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Crouzono-dermo-skeletal syndrome, Crouzon syndrome with acanthosis nigricans syndrome

Case presentation

A 3495 g infant girl was born at 39 weeks gestation to a 17-year-old gravida 1, para 0 mother. The mother had Crouzon 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).

Figure 1
figure1

Panels ac indicate axial computed tomography scans at bone windows; d and e show three-dimensional reconstructions. (a) Axial image, level parietal bones. Bilateral coronal synostosis (white arrows), more solidly ossified on the right than left. (b) Axial image level nose/ethmoidal sinuses. Bilateral choanal stenosis (white arrows). (c) Axial image level orbits. Bilateral exophthalmos, evidenced by orbits protruding beyond the ossified skull. (d, e) Three-dimensional reconstructions. Coronal synostosis with midfacial hypoplasia.

Figure 2
figure2

Axial head computed tomography (CT) images, brain windows. (a) Initial CT after delivery. Ventricles are at upper limits of normal size. (b) Axial images after coronal suture cranioplasty show hydrocephalus with moderately dilated lateral ventricles.

Figure 3
figure3

Frontal pelvis radiograph after ventriculoperitoneal shunt placement with shunt tubing coiled in abdomen. Narrowed interpedicular distances in lumbar spine (white arrowheads) and small sciatic notches (white arrows) are seen. The iliac wings have a rectangular or ‘squared-off’ appearance.

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 sequence by a GAG sequence in nucleotide 1172 of FGFR3.

Conditions associated with mutations in FGFR1 (locus 8p12) and FGFR2 (locus 10q26) genes characteristically involve abnormalities of membranous bone, including primarily craniosynostosis conditions such as Pfeiffer syndrome, Crouzon syndrome, Apert syndrome and Jackson Weiss syndrome. FGFR3 gene (locus 4p16.3) mutations are well-known causes of enchondral bone abnormalities. FGFR3 mutation-associated conditions include five skeletal dysplasias: achondroplasia, hypochondroplasia, thanatophoric dysplasia type 1, thanatophoric dysplasia type 2 and SADDAM syndrome.1 Thanatophoric dysplasia type 2 characteristically has craniosynostosis with a clover-leaf skull. SADDAN syndrome is a skeletal dysplasia occurring with AN. SADDAN is an acronym for severe achondroplasia, developmental delay and acanthosis nigricans. Patients with SADDAN syndrome have extreme short stature, tibial bowing, seizures and hydrocephalus.1 In addition, there are two craniosynostosis syndromes associated with FGFR3 gene mutations: CDSS and Muneke bicoronal syndrome. Muenke syndrome is characterized by bicoronal craniosynostosis, developmental delay, thimble shaped middle phalanges, carpal-tarsal coalitions and sensorineural hearing loss.1

CDSS has many Crouzonoid features which occur in all patients—bilateral coronal craniosynostosis, midfacial hypoplasia, exophthalmos, parrot beak (convex) nose, mandibular prognathism and posteriorly angled ears. However in addition, CDSS patients also have other craniofacial features not commonly occurring in Crouzon syndrome which should suggest CDSS. 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 growth factor receptors expressed in keratinocytes and fibroblasts.3 AN is a hyperkeratotic disorder occurring on the flexural 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.

References

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Correspondence to T E Herman.

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Herman, T., Sargar, K. & Siegel, M. Crouzono-dermo-skeletal syndrome, Crouzon syndrome with acanthosis nigricans syndrome. J Perinatol 34, 164–165 (2014). https://doi.org/10.1038/jp.2013.139

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