Relationship of thyroid function with genetic subtypes and treatment with growth hormone in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by a variety of mechanisms which include large deletions (70%-75%), maternal uniparental disomy (UPD) (20%-30%), and imprinting defects (2%-5%) or balanced translocations. Individuals often have a characteristic behavior disorder with mild intellectual disability, infantile hypotonia associated with poor sucking, short stature, and obesity. PWS is characterized by hypothalamic-pituitary axis dysfunction with growth hormone (GH) deficiency, hypogonadism, and several other hormonal deficiencies resulting in short stature, centrally driven excessive appetite (hyperphagia), central obesity, cryptorchidism, and decreased lean body mass. In this study, we determined and sought differences in the incidence of thyroid abnormalities among the common genetic subtypes in a cohort of 52 subjects with PWS because there was limited literature available. We also sought the effects of growth hormone (GH) treatment on the thyroid profile. Fifty-two subjects with a genetically confirmed diagnosis of PWS were included in this study at the University of California, Irvine. Blood samples for baseline thyroxine stimulating hormone (TSH) and free thyroxine (fT4) levels were obtained in the morning after an overnight fast for 8-12 h. Statistical analyses were performed with SPSS (SPSS Inc., 21.0). Mean values were analyzed by one-way ANOVA, and student's t-test and statistical significance were set at p < 0.05. The subjects included 26 males and 26 females with an age range of 3-38 years. There were 29 subjects with chromosome 15q11-q13 deletions and 23 with UPD; 28 were GH treated currently or in the past, and 24 never received GH. There was no significant difference in age or body mass index (BMI) (kg/m2) between GH-treated versus non-GH-treated groups. BMI was higher in the deletion group compared to the UPD group (p = 0.05). We identified two individuals who were clinically diagnosed and treated for hypothyroidism, one of whom was on GH supplements. We identified two additional individuals with subclinical hypothyroidism who were not on GH treatment, giving a frequency of 7.6% (4/52) in this cohort of patients. We did not find significant differences in thyroid function (TSH) in the deletion versus UPD groups. We found significant differences in thyroid function, however, between GH-treated and non-GH-treated groups. The mean TSH was lower (2.25 ± 1.17 uIU/M, range 0.03-4.92 uIU/M versus 2.80 ± 1.44 uIU/M, range 0.55-5.33 uIU/M respectively, p = 0.046), and the free T4 levels were significantly higher (1.13 ± 0.70 and 1.03 ± 0.11 ng/dL, respectively, p = 0.05) in the GH-treated individuals compared to non-GH-treated individuals. In this cohort of subjects with PWS, we identified two previously diagnosed individuals with hypothyroidism and two individuals with subclinical hypothyroidism (4/52, 7.6%), three of whom were not receiving GH treatment. We did not find any significant differences in thyroid function between molecular subtypes; however, we found that euthyroid status (lower TSH levels and higher free T4 levels) was significantly higher in individuals who were treated with GH compared to the untreated group. We recommend that individuals with PWS should be screened regularly for thyroid deficiency and start treatment early with GH in view of the potentially lower incidence of thyroid deficiency.

Neuromodulation and Disorders of Consciousness: Systematic Review and Pathophysiology.

INTRODUCTION: Disorders of consciousness (DoC) represent a range of clinical states, affect hundreds of thousands of people in the United States, and have relatively poor outcomes. With few effective pharmacotherapies, neuromodulation has been investigated as an alternative for treating DoC. To summarize the available evidence, a systematic review of studies using various forms of neuromodulation to treat DoC was conducted. MATERIALS AND METHODS: Adhering to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines for systematic literature review, the PubMed, Scopus, and Web of Science databases were queried to identify articles published between 1990 and 2023 in which neuromodulation was used, usually in conjunction with pharmacologic intervention, to treat or reverse DoC in humans and animals. Records were excluded if DoC (eg, unresponsive wakefulness syndrome, minimally conscious state, etc) were not the primary clinical target. RESULTS: A total of 69 studies (58 human, 11 animal) met the inclusion criteria for the systematic review, resulting in over 1000 patients and 150 animals studied in total. Most human studies investigated deep brain stimulation (n = 15), usually of the central thalamus, and transcranial magnetic stimulation (n = 18). Transcranial direct-current stimulation (n = 15) and spinal cord stimulation (n = 6) of the dorsal column also were represented. A few studies investigated low-intensity focused ultrasound (n = 2) and median nerve stimulation (n = 2). Animal studies included primate and murine models, with nine studies involving deep brain stimulation, one using ultrasound, and one using transcranial magnetic stimulation. DISCUSSION: While clinical outcomes were mixed and possibly confounded by natural recovery or pharmacologic interventions, deep brain stimulation appeared to facilitate greater improvements in DoC than other modalities. However, repetitive transcranial magnetic stimulation also demonstrated clinical potential with much lower invasiveness.