Fragile X syndrome in a girl with variant Turner syndrome and an isodicentric X chromosome.

Fragile X (FXS) and Turner (TS) syndromes are X-chromosome-associated disorders. Herein, we report the case of a girl in middle childhood with bicuspid aortic valve in infancy, growth failure, global developmental delay (GDD), visual problems, and coexisting attention-deficit/hyperactivity and anxiety disorders. A high-resolution karyotype in 20 cells revealed 46,X,Idic(X)(p11.21)[19]/45,X[1], suggestive of variant TS. Given her atypical phenotype, subsequent DNA testing was performed. Four FMR1 cytosine-guanine-guanine repeats (30, 410, 580 and 800) were identified, confirming the additional FXS diagnosis. This case study highlights the importance of additional genetic testing in individuals with atypical variant TS, such as unexplained GDD and distinct facial characteristics. The additional FXS diagnosis prompted new therapeutic development for the patient to advance precision healthcare.

Hypermobile Ehlers-Danlos syndrome (hEDS) phenotype in fragile X premutation carriers: case series.

BACKGROUND: While an association between full mutation CGG-repeat expansions of the Fragile X Mental Retardation 1 (FMR1) gene and connective tissue problems are clearly described, problems in fragile X premutation carriers (fXPCs) CGG-repeat range (55-200 repeats) of the FMR1 gene may be overlooked. OBJECTIVE: To report five FMR1 fXPCs cases with the hypermobile Ehlers-Danlos syndrome (hEDS) phenotype. METHODS: We collected medical histories and FMR1 molecular measures from five cases who presented with joint hypermobility and loose connective tissue and met inclusion criteria for hEDS. RESULTS: Five cases were female and ranged between 16 and 49 years. The range of CGG-repeat allele sizes ranged from 66 to 150 repeats. All had symptoms of hEDS since early childhood. Commonalities in molecular pathogenesis and coexisting conditions between the fXPCs and hEDS are also presented. The premutation can lead to a reduction of fragile X mental retardation protein, which is crucial in maintaining functions of the extracellular matrix-related proteins, particularly matrix metallopeptidase 9 and elastin. Moreover, elevated FMR1 messenger RNA causes sequestration of proteins, which results in RNA toxicity. CONCLUSION: Both hEDS phenotype and premutation involvement may co-occur because of related commonalities in pathogenesis.

Effectiveness of Parenting Training on Emotional and Behavioral Problems in First through Fourth Grade Thai Children with ADHD: A Randomized Controlled Study.

OBJECTIVE: To evaluate the effectiveness of parenting training on emotional and behavioral problems of first through fourth grade Thai children with ADHD compared with routine clinical care in a university hospital in southern Thailand. MATERIAL AND METHODS: Caregivers of the children were invited and assessed for eligibility. Eighty children with ADHD were randomly assigned to either a parenting training group or a routine clinical care group. The primary caregivers of the parenting training group participated in 6 120-minute weekly sessions in addition to routine clinical care. Caregiver and teacher ADHD ratings and oppositional-defiant disorder ratings were collected at the time of enrollment and after the 6 weeks of training in both groups. The differences in scores in both groups were analyzed using a mixed model ANOVA. RESULTS: Each arm had 40 participants. The mean (SD) age of the children was 8.3 (1.1) years and their mean (SD) age at the first diagnosis of ADHD was 6.8 (1.3) years. Most of them were receiving methylphenidate for treatment of their ADHD. The mother was the primary caregiver for 83.5% of the children. The ADHD symptoms and oppositional-defiant symptoms showed significant improvement after receiving the treatment in both groups; however, no significant differences were found between groups. CONCLUSION: Adding parenting training to the routine clinical care for children with uncomplicated ADHD who are being medicated was not more effective than the routine clinical care alone. However, the power of this study is limited, and follow-up is needed to evaluate the long-term effectiveness.

Fragile X premutation and associated health conditions: A review.

Fragile X syndrome (FXS) is the most common single gene disorder, which causes autism and intellectual disability. The fragile X mental retardation 1 (FMR1) gene is silenced when cytosine-guanine-guanine (CGG) triplet repeats exceed 200, which is the full mutation that causes FXS. Carriers of FXS have a CGG repeat between 55 and 200, which is defined as a premutation and transcription of the gene is overactive with high levels of the FMR1 mRNA. Most carriers of the premutation have normal levels of fragile X mental retardation protein (FMRP) and a normal intelligence, but in the upper range of the premutation (120-200) the FMRP level may be lower than normal. The clinical problems associated with the premutation are caused by the RNA toxicity associated with increased FMR1 mRNA levels, although for some mildly lowered FMRP can cause problems associated with FXS. The RNA toxicity causes various health problems in the carriers including but not limited to fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorders. Since some individuals with neuropsychiatric problems do not meet the severity for a diagnosis of a "disorder" then the condition can be labeled as fragile X premutation associated condition (FXPAC). Physicians must be able to recognize these health problems in the carriers and provide appropriate management.

Cardiovascular Problems in the Fragile X Premutation.

There is a dearth of information about cardiovascular problems in fragile X premutation carriers who have 55-200 CGG repeats in fragile X mental retardation 1 (FMR1) gene. The FMR1 expansion in the premutation range leads to toxic RNA gain-of-function resulting in cellular dysregulation. The mechanism of RNA toxicity underlies all of the premutation disorders including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorder. Cardiovascular problems particularly autonomic dysfunction, hypertension, and cardiac arrhythmias are not uncommon in premutation carriers. Some arterial problems and valvular heart diseases have also been reported. This article reviews cardiovascular problems in premutation carriers and discusses possible contributing mechanisms including RNA toxicity and mild fragile X mental retardation protein deficiency. Further research studies are needed in order to prove a direct association of the cardiovascular problems in fragile X premutation carriers because such knowledge will lead to better preventative treatment.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Pathophysiology and Clinical Implications.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in older premutation (55-200 CGG repeats) carriers of FMR1. The premutation has excessive levels of FMR1 mRNA that lead to toxicity and mitochondrial dysfunction. The clinical features usually begin in the 60 s with an action or intention tremor followed by cerebellar ataxia, although 20% have only ataxia. MRI features include brain atrophy and white matter disease, especially in the middle cerebellar peduncles, periventricular areas, and splenium of the corpus callosum. Neurocognitive problems include memory and executive function deficits, although 50% of males can develop dementia. Females can be less affected by FXTAS because of a second X chromosome that does not carry the premutation. Approximately 40% of males and 16% of female carriers develop FXTAS. Since the premutation can occur in less than 1 in 200 women and 1 in 400 men, the FXTAS diagnosis should be considered in patients that present with tremor, ataxia, parkinsonian symptoms, neuropathy, and psychiatric problems. If a family history of a fragile X mutation is known, then FMR1 DNA testing is essential in patients with these symptoms.

Coverage of tuberculosis and diabetes mellitus screening among household contacts of tuberculosis patients: a household-based cross-sectional survey from Southern Thailand.

BACKGROUND: The comorbid presence of tuberculosis and diabetes mellitus has become an increasingly important public health threat to the prevention and control of both diseases. Thus, household contact investigation may serve a dual purpose of screening for both tuberculosis and diabetes mellitus among household contacts. We therefore aimed to evaluate the coverage of screening for tuberculosis and diabetes mellitus among household contacts of tuberculosis index cases and to determine predictors of tuberculosis screening. METHODS: A household-based survey was conducted in February 2019 in Muang district of Phatthalung Province, Thailand where 95 index tuberculosis patients were newly diagnosed with pulmonary or pleural tuberculosis between October 2017 and September 2018. Household contacts of the index patients were interviewed using a structured questionnaire to ascertain their past-year history of tuberculosis screening and, if appropriate, diabetes mellitus screening. For children, the household head or an adult household member was interviewed as a proxy. Coverage of tuberculosis screening at the household level was regarded as households having all contacts screened for tuberculosis. Logistic regression and mixed-effects logistic regression models were used to determine predictors of tuberculosis screening at the household and individual levels, respectively, with the strengths of association presented as adjusted odds ratios (AOR) and 95% confidence intervals (CI). RESULTS: Of 61 responding households (64%), complete coverage of tuberculosis screening at the household level was 34.4% and among the 174 household contacts was 46.6%. About 20% of contacts did not receive any recommendation for tuberculosis screening. Households were more likely to have all members screened for tuberculosis if they were advised to be screened by a healthcare professional rather than someone else. At the individual level, contacts aged ≥35 years (AOR: 30.6, 95% CI: 2.0-466.0), being an employee (AOR: 0.1, 95% CI: 0.0-0.8) and those who had lived more than 5 years in the same household (AOR: 0.1, 95% CI: 0.0-0.8) were independent predictors for tuberculosis screening. Coverage of diabetes mellitus screening was 80.6% with lack of awareness being the main reason for not being screened. CONCLUSIONS: Compared to diabetes screening, the coverage of tuberculosis screening was low. A better strategy to improve coverage of tuberculosis contact screening is needed.

Ataxia as the Major Manifestation of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): Case Series.

Fragile X-associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disease developed by carriers of a premutation in the fragile X mental retardation 1 (FMR1) gene. The core clinical symptoms usually manifest in the early 60s, typically beginning with intention tremor followed by cerebellar ataxia. Ataxia can be the only symptom in approximately 20% of the patients. FXTAS has a slow progression, and patients usually experience advanced deterioration 15 to 25 years after the initial diagnosis. Common findings in brain imaging include substantial brain atrophy and white matter disease (WMD). We report three cases with an atypical clinical presentation, all presenting with gait problems as their initial manifestation and with ataxia as the dominant symptom without significant tremor, as well as a faster than usual clinical progression. Magnetic resonance imaging (MRI) was remarkable for severe brain atrophy, ventriculomegaly, thinning of the corpus callosum, and periventricular WMD. Two cases were diagnosed with definite FXTAS on the basis of clinical and radiological findings, with one individual also developing moderate dementia. Factors such as environmental exposure and general anesthesia could have contributed to their clinical deterioration. FXTAS should be considered in the differential diagnosis of patients presenting with ataxia, even in the absence of tremor, and FMR1 DNA testing should be sought in those with a family history of fragile X syndrome or premutation disorders.

Reliability of pubertal maturation self-assessment in a school-based survey.

AIM: To assess the reliability of pubertal self-assessment of Thai adolescents. SUBJECTS: Some 927 girls and 997 boys, aged 8-18 years, from nine schools in Hat-Yai municipality. METHODS: The adolescents evaluated their pubertal status after being shown a line drawing of the five Tanner stages with a short description. Girls assessed their breast and pubic hair development, and boys assessed their pubic hair development. The pubertal self-assessments were compared to pubertal assessments made by a pediatrician who examined the children after their self-assessment. Kappa coefficient and percent agreement were used for statistical analysis. RESULTS: The percent agreement of breast and pubic hair development between the girl's self-assessments and the assessments by the pediatrician were 60.8% and 78%, respectively. Kappa coefficient for breast assessment was 0.50 (95% confidence interval, CI 0.47-0.53) and for pubic hair 0.68 (95% CI 0.65-0.72). Nearly 30% of girls aged younger than 10 years overestimated their breast development status while 45% of girls aged over 14 years underestimated their breast development (p<0.001). For boys, the percent agreement of pubic hair development between the adolescents and the pediatrician was 76.4%, with a weighted kappa coefficient of 0.68 (95% CI 0.65-0.72). CONCLUSION: Pubertal self-assessment using line drawings with a short description can be used as a reliable method to assess pubic hair maturation in boys and girls, but can be used with less reliability to assess the breast maturation in young girls.