Raimo Voutilainen

Growth of patients with 21-hydroxylase deficiency: an analysis of the factors influencing adult height.

Growth of 92 Finnish patients with 21-hydroxylase deficiency (21-OHD) was analyzed retrospectively to study growth both before the diagnosis and during glucocorticoid substitution therapy. The patients were divided into two groups: those diagnosed at infancy (56 patients) and those diagnosed after the age of 1 y (36 patients). Birth lengths of those boys and girls diagnosed at infancy were greater than the national mean birth lengths (p < 0.001). Mean relative length diminished from +0.8 SD score (SDS) at birth to-1.0 SDS by the age of 1 y. Adult height was -1.0 SDS (159.9 cm) for women and-0.8 SDS (173.6 cm) for men. The difference from national mean height was significant only for women (p = 0.026). Mean relative weight during childhood correlated negatively with adult stature (r = -0.620;p = 0.006). In the group of children diagnosed later in their childhood, growth was already accelerated at infancy from +0.2 SDS at birth to+0.7 SDS by the age of 1 y (p = 0.023). The final height of girls diagnosed later in childhood was within normal limits (-0.5 SDS; 162.1 cm), whereas it was low in the corresponding group of boys (-2.1 SDS; 165.3 cm). Our data show increased mean birth length in babies with early diagnosis of 21-OHD and growth acceleration at infancy in children diagnosed later in their childhood, reflecting the growth accelerating effect of adrenal hyperandrogenism early during fetal life and infancy. To improve final height in patients with 21-OHD, lower doses of hydrocortisone should be used at infancy, and special attention should be paid to boys diagnosed later in childhood.

Reduced bone mineral density in long-term survivors of childhood acute lymphoblastic leukemia

Purpose Osteoporosis and pathologic fractures are occasionally found in patients with childhood acute lymphoblastic leukemia (ALL). This study was performed to determine the degree of possible osteopenia in long-term survivors of childhood ALL. Patients and Methods Lumbar spine (L2-L4) and femoral neck bone mineral densities (BMDs) (g/cm2) were measured in 29 survivors (aged 12 to 30 years, median 17) of childhood ALL 2 to 20 (median 8) years after discontinuation of chemotherapy. These results were compared with those from 273 healthy controls and expressed as a percentage of the age- and sex-matched control values (mean ± standard deviation). Results Lumbar and femoral BMDs were significantly reduced in survivors of childhood ALL. Particularly, male gender (lumbar: 91.7 ± 10.4%, p = 0.008; femoral: 91.9 ± 11.3%, p = 0.005) and a history of cranial irradiation (lumbar: 93.0 ± 8.9%, p = 0.005; femoral: 94.4 ± 13.3%, p = 0.03) were associated with low lumbar and femoral BMDs. Conclusions The detected deficit in bone density in survivors of childhood ALL may predispose these patients to osteoporotic fractures later in adulthood. A follow-up of BMD in survivors of childhood ALL should facilitate the identification of patients who would require specific therapeutic interventions to prevent further decrease of their skeletal mass and preserve their BMD.

RASSF1A promoter region CpG island hypermethylation in phaeochromocytomas and neuroblastoma tumours

Deletions of chromosome 3p are frequent in many types of neoplasia including neural crest tumours such as neuroblastoma (NB) and phaeochromocytoma. Recently we isolated several candidate tumour suppressor genes (TSGs) from a 120 kb critical interval at 3p21.3 defined by overlapping homozygous deletions in lung and breast tumour lines. Although mutation analysis of candidate TSGs in lung and breast cancers revealed only rare mutations, expression of one of the genes (RASSF1A) was absent in the majority of lung tumour cell lines analysed. Subsequently methylation of a CpG island in the promoter region of RASSF1A was demonstrated in a majority of small cell lung carcinomas and to a lesser extent in non-small cell lung carcinomas. To investigate the role of 3p TSGs in neural crest tumours, we (a) analysed phaeochromocytomas for 3p allele loss (n=41) and RASSF1A methylation (n=23) and (b) investigated 67 neuroblastomas for RASSF1A inactivation. 46% of phaeochromocytomas showed 3p allele loss (38.5% at 3p21.3). RASSF1A promoter region hypermethylation was found in 22% (5/23) of sporadic phaeochromocytomas and in 55% (37/67) of neuroblastomas analysed but RASSF1A mutations were not identified. In two neuroblastoma cell lines, methylation of RASSF1A correlated with loss of RASSF1A expression and RASSF1A expression was restored after treatment with the demethylating agent 5-azacytidine. As frequent methylation of the CASP8 gene has also been reported in neuroblastoma, we investigated whether RASSF1A and CASP8 methylation were independent or related events. CASP8 methylation was detected in 56% of neuroblastomas with RASSF1A methylation and 17% without RASSF1A methylation (P=0.0031). These results indicate that (a) RASSF1A inactivation by hypermethylation is a frequent event in neural crest tumorigenesis, particularly neuroblastoma, and that RASSF1A is a candidate 3p21.3 neuroblastoma TSG and (b) a subset of neuroblastomas may be characterized by a CpG island methylator phenotype.

Maternal Preeclampsia Predicts Elevated Blood Pressure in 12-Year-Old Children: Evaluation by Ambulatory Blood Pressure Monitoring

Ambulatory blood pressure (ABP) monitoring offers a reliable method for determining blood pressure (BP) in children. The aim of this cohort study was to examine whether maternal preeclampsia is associated with elevated BP in an offspring. The study population consisted of 57 children born to preeclamptic mothers (PRE) and their 57 age- and sex-matched control subjects born to normotensive mothers (non-PRE). We examined the 24-h ABP at 12 y of age in the PRE and non-PRE children. Within the two groups, the association of anthropometric measures, plasma catecholamine (epinephrine [E], norepinephrine [NE]) concentrations, and ABP was examined. The PRE children had significantly higher mean 24-h systolic and diastolic ABPs than the non-PRE children. The same was true for the mean daytime and nighttime systolic and diastolic ABPs. The PRE boys had higher 24-h systolic ABP than the PRE girls. In the PRE children, high plasma E concentration and being born small for gestational age (SGA) predicted high systolic 24-h ABP in logistic regression analysis. In the non-PRE children, high current body mass index (BMI) and high plasma E concentration was associated with high systolic 24-h ABP. In conclusion, systolic and diastolic ABP values were elevated in the PRE children. High plasma E concentration and being born SGA were associated with high systolic 24-h ABP in the PRE children. Presumably maternal preeclampsia affects offspring via several mechanisms, including genetic ones and metabolic consequences of restricted intrauterine growth.

Bone mineral density in relation to glucocorticoid substitution therapy in adult patients with 21‐hydroxylase deficiency

OBJECTIVE There are only limited data on bone mineral density (BMD) in adult patients with 21‐hydroxylase deficiency (21‐OHD). We have defined the effects of different glucocorticoid substitution therapies on BMD and body composition in these patients.

Serum Lipid Concentrations and Growth Characteristics in 12-year-old Children Born Small for Gestational Age

According to Barkers hypothesis, children born small for gestational age (SGA) are at increased risk for cardiovascular diseases in adulthood. The aim of our study was to determine whether retarded fetal growth is associated with dyslipidemia in childhood and, if so, to find predictive factors in the growth characteristics of SGA children. We studied the serum lipid concentrations of 55 SGA children and their 55 appropriate for gestational age control subjects at the age of 12 y. Growth variables were recorded at birth, 5 y, and 12 y of age. The study group consisted of all full-term SGA children born at our university hospital during a 22-mo period in 1984–1986. Nearly half of the SGA children (47.3%) were in the highest quartile for serum total cholesterol of the appropriate for gestational age children (p = 0.038). In multiple logistic regression analysis, poor catch-up growth in height (odds ratio, 13.8; 95% confidence interval, 2.0–97.5), female sex (odds ratio, 8.1; 95% confidence interval, 1.3–48.9), and early stage of puberty (odds ratio, 7.5; 95% confidence interval, 1.2–46.5) predicted high cholesterol level in the SGA children. By the age of 5 y, 20 (36.4%) SGA children showed catch-up growth of ≥ 2 SD scores in height, and 21 (38.2%) SGA children showed catch-up growth of ≥ 2 SD scores in weight from birth. At the age of 12 y, the SGA children were still significantly shorter (p < 0.001) and lighter (p < 0.05) than the appropriate for gestational age children, even though their pubertal development was similarly advanced. In conclusion, to be born SGA has long-term consequences for later growth and may already influence the level of serum total cholesterol before the teens. SGA children with poor catch-up growth in height may be at the highest risk for hypercholesterolemia.

BENIGN PREMATURE ADRENARCHE: CLINICAL FEATURES AND SERUM STEROID LEVELS

ABSTRACT. 18 girls with premature adrenarche were evaluated both clinically and by serum steroid measurements. Age at first appearance of the symptoms ranged from 3.0 to 7.8 years. Clinical findings included pubic or axillary hair, acne, accelerated growth, adult‐type perspiration and oily skin or hair. Bone age was 0.3–3.2 years ahead of chronological age. 15 of these 18 girls had accelerated growth and most of these already before the appearance of pubic hair. Five girls had severe acne requiring topical treatment. Serum dehydroepiandrosterone was elevated for age in all patients. Androstenedione and testosterone correlated positively with the dehydroepiandrosterone values. Dihydrotestosterone was also elevated in many girls. Administration of dexamethasone brought about a rapid normalization of the elevated steroid levels.

Reduced bone density at completion of chemotherapy for a malignancy

OBJECTIVES Osteoporosis and pathological fractures occur occasionally in children with malignancies. This study was performed to determine the degree of osteopenia in children with a malignancy at completion of chemotherapy. METHODS Lumbar spine (L2–L4) bone mineral density (BMD; g/cm2) and femoral neck BMD were measured by dual energyx ray absorptiometry in 22 children with acute lymphoblastic leukaemia (ALL), and in 26 children with other malignancies. Apparent volumetric density was calculated to minimise the effect of bone size on BMD. Results were compared with those of 113 healthy controls and expressed as age and sex standardised mean Z scores. RESULTS Patients with ALL had significantly reduced lumbar volumetric (−0.77) and femoral areal and volumetric BMDs (−1.02 and −0.98, respectively). In patients with other malignancies, femoral areal and apparent volumetric BMDs were significantly decreased (−0.70 and −0.78, respectively). CONCLUSIONS The results demonstrate that children with a malignancy are at risk of developing osteopenia. A follow up of BMD after the completion of chemotherapy should facilitate the identification of patients who might be left with impaired development of peak bone mass, and who require specific interventions to prevent any further decrease in their skeletal mass and to preserve their BMD.

Impaired Development of Bone Mineral Density During Chemotherapy: A Prospective Analysis of 46 Children Newly Diagnosed with Cancer

Osteopenia and osteoporosis are becoming increasingly recognized in children with cancer, though reasons for these changes are poorly understood. The purpose of the present study was to evaluate longitudinal changes in bone mineral density (BMD) and bone turnover in newly diagnosed children with a malignancy. Lumbar spine (L2–L4) and femoral neck bone mineral density (BMDareal, g/cm2) was measured by dual‐energy X‐ray absorptiometry in 46 children (age 2.9–16.0, median 8.0 years; 15 leukemias, 12 lymphomas, 19 solid tumors) at diagnosis, and after 6 months from the baseline. The apparent volumetric bone mineral density (BMDvol) was calculated to minimize the effect of bone size on BMD. Serum levels of osteocalcin (OC), type I collagen carboxy‐terminal propeptide (PICP), and type I collagen carboxy‐terminal telopeptide (ICTP) were analyzed at diagnosis, and during a 6‐month follow‐up. A significant decrease in lumbar BMDvol (–2.1%, p < 0.05), and in femoral BMDareal (–9.9%, p = 0.0001) and BMDvol (–8.5%, p = 0.0001) was observed after 6 months when compared with baseline measurements. The markers of bone formation (PICP, OC) were significantly decreased, and the marker of bone resorption (ICTP) was significantly increased at diagnosis as compared with normal values. By the end the follow‐up, the levels of PICP and OC were normalized, whereas the level of ICTP continued to increase indicating that there was a negative balance in bone turnover. A deficient accumulation of bone mass might predispose children with a malignancy to impaired development of peak bone mass. A controlled study determining the benefits of an early intervention on bone turnover should be considered in these patients.

Child rate, pregnancy outcome and ovarian function in females with classical 21‐hydroxylase deficiency

Background. Ovulatory disorders and decreased fertility rates have been found in females with classical 21‐hydroxylase deficiency (21‐OHD). We analyzed the pregnancies of 29 females with classical 21‐hydroxylase deficiency and examined 16 of these women in a cross‐sectional study.