Introduction

Hypophosphatasia (HPT) is a genetic disease caused by a mutation in the ALP genes which encode the alkaline phosphatase isoenzyme. In many cases, the mutation affects the ALPL gene which is the isoenzyme present throughout the skeleton and teeth [1]. This enzyme is important for mineralization of bone tissue, and therefore, its absence causes abnormally formed bone which is prone to fractures [2]–[4].

Cleidocranial dysplasia (CCD) is caused by mutations in the RUXN gene which is an important gene in osteoblast cell differentiation. As a result, patients with CCD have defective ossification which affects parts of the skull base and the cavalarium. Usual non-ossified skull sites include the anterior fontanelle and all cranial sutures. CCD is combined with teeth and craniofacial dysplasia [5, 6].

There is only one reported case with combined CCD-HPT in the literature. Therefore, this will be the second reported case. Since there is such a sparse number of CCD-HPT cases, there are no official guidelines for these patients. Study of these rare cases is needed to identify their unique properties and to understand their optimal management strategy.

The case

The case involves a 3.5-year-old female with congenital craniofacial dysplasia. She was born with an extended skull ossification defect which improved progressively with age. Genetic testing revealed a RUXN2 mutation (c.1191delC) with a concomitant heterozygous ALPL gene mutation (pSer181Leu). The child received two regimens of Stresniq for a total of 1 year, which induced significant ossification. On the first evaluation, the child had an extensive anterior fontanelle in addition to profoundly wide frontal, coronal, and sagittal sutures which are aspects compatible with cleidocranial dysplasia as shown in Fig. 1. Furthermore, the lambdoid suture was prematurely fused, an aspect typical of hypophosphatasia. Additionally, there were deficits on the pterion and asterion areas which is also a characteristic of hypophosphatasia as shown in Figs. 1, 2, and 3. On palpation, the defect areas were soft but included a more rigid area near the normal bone edges, which corresponded to osteomalacia (hypomineralized bone). In Fig. 4, using a different opacity window, it is possible to observe the actual lesser bone defect and understand the overestimation of the bone defects due to the osteomalacia which is interpreted as a defect in the initial CT scan.

Fig. 1
figure 1

3D reconstruction of the patient’s skull on first evaluation

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Fig. 2
figure 2

3D reconstruction of the patient’s skull on first evaluation

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Fig. 3
figure 3

3D reconstruction of the patient’s skull on first evaluation

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Fig. 4
figure 4

3D reconstruction of the patient’s skull on first evaluation. Zoom in on the occipital area with a different opacity window showing the hypomineralized bone

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Our management strategy was to follow the patient until the age of 5 and reevaluate the final defects. A helmet was utilized for protection during the observation period. On revaluation, the defects were evaluated clinically, without further imaging. Due to the mineralization induced by Strensiq, bone defects were minor on final evaluation and therefore the child did not require any neurosurgical intervention.

Discussion

The interesting aspect about this case is the combination of the hypophosphatasia and cleidocranial dysplasia phenotype with the combined mutation on both genes. The mode these mutations affect ossification is contradictory, with hypophosphatasia leading to formation of non-calcified soft bone, causing premature suture closure, while cleidocranial dysplasia causes ossification defects which lead to profoundly wide cranial sutures. The opposite pathophysiology of these two mutations worked in favor of this child bringing balance in suture closure which with the addition of Stresniq led to an acceptable result. This dynamic balance lessened the development of craniosynostosis and facilitated the response to alkaline phosphatase. There have been some cases reported in the literature involving patients with a combined CCD-HPT phenotype but only one with both phenotypes and genotypes [7, 8].

There is significant controversy in the management of patients with hyposphatasia [3]. The low number of cases impedes the development of guidelines. The consensus is to observe patients until preschool age when bone development is mostly complete. The syndrome commonly affects cranial sutures, causing either diastatic sutures or prematurely fused sutures. If patients develop craniosynostosis, they are usually operated on diagnosis [9]. When bone development is completed, the extent of bone deficits is evaluated. Usually, deficits are minor and do not require treatment [10]. In case of diastatic hypomineralized sutures which raise concerns for cranial vault safety, the option to utilize meshes and cover the defects is always taken under consideration, although this phenomenon has rarely been described [2].

Patients with cleidocranial dysplasia are even sparser, and therefore, management practices are affected by similar issues. The usual management strategy is to observe patients until the completion of bone development and repair extended defects accordingly with the use of cement or titanium meshes[6].

There has never been a reported case of typical cleidocranial dysplasia with a homozygous genotype with a combined typical hypophosphatasia phenotype in the literature[7, 8, 11]. There has been a reported case involving a heterozygous HPT mutation with an atypical RUXN2 CCD mutation and a mixed non-typical CCD-HPT phenotype [10] but without prominent HPT characteristics. There have been multiple cases described with a CCD-HPT phenotype combination harboring either a CCD or an HPT mutation [8]. The above patient is to our knowledge the second patient reported in the literature with a combination of the two genotypes and phenotypes. Although the HPT phenotype is heterozygous, it was expressed as a non-typical HPT phenotype with premature fusion of the lambdoid suture. There is no data on the management of this patient category. The logical strategy would be observation. In case of craniosynostosis or extended bone defects, cranioplasty should be performed accordingly. Additionally, patients should apply a protective helmet during the observation period.

It should be noted that bone formed without enzyme substitution is hypomineralized causing osteomalacia which corresponds to soft bone edges which are not visible in CT scans [4]. Enzyme replacement therapy increases bone mineralization and thus decreases visible bone defects. However, after medication tapering, visible defects increase.

Conclusions

In CCD-HPT patients, craniosynostosis is less likely to develop, and bone defects are more likely overestimated in imaging studies. Due to the presence of osteomalacia, management of these defects should not be as aggressive. Evaluation of these patients should be performed after administration of Stresniq and in preschool age. Surgical repair should be performed for craniosynostosis and for extended bone defects on final evaluation.