.

Zoom

Renal ultrasound

Required for infants subject to hypercalcemia and hypercalciuria, renal ultrasound enables screening for nephrocalcinosis. In severe forms, screening should be conducted every three months for the first year of life, and annually thereafter. In patients diagnosed after the neonatal period, and not subjected to hypercalcemia, renal ultrasound should be performed every 3-5 years and at the time of transition.

EOS radiography

This new mode of radiography uses ultrasensitive transducers that enable the dose of X rays administered to be reduced. It also allows imaging of the standing weight bearing patient and three-dimensional reconstructions. Because of the quality of images, the EOS tool is mostly indicated for follow-up purposes rather than diagnosis. Therefore, we recommend using the EOS system for the follow up of bone deformities, fractures and scoliosis.

Bone mineral density monitoring

It is currently very difficult to determine the real value of bone mineral density monitoring in patients with HPP. In an initial retrospective review, Michael Whyte et al. reported an approximate correlation between HPP severity and bone density (The severe forms had very low density and the moderate forms almost normal density) [7]. In children bone density tends to decrease gradually, reflecting a progressive exacerbation of the disease [10, 11]. The important point is not to orient patients toward an erroneous diagnosis of osteoporosis because they have a low bone density in the context of bone fragility [12]. Bone density is currently included in follow-up exams of patients affected with HPP although their precise contribution to the disease evolution has yet to be shown.

Conclusion

Imaging is critical at all stages both for diagnosis and management of patients affected with HPP. Imaging highly contribute to the diagnosis of the disease. It is essential to work closely with the teams of radiologists (for children and for adults) in order to set up a radiological sparing policy while optimizing monitoring. It is necessary to anticipate the changes in monitoring and expected modifications in the event of enzyme replacement therapy. To do so in-depth knowledge of the physiology is necessary, together with networking with the expert multidisciplinary centers.


Acknowledgements

We thank the department of pediatric radiology at Bicêtre Paris Sud hospital for their contribution in obtaining didactic images.

Statements of interests

A. Linglart and J.-P. Salles have received fees from Alexion Pharmaceuticals for occasional interventions and expert reviews, and have been or are principal investigators or investigators in clinical trials sponsored by the company.

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