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Archives de pédiatrie
Volume 24, n° 5S2
pages 561-565 (mai 2017)
Doi : 10.1016/S0929-693X(18)30016-2
Perinatal and infantile hypophosphatasia: clinical features and treatment
Hypophosphatasie, formes périnatale et infantile : présentation clinique et traitement
 

G. Baujat , C. Michot, K.H. Le Quan Sang, V. Cormier-Daire
 Centre de référence maladies osseuses constitutionnelles, Institut Imagine, université Paris-Descartes-Sorbonne-Paris Cité, hôpital Necker-Enfants malades, 149, rue de Sèvres, 75015 Paris, France 

*Corresponding author.
Summary

Hypophosphatasia (HPP) is a rare hereditary disease characterized by defective skeletal mineralization, and with a broad severity spectrum. The perinatal forms, lethal and non-lethal, are associated with severe neonatal respiratory distress, potential seizures, hypotrophy and marked hypotonia. The diagnosis is rapidly suggested by a combination of typical radiological signs, hypercalcemia, hyperphosphatemia and low alkaline phosphatase (ALP) activity. In the infantile form, the clinical signs appear before the age of six months, but the patients usually have no or very mild signs at birth. The diagnosis should be considered in the event of early deformation of the pectus, feeding difficulties, hypotonia, frequent respiratory tract infections, hypercalcemia, and even early constitution of craniosynostosis. Radiological signs may be less obvious characterized by irregular metaphyses and generalized hypomineralization. Management is initially symptomatic, and adjusted to the symptoms. Care should be provided by a multidisciplinary team, in close collaboration with Reference Centers experts for the disease. Currently, recombinant enzyme replacement therapy (ERT) is under development for the severe form of HPP. The course of the disease, depending on the degree of severity and the various types of management, requires long-term evaluation through joint prospective follow-up to assess the long-term outcomes of these patients. Multidisciplinary follow up is needed to identify the medical and socio-economic outcomes of children and adults affected by HPP.

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Résumé

L’hypophosphatasie (HPP) est une maladie héréditaire rare caractérisée par un défaut de minéralisation du squelette et dont le spectre de gravité est large. Les formes périnatales, létale ou non létale, sont associées à une atteinte respiratoire sévère dès la naissance, de possibles convulsions, une hypotrophie et une grande hypotonie. Le diagnostic est rapidement évoqué devant l’association de signes radiologiques typiques à une hypercalcémie avec hyperphosphorémie et à un taux de phosphatases alcalines (ALP) effondré. La forme infantile est définie par l’apparition des premiers signes avant 6 mois mais est pauci-symptomatique à la naissance. Elle doit être discutée devant des déformations précoces du pectus, des difficultés alimentaires, des infections respiratoires répétées, une hypercalcémie, voire la constitution précoce d’une craniosténose. Les signes radiologiques sont plus discrets, avec essentiellement des métaphyses irrégulières et une hypominéralisation généralisée. La prise en charge est d’abord symptomatique, adaptée aux symptômes, et assurée par une équipe multidisciplinaire, en lien avec les centres de référence experts pour cette pathologie. Elle est associée aujourd’hui à l’enzymothérapie recombinante (ERT), en cours de développement pour cette pathologie. L’évolution selon les degrés de sévérité et les différents types de prise en charge doit être évaluée à long terme, grâce à un suivi prospectif commun, afin de préciser le devenir médical et général de ces enfants à l’âge adulte.

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Introduction

Hypophosphatasia (HPP) (MIM 146300, 241500, 241510) is a rare hereditary disease that is characterized by defective mineralization of the bones and teeth. The disease is related to mutations of the Alkaline Phosphatase-Liver (ALPL ) gene coding for tissue nonspecific alkaline phosphatase (TNSALP). The latter is a membrane phospho-monoesterase, necessary for the dephosphorylation of certain substrates such as pyridoxal phosphate, involved in the production of the neurotransmitter gamma-aminobutyric acid (GABA), and inorganic pyrophosphate a central contributor to bone mineralization.

Clinically, the spectrum is broad, ranging from lethal antenatal forms to isolated dental form in adults. The most widespread classification is based on age at symptom onset, and distinguishes the following:

the perinatal forms, either lethal or non-lethal;
the infantile form (first signs before 6 months);
the juvenile form;
the adult form; and
the odonto form, whose manifestations is restricted to the teeth [1].

There is a sixth form, the benign perinatal form, which presents during the second trimester of pregnancy and is characterized by alleviation of the signs during the third trimester or after birth.

The inheritance is autosomal yet with variable mode of transmission. Recessive HPP is related to biallelic loss of function of ALPL (homozygotes or compound heterozygotes) and is usually associated with severe phenotypes diagnosed in utero . Dominant HPP is related to heterozygous mutations of ALPL , and is mostly associated to mild phenotypes. Phenotype – genotype correlation analysis is ongoing but has yet not been fully established [2]. This chapter is devoted to the perinatal and infantile forms.

Clinical presentations
Before birth

HPP is usually suspected when discovering through ultrasound imaging short long bones associated with an overall mineralization defect and, sometimes, the lack of imaging of certain bones (skull, ribs, vertebrae, pubis). Metaphyseal irregularities may be imaged by ultrasound. Cerebral structures are imaged too clearly and too easily. The long bones may simply be slightly short and the femurs curved. In that case, the main differential diagnosis is Osteogenesis Imperfecta (OI) [3]. Antenatal fractures are rare. The presence of diaphyseal bony spicules is specific of HPP; unfortunately, they are rarely observed. In addition to OI, the main differential diagnoses are cleidocranial dysplasia, type II mucolipidosis, Stüve-Wiedemann syndrome and Caffey’s disease [2]. If the diagnosis is suspected during the first trimester of the pregnancy, the prognosis is poor since the majority are quickly lethal. If the disease is suspected during the second trimester, both diagnosis and prognosis will be difficult to predict. From 28-30 weeks of amenorrhea, three-dimensional bone CT scan may be of great help, as it has good sensitivity and specificity for the diagnosis of the disease. Antenatal molecular diagnosis through amniocentesis and ALPL sequencing may confirm the diagnosis. However, the correlation between the genotype and the prognosis remains a challenge. Antenatal diagnosis, genetic counseling and assistance of the affected couple should be implemented in a complementary and coordinated manner in pluridisciplinary centers comprising obstetricians, radiologists, geneticists, and pediatricians specialized in foetal diseases. As it is a source of anxiety and irrevocable decisions for couples, this extremely difficult process must be optimally managed by experienced teams including key resource personnel such as genetic counseling specialists and psychologists.

The benign perinatal form is characterized by skeletal symptoms discovered during the prenatal period (bone deformations, foetal growth retardation, mineralization defect), yet presenting with a positive course from the third trimester of pregnancy. This prenatal form renders the antenatal diagnosis difficult when there is no familial history of HPP. It is therefore recommended to act cautiously when formulating a prognosis for fetuses detected during the second trimester of pregnancy. It is also necessary to follow the course of the fetus over several weeks before committing to definitive choices. Such cases are rare (17 in a series of 178 pediatric cases published by Wenckert et al . [4]). The improvement may be linked, at least in part, to maternal ALP crossing the placental barrier, which increase during the third trimester of pregnancy, therefore enabling fetal mineralization [4].

After birth

Among the early forms of HPP, the perinatal form (also known as the ‘lethal’ form, life-threatening as of the first hours of extrauterine life) is defined by the emergence of the initial signs at birth. The infantile form is defined by a later onset of symptoms, between zero and six months. Currently, thanks to the acuity of ultrasounds, affected babies are usually detected during pregnancy, and sometimes confirmed by bone CT scan or antenatal molecular diagnosis.

Perinatal form

The initial, sometimes revealing, signs vary, reflecting once again different degrees of severity. Inaugural manifestations may consist in a combination of the following:

Respiratory signs: neonatal respiratory distress from the outset with pulmonary hypoplasia, ‘rachitic lung’ (thin ribs) and hypotonia, requiring mechanical ventilation. The infant’s crying is high pitched, which is related to laryngeal hypotonia. The respiratory insufficiency may be delayed for a few hours or days, or simply present as occasional episodes of apnea. It may consist in unexplained, persistent, superficial polypnea in absence of infection [5];
Neurological signs: neonatal malaises or seizures. The seizures are recalcitrant to standard therapies but resolve on pyridoxine [6];
A pseudo-metabolic presentation: hypercalcemia with tremor and hyperphosphatemia. Hypercalcemia is always associated with hypercalciuria; it may in itself lead to feeding difficulties and vomiting, and be complicated by early nephrocalcinosis. Anemia and bradycardia are associated with a poor prognosis. Unexplained sudden death may occur.
In severe forms, a conjunctival bluish color may be observed, enabling differential diagnosis and ruling out OI.

‘Infantile’forms

‘Infantile’ forms are considered as less severe and detected later. The initial symptoms may be feeding difficulties, persistent axial and peripheral hypotonia, failure to thrive, and repeated ENT infections (rhinobronchitis), in an infant with a wide anterior fontanel. Skeletal deformations may be the initial sign, with pseudo-rachitic metaphyseal broadening, curved limbs (tibias), and progressive sternal hollowing. On palpation, the skull is soft and there is a tendency toward brachycephaly with progressive emergence of craniosynostosis. The presence of medial diaphyseal hollows (forearms, legs) is rare and reflects the diaphyseal spines already cited, but is considered specific. The hollows persist throughout growth [3]. The nephrocalcinosis may also be of early onset.

Radiological presentation

The radiological signs of severe infantile forms are characteristic: overall hypomineralization, sometimes irregularly distributed and predominating in certain bones and close to the metaphyseal area. In very severe forms, there may be no mineralization of the distal phalanges, cervical vertebrae, pedicles, and pubic bones, while the clavicles are correctly mineralized.

The ribs are thin and irregular. The cranium is poorly mineralized, with a peri-cranial border that is thin or lacking. The border is generally better conserved at the frontal and occipital bones. The ribs are thin. There is a marked appearance of ‘bone within the bone’ of the vertebrae, both frontally and laterally. The metaphyses are irregular, spicular and sometimes look torn. They may have a bifid (forked) appearance with a central radiolucency. The long bones may be curved and the sight of antenatal or peri-natal fractures. In the less marked infantile forms, the signs may be milder including mineralization defect and metaphyseal radiolucencies.

Laboratory profile

With regard to laboratory findings, low (or below the limit of quantitation) blood ALP levels are the cardinal sign of neonatal and infantile HPP. If the diagnosis is suspected, ALP is almost specific. Low ALP is accompanied by hypercalcemia, hyperphosphatemia and low PTH. Magnesium may also be elevated. Urinary phosphoethanolamine is abnormally elevated but the assay is not established in every country. Elevated levels of plasma pyridoxal 5′-phosphate (PLP) have a high specificity value but, as above, the assay is only available in few centers. In practice, clinical, radiological and biochemical profile usually rapidly allow a diagnosis of HPP which is then confirmed through a molecular analysis, after a genetic consultation in order to explain the disease and inherent genetic counseling to the parents. The study of ALPL is currently easier and faster thanks to Next-Generation Sequencing (NGS) panels, a subject addressed in another chapter [7].

Principles of treatment

Management of severe forms of the disease is initially symptomatic, multidisciplinary and, in France, supervised by the physicians of the reference and expert centers dedicated to constitutional bone diseases, metabolic disorders and rare odontological abnormalities.

Respiratory forms require adequate ventilation support, oxygen therapy ranging from nasal prongs to mechanical ventilation, and including non-invasive positive pressure neonatal ventilation. Severe forms with ventilatory dependence frequently require tracheotomy after the age of 3 months. Respiratory physiotherapy is problematic in the context of hypotonia and bone fragility.
Treatment of the hypercalcemia has been codified and consists in discontinuation of vitamin D, a low calcium diet (Locasol® milk), and oral or enteral hydration.
The neurological manifestations are very sensitive to vitamin B6 supplementation administered in the form of pyridoxine.
Feeding difficulties may require enteral nutrition through a nasogastric tube, or even, in patients necessitating long term ventilation, through gastrostomy. Discontinuous enteral nutrition regimens are often better tolerated than continuous regimens, which are associated with gastric stasis and promote vomiting. Maintaining and stimulating oral reflexes are important. Gastroesophageal reflux is almost constant and difficult to control by conventional measures (proclivous position, thickeners, prokinetics, antisecretories). Recourse to antireflux surgery is possible. Dieticians should be involved to enrich the meals and enteral nutrition.
Bone deformities (spine deformities, scoliosis, craniosynostosis) are followed up and managed by orthopedist surgeons and neurosurgeons.
Vitamin D supplementation should be carefully adjusted as a function of vitamin D and PTH levels. It should be discontinued in the event of hypercalcemia.
ERT (recombinant alkaline phosphatase) is currently under development and will be the subject of future updates. The first promising results have been reported in HPP children affected with the neonatal and the infantile form of the disease. They show a dramatic improvement of survival and function [9, 10]. Safety and efficacy will be assessed continuously through the implementation of registries.

Prognosis

Before ERT, patients with a perinatal form rarely survived. The price of survival was a long stay in intensive care, using high level technical care, leading to respiratory sequelae and neurological impairment of probably mixed etiology (an intrinsic component of GABA deficiency, impaired brain development, the sequelae of oxygen deprival, craniosynostosis with intracranial hypertension and early, sometimes recalcitrant, seizures [6, 8]). Survival of such forms has probably changed with the advent of enzyme replacement therapy. The one-year survival rate was estimated at 95% (75% being free of any ventilatory machine) and 42% in the ERT-treated and the historical cohort, respectively. The 5-years survival rate was estimated at 84 and 27% respectively. In infantiles forms, patients show a respiratory, growth, pain scores, functional and radiological after 7 years of therapy [9, 10, 11]. Side effects are described as moderate and rare, and mostly limited to site injections reactions. Clinical trials are however necessary to evaluate the best modalities to treat HPP patients given the variability of the disease and to evaluate the safety of the drug [12, 13]. teams involved in molecular diagnosis and radiologists experts in the disease is necessary to collate all the findings and provide the best, prudent and realistic diagnosis and prognosis to the affected family.

Long-term clinical trials designed to further elucidate the natural history of the disease and multidisciplinary management of the various forms of hypophosphatasia are currently ongoing with a view to improve understanding of the natural history, phenotype – genotype correlations and optimum treatment modalities; our common goal is to understand further the outcomes for the children affected at different ages.

Conclusion

The perinatal and infantile forms of hypophosphatasia are extremely rare and, in most cases, diagnosed before birth. Affected babies present with respiratory and neurological distress that may be life threatening for the most severe perinatal forms. When the diagnosis is made within the first months of life, the preeminent features are the muscular and skeletal symptoms. The diagnosis is readily suggested by the radiological findings and the assay of alkaline phosphatase activity. The elevated PLP level may be of great help as well. The molecular analysis conducted after a dedicated genetic consultation should be performed in laboratories with pertinent expertise. Treatment is currently evolving thanks to the advent of the recombinant enzyme therapy; ERT needs to be associated with the conventional symptomatic measures. Long-term multidisciplinary evaluation of the HPP children is of fundamental importance to refine further the optimal therapeutic modalities and their influence on the natural history of the disease.


Statements of interests

G. Baujat, C. Michot, K. H. Le Quan Sang and V. Cormier-Daire are investigators for Alexion Pharmaceuticals and have received investigator fees and grants for cooperative projects.

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