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Archives de pédiatrie
Volume 24, n° 5S2
pages 566-570 (mai 2017)
Doi : 10.1016/S0929-693X(18)30017-4
Hypophosphatasia in children and adolescents: clinical features and treatment
Hypophosphatasie chez l’enfant et l’adolescent : présentation clinique et traitement
 

A. Rothenbuhler , A. Linglart
 AP-HP, Centre de référence des maladies rares du métabolisme du calcium et du phosphate, Plateforme d’Expertise Maladies Rares Paris-Sud, filière OSCAR and service d’endocrinologie pédiatrique, hôpital Bicêtre Paris-Sud, Le Kremlin-Bicêtre, France 
 INSERM U1169, hôpital Bicêtre, Le Kremlin-Bicêtre, université Paris-Saclay 

*Corresponding author.
Summary

Hypophosphatasia (HPP) is a rare genetic disease due to loss of function mutations in the gene that encodes for Alkaline Phosphatase-Liver (ALPL ) that encodes for tissue non-specific alkaline phosphatase (TNSALP) or ALP. Juvenile HPP is, by definition, diagnosed between 6 months of age and adulthood. The clinical signs and symptoms of juvenile HPP are very heterogeneous in their presentation, severity and course. The bone (impaired bone mineralization, leg deformations, pain, rickets, growth abnormalities) and dental (premature loss of deciduous teeth) abnormalities are the best known. However, in juveniles, muscular and joint abnormalities are frequently predominant. Treatment options currently remain limited to the symptomatic treatment of pain and impaired function. Promising results of the enzyme replacement therapy have been demonstrated in severely affected children with HPP. Efficacy and long term benefits in patients affected with the juvenile form are still to be proven.

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Résumé

L’hypophosphatasie (HPP) est une maladie rare due à des mutations « perte de fonction » dans le gène Tissue-Nonspecific Alkaline Phosphatase (TNSALP ) qui code pour les phosphatases alcalines (PAL). L’HPP juvénile est, par définition, diagnostiquée entre l’âge de 6 mois et l’âge adulte. Ses symptômes cliniques sont très divers dans leur présentation, leur sévérité et leur évolution. Les atteintes osseuses (défaut de minéralisation osseuse, déformations des membres inférieurs, douleurs, rachitisme, anomalies de la croissance) et dentaires (perte précoce des dents de lait) sont les mieux connues. Cependant, à cet âge, les manifestations musculaires et articulaires sont souvent au premier plan. Les possibilités thérapeutiques restent limitées à ce jour à un traitement symptomatique des douleurs et du déficit fonctionnel. Alors que le traitement par enzymothérapie recombinante semble efficace dans les formes néonatales sévères d’HPP, il reste à démontrer son efficacité à long terme chez les patients atteints de la forme juvénile.

The full text of this article is available in PDF format.
Introduction

HPP is a rare disease due to defective ALP function. In the vast majority of cases, the patients have loss of function mutations of the gene Alkaline Phosphatase-Liver (ALPL ) that codes for the tissue non-specific ALP (TNSALP) or ALP. The neonatal, infantile and adult forms of HPP are described in specific articles in this edition. Here, we address the clinical presentations and therapeutic options of HPP in children and adolescents. The most difficult phase of diagnosis is the initial orientation since symptoms are diverse, of very variable severity, of low specificity and, poorly recognized. Once the diagnosis has been suspected, it is confirmed through a biochemistry investigation by low ALP levels, if possible, elevated PLP levels, and later on through a molecular analysis. This stage may necessitate ruling out other causes of low ALP (see differential diagnosis addressed in another chapter of this edition). The therapeutic options currently remain limited: symptomatic treatment of the pain, calcium intake to promote the mineralization and non-aggressive physiotherapy. Despite the very positive effects of recombinant ALP (ERT) in severe neonatal forms, its effects in less severe forms have yet to be elucidated.

Clinical presentation

HPP is a heterogeneous disease that may be revealed at any age by a wide range of symptoms due to the lack of ALP activity, resulting in defective mineralization of bone and the teeth and pathological accumulation of ALP substrates in tissues. Various forms of HPP are distinguished on the basis of age at diagnosis: neonatal, infantile, juvenile and adult. However, it should be borne in mind that they are forms of the same disease and that there is a continuity in disease course. Even though neonatal forms are more severe and may be life threatening, HPP diagnosed in childhood or adolescence may progress toward highly incapacitating dental, bone, joint and muscle involvement, and should not be erroneously considered as a benign form. Childhood and adolescent HPP, commonly referred to as the juvenile form’ is, by definition, diagnosed between age 6 months and adulthood [1, 2].

Disease history, personal and familial bone, dental and rheumatological history are of great diagnostic value and may suggest the diagnosis in paucisymptomatic forms and in patients presenting with muscle and rheumatological manifestations. In children or adolescents, there may be a history of early loss of lacteal teeth, which did not necessarily attract medical attention at the time, rickets that was spontaneously alleviated, or late acquisition of walking. Not only are the symptoms clinically heterogeneous, but they may spontaneously regress over the first years of life before emergence of muscle or joint symptoms. In familial forms, in parents and other relatives, there may be a history of repeated fractures, early adult tooth loss, chronic bone or joint pain, muscle weakness, early osteoporosis, chondrocalcinosis, pseudo-fractures, pseudarthrosis or late fracture consolidation (cf article on adult HPP). Bone and dental impairments are the best investigated features of the juvenile HPP. However, in juveniles, the muscle and joint manifestations are often predominant.

Dental impairment

Dental impairment is the subject of another article in this special edition and will not be addressed in detail here [2, 3, 4, 5]. Early loss of lacteal teeth (pathological before age 5 years but occurring often before the third year of life in HPP) with their roots is a frequent and almost pathognomonic sign of HPP. The absence of tooth loss does not rule out the diagnosis [1, 2]. Clinically, before loss, the tooth becomes abnormally loose and ‘long’ due to gradual recession of the gingival tissue. Despite this very specific sign, HPP may not be diagnosed.

Bone impairment

The bone impairment reflects defective mineralization of bone and growth cartilage [1, 2]. The clinical signs are again highly variable depending on the severity of the HPP. The child may be completely asymptomatic or the presentation may be like that of rickets with broad metaphyses, bone pain and varum or valgum deformation of the legs. Due to the pain (and muscle involvement, to be discussed later) the child may present with delayed motor acquisition, in particular delayed acquisition of walking. Bone pain may be predominant in children who have learned to walk but then refuse to do or who have fits of crying. In the absence of orientation via patient interview, rickets (due to deficiency or genetic defect) cannot be clinically distinguished from HPP; ALP assay enables the distinction between the 2 diseases. Repeated fractures have also been reported [6], as has early scoliosis in the first year of life [7]. Those two manifestations are however rare at that age. The signs of bone involvement and pain may regress spontaneously. The pulmonary hypoplasia resulting from defective thoracic mineralization often gives rise to pectus excavatum which may result in a persistent restrictive pulmonary syndrome.

Skeletal X rays (addressed in another article) may show hypomineralization, abnormalities of the mineralization of the metaphyses (which resemble those observed in rickets), radiolucent fields at the extremities of the long bones (known as HPP specific radiolucent ‘tongues’) bone deformities and slender bones.

Bone mineral density (BMD) has been poorly studied in the context of the juvenile forms of HPP. In adults, low bone mineralization may result in an erroneous diagnosis of osteoporosis and bisphosphonate treatment, which is not recommended for HPP [8]. Few data are available for children. However, it appears that BMD, expressed as Z-score, decreases over time and is impaired in severe forms of HPP (Figure 1) [2, 9]. Currently, BMD is not a diagnostic or therapeutic decision making factor in juvenile HPP.



Figure 1


Figure 1. 

Plot of height and weight Z-scores as a function of height and spinal bone mineral density (BMD spine) in 4 groups of patients classified as: infantile (INF); severe juvenile (Juv S); moderate juvenile (Juv M) and odontological (Od). Figure adapted from [2, 10].

Zoom

The bone mineralization defect may have an impact on growth resulting in a reduction in growth rate and stunting.

The growth retardation is proportional to the ALP deficiency and disease severity [2, 10]. It is always present when the disease emerges in early childhood and the patient presents with gastrointestinal symptoms [10]. When the diagnosis is made later in life -or in a context of minor symptoms- the final height is close to normal [2]. It should, however, be noted that the studies on the subject were not conducted on patients who had reached their final height [2, 10]. In the largest and most contributive study, the data were acquired between ages 4 months and 21 years, while it is highly probable that pubertal growth is impaired in some patients [2]. Growth retardation may therefore have been underestimated by that approach. In a Japanese study, a subgroup of patients with moderate growth hormone deficiency was evidenced [10].

Craniosynostosis may develop until the age of 4-5 years. Its diagnosis is essentially clinical through the follow-up of the cranial circumference and cranial deformation When of late onset, it may induce few clinical signs. Hence the importance of imaging and screening for deafness and chronic papillary edema.

While the bone and dental clinical manifestations of juvenile HPP have been clearly described, the muscle and joint manifestations are less known. Patients often complain of chronic pain, muscle and joint stiffness, and weakness of the legs. These symptoms are not fully explained by the bone lesions and result from the combined bone and muscle or joint impairment.

Joint disease or ‘pseudo-gout’

The pathophysiology of joint disease in HPP probably involves chronic inflammation secondary to the deposit of calcium pyrophosphate or phosphate crystals around joints (cartilage and fibro-cartilage) or in soft tissues. The substrates of TNSALP accumulate in the absence of hydrolysis. The deposits may induce acute synovitis, known as pseudo-gout, or potentially destructive pyrophosphate chronic joint disease [11]. The joint manifestations are also highly heterogeneous: chronic joint pain with or without local signs of inflammation; single joint acute arthritis or an acute multiple joint painful syndrome [2]. Non-steroidal anti-inflammatory drugs (NSAID) are effective in treating the chronic pain and improve the physical performance of patients with HPP, suggesting a mechanism involving inflammation [12].

Clinical pictures suggesting non-bacterial chronic recurrent multifocal osteomyelitis (CRMO) have also been reported in children and adolescents with HPP. The chronic non-specific bone pain responds to NSAID therapy. The radiological picture mimics infectious osteomyelitis as do the bone scintigraphy and the whole body magnetic resonance imaging (MRI) findings [13, 14]. MRI is the preferred imaging technique in that situation. In some cases, the joint and bone pain may be extremely incapacitating with major impact on quality of life despite long term NSAID therapy [12, 15].

Myopathy

The pathophysiology of muscle involvement is not known [2, 10, 16, 17]. However, clinically, some infants may experience retarded acquisition of motor skills (particularly walking), unstable waddling gait with muscle weakness predominating in the girdles, and muscle pain and stiffness. Children may have difficulty going up or down stairs.

Other signs

Gastrointestinal signs such as poor weight gain, anorexia, nausea, and vomiting, suggesting reflux, have been reported but their pathophysiology has yet to be elucidated.

Laboratory signs
ALP

Abnormally low ALP for age and gender should trigger a suspicion of HPP [16, 17]. Two points need to be stressed in the particular case of the juvenile form of HPP:

The ALP level is (broadly) inversely proportional to disease severity (the more severe the disease, the lower the ALP level) (Figure 2). Some patients may have a moderately low ALP level that may not be detected in a diagnostic panel since clinicians tend to focus on high rather than low levels.
In children with HPP and in normal children, the ALP level increases gradually during childhood and as puberty approaches. However, in HPP the values remain less than those of children of the same age and gender. It is therefore crucial to use appropriate normal ranges.



Figure 2


Figure 2. 

Plot of alkaline phosphatase levels in 3 groups of patients: infantile HPP (INF), juvenile HPP (Juv) and adult HPP (Adu). Figure adapted from [10, 23].

Zoom

ALP substrates

In the laboratory, accumulation of the natural substrates of ALP may be evidenced in blood and urine: inorganic pyrophosphate (PPi), pyridoxal 5-phosphate (PLP) and phosphethanolamine (PEA), but assay of those substrates is not routinely conducted in most countries [18]. Most patients with HPP have elevated urinary excretion of PPi but this is less patent in minor forms. Elevated blood and urine levels of PEA are not specific to HPP. Elevated PLP is a more specific marker and the values are correlated with disease severity.

Calcium and phosphate levels

Blood calcium and phosphate and urinary calcium may be elevated due to defective bone mineralization particularly in young children (up to 4-5 years), or if an event such as prolonged immobilization or a fracture promotes mineral release from the skeleton [16, 17, 19]. In consequence, parathyroid hormone (PTH) levels may be suppressed. Latent and prolonged hypercalciuria may induce nephrocalcinosis visible under ultrasound. After early childhood, calcium, phosphate and calciuria usually normalize enabling, in general, adjustment of calcium and vitamin D intakes.

Treatment options
General measures

Treatment has to take into account a set of very diverse problems: chronic pain; muscle, joint and skeletal impairment; fractures; and potential renal, psychological and dental issues. The objective is to alleviate the symptoms and avoid complications. The patient must be followed up by a multidisciplinary team in cooperation with a reference center. The team coordinates the overall management and the recourse, or non recourse, to the specific treatment of the disease by recombinant enzyme replacement therapy.

Only general rules will be formulated here. Potentially harmful treatments should be proscribed, such as bisphosphonates (which would further suppress TNSALP activity and be ineffective on bone mineralization) and high dose of vitamin D which could exacerbate the hypercalciuria by promoting excessive digestive absorption of calcium [4].

Overall management consists in ensuring appropriate nutritional support particularly in the event of poor weight gain or insufficient growth velocity. Antireflux therapy is often necessary and nutritional support may involve enteral nutrition via a gastric tube for several months or years. Vitamin D supplementation throughout growth is crucial. It should be given to target the lower limit of the normal range for 25-OH-vitamin D (about 20ng/mL). The objective is to prevent any secondary hyperparathyroidism due to vitamin D deficiency or excessive calcium absorption hence hypercalcemia/hypercalciuria due to excessive vitamin D levels. Therefore, the upper limit of the 25-OH-vitamin D target range is given by the PTH level (25-OH-vitamin D level that does not suppress PTH), generally about 40ng/mL. Calcium and phosphate supplementation should be avoided during the phases of hypercalcemia, hyperphosphatemia and hypercalciuria (whether or not complicated by nephrocalcinosis or renal calculi). In the absence of any laboratory or renal abnormalities, the supplementation should follow the recommendations adjusted for age. NSAID are used discontinuously as analgesics. If they are administered frequently, renal function should be monitored [15]. Physical exercise taking into account the patient’s fracture risk is also recommended together with physiotherapy, in particular to strengthen the girdle muscles.

The role of the orthopedic surgeon expert in HPP is important as fracture have delayed consolidation times and often require prolonged immobilization of the injured limb or the use of rods. Their role is crucial with regard to indicating and following up surgery for leg deformities, which may induce rheumatological sequelae, and for the management of patients who develop a scoliosis.

Enzyme recombinant therapy

A novel therapy by recombinant alkaline phosphatase was recently developed that targets the bone. In very young, severely affected children, encouraging results have been reported, showing a significant gain in survival rate and bone mineralisation. A significant number of patients developped craniosynostoses and tracheomalacia [20, 21]. Mid-term results (5-years) have demonstrated improvement in growth and function [22, 23].

Conclusion

Juvenile HPP has a wide variety of clinical presentations, which may sometimes render diagnosis difficult, particularly when the disease manifests as chronic pain, and/or bone and muscle impairment. The family interview is critical in suspecting the diagnosis by identifying a past history of dental and bone features. The measure of ALP activity rapidly and simply confirm the diagnosis, together with the mutation(s) of the ALPL gene. Currently, therapy often consists of symptomatic treatment of the pain by NSAID, physiotherapy and diet adjustment. The use of ERT in children affected with the juvenile HPP will depend on the results of clinical trials, the severity of the disease and its impact on the patient’s function and quality of life. Management must be comprehensive and multidisciplinary, involving experts from reference centers.


Statements of interests

A. Rothenbuhler is co-investigator in a clinical trial sponsored by Alexion pharmaceuticals. A. Linglart has received fees from Alexion Pharmaceuticals for occasional interventions and expert reviews, and has been or is principal investigator or investigator in clinical trials sponsored by the company.

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