Chromosome 4q28.3q32.3 duplication in a patient with lymphatic malformations, craniosynostosis, and dysmorphic features

Abstract

The proband, now a 4-year-old female of mixed Caucasian and Japanese ancestry, was born at 29 weeks gestation via spontaneous vaginal delivery following a pregnancy complicated by fetal ascites, echogenic bowel, polyhydramnios, and incompetent cervix. The mother had no other pregnancy complications and had no recognized teratogen exposures throughout the pregnancy. Her length was 37 cm (37th centile), weight was 1.478 kg (80th centile), and occipitofrontal circumference (OFC) was 27 cm (20th centile). The family history was significant for maternal family members with pregnancy losses of unknown etiology: one each for the mother and maternal grandmother. The great maternal grandmother reported at least 4 or 5 pregnancy losses. Consanguinity was denied. The proband remained in the neonatal intensive care unit for the next 8 months for management of severe respiratory issues, ascites and feeding difficulties. During that time, she underwent placement of a tracheostomy, a Denver (peritoneovenous) shunt for ascitic-fluid drainage, an intravenous port and a gastrostomy tube for feeds (Fig. 1). Additional pertinent findings then include retinopathy of prematurity, subglottal stenosis grade IV, hypothyroidism, 11 sets of ribs, mild bilateral hydronephrosis, accessory spleen and persistent ascites (Fig. 2). At 20 months dysmorphologic evaluation was significant for macrocephaly, open anterior and posterior fontanelles, bicoronal craniosynostosis on CT scan, right posterior plagiocephaly, brachycephaly, cupped and prominent ears with hypoplastic antihelices, broad forehead, a short and upturned nose, telecanthus, ocular hypertelorism, depressed nasal bridge (Figure 3A–B), moderate ascites, bilateral overriding of the second and fourth toes over the third toe, short stature and hypotonia. At this latter time, she exhibited significant developmental delays; she was unable to sit unassisted or feed herself. However, she was able to crawl, pull to a stand and sit independently. The proband could feed herself but still required a G-tube for much of her nutrition. She was nonverbal but able to use 12 signs. She continued to require a tracheostomy but only for night-time mechanical ventilation. At 33 months when last evaluated, her height was 79.2 cm (<1st centile), weight was 11.6 kg (7th centile) and OFC was 56 cm (>97th centile). The patient’s severe ascites persisted throughout the first 2 years of her life. At age 22 months, she underwent lymphatic imaging at the Children’s Hospital of Philadelphia that revealed multiple dilated perihepatic lymphatic vessels and leakage of contrast material into the peritoneum (Fig. 4A–D). Subsequently, she underwent successful embolization of these lymphatic vessels with resolution of her ascites.