Novel Insights into 46,XY Disorders of Sex Development due to NR5A1 Gene Mutation.

The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern. Endocrine evaluation showed hypergonadotropic hypogonadism, and the Sertoli cell markers inhibin B and anti-Müllerian hormone were also low. Several molecular genetic studies were initiated. While analyses of the androgen receptor gene, the SRD5A2 gene and HSD17B3 gene were uninformative, a novel p.L230R mutation was found in the NR5A1 gene. A mutant construct proved a severe dysfunction of this variant in functional analysis after recreation and transfection into HeLa cells. We conclude that the NR5A1 p.L230R mutation most likely leads to a spatial and time-dependent Leydig cell and Sertoli cell dysfunction during development not causing the classical gonadal dysgenesis phenotype. This case demonstrates that the current classification should be updated to encompass the overlapping phenotypes of some genetic conditions within 46,XY DSD.

May Functional Imaging be Helpful for Behavioral Assessment in Children? Regions of Motor and Associative Cortico-Subcortical Circuits Can be Differentiated by Laterality and Rostrality.

BACKGROUND: Cortico-subcortical circuits are organized into the sensorimotor, associative, and limbic loop. These neuronal preconditions play an important role regarding the understanding and treatment of behavioral problems in children. Differencing evidence argues for a lateralized organization of the sensorimotor loop and a bilateral (i.e., non-lateralized) organization of the associative loop. However, a firm behavioral-neurobiological distinction of these circuits has been difficult, specifically in children. OBJECTIVES: Thus, the aim was a comprehensive functional visualization and differentiation of the sensorimotor and the associative circuit during childhood. As a new approach, laterality and rostrality features were used to distinguish between the two circuits within one single motor task. METHODS: Twenty-four healthy boys performed self-paced index finger tapping with each hand separately during functional magnetic resonance imaging at 3 Tesla. RESULTS: A contrast analysis for left against right hand movement revealed lateralized activation in typical sensorimotor regions such as primary sensorimotor cortex, caudal supplementary motor area (SMA), caudal putamen, and thalamus. A conjunction analysis confirmed bilateral involvement of known associative regions including pre-SMA, rostral SMA, and rostral putamen. CONCLUSION: A functional visualization of two distinct corticostriatal circuits is provided in childhood. Both the sensorimotor and associative circuit may be discriminated by their laterality characteristics already in minors. Additionally, the results support the concept of a modified functional subdivision of the SMA in a rostral (associative) and caudal (motor) part. A further development of this approach might help to nurture behavioral assessment and neurofeedback training in child mental health.

Finger tapping-related activation differences in treatment-naïve pediatric Tourette syndrome: a comparison of the preferred and nonpreferred hand.

BACKGROUND: Disturbances of motor circuitry are commonly encountered in Tourette syndrome (TS). The aim of this study was to investigate simple motor performance differences between boys with TS and healthy controls. METHODS: We attempted to provide insight into motor network alterations by studying a group of treatment-naïve patients suffering from 'pure' TS, i.e., without comorbid symptomatology at an early stage of disease. We used functional MRI to compare activation patterns during right (preferred) and left (nonpreferred) index finger tapping between 22 TS boys (12.6 ± 1.7 years) and 22 age-matched healthy control boys. RESULTS: Boys with TS revealed altered motor network recruitment for right (dominant) and left (nondominant) index finger tapping. Brain activation patterns in response to index finger tapping of the nonpreferred left hand reflected the most prominent differences, including activation decrease in contralateral sensorimotor cortex while recruiting premotor and prefrontal regions along with the left inferior parietal lobule to a greater extent. CONCLUSIONS: This study demonstrates clear functional differences of simple index finger tapping in early-stage TS. We suggest that this reflects the requirement for additional brain networks to keep a normal performance level during the actual task and adaptive mechanisms due to continuous tic suppression and performance in TS.

Fine motor skills and interhemispheric transfer in treatment-naive male children with Tourette syndrome.

AIM: This study addressed whether Tourette syndrome is associated with an impairment of fine motor skills or altered interhemispheric transfer. We additionally investigated the association between interhemispheric transfer and size of the corpus callosum. METHOD: The sample, a subsample of our larger neuroimaging sample, included 27 treatment-naive males with 'pure' Tourette syndrome (age range 10y 2mo-14y 4mo; mean age 11y 10mo, SD 1y 2mo) and 26 matched healthy comparison children (age range 10y 2mo-14y 4mo; mean age 11y 10mo, SD 1y 1mo). A finger tapping task and the Purdue Pegboard were used to assess fine motor skills. Interhemispheric transfer time (ITT) was measured with the Poffenberger paradigm. The neuroanatomical data were derived from our previous neuroimaging study. RESULTS: ITT was negatively correlated with the size of callosal subregion 3 (r=-0.366, p=0.028), indicating that a shorter ITT was associated with a larger corpus callosum. INTERPRETATION: Our findings support the assumption that previously reported impairment of motor skills in Tourette syndrome does not directly result from tics but from other factors such as medication or comorbidities. Following the assumption that callosal subregion 3 in Tourette syndrome grows as a consequence of tic performance over years, our preliminary results suggest that this growth might accelerate interhemispheric transfer in Tourette syndrome.