Second-trimester Molecular Prenatal Diagnosis of Sporadic Apert Syndrome Following Sonographic Findings of Mild Ventriculomegaly and Clenched Hands Mimicking Trisomy 18

Apert syndrome (OMIM 101200) is a congenital disorder characterized by acrocephaly, craniosynostosis, midface hypoplasia, and syndactyly of the hands and feet [1]. The reported prevalence of Apert syndrome at birth has ranged from 1 in 160,000 [2] to 1 in 64,500 births [3]. The majority of cases of Apert syndrome arise sporadically as the result of a de novo mutation in the sperm, associated with a paternal age effect; only a few cases are inherited from affected parents in an autosomal dominant pattern [4,5]. Apert syndrome is caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene (OMIM 176943) located at 10q26. Two mutations of Ser252Trp (S252W) and Pro253Arg (P253R) account for over 98% of cases of Apert syndrome [6,7]. Although cases of prenatally diagnosed Apert syndrome have been reported, many cases remain undiagnosed until delivery, or are diagnosed in late gestation when polyhydramnios and craniofacial deformities become evident. Syndromes involving craniosynostosis may be associated with abnormalities of the digits. Crouzon syndrome is associated with normal hands and feet. Jackson-Weiss syndrome is associated with normal hands, medially deviated broad great toes and cutaneous syndactyly of the second and the third toes. Apert syndrome is associated with symmetric syndactyly of the hands and feet. Pfeiffer syndrome is associated with broad abducted thumbs, broad great toes, and brachymesophalangy and partial syndactyly of the hands and feet. In cases with mild ventriculomegaly, a thorough examination of the hands in the second trimester may lead to a specific diagnosis of Apert syndrome, as in the current case. A 30-year-old, gravida 1, woman was referred to Mackay Memorial Hospital for amniocentesis at 21 weeks of gestation because of mild ventriculomegaly and clenched hands detected on prenatal ultrasound. Her husband was 32 years of age. She and her husband were both healthy and unrelated, and there was no family history of congenital malformations. Prenatal ultrasound at 18 weeks of gestation revealed a male fetus with fetal biometry equivalent to 18 weeks, a normal skull shape, mild ventriculomegaly, and clenched hands (Figures 1 and 2). Trisomy 18 was highly suspected. Amniocentesis was performed at 21 weeks of gestation. Conventional cytogenetic analysis revealed a 46,XY karyotype. Oligonucleotide-based array comparative genomic hybridization using uncultured amniocytes demonstrated no deletions or duplications. SECOND-TRIMESTER MOLECULAR PRENATAL DIAGNOSIS OF SPORADIC APERT SYNDROME FOLLOWING SONOGRAPHIC FINDINGS OF MILD VENTRICULOMEGALY AND CLENCHED HANDS MIMICKING TRISOMY 18