ABSTRACT
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome (MIM# 610199) is a rare disease caused by autosomal recessive mutations in the GLIS3 gene. GLIS3 is an important transcription factor that might acts as both a repressor and activator of transcription. To date, 22 cases of NDH syndrome from 16 families and 11 countries have been described. Herein, we report a child who developed diabetes during the first week of age. Additionally, she suffered from congenital hypothyroidism, cardiac abnormalities, and polycystic kidney disease. Genetic analysis revealed that patient is a carrier of two novel heterozygous mutations, p.Pro444fsdelG (c.1330delC) and p.His647Arg (c.1940A > G) in the GLIS3 gene. Each was inherited from clinically healthy father and mother, respectively. Bioinformatic tools (SIFT, PolyPhen2, PROVEAN and SWISS-MODEL) declared that the p.His647Arg (c.1940A > G) variant has strong detrimental effect and disturbs Kruppel-like zinc finger domain. All but one so far described cases of NDH syndrome have been caused by homozygous of GLIS3, making the described case the second case of pathogenic, compound heterozygosity of GLIS3 worldwide posing substantial clinical novelty and detailing an interesting interplay between the observed variants and GLIS3 expression, which seems to be autoregulated. Hence, the damaging missense mutation may further reduce the expression of any remaining functional alleles. This case report expands our understanding of the clinical phenotype, treatment approaches, and outcome of infants with GLIS3 mutations and indicates the need for further research to deepen our understanding of the role of GLIS3.
Subject(s)
Congenital Hypothyroidism , Diabetes Mellitus , Infant, Newborn, Diseases , Congenital Hypothyroidism/complications , Congenital Hypothyroidism/genetics , DNA-Binding Proteins/genetics , Diabetes Mellitus/congenital , Diabetes Mellitus/genetics , Female , Humans , Infant, Newborn , Infant, Newborn, Diseases/genetics , Mutation , Repressor Proteins/genetics , Trans-Activators/genetics , Trans-Activators/metabolismABSTRACT
The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Ukrainian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 100 JIA patients (2% systemic, 44% oligoarticular, 20% RF-negative polyarthritis, 34% other categories) and 100 healthy children were enrolled at the paediatric rheumatology centre of the Western Ukrainian Specialised Children's Medical Centre. The JAMAR components discriminated well between healthy subjects and JIA patients. Notably, there was no significant difference between healthy subjects and their affected peers in the school-related problems variable. All JAMAR components revealed good psychometric performances. In conclusion, the Ukrainian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.
Subject(s)
Arthritis, Juvenile/diagnosis , Disability Evaluation , Patient Reported Outcome Measures , Rheumatology/methods , Adolescent , Age of Onset , Arthritis, Juvenile/physiopathology , Arthritis, Juvenile/psychology , Arthritis, Juvenile/therapy , Case-Control Studies , Child , Child, Preschool , Cultural Characteristics , Female , Health Status , Humans , Male , Parents/psychology , Patients/psychology , Predictive Value of Tests , Prognosis , Psychometrics , Quality of Life , Reproducibility of Results , Translating , UkraineSubject(s)
Abnormalities, Multiple/genetics , Craniofacial Abnormalities/genetics , Intellectual Disability/genetics , Proto-Oncogene Proteins/genetics , Wnt Proteins/genetics , Adult , Child , DNA Mutational Analysis , Female , Foot Deformities, Congenital/genetics , Hand Deformities, Congenital/genetics , Humans , Male , Signal Transduction , Syndrome , Wnt-5a ProteinABSTRACT
OBJECTIVE: To determine the effect of levothyroxine sodium starting dose on cognitive development, growth, or behavior in children with congenital hypothyroidism identified by neonatal screening. DESIGN: Systematic review of cohort studies. Two analyses were performed: a between-study comparison of mean starting dose with mean developmental score and an analysis of the within-study effects of starting dose on cognitive development, growth, or behavior. RESULTS: The between-study comparison (14 cohort studies based on 1321 patients) found that the standardized mean IQ or developmental quotient scores ranged from 90 to 115 but were not associated with the mean starting dose of levothyroxine (P =.48). The within-study comparison of 4 cohort studies (based on 558 patients) that reported the effect of the starting dose of levothyroxine on cognitive development found no consistent effects. There was weak evidence for an effect of starting dose on growth (1 study) and on behavior problems (1 study). CONCLUSIONS: The evidence for an effect of starting dose of levothyroxine on cognitive development, growth, or behavior is too weak to justify recommendations in favor of high- or standard-dose regimens. More reliable information, based on a randomized controlled trial of starting dose or a meta-analysis of the individual patient data currently available, is required to inform treatment policies.
