Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1.

ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic beta cell. These channels consist of two types of protein subunit: the sulfonylurea receptor SUR1 and the inward rectifying potassium channel Kir6.2. Mutations in the genes encoding these proteins are the most common cause of congenital hyperinsulinism (CHI). Since 1973, we have followed up 38 pediatric CHI patients in Finland. We reported previously that a loss-of-function mutation in SUR1 (V187D) is responsible for CHI of the most severe cases. We have now identified a missense mutation, E1506K, within the second nucleotide binding fold of SUR1, found heterozygous in seven related patients with CHI and in their mothers. All patients have a mild form of CHI that usually can be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of heterologous coexpression studies of recombinant Kir6.2 and SUR1 carrying the E1506K mutation. Mutant K(ATP) channels were insensitive to metabolic inhibition, but a partial response to diazoxide was retained. Five of the six mothers, two of whom suffered from hypoglycemia in infancy, have developed gestational or permanent diabetes. Linkage and haplotype analysis supported a dominant pattern of inheritance in a large pedigree. In conclusion, we describe the first dominantly inherited SUR1 mutation that causes CHI in early life and predisposes to later insulin deficiency.

Prediction of adult height with various methods in Finnish children.

Successive height predictions were made by several methods for a group of healthy Finnish children (30 boys and 30 girls), examined annually at ages of 7 to 17 years (1st series) and for 7 boys aged 14 to 19 years with familial delayed growth and puberty (2nd series). The methods used were those of Bayley & Pinneau (BP), Walker (W), Tanner et al. (T) and RWT, and two simple principles: the relative height method (RH) which assumes constancy of height S.D.S. throughout growth, and the index of potential height (IPH) method which assumes constancy of height S.D.S. for bone age (BA). The predictions with RH, W and IPH were inaccurate. BP, T and RWT were for the 1st series as accurate as for the basic series of the respective methods, and none was superior to the others. The BA of average Finns was delayed as compared with the standards of Greulich-Pyle Atlas. When corrections were made for this delay, the IPH method gave predictions comparable in accuracy to BP, T or RWT. In the 2nd series prediction was more accurate with the corrected IPH, BP and RWT methods than with those using BA according to TW2RUS.

Ultrasound imaging in diffuse thyroid disorders of children.

The diagnosis of diffuse thyroid disorders in children is based mainly on hormone and antibody determinations and a cytologic sample taken by aspiration biopsy. The cytologic sample is not always obtainable in small children or when the thyroid gland is not enlarged. Thyroid antibodies lead to diagnosis only in a proportion of cases. Gamma imaging is not recommended in children because of the radiation risk. The aim of this study was to demonstrate that ultrasound imaging can detect diffuse thyroid disorders in children. Ultrasound images were abnormal in 92% of all subjects; they were abnormal in 97% of cases with thyroiditis and in most cases ultrasound was diagnostic. With antibody determinations, only 60% of the cases of thyroiditis could be diagnosed. Ultrasound imaging--a risk-free method--should be included in the diagnostic investigation of thyroid disorders.

Ultrasonography in congenital hypothyreosis.

To our knowledge, ultrasonography has not so far been used as an additional source of information in the early screening for congenital hypothyreosis. This study demonstrated, firstly, that the normal neonatal thyroid gland could always be recognized by ultrasonography and, secondly, that in congenital hypothyreosis absence of thyroid tissue from the normal site could be detected by ultrasonography, whereas ectopic tissue in the tongue could not readily be identified. The findings may be useful in the diagnosis of congenital hypothyreosis.

Craniofacial features in patients with deficient and excessive growth hormone.

We studied the role of growth hormone (GH) in craniofacial growth by analyzing the craniofacial structures in patients with either deficient or excessive GH. The cephalogrammes of 21 patients with isolated or combined GH deficiency and of two patients with GH excess were compared with cephalogrammes of age and sex matched controls, and the patients with deficient GH also with height and sex matched controls. In cephalometric measurements, skeletal anatomy was followed as closely as possible. All patients had a Class I or an end-to-end dental occlusion. Head circumference was normal in all patients. Facial widths were significantly smaller in patients with deficient GH but at the level of + 2 SDs in the two with GH excess when compared to Finnish norms. In patients with deficient GH, facial heights were significantly smaller than in age matched controls, but of the same order with height controls for anterior facial height. Posterior facial height was smaller even in this comparison. In patients with GH excess, facial heights were much larger and at the levels of +3 and +6 SD. Clivus was shorter in patients with deficient GH and longer (+ 1.9 and +3 SD) in the two with GH excess. All angulations of the sphenoidal plane deviated from those of the controls in the group with GH deficiency. The cranial base angle (CL-SPhen) was smaller than in controls while it was normal in patients with GH excess. We are inclined to interpret the craniofacial structure of those with deficient GH as being unique to the condition rather than merely negative allometry.(ABSTRACT TRUNCATED AT 250 WORDS)

Oestrogen treatment of tall girls: effect decreases with age.

Fifty-nine tall girls were treated with oestrogen to reduce final height, starting at the ages of 9.1 to 16.2 years. We assessed the result of this treatment by comparison with matched controls. The epiphyseal bone age at the start of therapy, the final height, the Bayley-Pinneau (BP) and Roche-Wainer-Thissen (RWT) predictions of final height, and the errors in both predictions were evaluated. The matched pairs were divided into three groups according to bone age at the start of treatment; I less than 10.5 (n = 16), II 10.5-12.0 (n = 22) and III greater than 12.0 years (n = 21). The mean (SD) intrapair reduction of height for these groups was 9.7 (4.0) cm, 4.3 (4.3) cm and 3.5 (3.2) cm, respectively, according to BP predictions and 6.3 (4.3) cm, 3.4 (3.0) cm and 1.2 (3.3) cm according to RWT predictions. No method of predicting height is accurate for tall girls and simultaneous predictions may differ greatly. Close agreement between the BP and RWT predictions does not indicate greater accuracy. The earlier therapy is started, the greater is the effect. Young girls need psychosocial support with therapy.

Growth and adrenal androgen status at 7 years in very low birth weight survivors with and without bronchopulmonary dysplasia.

AIMS: To evaluate whether 7 year old VLBW (very low birth weight, <1500 g) survivors with and without bronchopulmonary dysplasia (BPD) evince similar growth status and higher adrenal androgen (AA) levels than term controls, and whether AA levels are higher in VLBW children born small for gestational age (SGA) than in non-SGA cases. METHODS: Assessment of height standard deviation score (SDs), body mass index (BMI), and serum androstenedione and dehydroepiandrostenedione sulphate levels in 31 VLBW children with BPD, 33 without BPD (no-BPD group), and 33 term controls. RESULTS: Lower median (range) height SDs was found in BPD (-1.0 (-3.4 to 1.4) SD) and no-BPD (-0.9 (-2.9 to 2.2) SD) children than in term controls (0.3 (-1.5 to 1.9) SD). Low BMI (below 10th centile) was more common in both the BPD (18 (58%)) and no-BPD (16 (49%)) children compared to term cases (3 (9%)). The median (range) androstenedione levels tended to be higher in the BPD (0.8 (0 to 2.8) nmol/l) and no-BPD (0.8 (0 to 2.3) nmol/l) groups than in term controls (0.6 (0 to 1.8)). Higher median (range) dehydroepiandrostenedione sulphate levels were detected in the no-BPD compared to the term group (0.9 (0 to 4.1) v 0.3 (0 to 2.3) micro mol/l). VLBW children born SGA had higher AA levels compared to non-SGA cases. CONCLUSIONS: At 7 years of age, VLBW children are shorter and tend to have higher AA levels than term controls, but VLBW children with and without BPD do not differ from each other in growth or AA status. Those born SGA have higher AA levels compared to non-SGA cases. The consequences of these findings to final height and to later metabolic and vascular health remain to be determined.

Turner syndrome: effect of hormone therapies on height velocity and adult height.

76 patients with Turner syndrome received estrogen alone, androgen and estrogen started simultaneously or, after preceding androgen therapy, estrogen with or without androgen. Six patients had spontaneous pubertal development and received no estrogen. Two patients received human growth hormone with androgen during greater than 2.0 years. Height velocity increased during all therapies to mean SD scores of 7.6 during androgen-estrogen started simultaneously, 4.6 during androgen alone, 4.2 during androgen-estrogen after preceding androgen, 2.7 during estrogen alone, and 0.6 during estrogen after preceding androgen. Adult height was measured in all cases, it was 145.5 +/- 5.7 (mean +/- SD) for the whole series without significant differences between the groups. It correlated strongly with midparent height, and was greater for patients with the 45,X karyotype than for the others combined.

Growth in Turner's syndrome: spontaneous and fluoxymesterone stimulated.

Spontaneous growth was analysed in a group of 55 girls with Turner's syndrome and various karyotypes. Their variation in height and its dependence on parental height were similar to that of normal girls. At all ages, the 45,X karyotype was associated with slightly greater mean stature than the other karyotypes together. The bone ages lagged progressively behind from 10 years onwards. Twenty-five patients aged between 9.1 and 17.2 years were given fluoxymesterone, 0.06-0.17 mg/kg daily, for at least 1 year. Their height velocities increased significantly. This brought about a clear psychological benefit. Their final heights were predicted before and after therapy, with a new method based on the spontaneous growth and bone maturation of our patients. The response was individually variable but, on average, the patients gained in predicted height from the therapy. This effect was not lost during a posttreatment year. Abnormal lowering of the voice occurred in patients receiving greater than or equal to 0.15 mg/kg fluoxymesterone daily, but never with less than 0.13 mg/kg. No other adverse effects appeared. Thus, fluoxymesterone is useful for promoting growth in girls with Turner's syndrome.

Acceleration of delayed growth with fluoxymesterone.

61 boys with constitutional delay of growth and maturation, aged 9-19 years and with a bone age (BA) lag of 1.3-5.5 years, were administered fluoxymesterone (0.05-0.24 mg/kg daily orally, relative dose increasing with age) to accelerate growth. The therapy was continuous and lasted 0.4-3.6 years. The findings are compared with 37 observation periods in a similar group of untreated boys. Growth velocity increased in every treated boy during the therapy, the mean first-year increment being 4.3 +/- 1.6 cm/year. For most boys this brought about a decrease in the height difference from peers, and so afforded the psychosocial relief that was the objective of the therapy. After therapy the velocity decreased slightly in most boys, from a mean of 9.1 +/- 1.4 to 7.1 +/- 3.3 cm/year. The effect of the intervention on final height was assessed by three relatively independent methods of prediction. These were found to be equally valid in the 15 control boys for whom final heights are known. The effect appeared to vary individually, but on the average there appeared to be no loss of height potential. No individual boy with initial BA greater than 10.5 years showed a substantial reduction in predicted final height.

Experiences of special gynaecological services for children and adolescents: a descriptive study.

Gynaecological examination of girls during childhood is undertaken somewhat infrequently. These genital examinations should not be taboo or a frightening experience for the girl, for her parents or for the physician. Studies of children suspected of sexual abuse have paid attention to the wide variety of gynaecological conditions already present in childhood. In 1988 we founded a special gynaecological outpatient clinic for girls under 16 y of age at a university hospital to develop the special knowledge and skills needed in children's gynaecology. In this gynaecological clinic for children and adolescents we were able to gain and offer expert knowledge of the problems of this age group. In this special clinic for children, gynaecological examination by special techniques and sonography led to a diagnosis in 71% of the patients without any instrumentation. Children and adolescent girls in need of special gynaecological care should be recognized specifically. Particular attention should be paid to the gynaecological care of victims of child sexual abuse and mentally or physically handicapped girls. In good co-operation with the girl, a gynaecological examination can become a positive experience during the development of female identity.

Normal growth of prepubertal nephrotic children during long-term treatment with repeated courses of prednisone.

The growth of 21 prepubertal children with steroid-dependent frequently relapsing nephrotic syndrome was studied before and during treatment with repeated courses of oral prednisone for 4 y. The height and height velocity standard deviation scores (HSDS and HVSDS) of the nephrotic children were -0.11 and -0.06, respectively, at the onset of the disease and -0.12 and +0.05, +0.14 and +1.02, +0.21 and +0.78 and +0.17 and +0.66, respectively, thereafter yearly during the treatment. The mean yearly cumulative dose of prednisone was 6300, 3459, 2677 and 2081 mg/body area (m2) at the first, second, third and fourth year, respectively. The nephrotic children grew normally for their age before onset of the disease and growth remained normal despite prednisone treatment.

Dental maturity in hypopituitarism, and dental response to substitution treatment.

In 25 patients with hypopituitarism the relation of skeletal and dental maturity and the effects on it of substitution therapy for 2-4 years were analyzed. Dental age was retarded less regularly and to a lesser degree than skeletal age and statural growth. In most patients dental age was within the range of 0-2 s.d. All components of dental development seemed equally retarded. Changes in dental delay during GH treatment were variable, but in most cases parallel to the changes in statural and skeletal delay. When treatment was discontinued the lag in dental age increased, showing a response similar to that of skeletal age.

Growth of asthmatic children is slower during than before treatment with inhaled glucocorticoids.

Reports on the influence of inhaled glucocorticoids on growth have been controversial. We studied the growth of prepubertal asthmatic children prior to and during glucocorticoid therapy. We collected retrospectively the notes of 201 asthmatic children aged 1-11 years receiving inhaled beclomethasone dipropionate or budesonide. We calculated their height and height velocity standard deviation scores (HSDS and HVSDS, respectively) before the treatment and up to 5 years during the treatment and compared those with the growth of healthy peers. The dose of the medication was calculated and the severity of asthma was assessed. The asthmatic children grew similarly to their healthy peers before treatment with inhaled glucocorticoids: the mean HSDS was +0.02 and the mean HVSDS +0.01 for boys and -0.16 and +0.13 for girls, respectively. Growth retardation took place soon after the start of the treatment, the most profound decrease in the growth velocity (the change in the mean HVSDS from +0.05 to -0.88) occurring during the first year of treatment. The growth-retarding effect of inhaled glucocorticoids was not dose dependent. In the covariance analysis the increasing severity of asthma had a significant interaction with repeated measurements, showing more growth retardation along with more severe asthma, especially during long-term treatment. Asthma per se does not impair growth, but inhaled glucocorticoids may do so. Careful monitoring of the growth of all asthmatic children receiving inhaled glucocorticoids is necessary because the growth-retarding effect of the medication is not dose dependent. Individual sensitivity might explain the differences seen in the growth patterns of children receiving inhaled glucocorticoids.

Fundamental voice frequence during normal and abnormal growth, and after androgen treatment.

A simple treatment was shown to be suitable for clinical measurement of fundamental voice frequency. Basal frequency (SFF) and lowest frequency (LF) were determined in 374 normal subjects aged 6 years to adulthood. SFF fell between ages 8 and 10 years in boys (from 259 to 247 Hz), but not in girls (253 Hz). LF fell between ages 6 and 10 years in boys (from 234 to 203 Hz) and girls (from 230 to 218 Hz), and a sex difference appeared. In puberty, parallel to pubic hair (PH) development, a gradual fall of SFF and LF occurred in both boys (to 100 and 90 Hz, respectively) and girls (to 213 and 180 Hz). As a group, young hypopituitary children and girls with Turner's syndrome had a high SFF, and prepubertal boys with delayed maturation a low SFF. In some children with prenatal growth failure, SFF was abnormally high. The girls with Turner's syndrome exhibited a high, though individually variable, sensitivity of voice to androgen; their voices became lower before the appearance of any other masculinising effects. The instrument is useful for characterisation of growth failure syndromes and stages of puberty. It is particularly recommended for monitoring an undesirable effect on the voice during androgen treatment.

Subnormal pubertal increases of serum androgens in Turner's syndrome.

60 patients (139 blood specimens) with Turner's syndrome were investigated in order to obtain information concerning the origin of the increments of androgens during puberty. The concentrations of serum FSH, LH, estradiol, testosterone, 5 alpha-dihydrotestosterone, dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone and pregnenolone in patients less than 10 years old were identical to those previously found in normal healthy girls of the same age. Hence, in adrenarche the early increase of androgen secretion is independent of gonadal hormone secretion. The later increases in serum testosterone and androstenedione in our patients were very small, and the age of 15 years, their concentrations were 50 and 60%, respectively, of the corresponding levels in normal girls of the same age. After 13 years of age, the mean serum dehydroepiandrosterone concentration was also slightly, but significantly (20-30%), lower than in normal girls of the same age. It is concluded that the ovaries are responsible for most of the pubertal rises in circulating testosterone and androstenedione, and possibly for a small part of the late pubertal rise in dehydroepiandrosterone.