Identification of a genetic cause for isolated unilateral coronal synostosis: A unique mutation in the fibroblast growth factor receptor 3

doi:10.1016/S0022-3476(98)70366-X

The Journal of Pediatrics

Volume 132, Issue 4, April 1998, Pages 714-716

https://doi.org/10.1016/S0022-3476(98)70366-X Get rights and content

Abstract

To determine whether the autosomal dominant fibroblast growth factor receptor 3 (FGFR3) Pro250Arg mutation causes anterior plagiocephaly, patients with either apparently sporadic unicoronal synostosis (N = 37) or other forms of anterior plagiocephaly (N = 10) were studied for this mutation. Of 37 patients with unicoronal synostosis, 4 tested positive for the Pro250Arg mutation in FGFR3, and 33 were negative for this mutation. In three mutation positive patients with full parental studies, a parent with an extremely mild phenotype was found to carry the same mutation. None of the 6 patients with nonsynostotic plagiocephaly and none of the 4 patients with additional suture synostosis had the FGFR3 mutation. Because it is impossible to predict the FGFR3 Pro250Arg mutation status based on clinical examination alone, all patients with unicoronal synostosis should be tested for it. To assess their recurrence risk, all parents of mutation positive patients should be tested regardless of their clinical findings, because the phenotype can be extremely variable and without craniosynostosis. (J Pediatr 1998;132:714-6.)

Section snippets

Methods

The patients were followed up in our plastic surgery department for plagiocephaly. None had an underlying complex craniofacial malformation, a known chromosomal abnormality, or a family history of craniosynostosis in first or second degree relatives. The plagiocephaly was classified in each patient on the basis of the preoperative clinical findings and imaging studies, such as radiographs or computed tomography scans, as unilateral coronal synostotic, synostotic with involvement of other

Results

The anterior plagiocephaly in 47 consecutive patients was classified as synostotic in 37 cases, as synostotic affecting the sagittal or lambdoidal sutures in addition to the unicoronal involvement in 4 cases, and as deformational in 6 (Table I). Four of the 37 patients with unicoronal synostosis tested positive for the mutation and 33 patients were negative for the mutation (Table I). None of the patients with additional suture involvement or deformational plagiocephaly carried the FGFR3

Discussion

The FGFR3 Pro250Arg mutation, which represents the first identified genetic cause of unicoronal synostosis, was present in 4 (11%) of 37 patients with unicoronal synostosis. This frequency is similar to that of familial cases (12 of 127, 9%) reported by Lajeunie et al.⁷ Therefore this mutation likely accounts for a significant proportion of all underlying genetic causes of unicoronal synostosis. Clinical examination and review of the medical history failed to distinguish the patients carrying

Acknowledgements

We are grateful to all patients and their family members for participation in this study.

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Mutations in the fibroblast growth factor receptors (FGFR) are believed to cause an abnormality of osteoprogenitor cells within cranial sutures.28 In 1998, Gripp et al. indeed found a single gene mutation of FGFR3 (Pro250Arg) to be associated with non-syndromic coronal CS.29 Another study recommended FGFR3-Pro250Arg testing for 1st line molecular genetic diagnosis for both non-syndromic unicoronal and bicoronal CS.30
Craniosynostosis (CS) is a congenital birth defect characterized by the premature fusion of one or several calvarial suture(s). CS could lead to serious complications, such as intracranial hypertension and neurodevelopmental impairment. There is an increasing trend in the prevalence of CS – 75% of which are of non-syndromic type (NSCS). In parallel, there is a steady rise in the average maternal age. The goal of this paper was to review the literature to clearly identify any associations between parental age and NSCS. This review was performed and reported in compliance with PRISMA guidelines.
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Nonsyndromic CS (NCS), usually affecting single sutures in an otherwise normal skull, accounts for up to 80% of all CS cases, yet the genetic factors contributing to the disorder remain largely unknown. To date, single gene mutations in only a few genes, namely FGFR3, TWIST1, EFNB1, and TCF12 [8–12] have been found to cause single suture CS, though usually in association with additional syndromic features. It has been shown that the development and maintenance of cranial sutures is controlled by several regulatory factors including those involved in the BMP/ TGF-β, FGF, hedgehog (HH), eph-ephrin, and Wnt signaling pathways.
Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a relatively common congenital anomaly, occurring in 3–5 per 10,000 live births. Nonsyndromic CS (NCS) accounts for up to 80% of all CS cases, yet the genetic factors contributing to the disorder remain largely unknown. The RUNX2 gene, encoding a transcription factor critical for bone and skull development, is a well known CS candidate gene, as copy number variations of this gene locus have been found in patients with syndromic craniosynostosis. In the present study, we aimed to characterize RUNX2 to better understand its role in the genetic etiology and in the molecular mechanisms underlying midline suture ossification in NCS. We report four nonsynonymous variants, one intronic variant and one 18 bp in-frame deletion in RUNX2 not found in our study control population. Significant difference in allele frequency (AF) for the deletion variant RUNX2 p.Ala84-Ala89del (ClinVar 257,095; dbSNP rs11498192) was observed in our sagittal NCS cohort when compared to the general population (P = 1.28 × 10⁻⁶), suggesting a possible role in the etiology of NCS. Dual-luciferase assays showed that three of four tested RUNX2 variants conferred a gain-of-function effect on RUNX2, further suggesting their putative pathogenicity in the tested NCS cases. Downregulation of RUNX2 expression was observed in prematurely ossified midline sutures. Metopic sites showed significant downregulation of promoter 1-specific isoforms compared to sagittal sites. Suture-derived mesenchymal stromal cells showed an increased expression of RUNX2 over matched unfused suture derived cells. This demonstrates that RUNX2, and particularly the distal promoter 1-isoform group, are overexpressed in the osteogenic precursors within the pathological suture sites.
A 24-month cost and outcome analysis comparing traditional fronto-orbital advancment and remodeling with endoscopic strip craniectomy and molding helmet in the management of unicoronal craniosynostosis: A retrospective bi-institutional review
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A number of associations such as intrauterine constraint, maternal valproate use, maternal cigarette smoking, excessive antacid use, and metabolic diseases (e.g., hypophosphatemic rickets)3 have been observed. The involvement of multiple sutures3 and extracranial anomalies suggests a unifying syndromic cause, of which mutations in FGFR and TWIST1 genes3,4 are the most common. Skull growth occurs perpendicular to the axis of the suture.2
Endoscopic strip craniectomy with helmeting (ESCH) has been shown to be a safe and efficacious alternative to fronto-orbital remodeling (FOR) for selected children with craniosynostosis. In addition to clinical factors, there may be economic benefits from the use of ESCH instead of FOR.
A retrospective review of 23 patients with nonsyndromic unicoronal craniosynostosis (UCS) treated with FOR was carried out at Great Ormond Street Hospital (GOSH) for Children in London, UK. Secondary data were used for the ESCH cohort from a paper published by Jimenez and Barone (2013). Data were collected on surgical time, transfusion rates, length of hospital stay, adverse event rates, reintervention rates, and overall costs. Costs were categorized and then assigned to the appropriate data sets.
The mean age of patients undergoing FOR (vs. ESCH) was 17.4 mo (vs. 3.1 mo) with a mean surgical time of 234 min (vs. 55 min), mean transfusion volume of 221.6 mL (vs. 80.0 mL), mean transfusion rate of 14/23 (vs. 2/115), and a total immediate overnight stay of 3.13 days (vs. 97% next-day discharge). The FOR group had a higher adverse event rate (5/23 vs. 4/115, p=<0.005) and a higher number requiring extraocular muscle surgery (4/23 vs. 7/109, p=0.16). There was a substantial difference in overall costs between the two groups. Total variance cost for the FOR group was £7436.5 vs. £4951.35, representing a cost difference of £2485.15 over the 24-month study period.
ESCH, in comparison to FOR, appears as a more economical method in the management of USC patients, as well as having clinical benefits including reduced adverse event rate and improved ophthalmic outcomes.
Diagnosis and Surgical Options for Craniosynostosis
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2015, Stem Cell Biology and Tissue Engineering in Dental Sciences
The craniofacial skeleton is made up of the neurocranium, which encases the brain, and the viscerocranium, which includes the bones of the face and cranial base. At birth, the human craniofacial skeleton is comprised of 44 bones that develop via both endochondral and intramembranous ossification, depending on the bone. Undifferentiated mesenchyme separates the bones for varying periods of postnatal life, playing a key role in regulating cranioskeletal growth. Appositional bone growth at the suture margins is regulated by a complex crosstalk between growth factor signaling pathways, some of which function more prominently in specific sutures. In this chapter, we review the embryology and current understanding of the molecular genetic basis of premature fusions (synostosis) of both the calvarial and facial sutures gleaned from genetic studies in humans and model organisms such as the mouse. In addition, we reassess the spectrum of mutations found in FGFR2, the most prominent factor implicated in craniofacial synostosis, and propose a new model for explaining the impact of many of the common amino acid substitutions that result in pathology. Finally, advancements that promise to enable use of mesenchymal stem cells in tissue engineering-based approaches are discussed with respect to prospects for more effective treatment of these craniofacial conditions.
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^☆: From The Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia,Pennsylvania.

^☆☆: Supported in part by NIH grants R29HD28732 and RO1HD29862 to M. Muenke.

^★: Dr. Gripp is sponsored by the Howard Hughes Medical Institute.

^★★: Reprint requests: Maximilian Muenke, MD, The Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology, 34th and Civic Center Blvd., Philadelphia, PA 19104-4399.

^♢: 9/21/85582

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Identification of a genetic cause for isolated unilateral coronal synostosis: A unique mutation in the fibroblast growth factor receptor 3☆,☆☆,★,★★,♢

Abstract

Section snippets

Methods

Results

Discussion

Acknowledgements

Lancet

Cell

Association between “plagiocephaly” and hemifacial microsomia

Am J Med Genet

Observations on a recent increase in plagiocephaly without synostosis

Pediatrics

Frontal plagiocephaly: synostotic, compensational, or deformational

Plast Reconstr Surg

Coronal craniostenosis: fetal head constraint as one possible cause

Pediatrics

Intrauterine constraint and craniosynostosis

Neurosurgery