[Prophylactic thyroidectomy in children who are carriers of a multiple endocrine neoplasia type 2 mutation: description of 20 cases and recommendations based on the literature]. / Profylactische thyreoïdectomie bij kinderen die drager zijn van een mutatie van multipele endocriene neoplasie type 2: beschrijving van 20 casussen en aanbevelingen op grond van de literatuur.

OBJECTIVE: Evaluation of treatment of children who are proven carriers of a multiple endocrine neoplasia type 2 (MEN 2)-associated rearranged during transfection (RET) gene mutation. DESIGN: Retrospective case study and review of the literature. METHOD: Between 1976 and 2005, 6 boys and 14 girls with a proven RET mutation or biochemical indication of MEN 2 had thyroid surgery at the University Medical Center, Groningen, The Netherlands. The median age was 10 years (range: 0-08). Preoperative assessment, surgical procedure, pathological findings, postoperative complications and treatment results were studied and compared with data from the literature. RESULTS: All 20 children underwent total thyroidectomy. In 17 children with preoperatively abnormal basal or stimulated calcitonin levels, total thyroidectomy was combined with tracheo-oesophageal exploration (n = 6) or central compartment dissection (n = 11). C-cell hyperplasia was found in 19 cases (95%) and medullary thyroid carcinoma in 14 (70%; aged 3-18 years). Lymph-node metastases were found in 3 children (15%), all over the age of 10. They underwent additional selective lateral neck dissection, unilateral in 2 cases and bilateral in 1. Two children developed hypoparathyroidism postoperatively, no recurrent laryngeal-nerve palsy was observed. All patients are clinically free of disease after a median follow-up of 9 years (range: 0.6-27). The patients with node metastases still have biochemical evidence of disease. The literature indicates that the progression of the malignant transformation to medullary thyroid carcinoma is connected to the type of RET-mutation. The treatment plan depends on the type of mutation. CONCLUSION: Medullary thyroid cancer occurs at a very young age in carriers ofgermline RET mutations. In patients with high-risk mutations prophylactic thyroidectomy is likely to be recommended before the child reaches the age of 2. Elective central lymph-node dissection can be omitted in this instance. After this age, however, the risk of lymph-node metastases increases and, for cases with increased basal or stimulated calcitonin levels, total thyroidectomy with central compartment dissection is indicated.

Genotype versus phenotype in families with androgen insensitivity syndrome.

Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, no or only minimal virilization may occur even in patients with significant (but still deficient) prenatal virilization. Wolffian duct remnants remain detectable but differentiation does not occur in the absence of a functional AR. In many CAIS patients, surgical elongation of the vagina is not indicated.

Can GnRH-agonist treatment cause slipped capital femoral epiphysis?

Slipped capital femoral epiphysis (SCFE) mainly occurs in pubertal children and is associated with delayed skeletal maturation, obesity, high growth velocity and tall stature. Furthermore, SCFE often coincides with endocrine disorders. This is the first report of a possible relationship between SCFE and GnRH agonist treatment: four patients developed SCFE during or shortly after treatment with GnRH agonists was stopped. We compared the clinical aspects of these patients with patients described in the literature who developed SCFE. Puberty started at the age of 3.3, 9.6, 0.0 and 5.6 years respectively. One patient developed sequential SCFE of both hips. SCFE occurred at the age of 11.9 (patient 1), 12.7 (patient 2), 14.3 (patient 2), 11.3 (patient 3) and 11.3 (patient 4) years. Of the five incidences of SCFE, one occurred during GnRH agonist treatment and four shortly after treatment was stopped. None of our patients met the typical criteria seen in SCFE and no 'regular' characteristics of patients with SCFE could be designated. Probably the hormonal changes during and shortly after treatment with GnRH agonists make the epiphysis more prone to slip. Considering our observations and by reviewing the literature, GnRH agonist treatment might present a risk factor for the occurrence of SCFE.

Normalization of height in girls with Turner syndrome after long-term growth hormone treatment: results of a randomized dose-response trial.

Short stature and ovarian failure are the main features in Turner syndrome (TS). To optimize GH and estrogen treatment, we studied 68 previously untreated girls with TS, age 2-11 yr, who were randomly assigned to one of three GH dosage groups: group A, 4 IU/m2 day (approximately 0.045 mg/kg x day); group B, first yr 4, thereafter 6 IU/m2 x day (approximately 0.0675 mg/kg/day); group C, first yr 4, second yr 6, thereafter 8 IU/m2 x day (approximately 0.090 mg/kg x day). In the first 4 yr of GH treatment, no estrogens for pubertal induction were given to the girls. Thereafter, girls started with 17beta-estradiol (5 microg/kg bw x day, orally) when they had reached the age of 12 yr. Subjects were followed up until attainment of adult height or until cessation of treatment because of satisfaction with the height achieved. Seven-year data of all girls were evaluated to compare the growth-promoting effects of three GH dosages during childhood. After 7 yr, 85% of the girls had reached a height within the normal range for healthy Dutch girls. The 7-yr increment in height SD-score was significantly higher in groups B and C than in group A. In addition, we evaluated the data of 32 of the 68 girls who had completed the trial after a mean duration of treatment of 7.3 yr (range, 5.0 - 8.75). Mean (SD) height was 158.8 cm (7.1), 161.0 cm (6.8), and 162.3 cm (6.1) in groups A, B, and C, respectively. The mean (SD) difference between predicted adult height before treatment and achieved height was 12.5 cm (2.1), 14.5 cm (4.0), and 16.0 cm (4.1) for groups A, B, and C, respectively, being significantly different between group A and group C. GH treatment was well tolerated in all three GH dosage groups. In conclusion, GH treatment starting in relatively young girls with TS results in normalization of height during childhood, as well as of adult height, in most of the individuals. With this GH and estrogen treatment regimen, most girls with TS can grow and develop much more in conformity with their healthy peers.

17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations.

17Beta-hydroxysteroid dehydrogenase-3 (17betaHSD3) deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the HSD17B3 gene. In a nationwide study on male pseudohermaphroditism among all pediatric endocrinologists and clinical geneticists in The Netherlands, 18 17betaHSD3-deficient index cases were identified, 12 of whom initially had received the tentative diagnosis androgen insensitivity syndrome (AIS). The phenotypes and genotypes of these patients were studied. Endocrine diagnostic methods were evaluated in comparison to mutation analysis of the HSD17B3 gene. RT-PCR studies were performed on testicular ribonucleic acid of patients homozygous for two different splice site mutations. The minimal incidence of 17betaHSD3 deficiency in The Netherlands and the corresponding carrier frequency were calculated. Haplotype analysis of the chromosomal region of the HSD17B3 gene in Europeans, North Americans, Latin Americans, Australians, and Arabs was used to establish whether recurrent identical mutations were ancient or had repeatedly occurred de novo. In genotypically identical cases, phenotypic variation for external sexual development was observed. Gonadotropin-stimulated serum testosterone/androstenedione ratios in 17betaHSD3-deficient patients were discriminative in all cases and did not overlap with ratios in normal controls or with ratios in AIS patients. In all investigated patients both HSD17B3 alleles were mutated. The intronic mutations 325 + 4;A-->T and 655-1;G-->A disrupted normal splicing, but a small amount of wild-type messenger ribonucleic acid was still made in patients homozygous for 655-1;G-->A. The minimal incidence of 17betaHSD3 deficiency in The Netherlands was shown to be 1: 147,000, with a heterozygote frequency of 1:135. At least 4 mutations, 325 + 4;A-->T, N74T, 655-1;G-->A, and R80Q, found worldwide, appeared to be ancient and originating from genetic founders. Their dispersion could be reconstructed through historical analysis. The HSD17B3 gene mutations 326-1;G-->C and P282L were de novo mutations. 17betaHSD3 deficiency can be reliably diagnosed by endocrine evaluation and mutation analysis. Phenotypic variation can occur between families with the same homozygous mutations. The incidence of 17betaHSD3 deficiency is 0.65 times the incidence of AIS, which is thought to be the most frequent known cause of male pseudohermaphroditism without dysgenic gonads. A global inventory of affected cases demonstrated the ancient origin of at least four mutations. The mutational history of this genetic locus offers views into human diversity and disease, provided by national and international collaboration.

Yearly stepwise increments of the growth hormone dose results in a better growth response after four years in girls with Turner syndrome. Dutch Working Group on Growth Hormone.

To optimize the growth promoting effect of growth hormone (GH), 65 previously untreated girls with Turner syndrome (TS), chronological age (CA) 2-11 yr, were randomized into 3 dosage regimen groups: A, B, and C, with a daily recombinant-human GH dose during 4 study years of 4-4-4-4, 4-6-6-6, and 4-6-8-8 IU/m2 b.s. The first GH dosage increase in groups B and C resulted in a significantly higher mean height velocity (HV) compared with constant dose group A. During the third year, when the dose was raised again only in group C, mean HV was significantly higher in groups B and C than in group A, and in group C compared with group B. In year 4 only group C mean HV remained significantly higher than group A. The pattern of change in HSDSCA (Dutch-Swedish-Danish Turner references) was identical; however, in year 4 mean delta HSDSCA in group B also remained significantly higher than group A. After 4 yr GH treatment, the following was determined. 1) The mean delta HSDSCA was significantly higher for groups B and C compared with group A, but not significantly different between groups B and C. 2) Although significantly higher compared with estimated values for untreated Dutch girls with TS, bone maturation of the GH treated girls was not significantly different between groups. 3) It was positively related with the degree of bone age (BA) retardation at start of study and negatively with baseline CA. 4) Both the modified Index of Potential Height (mIPHRUS) and a recently developed Turner-specific final height (FH) prediction method (PTSRUS), based on regression coefficients for H, CA, and bone age, showed significant increases in mean FH prediction, without significant differences between groups. PTSRUS values were markedly higher than the mIPHRUS values. Dose dependency could be shown for the area under the curve (AUC) for GH, but delta HSDSCA was not linearly related with AUC. Baseline GH binding protein (BP) levels were in 84% of the cases within the normal age range; the decrease in mean levels after 6 months GH was not significant. Mean insulin-like growth factor I (IGF-I) and IGFBP-3 plasma levels increased significantly, without significant differences between groups. delta HSDSCA during GH was dependent on IGF-I plasma levels at baseline and during the study period, beta-0.002 and beta-0.0004. Thus, a stepwise GH-dosing approach reduced the "waning" effect of the growth response after 4 yr treatment without undue bone maturation. FH prediction was not significantly different between treatment groups. Irrespective of the GH dose used, initiation of GH treatment at a younger age was beneficial after 4 yr GH when expressed as actual cm gained or as gain in FH prediction, but was not statistically significant when expressed as delta HSDSCA over the study period.

Total thyroidectomy in the treatment of thyroid carcinoma in childhood.

Between 1974 and 1993 ten girls and six boys aged 6-16 years underwent total thyroidectomy, with therapeutic selective neck dissection in six patients. All were treated after operation with radioactive iodine (131I) for ablation of thyroid tissue remnants. Papillary carcinoma occurred in ten patients, follicular carcinoma in two and medullary thyroid lesions in four. The patients were followed for a median of 11.5 (range 1-20) years with regular determinations of serum thyroglobulin levels and 131I whole-body scanning when indicated. Only one patient had a slight increase in thyroglobulin levels without evidence of disease on further screening. In children with medullary lesions the serum levels of basal and pentagastrin-stimulated calcitonin remained normal. Currently all patients are alive and without disease. Hypocalcaemia lasting for more than 1 year was observed in one patient. Recurrent nerves were not injured accidentally, but because of tumour invasion two of 32 recurrent nerves had to be sacrificed. This surgical approach is safe and well tolerated in children.

In utero diagnosis and treatment of fetal goitrous hypothyroidism, caused by maternal use of propylthiouracil.

A fetal goitre is a potentially dangerous phenomenon because of mechanical obstruction and possible fetal thyroid function disorders. In this report we describe a patient with Graves' disease diagnosed in early pregnancy and treated with propylthiouracil, which resulted in a large fetal goitre and fetal hypothyroidism. The diagnostic problems are discussed and we focus on the need for fetal thyroid hormone serum evaluation. The only reliable way to obtain information about the fetal thyroid status is percutaneous fetal umbilical cord blood sampling, since amniotic fluid levels do not properly represent the fetal thyroid function. Fetal hypothyroidism can thus be diagnosed in utero and treated with intra-amniotic injections of thyroxine. The recommended dose and frequency of injections are only based on a few case reports and for that reason we performed a second fetal blood sampling 1 week later to evaluate our therapy. Weekly intra-amniotic injections of 250 micrograms of thyroxine seem to be sufficient to reduce a fetal goitre and give a normal thyroid hormone level.

Urinary steroid profile of a newborn suffering from pseudohypoaldosteronism.

A case is described of a newborn, admitted to hospital because of severe salt loss at the age of 1 month. Subsequent analysis of urinary steroid excretion, by gas chromatography and gas chromatography-mass spectrometry, revealed that the patient suffered from pseudohypoaldosteronism. However, it was difficult to interpret the results unambiguously, since the first urinary analysis appeared to suggest 21-hydroxylase- or 18-hydroxylase deficiency. The final diagnosis was possible only after detecting high urinary levels of aldosterone and tetrahydroaldosterone. It is concluded that neonatal urinary steroid profiles should be interpreted cautiously in order to arrive at the correct diagnosis.

Kinetics and metabolism of 11-deoxycortisol in a patient with congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.

The kinetic features of 11-deoxycortisol (S) were studied in a 11 beta-hydroxylase deficient boy. After i.v. administration of 35 kBq [3H]S (11 pmol) together with 44 nmol [13C]cortisol all his urine was collected during the next 3 days. A recently reported kinetic model, by which the fate of radioactive cortisol (F) in the body can be described by analysis of only the urinary radioactivity, has been used to calculate the rate constants of S metabolism. The overall half-life of S in the circulation was 4.7 min, which is very close to a reported half-live of the rapid phase: 4.1 min determined from the plasma radioactivity. The time of maximal accumulation of S in the first metabolic pool--26 min is about one quarter of that found for F--109 +/- 20 min (n = 8). The half-live of the S metabolites in the body was 7.0 h, equal to that of F: 6.1 +/- 0.9 h (n = 8). Obviously S is taken up into the metabolic organs 4 times faster than F, but it is not metabolized faster. The production rates of S and F were 127 and 2.1 mumol/(m2*d), respectively, pointing to a severely deficient synthesis of F. However, from the urinary excretion of 3 alpha,21-dihydroxy-5 beta-pregnan-20-one in relation to 3 alpha,11 beta,21-trihydroxy-5 beta-pregnan-20-one it cannot be concluded that the synthesis of corticosterone was strongly impaired.