1). On amniocentesis, the karyotype was 46 XX, and a subsequent prenatal 135?K oligonucleotide microarray was normal. The initial concern was for skeletal dysplasia, but DNA testing of SOX9 and DTDST was normal. There were no internal malformations on ultrasound, chest, and head growth were normal, but progressive polyhydraminos led to preterm labor and delivery at 36 weeks. Birthweight was 2,490?g Selleck LY294002
(50th centile), birth length was 42?cm (<3rd centile), and occipital frontal circumference (OFC) was 35?cm (90th centile). The infant had extremely severe acrofacial dysostosis with severe micrognathia and microstomia, microtia with absent external auditory canals, downslanting palpebral fissures, absence <a href="http://www.selleckchem.com/products/epacadostat-incb024360.html
">Epacadostat of lashes on the lower lids, and hypoplasia of zygomatic arch, bilateral pre- and post-axial limb defects (absent thumbs, hypoplastic fifth fingers, absence of the radius and ulna, hypoplastic fifth toes with 4/5 syndactyly, absent fibula, and bowed tibia), and additional skeletal anomalies (normal length but proximally bifid humerii, hypoplastic scapulae, 11 ribs bilaterally, and vertebral segmentation abnormalities, but essentially normal pelvis and femora; Fig. 2). Following aggressive treatment of upper airway obstruction, she became stable on room air but requires tracheostomy and gastrostomy, despite some improvement in the micrognathia following mandibular distraction (Fig. 3). Echocardiogram was normal, and magnetic resonance imaging of the brain showed only increased extra-axial fluid. Postnatal growth has been extremely slow for weight as well as length. By 13 months, her length of 63?cm and weight of 5.7?kg were far below the 3rd centile, but her head circumference of 44?cm was in the normal range. At age 24 months she has a length of 72?cm (?3rd centile) and weight of 7.4?kg (?3rd centile). She is alert and responsive, though motor skills are limited due to her orthopedic Rapamycin
problems, and she remains non-verbal due to her tracheostomy. Additional genetic testing prompted by the recognition of acrofacial dysostosis with both pre- and postaxial limb defects included DHODH sequencing for postaxial acrofacial dysostosis (POADS), which was normal. Due to the severe primarily postaxial involvement in the lower limbs that has not been observed in Nager syndrome, her working diagnosis was Rodriguez syndrome. Because, at the time, no candidate gene for either Rodriguez syndrome or Nager syndrome had been reported, whole-genome sequencing was undertaken. Using whole-genome sequencing results, the search for de novo mutations resulted in the identification of five candidate genes (Table II), only one of which is not in introns: SF3B4. In the interim, SF3B4 had been identified as the gene for Nager syndrome, but the location of the mutation in SF3B4 in our case report is different from the report of Nager syndrome.