Crouzon syndrome associated with acanthosis nigricans: prenatal 2D and 3D ultrasound findings and postnatal 3D CT findings
A healthy 31-year-old woman had infertility treatment with ovulation induction and intrauterine homolog insemination at a private fertility clinic. In early pregnancy she experienced acute abdominal pain. At laparoscopy a ruptured tubal pregnancy was found, indicating a heterotopic pregnancy, and a salpingectomy was performed.\nShe had a first trimester scan which produced a combined risk for Down syndrome of 1:507. She chose to have a chorionic villus sample (CVS) taken, which showed a normal karyotype. At 19 + 6 weeks she had a normal anomaly scan. At 27 + 3 weeks she was referred to the fetal medicine unit (FMU) for a growth scan. This ultrasound showed intrauterine growth restriction (estimated fetal weight 24.8% compared to the normative mean value) and a small head circumference (227.8 mm). The anomaly scan was repeated and found to be normal. Fetal biometry was performed every second week showing normal growth, although the head circumference remained below the 5th centile.\nAt 35 + 5 weeks the woman was referred for an expert scan at the FMU because of an abnormally-shaped cranium (Fig. ). 2D and 3D scans were performed showing brachycephaly, hypertelorism, ocular proptosis, and a beaked nose (Fig. ). No hand or foot anomalies were seen. These findings gave rise to the suspicion of Crouzon syndrome. The fetal DNA saved from the CVS was analyzed for mutations in the FGFR2 gene (Crouzon, Apert, and Pfeiffer syndrome) and reflex tested for Muenke syndrome in the FGFR3 gene. No mutations were found.\nAt 39 + 6 weeks a Cesarean section was performed on maternal request and a boy was delivered (weight, 3.156 g; length, 51 cm; Apgar, 10/1 and 10/5; and normal cord blood gas values). Craniofacial abnormalities were evident, but choanal atresia was not suspected. At 7 days of age he developed intermittent obstructed nasal airways with compromised breastfeeding. Acceptable weight gain was obtained after introduction of formula milk. The boy was referred to the Copenhagen Craniofacial Unit at Rigshospitalet, University of Copenhagen.\nAt clinical examination at 5 weeks of age, he had pronounced oxycephaly (Kleeblatt-Schädel) and ocular proptosis. In addition he had pronounced maxillary hypoplasia and severe breathing difficulties with clinical suspicion of apnea. No skin changes such as hyperkeratotic papules or pigmentations were noted. He gradually developed hydrocephalus and at age 9 weeks a 3D craniofacial CT scan was done. The CT scan was performed using a Toshiba Aquillion helical CT-scanner (Toshiba, Zoetermeer, The Netherlands) (slice thickness, 0.5 mm; pixel spacing, 0.39/0.39; KVp, 120; X-ray tube current, 60mA; exposure, 24 mAs).\nThe 3D CT scan (Figs. and ) revealed a brachycephalic skull shape (the cephalic index, which describes the relationship between the long and short axis of the cranium was 85, normal values are 75–83) with protrusion of the forehead and flattened occiput. The skull was wide and the temporal regions were bulging. Both coronal and lambdoid sutures were prematurely fused. A wide midline defect of the skull extended from the nasal root to the occiput. The skull was paper thin with extremely increased digital markings, especially in the posterior portion of the skull. Markedly increased digital markings on CT may suggest that intracranial pressure (ICP) is increased or that ICP has been increased at an earlier stage. The synchondroses of the cranial base were patent and the cranial base angle was flat (platybasia). The nasal root was depressed; the orbital roofs were short and the distance between the orbits was increased (hypertelorism); the maxilla was hypoplastic, especially in the sagittal and vertical dimensions. Choanal height was decreased and the nasopharyngeal airway was constricted. The mandible was unremarkable.\nSince the child developed signs of increased intracranial pressure a ventriculoperitoneal shunt was placed.\nDue to the patient's physical findings consistent with the diagnosis of Crouzon syndrome, a full mutation screening for the more uncommon Crouzon mutations in the FGFR2 and FGFR3 gene was performed. It identified the heterozygous c.1172C > A; p.Ala391Glu mutation in the FGFR3 gene, which is responsible for Crouzon syndrome with acanthosis nigricans.\nFurther treatment involves multidisciplinary control and coordination by the Copenhagen Craniofacial Unit. Midface distraction will be performed at 7–10 years of age.