Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy.

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Exercise capacity and hormonal response in adults with childhood onset growth hormone deficiency during long-term somatropin treatment.

Growth hormone (GH) deficiency in adults in associated with reduced muscular strength and peak oxygen uptake (peak Vo2). How these variables are influenced by long-term somatropin therapy in adults with childhood onset GH-deficiency has not been precisely defined. The effect of somatropin treatment in 20 childhood onset GH-deficient adults on muscular strength, maximal exercise capacity, and hormonal response to exercise were therefore examined in a double-blind placebo-controlled study with recombinant human GH (rhGH, 12 microg/kg/day) for 6 months, followed by 36 months of open-labeled uninterrupted therapy, after which treatment was stopped for 9 months. After 6 months of treatment, exercise capacity increased significantly, as assessed by time to exhaustion [mean change (95% CI) 0.8 (0.2, 1.4) min, P<0.05], total (accumulated) work [11.6 (0.8, 22.4) kJ, P<0.05] and peak Vo2 [2.6 (0.3, 4.9) ml/kg/min, P<0.01], whereas no significant changes were observed during placebo. This effect on exercise capacity remained unchanged during long-term somatropin treatment, mainly due to increased capacity among patients with isolated GH deficiency. Nine months after stopping treatment, peak Vo2 decreased by 11% from 32.8+/-2.5 to 29.1+/-2.1 ml/kg/min (P<0.05). Maximal muscular handgrip strength was not affected by treatment. Long-term GH therapy resulted in decreased respiratory exchange value (R value) at rest and during exercise (P<0.001), suggesting a metabolic role with increased fat combustion. Resting and submaximal noradrenaline levels decreased during somatropin treatment (P<0.05), while no effect was observed for other exercise-induced hormonal responses, including adrenaline, insulin, prolactin, renin, and ACTH. We conclude that somatropin therapy to childhood onset GH deficient adults has a favourable effect on exercise capacity and may have a potentially beneficial effect on plasma catecholamines.

Generalized lipodystrophy, congenital and acquired (lipoatrophy).

This review is based on longitudinal studies on our seven patients with congenital generalized lipodystrophy, our patient with acquired generalized lipodystrophy, and published papers on these subjects. An inability to store energy in adipose tissue is of pathogenetic importance. In congenital lipodystrophy, insulin resistance is present from birth, resulting in hyperinsulinaemia, dyslipidaemia. and insulin-resistant diabetes with an anabolic syndrome worsened by a voracious appetite. Clinically, we observed increased height velocity in pre-school age children, and organomegaly with hypertrophic cardiomyopathy, which seems to be lethal in early adulthood: three of our patients died at the ages of 24, 32 and 37 years. The oldest alive, 39 years, suffers from stenocardia. Regarding treatment, it is most important to reduce energy consumption. The congenital form is recessively inherited. The aetiology may be related to insulin receptor or postreceptor mechanisms. Acquired generalized lipodystrophy seems to be an autoimmune disorder with secondary destruction of the adipose organ: the anabolic syndrome with insulin-resistant diabetes is secondary. Our patient died when 24 years old from pneumonia.

Studies of insulin resistance in congenital generalized lipodystrophy.

Two well-characterized patients with congenital, generalized lipodystrophy have been studied by the euglycaemic hyperinsulinaemic clamp technique in combination with indirect calorimetry. Furthermore, glycogen synthase in muscle biopsies was studied in one patient with regard to enzyme activity, immunoreactive protein and mRNA levels. The patients had fasting hyperinsulinaemia, and the rate of total glucose disposal was severely impaired, primarily due to a decreased non-oxidative glucose metabolism. In the patient studied with muscle biopsy, the expected activation of glycogen synthase by insulin did not occur. In both patients there was severely increased hepatic glucose output in the basal state, suggesting a failure of insulin to suppress hepatic gluconeogenesis. During insulin infusion a substantially elevated rate of lipid oxidation remained in the patients, in contrast to the almost completely suppressed lipid oxidation in the controls. It is concluded that patients with congenital generalized lipodystrophy may present severe insulin resistance with regard to hepatic glucose production as well as muscle glycogen synthesis and lipid oxidation. The results suggest a postreceptor defect in the action of insulin in congenital generalized lipodystrophy. The further localization of such a defect is hampered by the still incomplete understanding of the pathways that link insulin-stimulated tyrosine phosphorylation to the ultimate action of insulin upon target cells.

Genetics of the Berardinelli-Seip syndrome (congenital generalized lipodystrophy) in Norway: epidemiology and gene mapping. Berardinelli-Seip Study Group.

Five of the six families with the Berardinelli-Seip syndrome in Norway cluster in six adjacent rural municipalities of south-western Norway. The six patients from this area were born between 1951 and 1973, none between 1974 and 1995. The absence of new cases may be explained by a decrease in the intraregion marriage rate and inbreeding. Genealogical investigations show that the mutation must have occurred at least 400 years ago. The sixth family was clinically different and geographically sporadic from a Finnish-descent rural East Norwegian population. A genetic linkage study of all six families revealed fresh crossovers versus the disease allele in nine DNA marker systems and the absence of recombination in three (maximum lod score + 1.3). None of the last showed allelic association. These families are included in an international effort to map the CLBS locus. The patients have been included in the homozygosity testing of totally 28 patients in an international collaborative study. The three patients, assumed identical in descent from both parents, were jointly homozygous in none of the 250 dinucleotide markers tested. A heterochromatic 9qh + segregated from one parent in two families.

[Endocrine disorders in adolescents and young adults]. / Endokrine lidelser hos ungdom og unge voksne.

Evaluation of 158 patients younger than 25 years-of-age who had been hospitalized in a specialized adult endocrine department during an 11 year-period, brought to light specific endocrine problems connected both to pediatrics and internal medicine. There is need for close collaboration between pediatricians, as experts on disturbances in growth and pubertal development, and internists, with experience of diagnosing rare endocrinological disorders. Such collaboration might also improve the follow-up of young patients into adulthood.

Acne in pubertal boys undergoing treatment with androgens.

In the present study, the development of acne lesions was studied in boys deemed to be too tall, for which they were treated with injections of androgens. In a retrospective and a prospective group of pubertal boys, an increased incidence of acne was observed as a consequence of treatment with androgens.

Height reduction in 539 tall girls treated with three different dosages of ethinyloestradiol.

During the period 1970 to 1985, 539 constitutionally tall girls were treated with ethinyloestradiol in varying dosages to reduce final height. They all had a predicted final height above 181 cm (greater than +2.5 SD). The girls were all healthy and were treated with three different dosages of ethinyloestradiol. Throughout these 15 years recommended treatment regimens changed, and the treatments described followed these guidelines. Girls in group 1 (n = 263) were treated with 0.5 mg of ethinyloestradiol, group 2 (n = 178) with 0.25 mg, and group 3 (n = 98) with 0.1 mg. The total mean (SEM) reduction of final height was 5.9 (0.2), 5.3 (0.1), and 4.4 (0.2) cm when treated with 0.5, 0.25, and 0.1 mg respectively. Group 1 was treated for 2.02 (0.03) years and group 2 and 3 for 1.85 (0.04) and 1.63 (0.05) years respectively. When expressed in relation to the treatment period the reduction of final height was 3.0 (0.1), 3.1 (0.1), and 2.9 (0.2) cm/year of treatment respectively. All the girls were treated with ethinyloestradiol as a daily single dose, while progestogen was given daily the first 10 days of every month. In conclusion we found that a daily dose of ethinyloestradiol 0.1 mg for about 20 months is sufficient to reduce final height. We recommend starting treatment at a bone age of about 12 years.

Drugs in the treatment of bulimia nervosa.

The neuro-transmitter serotonin seems to be important in the treatment of disturbed eating behaviour. In Anorexia Nervosa (AN) a serotonin antagonist has been proposed, whereas in Bulimia Nervosa (BN) serotonin agonists have been used with success, e.g. fenfluramine. A new generation of antidepressants has been introduced. that selectively have a serotonergic effect. The previous tricyclic and particularly the tetracyclic antidepressants had a noradrenergic effect as well. Fluoxetine belongs to the new generation. A total of 30 females with BN were treated with fluoxetine in an open study. Clinical effect was observed after 2 to 6 weeks. One patient discontinued after 3 weeks, the other were treated for 3 to 10 months. A moderate effect with 75% reduction of bingeing and purging was observed in 15 patients, 14 stopped bingeing and purging. There was no serious side effects. However, drug treatment alone had no significant effect. The fluoxetine treatment is not instead of, but in addition to the traditional behavioral treatment with strict limits regarding food and meals.

[Development of acne in systemic androgen therapy in boys during puberty]. / Utvikling av akne ved systemisk androgenterapi hos gutter i puberteten.

Acne is a multifactorial disease. Hereditary factors and the hormonal influences of androgens are important. In this study the development of acne lesions are studied in boys treated with androgens for expected excessive bodily height. In two groups of pubertal boys increased incidense of acne was observed during the period of treatment.

Primordial birdheaded nanism associated with progressive ataxia, early onset insulin resistant diabetes, goiter and primary gonadal insufficiency. A new syndrome.

A new syndrome in two siblings with primordial birdheaded nanism, progressive ataxia, goiter, primary gonadal insufficiency and insulin resistant diabetes mellitus is presented. Plasma concentrations of TSH, PTH, LH, FSH, ACTH, glucagon and insulin all working through cell membrane receptors were elevated. A generalized cell membrane defect was suggested to be the pathophysiological abnormality in these patients.

Dietary n-3 fatty acids and children with hyperlipidaemia.

A review of the literature shows that no studies on children with primary genetic lipid disorders have been published. Case reports are presented indicating that hyperlipidaemias presenting in children--both familial hypercholestrolaemia and disorders with secondary hyperlipidaemia (triglycerides) may benefit of the intake of n-3 fatty acids.

Infantile autism and urinary excretion of peptides and protein-associated peptide complexes.

Sixty-nine early morning urine samples obtained from three groups of young adult males (autistic, mentally handicapped, and a group of men of normal intelligence) were analyzed using the methods described by Trygstad et al. (1980). No consistent patterns of urinary chromatographic profiles were identified. A number of possible contributing factors are discussed in relation to this failure to replicate the results of previous studies.

Oestrogen treatment of adolescent tall girls; short term side effects.

In 1980-1985 680 preadolescent tall girls were treated with pharmacological doses of oestrogen to reduce final height. Indications for the therapy were predicted final height greater than +2.5 SD (180.75 cm), idiopathic scoliosis, and psychosocial problems. Until 1976 141 girls were given diethyl stilboestrol 5 mg daily. By advice of Prader this was then replaced by ethinyl oestradiol and a progestin was given on days 5-10 each month. The mean duration of therapy was close to 2 years. The observed short-term unwanted effects were due to the pharmacological actions of the drugs, (11 girls had galactorrhoea at the end of therapy; no pituitary prolactinoma was observed) or events happening by chance.

Plasma concentrations of vitamin D metabolites in pubertal girls with anorexia nervosa.

Plasma concentrations of 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D (1,25-(OH)2D), 24,25-dihydroxyvitamin D (24,25-(OH)2D) and vitamin D-binding protein (DBP) were measured in 12 pubertal girls (aged 10-18 yr) with anorexia nervosa in relapse. The results were compared with similar data obtained in 81 healthy girls representing all stages of puberty. The patients with anorexia nervosa had significantly lower 1,25-(OH)2D levels (71 vs. 124 pmol/l; p less than 0.0005), and significantly higher 24,25-(OH)2D levels (6.0 vs. 3.2 nmol/l; p less than 0.0005), whereas the 25-OHD concentrations were similar in the two groups (85.7 vs. 86.7 nmol/l). The molar ratios of 24,25-(OH)2D to 25-OHD, which reflects the relative activity of the 24-hydroxylation, were significantly higher in the anorectics (6.6% vs. 3.6%; p less than 0.0005). The mean level of DBP did not differ between the two groups, and accordingly the calculated "free-fraction of 1,25-(OH)2D" was significantly lower in the anorectic patients (p less than 0.0005). It appears that the regulatory mechanisms of the vitamin D endocrine system are altered in the patients with anorexia nervosa at puberty resulting in a relative decrease of the plasma concentration of 1,25-(OH)2D and increase of the 24,25-(OH)2D concentration.

Echocardiographic assessment of cardiac function and morphology in patients with generalised lipodystrophy.

Because cardiomegaly has been observed in lipodystrophic patients we studied cardiac morphology and function with one- and two-dimensional echocardiography in addition to general cardiologic examination in a series of seven patients. Muscular hypertrophy with increased chamber size and myocardial indentations were found. Two patients had asymmetrical septal hypertrophy (ASH), and two patients demonstrated systolic anterior movement (SAM) of the mitral valve. Wall motion analysis showed anomalities in four patients during contraction, in three during the early relaxation phase. Since pathological findings, probably increasing with age, were made in the majority of the patients, these findings add an additional unfavourable aspect to the syndrome.

Spinal deformities in tall girls.

In a prospective study, 62 girls who consulted the paediatric department because of tall stature were examined for spinal deformities. Thirteen cases of scoliosis measuring 10 degrees or more were found. Eighteen girls had a thoracic kyphosis of more than 40 degrees and 11 had additional vertebral abnormalities indicating Scheuermann's disease. The incidence of scoliosis and Scheuermann's disease was much higher in our material than normal.