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Archives de pédiatrie
Volume 24, n° 5S2
pages 589-592 (mai 2017)
Doi : 10.1016/S0929-693X(18)30022-8
Craniosynostosis and hypophosphatasia
La craniosténose dans l’hypophosphatasie
 

F. Di Rocco 1, , G. Baujat 2, V. Cormier-Daire 2, A. Rothenbuhler 3, A. Linglart 3, 4
1 Neurochirurgie pédiatrique Hôpítal Femme-Mère-Enfant, Lyon, université Claude-Bernard Lyon 1, France 
2 Centre de référence maladies osseuses constitutionnelles (MOC), filière OSCAR, Institut Imagine, AP-HP, hôpital Necker, Paris, France 
3 AP-HP, Centre de référence pour les maladies rares du calcium et du phosphate, Plateforme d’Expertise Maladies Rares Paris-Sud, filière OSCAR and service d’endocrinologie pédiatrique, hôpítal Bicëtre Paris-Sud, Le Kremlin-Bicêtre, France 
4 INSERM U1169, hôpital Bicëtre, Le Kremlin-Bicêtre, université Paris-Saclay, France 

*Corresponding author.
Summary

Hypophosphatasia (HPP) when diagnosed at a young age may induce premature fusion of one or several cranial sutures, resulting in a craniocerebral disproportion. The main forms of craniosynostosis associated with HPP are loss of the sagittal suture (scaphocephaly), alone or associated with loss of the coronal sutures (oxycephaly) or associated with loss of the coronal and lambdoid sutures (pansynostosis). Craniosynostosis is accompanied by putatively functional consequences. Diagnosis must thus be early and lead to management by a specialized team.

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Résumé

L’hypophosphatasie (HPP) peut entraȋner dans ses formes infantiles la fermeture prématurée d’une ou plusieurs sutures crâniennes entraȋnant une disproportion cranio-encéphalique. Les principales atteintes associées à l’HPP sont la perte isolée de la suture sagittale (scaphocéphalie) ou associée aux sutures coronales (oxycéphalie), voire aussi aux lambdoīdes (pansynostose). Ces craniosténoses s’accompagnant de risques fonctionnels potentiellement graves, leur diagnostic doit être précoce et amener à une prise en charge en milieu spécialisé.

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Introduction

Craniosynostosis is defined as craniofacial skeletal deformations related to growth impairment and premature closure of one or more cranial sutures. Most cases are isolated and idiopathic. Some cases are included into syndromes and causing genes involved in cranial morphogenesis have been identified. The genes most frequently involved are: Fibroblast Growth Factor Receptor (FGFR) 1, 2 and 3, TWIST and Transcription Factor (TCF) 12 . In other cases, the craniosynostosis is secondary to a disease or syndrome affecting the entire body. In particular, metabolic diseases and rickets cause craniosynostosis. The association between craniosynostosis and rickets has long been recognized since it was first reported by Heschl in 1873 [1]. At that time, vitamin D deficiency was the main cause of rickets. Since then, the epidemiology of rickets has evolved, ‘vitamin D deficient’ craniosynostosis has become excessively rare and mainly consists in exceptional cases such as those reported by Wang et al. (child subjected to a deficient diet) or Shetty et al. (child on anti-acid treatment) [2, 3]. Most cases of craniosynostosis secondary to rickets are familial, genetically inherited, and occur in the context of two main diseases: HPP and X-linked hypophosphatemia [4, 5, 6]. The forms of craniosynostosis potentially associated with HPP are addressed herein [7, 8].

Epidemiology and diagnosis

Since the number of cases of vitamin D deficiency rickets has markedly decreased in France, cases of craniosynostosis classified as “secondary” are rare. Only a few series have been reported. However, it may be estimated that between one and two thirds of HPP cases present with craniosynostosis [9, 10]. The pathophysiological reasons for which some patients with HPP develop craniosynostosis are not known. Biochemical analyses of bone from surgically treated patients and the various mutations of the gene ALPL have not enabled identification of specific risk factors for this skeletal complication [10].

The age at which craniosynostosis in HPP is diagnosed ranges from a few months to a few years. Its recognition generally occurs earlier if HPP has been diagnosed at birth or in infancy, since craniosynostosis is one of the very well known features of the infantile form [6, 11, 12]. However, craniosynostosis is sometimes detected before HPP is diagnosed and should trigger the measurement of alkaline phosphatase. The diagnosis of craniosynostosis is essentially clinical and based on recognition of the cranial deformation induced by the loss of one or several sutures and/or the absence of cranial circumference growth. Noteworthy, in the context of HPP, the emergence of craniosynostosis may be late, at a stage at which the degree of skull deformation is limited, rendering difficult a clinical diagnosis. Complementary imaging then plays an essential role. Sometimes, even the radiological presentation may be challenged: the suture may still be visible on X-rays but made of sclerotic / not active tissue [13, 14].

Forms of craniosynostosis

The suture closure in HPP can be divided in two different groups:

isolated fusion of the sagittal suture;
fusion of more than one suture leading to oxycephaly, or even pansynostosis.

In the event of premature closure of the sagittal suture, the skull undertakes a scaphocephalic shape (Figure 1 and Figure 2): growth occurs in an anterioposterior direction at the expense of the biparietal diameter, the forehead is tight and bulges, and the posterior part of the skull may form an occipital ‘bun’. However, if closure of the sagittal suture occurs later, in early childhood, the cranial deformation is limited. This explains why, in certain cases, loss of the sagittal suture may not be associated with cranial deformation and only be detected by imaging. In other cases, sagittal and coronal sutures are closed, imparting an oxycephalic appearance (Figure 1 and Figure 3) to the head. A bregmatic bulge is palpable, or even visible, and there may be a degree of retrusion of the supraorbital ridge. The lamboidal sutures may also be fused in certain cases (pansynostosis). Sometimes, while only the sagittal suture fuses initially, the other sutures may gradually close resulting in pansynostosis [10].



Figure 1


Figure 1. 

Diagrammatic representation of the suture system viewed from above and laterally. From top to bottom: normal skull shape, scaphocephaly and oxycephaly.

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Figure 2


Figure 2. 

Cranial CT scan: three-dimensional reconstruction; premature fusion of the sagittal suture (scaphocephaly).

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Figure 3


Figure 3. 

Lateral radiography of the skull: loss of all the cranial sutures (pansynostosis) with diffuse digitiform impressions.

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Progressive consequences

The risks associated with craniosynostosis are functional and esthetic. Since the deformation is often moderate, the esthetic consequences are usually mild. However, the risk of developing functional complications is high, and probably higher in HPP than in idiopathic craniosynostosis. The main risk associated to craniosynostosis is intra-cranial hypertension (ICHT) mediated by the craniocerebral disproportion. The growth of the skull is impaired; its volume and compliance are insufficient for the brain. In mild forms, patients complain of recurrent headaches. Chronic ICHT may have long term repercussions on the overall quality of psychomotor development and on sight (papillary edema, optic nerve atrophy). On the long run there is a risk of cognitive deficiency and blindness. The risk is proportional to the number of fused sutures. The cranio-cerebral disproportion also induces prolapse of the cerebellar tonsils, hence type 1A Chiari’s malformation and syringomyelia. The potential lesion is thus not limited to the roof of the skull but involves the craniovertebral junction region or even the entire spinal cord.

Additional investigations

Standard frontal and lateral cranial radiography is of limited value. It evidences the loss of one or more sutures and the presence of digitiform impressions reflecting craniocerebral disproportion. Cranial CT scan with three-dimensional reconstructions not only enables the entire suture system to be imaged with great precision but also visualizes the cerebral and cerebellar contents. Due to the radiation administered, CT scanning must be as limited as possible. Magnetic resonance imaging (MRI) provides clear images of the brain, together with the craniovertebral junction and the spinal cord (investigation for type 1a Chiari’s malformation and syringomyelia). However, MRI does not image correctly the suture system. It may require sedation or even anesthesia for children. The consequences of the craniosynostosis should be investigated through ocular fundus examination to look for ICHT (papillary edema or even optical nerve atrophy). Normal ocular fundus findings do not, however, rule out potential chronic ICHT.

Treatment and management

The treatment of HPP-associated craniosynostosis is currently surgical while waiting for pharmacological progress to enable development of other therapeutic approaches. [15, 16, 17]. Surgery allows the cure of functional and esthetic complications of the craniosynostosis. Surgery is indicated as of diagnosis if the patient is symptomatic or if several sutures are involved, particularly if presence of oxycephaly because of the high risk of ICHT and blindness. When only the sagittal suture is fused (usually asymptomatic), ‘preventive’ surgery may be considered to correct the craniocerebral disproportion and prevent the emergence of ICHT and prolapse of the cerebellar tonsils. However, the disproportion associated with craniosynostosis may not be fully attenuated by the surgery. It is thus only possible in cases of moderate and well tolerated impairment to refrain from surgical intervention. Patient follow-up then needs to be extremely rigorous so as not to overlook any clinical degradation (neuropsychological or ophthalmological) or anatomical (emergence of syringomyelia) degradation. Overall, half to two thirds of HPP patients require corrective surgery.

Several surgical techniques are available. The choice of the technique depends on the symptoms, the sutures involved, the skull shape and the patient’s age. When IHCT motivates the surgery, the surgical technique consists in cranial remodeling, either frontal and orbital or parietal and occipital. The surgeon removes all the abnormal areas of cranial bone (including the orbital walls when deformed) and reconstructs using bone material of selected size and curvature. The principal risk associated with the procedure is bleeding. Overall, the results are highly satisfactory. The ICHT resolves in almost all cases, as do the radiological and ophthalmological manifestations. The results with radio-respect to cognitive development depend on pre-operative développement cognitive function (the earlier the surgery, the better the results).

Due to the genetic/metabolic cause of the disease, if the surgery occurs early in life, recurrence may occur.

For that reason, even in the event of ‘preventive’ surgery, it is necessary to pursue the cranial monitoring up to age of 6-7 years to detect any sign of ICHT.

Conclusion

Given the putative cognitive and ophthalmologic deleterious consequences on the future of children with HPP, early detection of craniosynostosis is essential. HPP-related craniosynostosis is more severe than idiopathic forms because of the risk of progression, the potential consequences for cranial growth, and the high recurrence rate. Craniosynostosis requires multidisciplinary management and assessment by a rare disease expert center.


Statements of interests

F. Di Rocco has no conflicts of interests to report. A. Rothenbuhler is co-investigator in a clinical trial sponsored by Alexion Pharmaceuticals. G. Baujat and V. Cormier-Daire are investigators for Alexion Pharmaceuticals and have received investigator fees and grants for cooperative projects. 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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