Constitutional de novo interstitial deletion of 8 Mb on chromosome 22q12.1-12.3 encompassing the neurofibromatosis type 2 (NF2) locus in a dysmorphic girl with severe malformations

We report on the cytogenetic and molecular characterisation of a constitutional de novo interstitial deletion of chromosome 22q12.1-q12.3 in a dysmorphic girl. The deletion extends over approximately 8 Mb including the NF2 gene region. The corresponding deletion syndrome is characterised by severe developmental delay accompanied by multiple malformations at an age when clinical manifestation of NF2 is not expected. The proband is the second daughter of a 28 year old, gravida 2, para 2 woman and her unrelated 35 year old husband. The pregnancy was uncomplicated until 30 weeks, when polyhydramnios and congenital heart disease were diagnosed by ultrasonography. Because of these abnormalities, karyotype analysis was performed on fetal blood obtained by percutaneous umbilical cord blood sampling. Spontaneous delivery occurred at 31 weeks of gestation after premature labour (birth weight 1360 g, 25th centile; length 41.5 cm, 50th centile; OFC 29.8 cm, 75th centile). Dysmorphic features (fig 1) consisting of depressed nasal root, hypertelorism, small and downward slanting palpebral fissures, short philtrum with a tented upper lip, mandibular hypoplasia, low set, and posteriorly rotated ears, overlapping fingers and toes, and a large cleft palate were noted. The child presented with visceral situs inversus with dextrocardia, interrupted aortic arch type A, a large ventricular septal defect, subaortic stenosis secondary to conoventricular malalignment, hypoplastic ascending aorta, and bilateral superior caval veins with drainage of the right sided caval vein via a coronary sinus into the right atrium. Prostaglandin E1 infusion was given to maintain ductal patency until the age of 4 months when surgical repair of the aortic arch abnormality and subaortic stenosis was done. Furthermore, duodenal stenosis with annular pancreas were detected requiring surgical intervention at the age of 1 week. Cranial ultrasound showed a congenital malformation of the central nervous system with dilated, abnormally shaped lateral and third ventricles, …