Crouzono-Dermo-Skeletal Syndrome, Crouzon Syndrome with Acanthosis Nigricans Syndrome

Home , Apert syndrome, Brachydactyly, Crouzon syndrome, Muenke syndrome, Pfeiffer syndrome, Thanatophoric dysplasia

IMAGING CASE REPORT Crouzono-dermo-skeletal syndrome, Crouzon syndrome with acanthosis nigricans syndrome

TE Herman, K Sargar and MJ Siegel

Journal of Perinatology (2014) 34, 164–165; doi:10.1038/jp.2013.139

CASE PRESENTATION mutation-associated conditions include ﬁve skeletal dysplasias: A 3495 g infant girl was born at 39 weeks gestation to a 17-year- achondroplasia, hypochondroplasia, thanatophoric dysplasia type 1 old gravida 1, para 0 mother. The mother had Crouzon syndrome 1, thanatophoric dysplasia type 2 and SADDAM syndrome. and hydrocephalus. She had undergone 11 craniofacial and plastic surgical procedures. The mother previously had genetic testing, which demonstrated a mutation in exon 10 of the FGFR3 (ﬁbroblast growth factor receptor number 3) gene consistent with Crouzon syndrome with acanthosis nigricans (AN), also called Crouzono-dermo-skeletal syndrome (CDSS). No sonographic abnormalities were detected in the fetus during the pregnancy. At delivery, the infant had Apgars of 1 at 1 min, 6 at 5 min and 7 at 10 min. A nasogastric tube could not be passed. The patient was noted to have proptosis, depressed nasal bridge, hypertelorism, an anterior ectopic anus and normal appearing skin. Craniofacial computed tomography (CT) scan was performed (Figures 1 and 2) and plain radiographs of the pelvis and lumbar spine obtained (Figure 3).

DENOUEMENT AND DISCUSSION The craniofacial CT scan demonstrates bicoronal synostosis with marked midface hypoplasia, with exophthalmos and hypertelorism. In addition, there was bilateral marked choanal stenosis. The pelvis (Figure 3) demonstrates squared-off iliac wings with small sciatic notches and narrowing of the lumbar interpediculate distances. Subsequently, the patient at 2 months of life underwent endoscopic release of bilateral coronal synostosis. A follow-up CT demonstrated the open sutures, but the interval development of hydrocephalus (Figure 2b). These findings are those of CDSS or Crouzon syndrome with AN (CAN).1,2,3 CDSS is an uncommon autosomal dominant condition with variable expressivity accounting for 1% to 2% of all craniosynostosis syndromes.4 CDSS has a female predominance of 2.4:1, although the manifestations are identical in male and female patients. CDSS is distinctly different from Crouzon syndrome with which it, however, shares phenotypic features. Crouzon syndrome is an autosomal dominant condition, in which 95% of cases are associated with mutations in exons IIIA and IIIC of the FGFR2 gene.5 CDSS is due to a characteristic mutation in the FGFR3 gene. The unique mutation accounting for CDSS is a change in a GCG Figure 1. Panels a–c indicate axial computed tomography scans at bone windows; d and e show three-dimensional reconstructions. sequence by a GAG sequence in nucleotide 1172 of FGFR3. (a) Axial image, level parietal bones. Bilateral coronal synostosis Conditions associated with mutations in FGFR1 (locus 8p12) and (white arrows), more solidly ossified on the right than left. (b) Axial FGFR2 (locus 10q26) genes characteristically involve abnormalities of image level nose/ethmoidal sinuses. Bilateral choanal stenosis membranous bone, including primarily craniosynostosis conditions (white arrows). (c) Axial image level orbits. Bilateral exophthalmos, such as Pfeiffer syndrome, Crouzon syndrome, Apert syndrome and evidenced by orbits protruding beyond the ossified skull. (d, e) Jackson Weiss syndrome. FGFR3 gene (locus 4p16.3) mutations Three-dimensional reconstructions. Coronal synostosis with mid- are well-known causes of enchondral bone abnormalities. FGFR3 facial hypoplasia.

Mallinckrodt Institute of Radiology, St Louis Children’s Hospital, Washington University School of Medicine, St Louis, MO, USA. Correspondence: Dr TE Herman, Mallinckrodt Institute of Radiology, St Louis Children’s Hospital, Washington University School of Medicine, 510 South Kingshighway Blvd, St Louis, MO 63110, USA. E-mail: [email protected] Received 17 September 2013; accepted 3 October 2013 CDSS or CAN TE Herman et al 165 These include choanal atresia and/or stenosis and hydrocephalus often with a Chiari I malformation.4 Choanal stenosis is uncommon in Crouzon syndrome and its presence in a patient with Crouzonoid features should suggest CDSS.3 Hydrocephalus occurs in only 4% to 10% of craniosynostosis syndromes, except for Crouzon syndrome which has an incidence of hydrocephalus of 25% to 38%, and CDSS which has an incidence of hydrocephalus of 43%.3 In addition, patients affected with CDSS characteristically develop AN; 80% within the first decade of life.3 AN is a skin disorder caused by inadequate stimulation of various fibroblast Figure 2. Axial head computed tomography (CT) images, brain growth factor receptors expressed in keratinocytes and fibro- windows. (a) Initial CT after delivery. Ventricles are at upper limits of 3 normal size. (b) Axial images after coronal suture cranioplasty show blasts. AN is a hyperkeratotic disorder occurring on the flexural hydrocephalus with moderately dilated lateral ventricles. skid of the skin of the extremities, but also the neck, axillae, inguinal and perianal regions. Overall, 25% of patients with CDSS will also develop melanocytic nevi.3 These are the dermatological features of CDSS. The skeletal features of CDSS include cementomas and cemental dysplasia of the jaws.6 In addition there may be features of achondroplasia,1,2,3 including broad iliac wings, small sciatic notches, interpediculate distance narrowing and brachydactyly. The patient described here has characteristic features of CDSS: bicoronal craniosynostosis, choanal stenosis, hydrocephalus and features of achondroplasia. Skin and jaw manifestations will probably develop during the first decade of life. Dental and dermatological follow-up in addition to neurosurgical, plastic surgery will be required.

Figure 3. Frontal pelvis radiograph after ventriculoperitoneal shunt CONFLICT OF INTEREST placement with shunt tubing coiled in abdomen. Narrowed interpedicular distances in lumbar spine (white arrowheads) and The authors declare no conflict of interest. small sciatic notches (white arrows) are seen. The iliac wings have a rectangular or ‘squared-off’ appearance. REFERENCES 1 Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast Thanatophoric dysplasia type 2 characteristically has cranio- growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, synostosis with a clover-leaf skull. SADDAN syndrome is a skeletal Muenke craniosynostosis and Crouzon syndrome with acanthosis nigricans. Endocr dysplasia occurring with AN. SADDAN is an acronym for severe Rev 2000; 21: 23–39. achondroplasia, developmental delay and acanthosis nigricans. 2 Schweitzer DN, Graham JM, Lachman RS, Jabs EW, Okajima K, Przylepa KA et al. Subtle radiographic findings of Achondroplasia in patients with Crouzon syndrome Patients with SADDAN syndrome have extreme short stature, tibial 1 with acanthosis nigricans due to an Ala391Glu substitution in FGFR3. Am J Med bowing, seizures and hydrocephalus. In addition, there are two Genet 2001; 98: 75–91. craniosynostosis syndromes associated with FGFR3 gene mutations: 3 Arnaud-Lopez L, Fragoso R, Mantilla-Capacho J, Barros-Nunez P. Crouzon with CDSS and Muneke bicoronal syndrome. Muenke syndrome is ancanthosis nigricans. Further delineation of the syndrome. Clin Genetic 2007; 72: characterized by bicoronal craniosynostosis, developmental delay, 405–410. thimble shaped middle phalanges, carpal-tarsal coalitions and 4 DiRocco F, Collet C, Legeai-Mallet L, Arnaud E, Le Merrer M, Hadj-Rabia S et al. sensorineural hearing loss.1 Crouzon syndrome with acanthosis nigricans: a case-based update. Childs Nerv Syst CDSS has many Crouzonoid features which occur in all 2011; 27: 349–354. patients—bilateral coronal craniosynostosis, midfacial hypoplasia, 5 Sharma VP, Wall SA, Lord H, Lester T, Wilkie AOM. Atypical Crouzon syndrome with a novel Cys62Arg mutation in FGFR2 presenting with Sagittal synostosis. Cleft exophthalmos, parrot beak (convex) nose, mandibular prognath- Palate-Craniofacial J 2012; 49: 373–376. ism and posteriorly angled ears. However in addition, CDSS 6 Nagase T, Nagase M, Hirose S, Ohmori K. Crouzon syndrome with acanthosis patients also have other craniofacial features not commonly nigricans: case report and mutational analysis. Cleft Palate-Craniofacial J 2000; 37: occurring in Crouzon syndrome which should suggest CDSS. 78–82.

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