Abstract
Crouzon syndrome is a rare genetic disorder characterised mainly by distinctive malformations of the skull and facial region and caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. No study reported on oedemas related to lymphatic system abnormalities in these patients. A case of Crouzon syndrome displaying classic facial anomalies but also with bilateral lower limb oedema is reported in whom lymphoscintigraphic investigation of the limbs clearly delineated the presence of lymphatic system anomalies.
BACKGROUND
Premature craniosynostosis, midfacial hypoplasia and exophthalmos (optic disc oedema and proptosis) form the triad now known as Crouzon syndrome.1 Other clinical features include hypertelorism, strabismus, beaked nose, short upper lip, hypoplastic maxilla, relative mandibular prognathism and acanthosis nigricans. No report has either clinically observed or technically investigated anomalies of the lymphatic system in these patients. This is the aim of the present report.
CASE PRESENTATION
A girl with a craniofacial dysostosis typical of Crouzon syndrome and found to be heterozygous for the 833G>T mutation in the fibroblast growth factor receptor 2 (FGFR2) gene corresponding to the Cys278Phe amino acid substitution2 developed at 16 years of age bilateral upper and lower limb oedema of unclear origin. At 1, 3 and 5 years later, she underwent lymphoscintigraphic investigations of the lower limbs performed according to a well established protocol.3
In all studies, large nodal gaps were observed at the middle part of the right inguinal group, the left iliac external group and the right ilio-lumbo-aortic junction (fig 1C).
Figure 1.
Lymphoscintigraphic investigation of our subject: from left to the right, whole body imaging in anterior views (from the feet, bottom, to the head, top) obtained after 30 min of no movement of feet and toes (A), after 5 min of tiptoeing (B) and after 1 h of walking (C).
Furthermore, at the level of the injection sites, the extraction of the tracer was decreased (data from 2007 showed −26.7% on the right side and −20.4% on the left side, compared to more than 30% in normal patients).
After phase I (fig 1A), we also observed an unusual direct lymphatic vessel drainage into the intra-abdominal lymph nodes on the left side (and not into low femoro-inguinal node as observed on the right side) three times.
No distichiasis was observed and Forkhead box c2 (FOXC2) mutation was excluded in our patient.
DISCUSSION
Lymphoscintigraphy using 99mTc labelled colloids is a simple, relatively non-invasive way to investigate diseases of the lymphatic system. These investigations are commonly used to demonstrate and/or to evaluate lymph nodes draining cancer-bearing areas, but several papers have reported on their interest to use them to assess limb oedemas in adults as well as in paediatric patients.6 In these young patients with lower limb oedema(s), nodes are noted either to be absent, or to be small and few in number.
Our lymphoscintigraphic observation in this patient with Crouzon syndrome may result from the genetic defect that underlies the syndrome. Crouzon syndrome is caused by mutations in the FGFR2 gene and fibroblast growth factor 2 (FGF-2) was reported to induce lymphatic vessel growth in mouse cornea assay by promoting the secretion of the potent lymphangiogenic factor, vascular endothelial cell growth factor (VEGF)-C, by blood vascular endothelial cells.4,5 Moreover, systemic treatment with an antibody against vascular endothelial cell growth factor receptor (VEGFR)-3, the major receptor for VEGF-C, reduced the FGF-2-induced lymphangiogenesis.4,5 These findings in one animal model indicate that the effects of FGF-2 on lymphangiogenesis might be through activation of the VEGF-C/VEGFR-3 signalling pathway. The true role of FGF-2 in Crouzon syndrome and other craniosynostosis still remains unclear, and warrants further investigations.
LEARNING POINTS
Our observation suggests that the mutation in the fibroblast growth factor receptor 2 (FGFR2) may have consequences on the development of the human lymphatic system.
These anomalies of the lymphatic system should be researched in patients with Crouzon syndrome and, based on the eventual demonstration of dermal backflows, superficial lymphatic collateralisation or large lymph node blockade, recommendations for prevention should be given.
Footnotes
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.
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