Chromosome 6 microdeletion in a patient with syndromic congenital cranial dysinnervation disorder

T congenital cranial dysinnervation disorders (CCDDs) encompass most congenital, static restrictions of ocular motility, often associated with ptosis, and retraction of the globe.1 The CCDDs can be monogenic or chromosomal in origin. Although chromosomal copy number variations (CNVs) has been reported in patients with syndromic CCDDs,2 but there are still patients for whom the genetic basis has not been identified yet. In this report, we describe the evaluation of a girl with CCDD and other congenital abnormalities by high-resolution array-comparative genomic hybridization (array CGH), which revealed a microdeletion in chromosome 6. A 6-year-old girl with strabismus and multiple congenital anomalies was referred for genetic evaluation. She had a history of mild pulmonary valve stenosis and neonatal seizures that did not recur after the neonatal period. Esotropia, ptosis on the right, polydactyly of both hands, and cleft palate were noted at birth. She had a cleft palate repair, strabismus surgery (uncomplicated bilateral medical rectus muscle recessions for esotropia), and ptosis surgery (uncomplicated right frontalis sling) during early life. She had no other known general medical problems. Examination revealed a pleasant and alert girl who appeared small for her age (head circumference 48 cm, height 90 cm, weight 11.95 kg). Ophthalmologic examination was significant for ptosis on the right and an alternating esotropia of approximately 20 prism diopters. She had bilateral complete abduction defects (Figure 1) with retraction of each globe on abduction consistent with co-contraction of the medial and lateral rectus muscles. She was also unable to supraduct either eye. Adduction, infraduction, and pupillary examination were normal. The ptotic lid on the right eye elevated during adduction. Cycloplegic refraction revealed mild myopia with an otherwise normal posterior pole in both eyes. Clinically, she did not have any skeletal abnormalities other than polydactyly, and a plain film skeletal survey did not show unusually long tubular bones, tall vertebral bodies, or other significant bony abnormalities. A head CT performed soon after birth was reported as normal, but subsequent neuroimaging was not performed because she was cognitively normal. The patient’s parents were not related, and she had 2 siblings, a normal older brother and a sister who had decreased vision by history (Figure 1E). The study adhered to the principles of Helsinki Declaration. The patient and 5 family members were recruited under an institutional review board protocol approved at the King Khalid Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia (KSA) (0424-P). The informed consents were obtained. The patient was examined, and her chart was reviewed at the Ophthalmic Genetics Laboratory, King Abdulaziz University Hospital, King Saud University, Riyadh, KSA from May to August 2013. Candidate genes associated with syndromic DRS (HOXA1, SALL4, CHN1, TUBB3, and KIF21A) were screened. The complete coding regions of the SALL4, CHN1, HOXA1, and TUBB3 genes and exons 8, 20, and 21 considered hotspot for mutations in the KIF21A gene were sequenced