Tuija Löppönen

GJB2 Mutations and Degree of Hearing Loss: A Multicenter Study

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.

Prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children

We studied the prevalence, segregation, and phenotype of the mitochondrial DNA 3243A>G mutation in children in a defined population in Northern Ostrobothnia, Finland.

Atypical phenotypes in titinopathies explained by second titin mutations

Several patients with previously reported titin gene (TTN) mutations causing tibial muscular dystrophy (TMD) have more complex, severe, or unusual phenotypes. This study aimed to clarify the molecular cause of the variant phenotypes in 8 patients of 7 European families.

Accelerated pubertal development in patients with shunted hydrocephalus.

OBJECTIVE: To evaluate pubertal development and peripheral concentrations of gonadotrophins and sex hormones in children with shunted hydrocephalus compared with healthy controls. STUDY DESIGN: 114 patients (52 females, 62 males) and 73 healthy controls (35 females, 38 males) aged 5 to 20 years were analysed for stage of puberty, age at menarche, testicular volume, basal serum follicle stimulating hormone (FSH), luteinising hormone (LH), sex hormone binding globulin (SHBG), testosterone and oestradiol concentrations, and free androgen index. RESULTS: Male gonadal and male and female pubic hair development occurred significantly earlier in the patients than in the controls. The mean age at menarche was significantly lower in the female patients than in their controls (11.7 v 13.2 years; p < 0.001), and lower than it had been for their mothers (v 13.1 years; p < 0.001). Relative testicular volume was higher in the male patients than in their controls (1.2 standard deviation score (SDS) v 0.2 SDS; p < 0.001). The prepubertal patients had higher basal LH (0.13 U/l v 0.08 U/l; p < 0.001) and SHBG (132.3 nmol/l v 109.1 nmol/l; p < 0.01) than the controls. Both the prepubertal and pubertal females had significantly higher basal FSH than their controls (1.57 U/l v 1.03 U/l; p < 0.05, and 4.0 U/l v 2.9 U/l; p < 0.01, respectively). CONCLUSIONS: Hydrocephalic children experience accelerated pubertal maturation, reflected in a younger age at menarche in females and an increased testicular volume in males. This may be because of enhanced gonadotrophin secretion, possibly resulting from unphysiological variations in intracranial pressure.

Pituitary size and function in children and adolescents with shunted hydrocephalus

Most previous reports of endocrine disorders in children with shunted hydrocephalus have been case reports and there is a lack of systematic information on pituitary anatomy and function among these children. We have obtained these data in a large group of individuals with shunted hydrocephalus.

Reduced levels of growth hormone, insulin-like growth factor-I and binding protein-3 in patients with shunted hydrocephalus

OBJECTIVE Children with hydrocephalus are characterised by slow linear growth in prepuberty, accelerated physical maturation during puberty, and reduced final height. We aimed to study the possible roles of growth hormone, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 (IGFBP-3) in this growth pattern. STUDY DESIGN One hundred and fourteen patients with shunted hydrocephalus (62 males) aged 5 to 20 years, of whom 17 had spina bifida (six males), and 73 healthy controls (38 males) were studied. Anthropometric measures, body mass index, and body fat mass were assessed and the stage of puberty was determined. Serum growth hormone and plasma IGF-I and IGFBP-3 concentrations were measured. RESULTS The patients comprised 44 (26 males) who were prepubertal and 70 (36 males) pubertal or postpubertal, while 32 of the controls (19 males) were prepubertal and 41 (19 males) pubertal or postpubertal. The prepubertal children with hydrocephalus had lower IGF-I (p = 0.002) and IGFBP-3 concentrations (p< 0.001) than the controls, and the pubertal children had four times lower basal growth hormone concentrations (p< 0.001). There was a correlation between height SD score and IGF-I levels in the total patientpopulation (r = 0.23; p = 0.01). Peripheral IGF-I concentrations peaked at pubertal stages 2–3 in the female patients and at stage 4 in the controls. The prepubertal patients on antiepileptic treatment, carbamazepine in most cases (73%), had higher IGF-I (p = 0.01) and IGFBP-3 concentrations (p = 0.03) than those who had never been treated with antiepileptic drugs, but still lower IGFBP-3 levels than the controls (p = 0.01). CONCLUSION Based on these findings, it can be concluded that reduced growth hormone secretion may contribute to the pattern of slow linear growth and reduced final height observed in these patients. Key messages • Prepubertal children with shunted hydrocephalus have reduced circulating IGF-I and IGFBP-3 concentrations • Pubertal children with shunted hydrocephalus have reduced basal serum growth hormone concentrations • Reduced growth hormone secretion may contribute to slow linear growth and reduced final height in hydrocephalic children • Carbamazepine treatment may increase IGF-I and IGFBP-3 concentrations in the peripheral circulation

Information value of magnetic resonance imaging in shunted hydrocephalus.

OBJECTIVE--To study the role of magnetic resonance imaging (MRI) in evaluating children with shunted hydrocephalus. METHODS--Sixty one asymptomatic children with shunted hydrocephalus or cystic cerebrospinal fluid collections were studied by cranial MRI. The information obtained from the images was classified into three categories: provided (1) a new diagnosis, (2) additional information, or (3) no essential new information. The findings were compared with those of the last follow up computed tomograms. RESULTS--MRI provided a new diagnosis in seven cases (11.5%), and additional information was obtained in 34 (55.7%) cases. In 20 cases (32.8%) no essential new information was obtained. MRI visualised white matter lesions and corpus callosum pathology more often than computed tomograms. CONCLUSIONS--MRI provided new important information in cases of children with shunted hydrocephalus to such an extent that it can be recommended as the primary imaging method for every child with this disorder.