Discussion

This study is the first to address systematically the cognitive behavioural phenotype of boys with X-linked ichthyosis,and provides evidence for an increased risk of inattentive ADHD subtype diagnosis and autistic spectrum difficulties.
Within the general population, rates of ADHD in boys in the UK are reported as 3.6%(1% have the in attentive subtype, 0.28% the hyperactive subtype and 2.34% the combined subtype).
In this study, 40% fulfil DSM-IV criteria for ADHD; even after removing the two children with an ASD, a 32% diagnostic rate is still considerably higher than the general population.
A major strength of the study was the ascertainment of families through the maternal serum screening programme, in orderto avoid bias, suggesting that these results are generalisableto boys with XLI in general.
Intriguingly, of the 32% with an ADHD diagnosis, all of these children fulfilled criteria for inattentive subtype only, and there was no correlation with the underlying molecular pathology of the STS gene.
Both deletions and presumed point mutations were associated with these symptoms, suggesting that it may be STS deficiency per se that is causing the increased risk if inattentive symptoms in these boys, rather than the presence of the deletion.
There are several lines of evidence in the literature to support this hypothesis.
Of particular interest is a recent finding from animal studies suggesting that haploinsufficiency of the STS gene may account for the attentional deficits seen in 39XO mice.
STS converts the sulfated from of dehydroepiandrosterone, know as DHEA-S, to DHEA.
Both are neurosteroids with effects on neurophysiological and bshavioural processes, including some evidence for an inverse relationship between DHEA blood values and clinical symptomatology in boys with ADHD.
Additionally, a 3 month treatment course of methylphenidate, the most common treatment for ADHD, produced significant clinical improvement in the boys with ADHD and increases in serum concentrations of DHEAS and DHEA, suggesting that these neurosteroids may play a role in the therapeutic effects of methylphenidate.
DHEA administration to patients with schizophrenia, alongside their usual antipsychotic medication, has also been shown to improve visual sustained attention.
We have identified three unrelated families with boys with XLI and large deletions associated in all cases with either autism or language/communication problems.
It is possible that in all three families deletion of the NLGN4 gene accounts for the autistic difficulties, as several cases of autistic spectrum disorders associated with mutations within this gene have been previously reported.
One of the boys originally described by jamain et al, in addition to the diagnosis of Asperger's syndrome, also had communication difficulties described as "dysarthria" which may be relevant to one of the boys described here with severe verbal dyspraxia.