16p11.2 Duplication Syndrome – a Case Report

16p11.2 duplication syndrome is a rare disorder, often associated with intellectual disability, attention deficit, hyperactivity disorder, and a predisposition to epilepsy and schizophrenia. There are no specific dysmorphic features for this genetic condition, but microcephaly, micrognathia and hypertelorism could be present. We report a case of 16p11.2 duplication syndrome which has the typical clinical presentation – slight facial dysmorphism, impaired intellectual development, and autistic behavior. Whole-exome sequencing was performed, but no pathogenic or likely pathogenic mutations were identified. Array comparative genomic hybridization analysis established the diagnosis of 16p11.2 duplication syndrome, which illustrates the importance of this method when diagnosing children with unexplained intellectual disability.


INTRODUCTION
16p11.2 duplication syndrome is characterized by impaired intellectual development, attention deficit hyperactivity disorder and microcephaly. 1 Although this disorder is rare in the general population, it affects approximately 1% of the patients with autistic behaviour. 2 That is why the identification of this duplication could be important when establishing the genetic reason for intellectual disability. In the present article we report a case of 16p11.2 duplication syndrome, which has the typical clinical presentation and is confirmed by array comparative genomic hybridization (array CGH).

CASE REPORT
Our patient was a 4-year-old girl, born per vias naturales after a second uneventful pregnancy. The pregnancy was not followed up by an obstetrician. The birth weight of the patient was 2900 gr, birth length -49 cm, head circumference -32 cm. Apgar score was 8 points at 1 minute and 9 points at 5 minutes. A foramen ovale together with a pulmonary stenosis was found after birth, which did not require surgical correction. At the age of around one year the biological mother of the patient abandoned her and the child was raised by foster parents.
The patient demonstrated delayed motor and neurological development: she started walking at the age of 1 year and 6 months and could not talk. When the girl was two years old, the foster parents noticed that she had a vacant stare together with sudden hand movements, but no seizures. She was admitted to hospital and diagnosed with petit mal epilepsy.
On admission, the girl presented with microcephaly, craniosynostosis, hypertelorism, epicantic folds, depressed nasal bridge and wide nose, micrognathia, low set ears and a helix deformity of the right ear (Fig. 1). She also had a single pal-mar crease on both hands, clinodactily of the 2nd and 3rd finger of the hands and pes equinovarus congenitus of the left foot. She also presented with lack of coordination and an unsteady gait.  2 location (Fig. 2).
The parents could not be tested in order to check if it was a de novo mutation.

DISCUSSION
16p11.2 duplication syndrome is associated with leading manifestation of intellectual disability and especially hyperactivity and speech delay, which was also observed in our case. 2 The intellectual disability, which is the leading symptom, could be due to an impaired transmission of Gamma aminobutyric acid in the synapses in animal models. 3 Also, there is an increased incidence of epilepsy and schizophrenia. 2 However, there are no specific dysmorphic features for this genetic condition, but microcephaly, micrognathia and hypertelorism have been documented in other patients with this disorder. 4,5 Moreover, there could be also a deletion in this region and similar phenotype is observed, which makes the clinical diagnosis very hard to recognize. 6,7 That is why in patients with leading symptoms of delayed mental development, psychiatric disorders no matter the absence of specific dysmorphic features the array-CGH should be a first method of choice. 8 However, in our case we started with WES as a part of an on-going research project for craniosynostosis.
CTNND2 gene has not been described as a cause for a genetic disorder, but it may be related to severe mental retardation in patients with 5p deletion. 9 Unfortunately, we were not able to test for de novo occurrence of this variant of yet uncertain significance as this child was adopted and we did not have access to parental DNA. Nevertheless, this might be a good candidate gene and an additional cause for intellectual disability.
The presented case of 16p11.2 duplication illustrates the need for routine array-CGH testing in patients with autistic behavior/attention deficit disorder because there is no evident phenotype of this condition. With the help of this analysis there could a major improvement in the diagnostic process of patients with delayed mental and motor development.