Medical and neurobehavioural phenotypes in carriers of X-linked ichthyosis-associated genetic deletions in the UK Biobank.

BACKGROUND: X-linked ichthyosis (XLI) is an uncommon dermatological condition resulting from a deficiency of the enzyme steroid sulfatase (STS), often caused by X-linked deletions spanning STS. Some medical comorbidities have been identified in XLI cases, but small samples of relatively young patients has limited this. STS is highly expressed in subcortical brain structures, and males with XLI and female deletion carriers appear at increased risk of developmental/mood disorders and associated traits; the neurocognitive basis of these findings has not been examined. METHODS: Using the UK Biobank resource, comprising participants aged 40-69 years recruited from the general UK population, we compared multiple medical/neurobehavioural phenotypes in males (n=86) and females (n=312) carrying genetic deletions spanning STS (0.8-2.5 Mb) (cases) to male (n=190 577) and female (n=227 862) non-carrier controls. RESULTS: We identified an elevated rate of atrial fibrillation/flutter in male deletion carriers (10.5% vs 2.7% in male controls, Benjamini-Hochberg corrected p=0.009), and increased rates of mental distress (p=0.003), irritability (p<0.001) and depressive-anxiety traits (p<0.05) in male deletion carriers relative to male controls completing the Mental Health Questionnaire. While academic attainment was unaffected, male and female deletion carriers exhibited impaired performance on the Fluid Intelligence Test (Cohen's d≤0.05, corrected p<0.1). Neuroanatomical analysis in female deletion carriers indicated reduced right putamen and left nucleus accumbens volumes (Cohen's d≤0.26, corrected p<0.1). CONCLUSION: Adult males with XLI disease-causing deletions are apparently at increased risk of cardiac arrhythmias and self-reported mood problems; altered basal ganglia structure may underlie altered function and XLI-associated psychiatric/behavioural phenotypes. These results provide information for genetic counselling of deletion-carrying individuals and reinforce the need for multidisciplinary medical care.

Behavioural and psychiatric phenotypes in female carriers of genetic mutations associated with X-linked ichthyosis.

X-linked ichthyosis (XLI) is a rare X-linked dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). STS is normally expressed in the brain, and males with XLI exhibit personality differences from males in the general population, and are at increased risk of developmental and mood disorders. As the STS gene escapes X-inactivation, female carriers of XLI-associated genetic mutations have reduced STS expression/activity relative to non-carrier females, and could manifest similar behavioural phenotypes to males with XLI. Additionally, as STS activity normally increases in female tissues towards late pregnancy and into the puerperium, carrier females could theoretically present with increased rates of postpartum psychopathology. Using a worldwide online survey comprising custom-designed demographic questionnaires and multiple validated psychological questionnaires, we collected detailed self-reported information on non-postpartum and postpartum behaviour in confirmed adult (>16yrs) female carriers of genetic mutations associated with XLI (n = 94) for statistical comparison to demographically-matched previously-published normative data from female controls (seven independent studies, 98≤n≤2562), adult males with XLI (n = 58), and to newly-obtained online survey data from a general population sample of mothers from the United Kingdom and United States of America (n = 263). The pattern of results in carrier females relative to controls was remarkably similar to that previously observed in males with XLI, with evidence for increased rates of developmental and mood disorders, and elevated levels of inattention, impulsivity, autism-related traits and general psychological distress. Carrier females exhibited a significantly elevated rate of postpartum mental health conditions (notably mild depression) relative to controls which could not be accounted for by social factors. Our data confirm the psychological profile associated with XLI-associated mutations, and suggest that female carriers may be at increased risk of psychopathology, including in the postpartum period. These findings are relevant to families affected by XLI, to clinicians involved in the care of these families, and to genetic counsellors.

X-linked ichthyosis associated with psychosis and behavioral abnormalities: a case report.

BACKGROUND: X-linked ichthyosis is a dermatological condition caused by deficiency for the enzyme steroid sulfatase. Previously, X-linked ichthyosis/steroid sulfatase deficiency has been associated with developmental and neurological phenotypes. Here, we show for the first time, that X-linked ichthyosis may be comorbid with an additional psychiatric phenotype (psychosis). CASE PRESENTATION: We report the case of an 11-year-old Saudi Arabian boy with X-linked ichthyosis associated with psychosis, mental retardation, autism spectrum disorder, inattentive attention deficit hyperactivity disorder, and epilepsy. Genetic analysis revealed a 1.68 Mb deletion encompassing STS in 95% of cells while biochemical analysis revealed correspondingly low steroid sulfatase activity consistent with a diagnosis of X-linked ichthyosis. The psychotic symptoms could be reasonably well controlled by administration of an atypical antipsychotic. CONCLUSIONS: This report describes a case of comorbid X-linked ichthyosis and psychosis (most closely corresponding to early-onset schizophrenia) for the first time, and suggests that deficiency for steroid sulfatase and contiguous genes may increase vulnerability to psychosis as well as other psychological disorders.

Behavioural and Psychiatric Phenotypes in Men and Boys with X-Linked Ichthyosis: Evidence from a Worldwide Online Survey.

BACKGROUND: X-linked ichthyosis (XLI) is a rare dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). Preliminary evidence in boys with XLI, and animal model studies, suggests that individuals lacking STS are at increased risk of developmental disorders and associated traits. However, the behavioural profile of children with XLI is poorly-characterised, and the behavioural profile of adults with XLI has not yet been documented at all. MATERIALS AND METHODS: Using an online survey, advertised worldwide, we collected detailed self- or parent-reported information on behaviour in adult (n = 58) and younger (≤18yrs, n = 24) males with XLI for comparison to data from their non-affected brothers, and age/gender-matched previously-published normative data. The survey comprised demographic and background information (including any prior clinical diagnoses) and validated questionnaires assaying phenotypes of particular interest (Adult ADHD Self-Report Scale v1.1, Barrett Impulsiveness Scale-11, adult and adolescent Autism Quotient, Kessler Psychological Distress Scales, and Disruptive Behaviour Disorder Rating Scale). RESULTS: Individuals with XLI generally exhibited normal sensory function. Boys with XLI were at increased risk of developmental disorder, whilst adults with the condition were at increased risk of both developmental and mood disorders. Both adult and younger XLI groups scored significantly more highly than male general population norms on measures of inattention, impulsivity, autism-related traits, psychological distress and disruptive behavioural traits. CONCLUSIONS: These findings indicate that both adult and younger males with XLI exhibit personality profiles that are distinct from those of males within the general population, and suggest that individuals with XLI may be at heightened risk of psychopathology. The data are consistent with the notion that STS is important in neurodevelopment and ongoing brain function, and with previous work suggesting high rates of developmental disorders in boys with XLI. Our results suggest that individuals with XLI may require medical care from multidisciplinary teams, and should help to inform genetic counselling for the condition.

[X-linked recessive ichthyosis (XRI), cerebellar ataxia and neuropsychiatric symptoms]. / X-chromosomal-rezessive Ichthyose (XRI) mit zerebellärer Ataxie, Angsterkrankung und Depression.

X-Linked ichthyosis (XRI) is a keratinisation disorder caused by a mutation of the steroid sulfatase gene. An association with mental retardation and epilepsy has been reported earlier. Here, we report on a patient suffering from cerebellar symptoms such as yes/yes head tremor, scanning dysarthria, pronounced dysmetria and intention tremor, without any abnormalities of the cerebellum in MRI, in addition to XRI proven by molecular genetics. Furthermore, the patient suffered from anxiety disorder, depression, and a male pattern baldness. One of the patient' s brothers and a nephew showed a similar clinical presentation. Because of the fact that several members of the patient's family suffered from similar symptoms, we consider a syndromic link between XRI and cerebellar disorder to be possible.

Steroid sulfatase-deficient mice exhibit endophenotypes relevant to attention deficit hyperactivity disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition characterised by inattention, impulsivity and hyperactivity; it is frequently co-morbid with anxiety and conduct disorders, sleep perturbation and abnormal consummatory behaviours. Recent studies have implicated the neurosteroid-modulating enzyme steroid sulfatase (STS) as a modulator of ADHD-related endophenotypes. The effects of steroid sulfatase deficiency on homecage activity, feeding/drinking behaviours, anxiety-related behaviours (assayed in light-dark box and open field paradigms), social dominance and serum steroid hormone levels were determined by comparing 40,XY and 39,X(Y*)O mice. Subsequently, mice administered the steroid sulfatase inhibitor COUMATE acutely were compared to vehicle-treated mice on behavioural tasks sensitive to enzyme deficiency to dissociate between its developmental and ongoing effects. 39,X(Y*)O mice exhibited heightened reactivity to a novel environment, hyperactivity in the active phase, and increased water (but not food) consumption relative to 40,XY mice during a 24h period; the former group also demonstrated evidence for heightened emotional reactivity. There was no difference in social dominance between the 40,XY and 39,X(Y*)O mice. COUMATE administration had no effect on homecage activity, water consumption or anxiety measures in the open field. 39,X(Y*)O mice exhibited significantly lower dehydroepiandrosterone (DHEA) serum levels than 40,XY mice, but equivalent corticosterone levels. Together with previous data, the present results suggest that steroid sulfatase may influence core and associated ADHD behavioural endophenotypes via both developmental and ongoing mechanisms, and that the 39,X(Y*)O model may represent a useful tool for elucidating the neurobiological basis of these endophenotypes.

Managing ichthyosis: a case study.

Ichthyoses-- rare, genetic, incurable dermatologic diseases characterized by dry, thickened, scaling skin-- affect more than 1 million Americans and can cause devastating disfigurement with numerous physical, social, and emotional consequences. Topical treatments typically focus on symptom management. A 44-year-old man presented with severe X-linked type ichthyosis. When his condition did not improve with the use of a variety of topical and systemic treatments, a once-a-day, over-the-counter skin care regimen consisting of a surfactant-free cleanser followed by the application of moisturizer containing amino acids, vitamins, antioxidants, and methylsulfonylmethane was prescribed. After 4 weeks of using this management regimen on a test area on his left arm, the skin was clear and discomfort and itching had subsided. Subsequent application of the skin care products on other affected areas also did not cause any adverse reactions and his skin continued to improve. Symptom resolution and patient satisfaction indicate the product line may be a viable consideration for use in patients with similarly compromised skin.

The pediatric team and the consulting child psychiatrist and the hospitalized depressed infant.

The link between pediatricians and child mental health professionals is a complex, but fascinating issue. Based on our clinical experience, this paper will discuss the issue of depression in very young children hospitalized for serious illness in a general pediatric ward, and its theoretical implications. We begin with a clinical vignette, followed by a review of several clinical phenomena including anticipated bereavement (either by the parents or the medical team, or both), some high-tech medical conditions specific to neonatology and joint parents-infant hospitalization as well as relating the above to psychoanalytical concepts. The significance and importance of adopting a dual perspective, from both the pediatric and the psychopathological viewpoint, while treating the very sick hospitalized young child and his/her parents, is underlined.