Clinically-mild CHD8-related neurodevelopmental disorder with overgrowth in adulthood

A 42-year-old man attended his first clinical genetics reassessment since childhood.
He had been recently diagnosed with unspecified neurodevelopmental disorder (DSM-5). His current full-scale IQ score on the WAIS-IV was 93, with a strength in digit span and a weakness in symbol search subscores. An initial hypothesis (RAADS-R: 135 points, AQ: 31 points, EQ: 22 points) of comorbidity with autism spectrum disorder was formulated, but later not confirmed.
The WHODAS 2.0 scale showed a slight impairment in overall functioning (total score = 31.91%). Specifically, he complained of difficulty in social integration (he still lived with his parents, had completed compulsory schooling without pursuing higher studies, and had held temporary job positions on an intermittent basis), although his independence in common activities of daily living was fair, overall.
Brain MRI showed symmetrically enlarged perivascular spaces in the deep temporal regions, coronae radiatae and centra semiovalia.
EEG was normal.
There was also symmetrical sensorineural hearing loss (mild at 2 kHz and moderate in the higher frequencies), discovered in adulthood.
Clinical examination showed absolute macrocephaly with high forehead, elongated face, high palate, and deep nasolabial folds, which were not seen in the parents; diffuse melanocytic nevi were also observed (some suspicious lesions had been removed, showing dysplasia on microscopic examination) and nasal septum deviation.
The main points of his past medical history were
- delayed gross motor milestones
- absolute macrocephaly since birth; subsequent growth of height, weight, and head circumference slightly and consistently above +2.5 SD; final height is approximately 7 cm above midparental height
- learning difficulties and relational disorders more evident during adolescence
- borderline intellectual functioning (DSM-III-R) in his early teens, when instrumental and laboratory testing for Sotos, Marfan, and Fragile X syndromes was performed, with negative results
- mild scoliosis noted since adolescence.
- difficulty falling asleep.
He was the second and last child of healthy, non-consanguineous parents of Southern European origin. There was no family history of overgrowth, NDD, or MCA.
Singleton WES analysis showed a heterozygous de novo loss-of-function variant in CHD8 (NM_001170629.2:c.3322dupA NP_001164100.1:p.(Ile1108AsnfsTer7), reported in ClinVar w/ ID VCV000589730).
This case highlights the need to collect natural history data to design evidence-based (and thus less resource-intensive) care pathways even for low-prevalence diseases such as CHD8-related developmental syndrome.