ESPE Abstracts

Background: Activity dependent neuroprotective protein (ADNP) syndrome (OMIM: 615873), also known as Helsmoortel Van Der Aa syndrome (HVDAS), is an autosomal dominant monogenic neurodevelopmental disorder caused by ADNP gene mutations. It is characterized with impaired learning and motor skills, hypotonia, dysmorphic features, organ anomalies, behavioral and psychiatric problems.

Aim: To present a female patient with HVDAS due to a novel ADNP gene variant associated with the development of early-onset obesity and intellectual disability.

Case presentation: Our patient was a 20 month-old-girl born from fifth IVF twin pregnancy of healthy parents with unremarkable family history. She was born at 36⁺⁵ gestational weeks with a birth weight of 2.300 kg (-1.53 SDS) and а birth length of 48 cm (-0.33 SDS). She had a retarded cardiopulmonary adaptation being hypotonic from birth onwards. At four months the child started gaining weight developing severe obesity at the time of her referral to our center. At 18 months of age the girl had delayed motor skills and speech development. She demonstrated behavioral problems and had difficulties in social interaction and communication. She was assessed by a psychologist with an estimated IQ score of 57. On physical examination the patient presented severe adiposity, her weight was 17.7 kg (+5.4 SDS) and her height 89 cm (+2.25 SDS). Her facial dysmorphic features included high anterior hairline, hypertelorism, epicanthial folds, long smooth philtrum, thin upper lip, broad nasal bridge, upturned nasal tip, ptosis of the right eyelid and right-sided divergent strabismus, downturned mouth corners, low-set, cup shaped ears, high palate and almost full erupted milk dentition. She had normal lung and heart function, her extremities were hypotonic with shorter toes and pencil-like fingers of both hands. The child had elevated total cholesterol and LDL-cholesterol but all other laboratory tests were normal. The echocardiography and abdominal sonography were also normal. A brain magnetic resonance imaging (MRI) was performed demonstrating abnormalities including mild periventricular leukomalacia, moderate ventriculomegaly affecting the lateral ventricles and right parietal developmental venous anomaly within the periventricular white matter. The karyotype as well as the multiplex ligation probe amplification technique which did not detect any abnormalities. The whole exome sequencing analysis identified a new heterozygous missense variant c.1538C>T, p.(Ser513Phe) in the ADNP gene. Based on the clinical symptoms and the genetic result, the patient has been diagnosed as having HVDAS.

Conclusion: Patients with HVDAS may develop severe early-onset obesity with an increased risk for cardio-metabolic abnormalities.