Biomedical subjects
Publications and source records attributed to B J Otten.
We report a young girl who died in an Addisonian crisis due to previously undiagnosed congenital adrenal hyperplasia (CAH), in whom ovarian adrenal rest tissue was detected at postmortem histopathological examination. This is a very rare complication in female patients with CAH with only two previously reported cases.
Congenital adrenal hyperplasia (CAH) is generally regarded as a paediatric endocrine disease, but nowadays nearly all patients reach adulthood as a result of improved diagnosis and treatment. It is now increasingly recognised that treatment goals shift during life: one of the major treatment goals in childhood and puberty, i.e. normal growth and development, is no longer relevant after childhood, whereas other aspects, such as fertility and side effects of long-term glucocorticoid treatment, become more important in adulthood. This paper focuses on fertility in male and female adult patients with CAH. In males with CAH the fertility rate is reduced compared with the normal population, the most frequent cause being testicular adrenal rest tumours. Development and growth of these tumours is assumed to be ACTH dependent and undertreatment may play an important role. If intensifying glucocorticoid treatment does not lead to tumour decrease, surgical intervention may be considered, but the effect on fertility is not yet known. In females with CAH the degree of fertility depends on the phenotype of the CAH. Most fertility problems are seen in the classic salt-wasting type. Age of menarche and regularity of the menstrual cycle depends on the degree of adrenal suppression. Not only adrenal androgens have to be normalised but also the levels of adrenal progestins (progesterone and 17-OH-progesterone) that interfere with normal ovulatory cycles. The regularity of menstrual cycles can be considered as an important measure of therapeutic control in adolescent females with CAH and therefore as a therapeutic goal from (peri)pubertal years on. Other factors that contribute to impaired fertility in females with CAH are ovarian hyperandrogenism (polycystic ovary syndrome), ovarian adrenal rest tumours, genital surgery and psychological factors. Subfertility in CAH can have its origin already in the peripubertal years and is therefore of interest to the paediatric endocrinologist.
BACKGROUND: An optimal treatment for tall stature in boys in terms of efficacy and safety is not available. Treatment with somatostatin analogue 201-995 (SMS) has been tried with positive short-term results. METHODS: We evaluated the effect of SMS treatment on reducing adult height. Over 2 years, 16 boys presenting to our university hospital with tall stature (constitutional tall stature (n = 13), Marfan syndrome (n = 2) and tethered spinal cord (n = 1)) with a predicted final height above 197 cm were included in the study and prospectively followed until final height was reached. As one boy was lost to follow-up we have reported on 15 boys. Treatment with SMS as a single subcutaneous dose was started and continued until final height was reached. In eight boys androgens were given to induce puberty after the start of SMS and five boys were on treatment with androgens prior to SMS treatment. Effect on reduction of final height prediction, calculated with the index of potential height based on the bone age of Greulich and Pyle, was the main outcome measure. Standard anthropometric assessments were performed a year before and every 3 months during treatment. Bone age was assessed by the method of Greulich and Pyle at the start and after 6 and 12 months. RESULTS: Mean reduction in final height prediction (predicted adult height minus achieved adult height) was -0.1 cm (range -6.4 to +5.7). In three boys, asymptomatic microlithiasis of the gall bladder was diagnosed. CONCLUSIONS: We have concluded that, in spite of encouraging short-term results, long-term treatment with SMS does not reduce final height in a manner sufficient to justify SMS treatment in tall stature.
Congenital adrenal hyperplasia (CAH) is a disorder of adrenal steroid synthesis. The symptoms and signs of CAH depend on the degree of enzyme deficiency; severe salt-wasting (SW) form, less severe simple virilizing (SV) form and mild nonclassic (NC) form. In this paper, puberty and fertility in CAH are discussed. The time of onset of puberty and progress of pubertal development is quite normal, except in NC patients (earlier). Also the age of menarche in CAH girls is normal, but it can depend on the level of therapeutic control. In prepuberty, bone age is advanced. In puberty, peak height velocity is normal but occurs at a younger age and can therefore be considered to be low (compared to healthy early maturers). In puberty there seems to be an increased sensitivity for glucocorticoids leading to growth inhibition. All three above factors can play a role in reducing adult height. Subfertility is frequently found in both female and male CAH patients. In females, the pregnancy rate depends on the severity of 21-hydroxylase deficiency (SW<SV<NC). Adrenal progestagens and androgens are the main cause of disturbed ovarian activity. In addition psychosexual problems (e.g. as a result of genital surgery) are an important factor. In males, the main cause of subfertiltiy is the presence of testicular adrenal rest tumors, which are thought to originate from aberrant adrenal tissue and respond to treatment with glucocorticoids. Although in general fertility is not a paediatric item, in CAH most fertility problems have their origins in childhood years. Therefore prevention of subfertility has to be implemented as a treatment goal in paediatric endocrinology from the start of puberty.
During operation for a right inguinal hernia, a baby boy aged 3 months was discovered to have internal female genitalia. Biopsies were taken from the gonads and blood was sent for karyotyping. The biopsies showed normal testicular tissue and the karyotyping result was 46XY, so the diagnosis of persistent Müllerian duct syndrome (PMDS) was made. Recovery was uneventful. At the age of 2 he underwent bilateral orchidopexy. PMDS is a rare disorder of the MIF synthesis or receptor. Patients present with cryptorchism, inguinal herniation of Müllerian structures, or problems related to the abnormal urinary tract, such as infection or stone formation. In cryptorchism, orchidopexy and life-long palpatory follow-up are advised. If urological symptoms occur, surgical removal of the Müllerian remnants may be considered. The prognosis for fertility is poor.
Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by metaphyseal chondrodysplasia with severe growth retardation and impaired immunity. We studied the effects of growth hormone treatment on growth parameters and the immune system in four children with CHH. The effects of growth hormone on growth parameters are the most prominent in patients with the mildest growth retardation. However, the effects are temporary and last only for 1 year. There is no gain in final height. Serum immunoglobulins did not change during growth hormone treatment. We conclude that growth hormone treatment is not beneficial in children with CHH.
The clinical safety, use and pharmacokinetics of a new needle-free device for delivery of growth hormone (GH) were compared with those of conventional needle injection devices. In an open-label, randomized, 4-period crossover study, 18 healthy adults received single subcutaneous injections of Genotropin administered by the Genotropin ZipTip needle-free device and by conventional injection. Bioequivalence was established between the devices. In a separate open-label, randomized, multicenter, 2-period crossover study, pediatric patients underwent 2-weeks Genotropin treatment administered by the Genotropin ZipTip and by a fine-gauge needle device (>95% used the Genotropin Pen). In total, 128/133 patients who were treated completed the study. Genotropin ZipTip was well tolerated and >50% of patients found no difference between the devices for all parameters assessed. After study completion, >20% patients preferred to continue using Genotropin ZipTip. Although statistical analyses demonstrated superiority of the Genotropin Pen versus Genotropin ZipTip for bleeding, pain, soreness, and bruising, Genotropin ZipTip was considered to provide a safe and bioequivalent alternative to needle injection.
Congenital adrenal hyperplasia (CAH) is a disorder of adrenal steroid synthesis. In 95% of CAH cases, it is caused by 21-hydroxylase deficiency, leading to cortisol deficiency and (in most cases) aldosterone deficiency. The compensatory increase in ACTH secretion by the pituitary gland leads to stimulation of the adrenal glands and, consequently, overproduction of androgens. The classic form is well known due to the congenital virilisation seen in affected girls. However, the cortisol and aldosterone deficiency is at least equally important in both sexes as it can cause an Addisonian crisis within the first weeks of life. For these reasons, a neonatal CAH screening program has been introduced in the Netherlands. Screening results in earlier detection and treatment. The prevalence of the classic form of the disease is 1:12.000 in the Netherlands. Non-classic 21-hydroxylase deficiency is more frequent, presenting with signs of androgen excess from childhood through to adulthood. Treatment of CAH consists of hormonal replacement and surgical correction in case of congenital virilisation in girls. Long-term treatment results, including height at adulthood, have improved over the last decades. Nevertheless, fertility problems can occur in both sexes.
In an 18-year-old woman non-classic 21-hydroxylase deficiency was diagnosed and dexamethasone treatment was instituted. Ten years later, she became pregnant for the first time; at 37 weeks unexpected intrauterine foetal death was found to have occurred. A second pregnancy ended with a spontaneous abortion following a 12-week period of amenorrhoea. At the third pregnancy, the medication was replaced with hydrocortisone as it was suspected that the use of dexamethasone may have played a role in the intrauterine foetal death and the spontaneous abortion. The patient gave birth to a healthy, but dysmature, daughter. Female patients with non-classic congenital adrenal hyperplasia present with signs of androgen excess. Treatment with glucocorticoids reduces the symptoms and restores the menstrual cycle and fertility. Preconceptional advice by a clinical geneticist is recommended, because of the risk of an affected child. If there is no risk of having a child with congenital adrenal hyperplasia, hydrocortisone or prednisone is the treatment of choice during pregnancy as neither cross the placenta.
AIMS: To evaluate growth from diagnosis until final height (FH) in 21-hydroxylase deficiency patients. METHODS: A retrospective longitudinal study was performed. Only patients treated with hydrocortisone and fludrocortisone (in case of salt wasting) were evaluated. This resulted in a sample of 34 (21 male, 13 female) salt wasting patients (SW) and 26 (13 male, 13 female) non-salt wasting patients (NSW). Auxological data were compared to recent Dutch reference values. RESULTS: In the first three months of life, the mean length SDS decreased to -1.50, probably because of the high average glucocorticoid dose (40 mg/m2/day). FH corrected for target height (FH(corr)TH) was -1.25 and -1.27 SDS in females and males, respectively. Patients treated with salt supplements during the first year, had a better FH(corr)TH (-0.83 SDS). In NSW patients, FH(corr)TH was -0.96 and -1.51 SDS in females and males, respectively. In SW and NSW, age at onset of puberty was within normal limits, but bone age was advanced. Mean pubertal height gain was reduced in males. Body mass index was only increased in NSW females. CONCLUSION: In SW, loss of final height potential might be a result of glucocorticoid excess in the first three months and sodium depletion during infancy. In NSW, loss of FH potential was caused by the delay in diagnosis. In SW and NSW, the advanced bone age at onset of puberty (undertreatment in prebertal years) resulted in loss of height gain during puberty. The effect of intensive sodium chloride support in early infancy should be examined prospectively. Neonatal screening is required if the height prognosis in NSW patients is to be improved.
We assessed bone mineral density (BMD) and body composition in children with Noonan's syndrome (NS) before and during growth hormone (GH) treatment. Sixteen children (12 boys, 4 girls) with NS aged 5.8-14.2 (mean 10.0) years were studied for 2 years. Anthropometry, BMD measurements by radiographic absorptiometry and bioimpedance measurements (Akern-BIA 101/S) were performed at baseline and after 3, 6, 12 and 24 months. Daily GH dosage was 0.05 mg/kg. Trabecular volumetric BMD was normal; cortical BMD was in the lower normal range at baseline and slightly increased over the 2 years. Fat free mass and total body water were below normal at the start and increased significantly over the first 3 months, with a slight increment thereafter. Percentage fat mass decreased over the first 6 months and increased thereafter. These findings are comparable to the data on body composition in short normal children and girls with Turner's syndrome treated with GH.
ACTH-independent Cushing's syndrome may be secondary to the expression of ectopic hormone receptors in adrenal tissue. In food-dependent Cushing's syndrome the adrenals aberrantly express receptors for gastric inhibitory polypeptide (GIP). We present the first case of food- and GIP-dependent adrenal adenoma in an adolescent. A 15 year-old girl presented with signs of hypercortisolism. Urinary cortisol excretion was clearly elevated. Upon the finding of very low fasting plasma cortisol levels with a rise during the morning, food-dependent cortisol secretion was suspected. Hourly measurements of plasma cortisol and GIP levels during a day with and a day without meals showed meal- and GIP-related cortisol secretion. Plasma ACTH levels were undetectable. Abdominal computed tomography showed a tumor of 2.5 x 2.5 x 2 cm in the left adrenal. Unilateral adrenalectomy was performed and microscopic examination of the tumor showed an adrenocortical adenoma. Incubation of adenomatous cells prepared from this tumor with GIP resulted in increased cortisol secretion. Using RT-PCR amplification and cDNA hybridization, the GIP receptor was found to be overexpressed in the adenoma tissue but not in the adjacent adrenal tissue. Twelve months after the operation, hourly measurements of plasma cortisol, GIP and ACTH levels on a day with and a day without meals no longer showed GIP-related cortisol production. The present report shows that in an adolescent with corticotrophin-independent Cushing's syndrome, food-dependent hypercortisolism is a possible diagnosis.
OBJECTIVE: The objective of this study was to evaluate the characteristics of puberty and response to gonadotrophin-releasing hormone (GnRH) agonist treatment in adopted children compared with children with idiopathic precocious puberty (IPP). METHODS: We studied 17 girls with central IPP (group A) and 11 girls adopted from Asia and Central and South America (group B) with respect to auxological data at presentation of puberty and response to GnRH agonist treatment. RESULTS: In adopted girls, age at onset of puberty was later and duration of treatment was shorter. At the start of treatment, height-standard deviation score (H-SDS) was +1.67 s.d. in group A. In group B, H-SDS was comparably increased (+0.04 s.d.) assuming that the mean H-SDS in their native country is lower than the mean on the Dutch curve. During treatment, H-SDS decreased in both groups. Group A reached a final height (FH) of 166.2 cm (-0.3 s.d.) and group B of 156.1 cm (-1.9 s.d.). Predicted adult height (PAH) at the start of treatment underestimated FH in group A and overestimated FH in group B. At the end of treatment, PAH overestimated FH in both groups. The SDS for weight was above the mean in both groups at the start of treatment and increased even more during treatment. The age of occurrence of menses after treatment was stopped was the same in both groups (12.7 and 12.8 Years respectively). CONCLUSION: Despite the difference in timing of puberty between girls with IPP and adopted girls with early puberty, their response to treatment was similar in many aspects.
We measured the quantitative ultrasound (QUS) parameters broadband ultrasound attenuation (BUA) and speed of sound (SOS) at the calcaneus using an ultrasound imaging device (UBIS 3000) in 698 healthy Caucasian male and female subjects (110 prepubertal, 356 pubertal/adolescent and 210 adult) between 6 and 77 years of age. The influence of different region of interest (ROI) diameters (6-20 mm) and software techniques (automatic (ROIaut), copied (ROIcop) and fixed coordinate (ROIfix) measurements) on annual rate of change, trend assessment interval (TAI; an estimate of the follow-up time required for measuring a true change), percentage of positioning errors (positioning of the ROI partly at the cortical edge or even partly beyond the calcaneus) and short-term precision error was studied. When using ROI diameters increasing from 8 to 20 mm, the annual rate of change of BUA and SOS did not change in adults, but was higher in prepubertal subjects (when subjects with positioning errors were excluded) as well as in pubertal/adolescent subjects. TAIs for BUA were shortest when using ROIaut with ROI diameters between 8 and 14 mm (TAI between 1.2 and 1.5 years for prepubertal boys and pubertal/adolescent subjects, 2.4 years for prepubertal girls, 2.7 years for postmenopausal women, and 9 years in men and premenopausal women). TAIs for SOS were 4 years or more, except for postmenopausal women (2.1 years) and prepubertal boys (3.2 years). Measurements with large ROI diameters, especially with fixed region coordinates, resulted in a high percentage of positioning errors and mostly in longer TAIs. Analysis of the short-term precision errors did not reveal these important differences between the various ROI diameters. Our results indicate that calcaneal ultrasound imaging may be useful for measuring skeletal changes in healthy children, especially with BUA, and in postmenopausal women with BUA and SOS using an automatic measurement in the region of lowest attenuation. ROI diameters of 12 mm should be used in prepubertal subjects and of 14 mm in pubertal/adolescent and adult subjects.
The role of GH insufficiency in the pathogenesis of short stature in Noonan syndrome is unclear. Cross-sectional study. Seventeen patients with Noonan syndrome (13 boys, 4 girls; aged 4.8-13.3 (mean 9.2) years) and short stature before start of GH treatment. Spontaneous 12-h overnight GH secretion by continuous sampling analysed using Pulsar, plasma IGF-I and IGFBP-3 levels, and 24-h urinary GH excretion were measured at start of GH treatment. A glucagon stimulation test was performed. Height and height velocity were monitored before and after 1 year of GH treatment. IGF-I and IGFBP-3 were remeasured after 1 year of GH treatment. Nine of the 17 children had a mean overnight GH concentration below the lower limit of the normal range. In six of the 17 patients, overnight GH profiles showed high trough GH concentrations. Glucagon stimulation tests were normal in 16 of the 17 patients. Mean IGF-I level was below normal (-0.4 SD). None of the parameters regarding GH secretion obtained from the overnight profile or provocative test was related to height or height velocity, nor to first year response to GH treatment. IGF-I and IGFBP-3 did not correlate with any of the GH secretion data. IGF-I and IGFBP-3 were related to height and height velocity at the start of GH treatment (r = 0.53 (P < 0.01) and r = 0.61 (P < 0.03) respectively). Rises in IGF-I and IGFBP-3 under GH treatment were related to the increment in height velocity (r = 0.70 (P < 0.01) and r = 0.71 (P < 0.02) respectively). Abnormalities in GH secretion are frequent in patients with Noonan syndrome and short stature. These abnormalities were not related to auxology at start of or response to GH treatment. Clinically GH insufficiency is not important in Noonan syndrome and monitoring spontaneous GH secretion is not necessary before the start of GH treatment.
3-M syndrome combines pre- and postnatal growth retardation and dysmorphic facial features with autosomal recessive inheritance. Six new patients with 3-M syndrome are described and compared with 28 cases from the literature. Our six patients have a growth pattern, which parallels that of Silver-Russell syndrome (SRS). Final height is ISD less in 3-M syndrome than in SRS. Growth hormone treatment significantly increased final height in two of our patients. 3-M syndrome can be differentiated from other types of dwarfism by clinical criteria and by the demonstration of characteristically slender long bones and foreshortened vertebral bodies. We propose that calculating the metacarpal and vertebral indices can be used to measure and document this important diagnostic feature. While the gonadal status of female patients with 3-M syndrome is completely normal, male patients have a gonadal dysfunction and sub- or infertility.
OBJECTIVE: To study the effects of long-term growth hormone (GH) treatment on left ventricular (LV) dimensions in children with Noonan's syndrome (NS). METHODS: Echocardiographic measurements of LV dimensions were performed before and during GH treatment in 27 participants (21 boys, 6 girls) in a partly controlled 3-year trial of high-dose GH treatment (0.15 IU/kg/day). Nineteen children had a congenital heart defect, 1 of them had hypertrophic obstructive cardiomyopathy. In the first 3 years, the children were assigned to 1 of 2 groups: group A with discontinuation of GH treatment in the 3rd year, or group B without GH treatment in the 1st year. After the 3rd year, 12 of the 27 children were followed up for 2 additional years to evaluate the long-term effects of GH treatment on the heart. RESULTS: At baseline, LV internal diameters were smaller, while posterior wall thickness were thicker than normal. Over the 1st year, changes in LV dimensions were comparable between the 2 groups. No significant differences were found in LV dimensions between the situation at baseline and after 4 years of GH treatment. CONCLUSION: Long-term high-dose GH treatment does not have clinically significant adverse effects on LV dimensions in children with NS.
In male patients with congenital adrenal hyperplasia, testicular tumors, or so-called adrenal rest tumors, have been described, but their presence in well controlled patients is thought to be rare. In this study, the prevalence of testicular tumors in 17 adolescent and adult male patients with congenital adrenal hyperplasia (age, 16-40 yr) was investigated. In 16 of 17 patients, one or more testicular tumors, ranging in maximal length from 0.2-4.0 cm, were found on ultrasonography. In 6 patients, the testicular tumors were palpable. Undertreatment, defined as the presence of a salivary androstenedione level (mean of 6 saliva samples collected over 24 h with intervals of 4 h) above the upper reference morning level, was found in 5 of 17 patients at the time of investigation. The other 12 patients were treated adequately or even over treated at the time of investigation. Nevertheless, 11 of these 12 patients showed testicular tumors on ultrasonography. Neither the presence of undertreatment at the time of investigation nor characteristics of the therapeutic regimen (daily dose of hydrocortisone equivalents per body surface, the use of glucocorticoid medication either two or three times a day, or the time of taking the highest glucocorticoid dose either in the morning or the evening) could predict tumor size (maximal diameter of largest tumor). In patients who were heterozygous or homozygous for the deletion or conversion of the CYP21 gene, tumor size was significantly larger than in patients who did not have this genotype. Impairment of Leydig cell function as manifested by decreased plasma levels of T was found in 6 of 17 patients. Semen analysis in 11 patients revealed azoospermia in 3 patients and poor semen quality in 4 patients. We conclude that, when carefully sought for, testicular adrenal rest tumors are frequently present in adolescent and adult males with congenital adrenal hyperplasia and are often accompanied by impaired spermatogenesis and Leydig cell failure.