Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions.

A variety of adrenal tumors and bilateral adrenocortical hyperplasias (BAH) leading to Cushing syndrome (CS) may be caused by aberrant cAMP signaling. We recently identified patients with a micronodular form of BAH that we have called "isolated micronodular adrenocortical disease" (iMAD) in whom CS was associated with inactivating mutations in phosphodiesterase (PDE) 11A ( PDE11A). In the present study, we examined PDE11A expression in normal adrenocortical tissue, sporadic tumors, and hyperplasias without PDE11A mutations, and primary pigmented nodular adrenocortical disease (PPNAD) and adenomas from patients with PRKAR1A and a single tumor with a GNAS mutation. The total number of the tumor samples that we studied was 22. Normal human tissues showed consistent PDE11A expression. There was variable expression of PDE11A in sporadic adrenocortical hyperplasia or adenomas; PPNAD tissues from patients with PRKAR1A mutations expressed consistently high levels of PDE11A in contrast to adenomas caused by GNAS mutations. Phosphorylated CREB was the highest in tissues from patients with iMAD compared to all other forms of BAH and normal adrenal tissue. We conclude that PDE11A is expressed widely in adrenal cortex. Its expression appears to be increased in PPNAD but varies widely among other adrenocortical tumors. PRKAR1A expression appears to be higher in tissues with PDE11A defects. Finally, sequencing defects in PDE11A are associated with a high state of CREB phosphorylation, just like PRKAR1A mutations. These preliminary data suggest that these two molecules are perhaps regulated in a reverse manner in their control of cAMP signaling in adrenocortical tissues.

Protein kinase A subunit expression is altered in Bloom syndrome fibroblasts and the BLM protein is increased in adrenocortical hyperplasias: inverse findings for BLM and PRKAR1A.

Bloom syndrome is a genetic disorder associated with chromosomal instability and a predisposition to tumors that is caused by germline mutations of the BLM gene, a RecQ helicase. Benign adrenocortical tumors display a degree of chromosomal instability that is more significant than benign tumors of other tissues. Cortisol-producing hyperplasias, such as primary pigmented nodular adrenocortical disease (PPNAD), which has been associated with protein kinase A (PKA) abnormalities and/or PRKAR1A mutations, also show genomic instability. Another RecQ helicase, WRN, directly interacts with the PRKAR1B subunit of PKA. In this study, we have investigated the PRKAR1A expression in primary human Bloom syndrome cell lines with known BLM mutations and examined the BLM gene expression in PPNAD and other adrenal tumor tissues. PRKAR1A and other protein kinase A (PKA) subunits were expressed in Bloom syndrome cells and their level of expression differed by subunit and cell type. Overall, fibroblasts exhibited a significant decrease in protein expression of all PKA subunits except for PRKAR1A, a pattern that has been associated with neoplastic transformation in several cell types. The BLM protein was upregulated in PPNAD and other hyperplasias, compared to samples from normal adrenals and normal cortex, as well as samples from cortisol- and aldosterone-producing adenomas (in which BLM was largely absent). These data reveal an inverse relationship between BLM and PRKAR1A: BLM deficiency is associated with a relative excess of PRKAR1A in fibroblasts compared to other PKA subunits; and PRKAR1A deficiency is associated with increased BLM protein in adrenal hyperplasias.

Severe hypothyroidism due to atrophic thyroiditis from second year of life influenced developmental outcome.

UNLABELLED: From the second year of life a girl showed an insidious development of clinical hypothyroidism due to a non-goitrous lymphocytic thyroiditis without traceable circulating levels of thyroid antibodies measured by routine immunoassays. The diagnostic delay of this rare variant of atrophic thyroiditis caused persistent neuropsychological deficits. CONCLUSION: Her difficulties with speed of processing and working memory in particular could suggest a frontal deficit, possibly in the dorsolateral prefrontal circuit. This contrasts with findings in congenital hypothyroidism, suggesting a relatively preserved frontal function, and could illustrate different neuropsychological deficits of hypothyroidism at different ages in early childhood.

Congenital hypothyroidism: no adverse effects of high dose thyroxine treatment on adult memory, attention, and behaviour.

BACKGROUND: In congenital hypothyroidism (CH) it has been questioned whether high dose thyroxine replacement therapy has detrimental effects on memory, attention, and behaviour. AIMS: To describe memory, attention, and behaviour problems in young adults with CH, and to study possible negative effects of high dose thyroxine replacement therapy. METHODS: A cohort based follow up study of 49 young adults (mean age 20 years) with early treated CH, and sibling controls (n = 41). RESULTS: Controlled for age and sex, the CH group attained significantly lower scores than sibling controls on some tests of memory (Wechsler Logical Memory part II: 12.9 versus 17.8; difference 5.2, 95% CI 3.6 to 6.8) and attention (Wechsler Freedom From Distractibility factor: 95.6 versus 104.8; difference 9.9, 95% CI 6.4 to 13.4). They rated themselves with more behaviour problems than did sibling controls (52.7 versus 44.7; difference -7.6, 95% CI -11.2 to -4.0) on the Achenbach Self Report. A high thyroxine starting dose, high serum thyroxine treatment levels during the first six childhood years, and high levels at assessment had no adverse effects on outcome measures at age 20. On the contrary, the results suggest better outcome with higher childhood treatment levels. CONCLUSIONS: Long term outcome revealed deficits in some aspects of memory, attention, and behaviour in young adults with CH relative to sibling controls. No adverse effects of high dose thyroxine therapy were found on measures of memory, attention, and behaviour problems.

Psychiatric symptoms and disorders in adolescents with low birth weight.

OBJECTIVE: To evaluate the prevalence of psychiatric symptoms and disorders associated with low birth weight.Design/study groups: A population based follow up study of 56 very low birthweight (VLBW: birth weight < or = 1500 g), 60 term small for gestational age (SGA: birth weight < 10th centile), and 83 term control (birth weight > or = 10th centile) children at 14 years of age. OUTCOME MEASURES: Schedule for affective disorders and schizophrenia for school aged children, attention deficit/hyperactivity disorder (ADHD) rating scale IV, autism spectrum screening questionnaire, and children's global assessment scale. RESULTS: VLBW adolescents had a higher prevalence of psychiatric symptoms (46%) than controls (13%) (odds ratio (OR) 5.7, 95% confidence interval (CI) 2.5 to 13.0) and more psychiatric disorders (25%) than controls (7%) (OR 4.3, 95%CI 1.5 to 12.0), especially anxiety disorders. Although 25% of the VLBW adolescents had attention problems, ADHD was diagnosed in only 7%. Four VLBW adolescents had symptoms of Asperger's disorder, and the VLBW group had a higher sum score than controls on the autism spectrum screening questionnaire. Although more SGA adolescents had psychiatric symptoms than controls (23% v 13%), the difference was not statistically significant. Results remained essentially the same when adolescents with low estimated intelligence quotient were excluded, and persisted after possible psychosocial confounders had been controlled for. CONCLUSION: VLBW, but not SGA adolescents, have a high risk of developing psychiatric symptoms and disorders by the age of 14, especially attention deficit, anxiety symptoms, and relational problems.

[Psychiatric and cognitive aspects of hypothyroidism]. / Psykiatriske og kognitive aspekter ved hypotyreose.

BACKGROUND: Diffuse and initial changes of behaviour, mood and cognition in hypothyroidism represent diagnostic and therapeutic challenges. MATERIAL AND METHODS: We present four cases and discuss relevant literature. Patients were followed from time of diagnosis through the first 6-12 months of thyroxine treatment. Symptoms were identified using interviews, questionnaires and tests. RESULTS: The patients had reduced quality of life, depression, anxiety and impaired short time memory. All symptoms improved with thyroxine treatment, although patients did not necessarily reach premorbid functioning in 6-12 months. In the literature, depression in hypothyroidism is hypothesised to be at least partly caused by relative hypothyroidism in the central nervous system, and local brain triiodothyronine deficiency may be a possible explanation for affective and cognitive symptoms in subclinical hypothyroidism. INTERPRETATION: Physicians should actively address psychiatric and cognitive aspects of hypothyroidism and in addition to thyroxine offer supportive treatment, especially to those depressed.

Parent reports of child behavior problems in young Sami children: a cross-cultural comparison.

In a general population study of 4-year-olds, using the Child Behavior Checklist (CBCL), parent reports of child behavior problems were compared in samples of 67 monoethnic Sami, 52 multiethnic Sami/Norwegian, and 63 monoethnic Norwegian children from the Sami core area in northern Norway. Mean CBCL total problem scores were low for all three groups [Sami: 21.1 (SD 15.5), Sami/Norwegian: 19.4 (SD 12.2) and Norwegian: 18.8 (SD 13.6)]. No significant differences across ethnic groups were found for the Total Problems scale and the Internalizing and Externalizing scales, nor for the syndrome scales, except for the Withdrawn scale, the Sami/Norwegian sample showing the highest scores. However, significant ethnicity x gender interactions emerged, indicating that the effect of ethnicity was different for boys versus girls. Sami mothers reported the highest and the Norwegian mothers the lowest scores for girls, whereas the opposite pattern was found for boys. Correlations between mothers' and fathers' reports were generally low. Differences in mean scale scores between pairs of parents (n = 122) were found for boys but not for girls, mothers scoring higher than fathers. The authors underline the importance of taking gender differences, age and ethnic context into account when assessing problem behavior in minority children. Methodological problems in cross-cultural assessments, including the influence of cultural norms of child behavior on parents' problem ratings, are discussed.

Influence of ethnic factors on behavior problems in indigenous Sami and majority Norwegian adolescents.

OBJECTIVE: To explore the relationship between behavior problems and ethnic factors in indigenous minority Sami and Norwegian majority adolescents in northern Norway. METHOD: The Youth Self-Report (YSR) was completed by 249 Sami and 210 Norwegian students in junior high school, aged 13 to 16 years. Parents completed the Child Behavior Checklist (CBCL). Behavior problems were assessed in relation to ethnicity and ethnic context (geographic region and family context). RESULTS: Rates of behavior problems (CBCL and YSR) were generally high in both ethnic groups and were highest among girls. Sami adolescents, particularly those living in assimilated ethnic communities, reported more behavior problems than Norwegian adolescents. CONCLUSION: Ethnic factors have significant impact on behavior problems in indigenous minority adolescents living in a multiethnic context.

Linear growth in early treated children with congenital hypothyroidism.

Length/height was studied from birth to 6 years of age in 103 children with congenital hypothyroidism identified by the Norwegian or Swedish screening programs. We used the "infancy-childhood-puberty (ICP) growth model". This model describes normal linear growth during the first 3 years of life by an infancy component with the addition of a childhood component, the latter acting from the second half of the first year. In comparison with reference children, children with hypothyroidism had reduced growth from 6 to 12 months, and increased growth after 12 months of age. Mean onset of the childhood component of growth was delayed from 8.1 months (SD 1.9) to 10.4 months (SD 2.2) in girls, and from 8.9 months (SD 2.0) to 11.0 months (SD 2.1) in boys. Age at onset of the childhood component was correlated with age at start of treatment (r = 0.24), and in children with more severe hypothyroidism (pretreatment serum thyroxine < 40 nmol/l) inversely correlated with the L-thyroxine dose at start of treatment (r = -0.40). Change in height standard deviation score from 1 to 3 years of age was correlated with the serum thyroxine concentration at age 1 year (r = 0.30). The delay in the onset of the childhood component of growth and the association with age at start of treatment and initial L-thyroxine dose indicate that thyroid hormones during the first months of life are essential for normal onset of the childhood component of growth, which otherwise is assumed to be growth hormone-dependent.

Ethnic identity in aboriginal Sami adolescents: the impact of the family and the ethnic community context

The influence of parentage and ethnic community context on ethnic self-identification and ethnic attitudes and behaviour were examined in 245 indigenous Sami adolescents in northern Norway. Ethnic identity was strongly related to both parentage and type of ethnic community. Monoethnic adolescents at the coast (with great integration and assimilation) identified themselves mostly as bicultural or Norwegian, but in the highland (with strong ethnic support), they identified strongly as Samis. Adolescents with mixed parentage identified strongly as Norwegian at the coast but mostly as bicultural in the highland. Ethnic behaviour and attitudes were significantly associated with both family and regional context; ethnic self-identification was related to other components of ethnic identity.

Treatment variables as predictors of intellectual outcome in children with congenital hypothyroidism.

UNLABELLED: The purpose of this study was to assess how much of the variance in intellectual outcome at 2 and 6 years of age could be attributed to treatment variables in children with congenital hypothyroidism, and which of the parameters used for monitoring treatment predicted later development. Forty-five children, early treated according to general recommendations, were studied. Linear multiple regression analysis was used, controlling for socio-economic status and the pretreatment serum thyroxine concentration. At 2 years of age, 19% of the variance in Mental Development Index (Bayley Scales of Infant Development) was attributed to treatment variables: combinations of serum thyroxine and serum TSH during the 1st year and bone age at mean age 1.5 years (mean z-scores). At 6 years of age, 35% of the variance in Verbal IQ (Wechsler Preschool and Primary Scale of Intelligence) was attributed to treatment variables: 13% to the mean serum thyroxine concentration during the 1st year, 12% to the initial L-thyroxine dose per kilogram body weight per day, and 10% to a combined measure for serum thyroxine and serum TSH during the 2nd year (mean z-score). CONCLUSION: Both the initial L-thyroxine dosage and treatment variables during the 1st and the 2nd year (serum thyroxine, serum TSH and bone age) predicted later intellectual outcome in children with congenital hypothyroidism.

Significance of elevated serum thyrotropin during treatment of congenital hypothyroidism.

Serum thyrotropin concentrations are frequently elevated during treatment of children with congenital hypothyroidism. It is unclear if elevated thyrotropin during early treatment indicates non-optimal treatment. In a cohort of 49 children with congenital hypothyroidism, we studied the decline in serum thyrotropin concentration after initiating L-thyroxine treatment, the relationship between elevated thyrotropin and treatment variables, and non-compliance with the treatment as a possible cause of elevated thyrotropin. The initial mean dose of thyroxine was 8.5 (SD 3.3) micrograms/kg body weight/day: 71% of the serum samples obtained 15-21 days after the start of treatment had serum thyrotropin concentrations < 10 mU/l. Six children had no samples with serum thyrotropin < 10 mU/l during the first 3 months of treatment. These children had a lower thyroxine dose prescribed, and serum thyrotropin was normalized when the dose was sufficiently increased. During treatment, from 6 weeks of age, serum thyrotropin > 10 mU/l was related to a lower dose of thyroxine and lower serum thyroxine, and was not due to non-compliance with treatment.

[Screening of newborn infants in Norway for severe metabolic disease]. / Screening av nyfødte i Norge for alvorlig metabolsk sykdom.

The objective of neonatal screening for phenylketonuria and congenital hypothyroidism is early diagnosis and initiation of treatment to prevent brain damage and mental retardation. We present the results of the Norwegian national neonatal screening programme for phenylketonuria and congenital hypothyroidism. Screening for phenylketonuria based on serum phenylalanine determinations started in 1967 and covered the whole country in 1978. National screening for congenital hypothyroidism started in 1979. One hundred children with phenylketonuria and 280 children with a strong indication of congenital hypothyroidism have been detected up to 1 October 1994. Screening-related challenges and principles of treatment are discussed.

Skeletal maturation during thyroxine treatment in children with congenital hypothyroidism.

The aim of this investigation was to study if bone age development (assessed by the Greulich & Pyle atlas) was related to L-thyroxine treatment in 47 children with congenital hypothyroidism, treated early and according to general recommendations. In spite of frequent delay in skeletal maturation at diagnosis, the delay in mean bone age at a mean chronological age of 1.5 years was slight (0.5 months), and 30% of the variation in bone age SD score (SDS) at 1.5 years was accounted for by the dose of L-thyroxine and serum thyroxine during the first year. The children with a bone age within +/- 1 SDS had a prescribed mean dose of L-thyroxine per kg body weight from 3 to 12 months of age of 5.4 +/- 1.7 micrograms/kg/day, and their mean serum thyroxine concentration during the first year was 175 +/- 29 nmol/l. We conclude that bone age at 1.5 years of age was positively correlated with the dose of L-thyroxine and the serum thyroxine concentrations during the first year. This supports the general use of bone age assessments as a complement to other treatment variables in the follow-up of children with congenital hypothyroidism.

Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment.

The relationship between the treatment serum thyroxine level and intellectual development at 2 and 6 years was investigated in 46 Norwegian children with congenital hypothyroidism identified by neonatal screening. The level of serum thyroxine during the first 2 years was positively correlated with the Mental Development Index at 2 years of age (Bayley Scales of Infant Development) and the Verbal IQ at 6 years of age (Wechsler Preschool and Primary Scale of Intelligence). Children with a mean serum thyroxine level greater than 180 nmol/L (14 micrograms/dl) during the first year had a significantly higher Mental Development Index at 2 years and Verbal IQ at 6 years than children with serum thyroxine values less than 129 nmol/L (10 micrograms/dl). Boys had a lower Mental Development Index at 2 years of age than girls (86.9 vs 105.1; p less than 0.001) and a higher frequency of elevated serum levels of thyroid-stimulating hormone during the first year (p = 0.001). No signs of toxic effects of a high hormone level at the time of IQ assessment were detected. However, high serum levels of thyroxine at ages 2 to 4 years in girls were related to lower Performance IQ at age 6 years. The results demonstrate that the serum level of thyroxine is of importance in relation to intellectual development. Thyroxine levels above the upper reference range during the first 2 years were related to best intellectual development at 2 and 6 years.

[Children with phenylketonuria (Fölling's disease). Intellectual functions and psychological adaptation]. / Barn med fenylketonuri (Føllings sykdom). Intellektuell funksjon og psykologisk tilpasning.

Untreated phenylketonuria (PKU) leads to serious mental retardation. The prognosis of PKU has been dramatically improved by neonatal screening and dietary treatment. This study evaluates 25 children, ages 10 to 16 years. Children who receive early and adequate treatment have a mean IQ slightly below normal, and few psychological problems. The disease causes considerable strain on the families, however, because of the very strict diet. Recent evidence suggests that children with PKU can only rarely terminate the diet, although in many cases the diet can be relaxed. It is essential to teach the children the diet and promote autonomy in relation to phenylketonuria.