This review summarises the key clinical features of septo-optic dysplasia (SOD), the significant inroads that progress in genetics has made into our understanding of the aetiology of the condition over the last decade, and the pitfalls and challenges that we face in the management of these phenotypically variable patients.

BackgroundMany studies have demonstrated early generalised cognitive impairment in schizophrenia.AimsTo examine executive function in first-episode schizophrenia, characterise the nature of the impairment and specify any relationships with symptoms and duration of untreated psychosis (DUP).MethodPatients (n=136) and normal controls (n=81) were assessed with the Cambridge Automated Neuropsychological Test Battery, National Adult Reading Test IQ, and Scales for the Assessment of Positive and Negative Symptoms.ResultsMemory and executive impairments in patients were independent of IQ level. Spatial working memory was impaired because of inadequate strategy use. On a planning task, patients showed reduced planning times and suboptimal problem-solving. On an attentional set-shifting task, 75% of patients were able to perform an extra-dimensional shift thought to be a core attribute of prefrontal cortex function. Those who failed had significantly longer DUP.ConclusionsPrefrontal cortex function deteriorates at the onset of psychosis and continues to worsen over time.

At the initiation of drug treatment, attitudes toward medication and insight appear more relevant to medication adherence than side effects. Adherence appears to reflect a complex interaction of influences, which may change over time.

The diagnosis of GH deficiency (GHD) in childhood is a multistep process involving clinical history, examination with detailed auxology, biochemical testing, and pituitary imaging, with an increasing contribution from genetics in patients with congenital GHD. Our increasing understanding of the factors involved in the development of somatotropes and the dynamic function of the somatotrope network may explain, at least in part, the development and progression of childhood GHD in different age groups. With respect to the genetic etiology of isolated GHD (IGHD), mutations in known genes such as those encoding GH (GH1), GHRH receptor (GHRHR), or transcription factors involved in pituitary development, are identified in a relatively small percentage of patients suggesting the involvement of other, yet unidentified, factors. Genome-wide association studies point toward an increasing number of genes involved in the control of growth, but their role in the etiology of IGHD remains unknown. Despite the many years of research in the area of GHD, there are still controversies on the etiology, diagnosis, and management of IGHD in children. Recent data suggest that childhood IGHD may have a wider impact on the health and neurodevelopment of children, but it is yet unknown to what extent treatment with recombinant human GH can reverse this effect. Finally, the safety of recombinant human GH is currently the subject of much debate and research, and it is clear that long-term controlled studies are needed to clarify the consequences of childhood IGHD and the long-term safety of its treatment.

Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50–70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes.

ContextBrain white matter hyperintensities are seen on routine clinical imaging in 46% of adults with congenital adrenal hyperplasia (CAH). The extent and functional relevance of these abnormalities have not been studied with quantitative magnetic resonance imaging (MRI) analysis.ObjectiveTo examine white matter microstructure, neural volumes, and central nervous system (CNS) metabolites in CAH due to 21-hydroxylase deficiency (21OHD) and to determine whether identified abnormalities are associated with cognition, glucocorticoid, and androgen exposure.Design, Setting, and ParticipantsA cross-sectional study at a tertiary hospital including 19 women (18 to 50 years) with 21OHD and 19 age-matched healthy women.Main Outcome MeasureRecruits underwent cognitive assessment and brain imaging, including diffusion weighted imaging of white matter, T1-weighted volumetry, and magnetic resonance spectroscopy for neural metabolites. We evaluated white matter microstructure by using tract-based spatial statistics. We compared cognitive scores, neural volumes, and metabolites between groups and relationships between glucocorticoid exposure, MRI, and neurologic outcomes.ResultsPatients with 21OHD had widespread reductions in white matter structural integrity, reduced volumes of right hippocampus, bilateral thalami, cerebellum, and brainstem, and reduced mesial temporal lobe total choline content. Working memory, processing speed, and digit span and matrix reasoning scores were reduced in patients with 21OHD, despite similar education and intelligence to controls. Patients with 21OHD exposed to higher glucocorticoid doses had greater abnormalities in white matter microstructure and cognitive performance.ConclusionWe demonstrate that 21OHD and current glucocorticoid replacement regimens have a profound impact on brain morphology and function. If reversible, these CNS markers are a potential target for treatment.

The growth hormone-insulin-like growth factor-1 axis plays a role in normal brain growth but little is known of the effect of growth hormone deficiency on brain structure. Children with isolated growth hormone deficiency (peak growth hormone <6.7 µg/l) and idiopathic short stature (peak growth hormone >10 µg/l) underwent cognitive assessment, diffusion tensor imaging and volumetric magnetic resonance imaging prior to commencing growth hormone treatment. Total brain, corpus callosal, hippocampal, thalamic and basal ganglia volumes were determined using Freesurfer. Fractional anisotropy (a marker of white matter structural integrity) images were aligned and tract-based spatial statistics performed. Fifteen children (mean 8.8 years of age) with isolated growth hormone deficiency [peak growth hormone <6.7 µg/l (mean 3.5 µg/l)] and 14 controls (mean 8.4 years of age) with idiopathic short stature [peak growth hormone >10 µg/l (mean 15 µg/l) and normal growth rate] were recruited. Compared with controls, children with isolated growth hormone deficiency had lower Full-Scale IQ (P < 0.01), Verbal Comprehension Index (P < 0.01), Processing Speed Index (P < 0.05) and Movement-Assessment Battery for Children (P < 0.008) scores. Verbal Comprehension Index scores correlated significantly with insulin-like growth factor-1 (P < 0.03) and insulin-like growth factor binding protein-3 (P < 0.02) standard deviation scores in isolated growth hormone deficiency. The splenium of the corpus callosum, left globus pallidum, thalamus and hippocampus (P < 0.01) were significantly smaller; and corticospinal tract (bilaterally; P < 0.045, P < 0.05) and corpus callosum (P < 0.05) fractional anisotropy were significantly lower in the isolated growth hormone deficiency group. Basal ganglia volumes and bilateral corticospinal tract fractional anisotropy correlated significantly with Movement-Assessment Battery for Children scores, and corpus callosum fractional anisotropy with Full-Scale IQ and Processing Speed Index. In patients with isolated growth hormone deficiency, white matter abnormalities in the corpus callosum and corticospinal tract, and reduced thalamic and globus pallidum volumes relate to deficits in cognitive function and motor performance. Follow-up studies that investigate the course of the structural and cognitive deficits on growth hormone treatment are now required to confirm that growth hormone deficiency impacts significantly on brain structure, cognitive function and motor performance.

Context Current knowledge on gonadal function in congenital adrenal hyperplasia (CAH) is mostly limited to single-center/country studies enrolling small patient numbers. Overall data indicate that gonadal function can be compromised in men with CAH. Objective To determine gonadal function in men with CAH within the European ‘dsd-LIFE’ cohort. Design Cross-sectional clinical outcome study, including retrospective data from medical records. Methods Fourteen academic hospitals included 121 men with CAH aged 16–68 years. Main outcome measures were serum hormone concentrations, semen parameters and imaging data of the testes. Results At the time of assessment, 14/69 patients had a serum testosterone concentration below the reference range; 7 of those were hypogonadotropic, 6 normogonadotropic and 1 hypergonadotropic. In contrast, among the patients with normal serum testosterone (55/69), 4 were hypogonadotropic, 44 normogonadotropic and 7 hypergonadotropic. The association of decreased testosterone with reduced gonadotropin concentrations (odds ratio (OR) = 12.8 (2.9–57.3)) was weaker than the association between serum androstenedione/testosterone ratio ≥1 and reduced gonadotropin concentrations (OR = 39.3 (2.1–732.4)). Evaluation of sperm quality revealed decreased sperm concentrations (15/39), motility (13/37) and abnormal morphology (4/28). Testicular adrenal rest tumor (TART)s were present in 39/80 patients, with a higher prevalence in patients with the most severe genotype (14/18) and in patients with increased current 17-hydroxyprogesterone 20/35) or androstenedione (12/18) serum concentrations. Forty-three children were fathered by 26/113 patients. Conclusions Men with CAH have a high risk of developing hypothalamic-pituitary-gonadal disturbances and spermatogenic abnormalities. Regular assessment of endocrine gonadal function and imaging for TART development are recommended, in addition to measures for fertility protection.