Hereditary hypophosphatemic rickets and craniosynostosis

J Pediatr Endocrinol Metab. 2021 Jun 21;34(9):1105-1113. doi: 10.1515/jpem-2021-0042. Print 2021 Sep 27.


Background: Craniosynostosis is an underdiagnosed complication associated with hypophosphatemic rickets. The study aims to describe the clinical and auxological characteristic of children with hypophosphatemic rickets and craniosynostosis, describe the usual treatment, and compare the characteristics with those of children without craniosynostosis.

Methods and patients: An observational and retrospective cohort study was conducted. Clinical notes and cranial images were reviewed. Out of 96 children, only the 50 patients who had skull images were included.

Results: Out of 50 patients, 26 (15 males) had craniosynostosis (52%). No differences were observed in birth size, age, height, body proportions, alkaline phosphatase, serum phosphate, or percent tubular reabsorption of phosphate at first appointment among children with or without craniosynostosis. Among patients with craniosynostosis, dolichocephaly was prevalent. The sagittal suture was affected in all patients with craniosynostosis, with 19 of 26 children (73%) affected with isolated scaphocephaly. Pan-sutural craniosynostosis was present in 7 children (27%). None of the children had microcephaly, 7 of them presented macrocephaly and, in the remaining subjects, head circumference was normal. Five patients had undergone at least 1 cranial remodeling surgery. One patient with craniosynostosis was diagnosed with a Chiari I malformation. Molecular characterization of PHEX gene was performed in 14 cases.

Conclusions: Craniosynostosis is an underdiagnosed complication of hypophosphatemic rickets. Many patients with normal head size and growth may go undiagnosed, thus it is important to consider this association for early diagnosis and possible surgical treatment. A multidisciplinary approach is necessary for a correct long-term follow-up.

Keywords: craniosynostosis; growth; head circumference; hypophosphatemic rickets.

Publication types

  • Observational Study

MeSH terms

  • Child
  • Child, Preschool
  • Craniosynostoses / etiology
  • Craniosynostoses / metabolism
  • Craniosynostoses / pathology*
  • Craniosynostoses / surgery
  • Familial Hypophosphatemic Rickets / complications*
  • Female
  • Follow-Up Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mutation*
  • PHEX Phosphate Regulating Neutral Endopeptidase / genetics*
  • Prognosis
  • Retrospective Studies


  • PHEX Phosphate Regulating Neutral Endopeptidase
  • PHEX protein, human