Craniosynostosis as the Presenting Feature of X-linked Hypophosphatemic Rickets

Discussion

We describe 2 patients who were diagnosed with congenital sagittal craniosynostosis in early infancy, before any other signs of rickets developed and before the diagnosis and initiation of treatment of XLH. Although multiple reports have described secondary craniosynostosis in older children with XLH, congenital craniosynostosis as a presenting feature of XLH in children <1 year old has not been described. In a case series of 3 children with XLH and craniosynostosis, authors described 1 boy with a scaphocephalic head shape from birth, which suggested early development of craniosynostosis, but evaluation for and diagnosis of sagittal synostosis did not occur until he was 2 years old.⁸ In our 2 cases, we suggest expansion of the previously described time line of craniosynostosis development in children with XLH.

In a retrospective study, Seruya et al⁷ assessed the age of initial craniofacial evaluation in 211 children with craniosynostosis due to a variety of etiologies. In the entire cohort, the median age of presentation with craniosynostosis was 4.1 months. Patients with syndromes associated with craniosynostosis and those without syndromes presented at similar median ages of 4.0 to 4.1 months. In contrast, the 3 patients with XLH in that study presented at a much later median age (32.3 months).⁷ In one study of 59 children with different forms of rickets, the authors identified 16 children with craniosynostosis who were diagnosed at a median age of 45.6 months.⁶ In another study, the authors looked at 10 children with hypophosphatemic rickets, 5 of which had XLH, and described the evaluation of craniosynostosis in those with XLH ranging from 13 months to 5 years, with the median age of 24 months.⁵

The development of craniosynostosis in general, and particularly in XLH, is not fully understood, and a variety of mechanisms have been proposed. Elevated concentrations of fibroblast growth factor 23 (FGF23) due to the loss of function mutation in the PHEX gene has been thought to lead to the deregulation of phosphate and vitamin D metabolism in patients with XLH.^5,9 Interaction of FGF23 with FGF receptors 2 and 3 along cranial sutures has also been hypothesized as a mechanism of developing secondary craniosynostosis.^10,11 Additionally, in mouse models, PHEX interacts with a matrix extracellular phosphoglycoprotein, which inhibits bone mineralization.¹² Abnormal phosphate metabolism and inhibition of bone mineralization both have the potential to contribute to craniosynostosis. Vitamin D toxicity has previously also been suggested as a contributing factor in craniosynostosis development, and authors of 1 report described a 14-month old boy with XLH who developed craniosynostosis after 6 months of treatment with 1-α -cholecalciferol. The boy had symptoms of vitamin D toxicity, including anorexia, irritability, and failure to thrive, and was diagnosed with scaphocephaly and increased intracranial pressure.¹³ However, vitamin D is unlikely to be the only factor in development of craniosynostosis in children with XLH because many other cases of craniosynostosis develop in children without laboratory or clinical evidence of vitamin D toxicity.^6,8,10,14

Proposed mechanisms contributing to primary craniosynostosis include in utero fetal head constraint,^15,16 prenatal exposures to valproic acid, maternal hyperthyroidism,⁴ and several genetic mutations.¹⁷ Mutations associated with syndromic craniosynostosis include twist homolog 1, fibroblast growth factor receptor 2, fibroblast growth factor receptor 3, and ephrin-B1.^3,17,18 Mutations in twist homolog 1 are the cause of Saethre Chotzen syndrome, whereas fibroblast growth factor receptor mutations cause Pfieffer and Crouzon syndromes, and mutations in ephrin-B1 cause craniofrontonasal dysplasia. These syndromes are often associated with bicoronal synostosis and midface anomalies, which were not found in our patients. Because genetic testing has not been shown to be helpful in cases of isolated sagittal suture synostosis,¹⁹ additional testing was not performed in our patients. In contrast, genetic testing is often performed for bicoronal or multisuture synostosis or craniosynostosis with other phenotypic features.^17,18,20 Treatment, including surgery to allow for cranial expansion and normalization of head shape, and may be performed via strip craniectomy or open cranial vault remodeling, which is largely dependent on institutional preference.

To date, an association between congenital craniosynostosis and rickets has not been described. Previous reports on children with rickets suggest monitoring for skull changes once the rickets diagnosis is made,^7,21 which often occurs after infancy. Our patients show that craniosynostosis can present early in life, before any other symptoms or treatment of rickets. We now suggest that screening for XLH and other forms of hypophosphatemic rickets could be included in the evaluation of primary or congenital craniosynostosis in patients with either a family history and/or clinical features of rickets. Initial tests may include serum alkaline phosphatase and phosphorous as well as urine phosphorous. These tests are a cost-effective method for the initial evaluation of primary craniosynostosis in patients with a family history of bone mineralization diseases or those with evidence of rickets. We also recommend surveillance for skull shape abnormalities by careful physical examination in all children at the time of diagnosis of XLH or other forms of rickets and repeated over time. We recommend that this monitoring is extended to infants and children who are at risk for familial forms of rickets.