First report of de novo 12q14.2-q23.3 duplication: Patient with multiple congenital anomalies, neurodevelopmental delay, and a connective tissue disorder-like phenotype including cutis laxa

We present the case of a 14-year-old male with a previously undescribed 12q14.2-q23.3 duplication. Prior literature has suggested that significant non-mosaic alterations to 12q, particularly including the 12q13-21.2 region, are non-viable (Patil et al., 1983; Pratt and Bulugahapitiya, 1983; Dixon et al., 1993). Our patient was born at term to nonconsanguineous parents after an unremarkable pregnancy. He was delivered via cesarean section after he was found to have a true umbilical cord knot and the cord wrapped twice around his neck. His birth weight was 3770 g (68th centile). Multiple congenital anomalies were identified after delivery, including bilateral retinal colobomas, ptosis, hypospadias and penile torsion, right talipes equinovarus, sacral dimple, brachydactyly of the right foot (digits 1-5), and syndactyly of the left foot (digits 2-3). The patient had global developmental delay predominately affecting his language, motor, and social skills. He was able to sit without support at 12 months and ambulated independently at 24 months. At 14 years, he remains non-verbal. Growth parameters were in normal range (25th centile for height and weight) until around 8 years of age. Growth has plateaued from this time to present evaluation (<first centile for height and weight). The patient has not yet displayed signs of puberty. The patient was evaluated in the genetics clinic at 14 years, 10 months old, following microarray detection of a 41.7 Mb duplication of chromosomal region 12q14.2-q23.3. He has facial dysmorphisms (Fig. 1a, b, d, and e), including asymmetric brachycephaly, bilateral ptosis, hypertelorism with significant telecanthus, maxillary hypoplasia, gum hyperplasia, macroglossia, and asymmetrically protuberant, large ears with symmetrical postauricular divots. The patient also has bilateral retinal colobomas, high myopia, and photophobia on ocular exam. The patient's feet are remarkable (Fig. 1f-i), with the right foot having brachydactyly and nail aplasia of all five digits and the left having a large great toe, syndactyly of digits 2-3, and hypoplasia of digits 3-5. The patient also has cutis laxa, making him appear much older than his actual age. Other skin findings include multiple lentigines and a single large hyperpigmented macule on the patient's knee (Fig. 1c).