Wolfgang Hoepffner

Phenotypic classification of male pseudohermaphroditism due to steroid 5α‐reductase 2 deficiency

Conversion of testosterone (T) to dihydrotestosterone (DHT) in genital tissue is catalysed by the enzyme 5 alpha-reductase 2, which is encoded by the SRD5A2 gene. The potent androgen DHT is required for full masculinization of the external genitalia. Mutations of the SRD5A2 gene inhibit enzyme activity, diminish DHT formation, and hence cause masculinization defects of varying degree. The classical syndrome, formerly described as pseudovaginal perineoscrotal hypospadias, is characterized by a predominantly female phenotype at birth and significant virilization without gynecomastia at puberty. We investigated nine patients with steroid 5 alpha-reductase 2 deficiency (SRD). Phenotypes, which were classified according to the severity of the masculinization defect, varied between completely female (SRD type 5), predominantly female (SRD type 4), ambiguous (SRD type 3), predominantly male with micropenis and hypospadias (SRD type 2), and completely male without overt signs of undermasculinization (SRD type 1). T/DHT-ratios were highly increased ( > 50) in the classical syndrome (SRD type 5), but variable in the less severe affected patients (SRD types 1-4) (14-35). Mutations in the SRD5A2 gene had been characterized using PCR-SSCP analysis and direct DNA sequencing. A small deletion was encountered in two patients, while all other patients had single base mutations which result in amino acid substitutions. We conclude that phenotypes may vary widely in patients with SRD5A2 gene mutations spanning the whole range from completely female to normal male without distinctive clinical signs of the disease. Hence, steroid 5 alpha-reductase deficiency should be considered not only in sex reversed patients with female or ambiguous phenotypes, but also in those with mild symptoms of undermasculinization as encountered in patients with hypospadias and/or micropenis. A classification based on the severity of the masculinization defect may be used for correlation of phenotypes with enzyme activities and genotypes, and for comparisons of phenotypes between different patients as the basis for clinical decisions to be made in patients with pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency.

Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development

Background SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517–595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders. Results By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516–584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1–639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells. Conclusions Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination.

Early onset lymphoedema, recessive form — a new form of genetic lymphoedema syndrome

We report on two brothers with chronic congenital lymphoedema. Besides the oedemas of limbs we found an unusual facial appearance, abnormalities of external genitals as a deformation sequence resulting from intrauterine oedemas and intestinal lymphoedema. This X-linked or autosomal recessive trait may be a new entity, to be differentiated from other genetic lymphoedema syndromes, the so-called familial protein-losing enteropathy, and dominantly inherited intestinal lymphangiectasia. A prominent sign of the syndrome is chemosis and injection of conjunctiva.

Blood pressure in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND In patients with congenital adrenal hyperplasia (CAH) recording of blood pressure (BP) must be included in monitoring treatment to detect hypertension. AIM To investigate the BP patterns in patients with CAH. METHODS Twenty-three children and adolescents (age 6-17 years) and 11 adult patients (age 18-26 years) were studied (21 females, 13 males; 28 salt-wasting patients). In the whole group BP in the outpatient clinic was compared with BP under hospitalisation and in 11 of the children and adolescents also with 24-hour ambulatory blood pressure monitoring (ABPM). RESULTS BP in the ward in children and adolescents but not in adults was significantly higher than BP in the outpatient clinic, where BP was in the upper normal range. There was also a significant difference between BP in the outpatient clinic and the lower ABPM in the 11 patients tested. Atrial natriuretic peptide (ANP) in blood serum showed normal values. CONCLUSIONS BP measured in outpatients in a relaxed and calm atmosphere meets the requirements for monitoring of treatment. Measurement of BP on the ward leads to falsely high results. ABPM is not necessary. Estimation of ANP provides no additional information.

Prediction of height velocity of prepubertal children with growth hormone deficiency in the first year of treatment with recombinant human growth hormone.

AIM Several methods have been developed to predict the outcome of growth hormone (GH) therapy in children with growth hormone deficiency (GHD). METHODS Over 50 factors for each of 92 prepubertal patients with GHD (26 patients with total and 45 patients with partial GHD, 21 patients with neurosecretory dysfunction) were collected and included in multiple regression analyses and other nonlinear models to predict height velocity (HV) (cm/yr) in the first year of treatment. Afterwards the model was validated by two other cohorts of patients from other universities, which followed the same treatment regime as our clinic. RESULTS Twelve parameters had a significant correlation to HV (p<0.05) and a coefficient of determination >20%. Two parameters (In BA, In GHmax) showed a coefficient of determination >60% for children with GHD in multiple regression analysis. The validation of the mathematical model against another data set showed different results. GH was measured by the same method, but BA was scored at the first clinic as in our clinic by only one doctor and in the other university by several radiologists. The accuracy of prediction in the first clinic was significantly higher than in the other university. CONCLUSION This model demonstrates that exact scoring of BA and precise measurement of GHmax in the stimulation test is necessary, and if carried out carefully leads to useful prediction values for determining height velocity.

Prevention for obesity in childhood.

BACKGROUND AND OBJECTIVE Obesity in children is characterized by a rapid gain of weight starting at an age of 4 to 5 years. We investigated whether low threshold prevention prevented a further increase of the Standard-Deviation-Score of the BMI (BMI SDS) in children with impending obesity. PATIENTS AND METHODS The network CrescNet collected data from more than 300,000 children. We selected 365 children with impending obesity (age 4 to 7 years). After randomisation the study population was divided into an intervention group (180 children) and a control group (185 not informed children). The paediatrician carried out a low threshold intervention consisted of an age-adapted nutrition and exercise program to inspire the awareness of the adequate nourishment and motion. RESULTS 59 children of the intervention group opted for a participation and 49 of them took part to the end of the study. This study population stabilized their BMI SDS (p < 0.025). The children randomised in the intervention group who were not interested to participate, and the children of the control group increased their BMI SDS within the observation period of one year (p < 0.001, p = 0.002). According to nutrition diaries a decrease energy intake of the participants of the intervention group was detected. The percentage of protein intake was particularly remarkable, amounting to 363 % fulfillment of demand at the beginning of the study and 274 % at the end. A regression analysis suggests that an intervention and also the approval to take part in the study had a significant influence on changes in BMI SDS. CONCLUSION A low threshold intervention in early childhood could successfully prevent an increase of obesity.

Selective primary obesity prevention in children

BACKGROUND AND OBJECTIVE Obesity in children is characterized by a rapid gain of weight starting at an age of 4 to 5 years. We investigated whether low threshold prevention prevented a further increase of the Standard-Deviation-Score of the BMI (BMI SDS) in children with impending obesity. PATIENTS AND METHODS The network CrescNet collected data from more than 300,000 children. We selected 365 children with impending obesity (age 4 to 7 years). After randomisation the study population was divided into an intervention group (180 children) and a control group (185 not informed children). The paediatrician carried out a low threshold intervention consisted of an age-adapted nutrition and exercise program to inspire the awareness of the adequate nourishment and motion. RESULTS 59 children of the intervention group opted for a participation and 49 of them took part to the end of the study. This study population stabilized their BMI SDS (p < 0.025). The children randomised in the intervention group who were not interested to participate, and the children of the control group increased their BMI SDS within the observation period of one year (p < 0.001, p = 0.002). According to nutrition diaries a decrease energy intake of the participants of the intervention group was detected. The percentage of protein intake was particularly remarkable, amounting to 363 % fulfillment of demand at the beginning of the study and 274 % at the end. A regression analysis suggests that an intervention and also the approval to take part in the study had a significant influence on changes in BMI SDS. CONCLUSION A low threshold intervention in early childhood could successfully prevent an increase of obesity.

Acute ingestion of thyroxine and triiodothyronine in young children

The present observations on 30 children, most of them having accidentally ingested large amounts of triiodothyronine (T3) and thyroxine (T4), demonstrate that amounts as great as 630 lg T3 together with 2500 lg levothyroxine were tolerated without symptoms of severe intoxication as has already been reported for the ingestion of pure levothyroxine alone. Most of those reports are based on the ingestion of high amounts of T4 followed by high T4 levels in serum and there are only occasional reports of high T3 concentrations in the blood following the ingestion of mixtures of T3 and T4 or more rarely pure T3 preparations [4]. In view of this, we report our experience with the accidental ingestion of thyroid hormones in young children to include a representative number of patients with a high concentration of T3 in the blood following ingestion of mixtures of T4 and T3. The data on 30 patients seen between January 1983 and January 2000 in our department because of acute ingestion of thyroid hormones were analysed. Criteria for inclusion in the study were the history of acute ingestion of thyroid hormones in patients less than 5 years old, the documented concentrations of T4 and T3 in the blood and no history of therapeutic thyroid hormone administration. Diagnosis and treatment mainly followed the standard practice in our department. These included an interview with the parents concerning the number of tablets ingested and the time of ingestion. In all children, gastric lavage followed by the administration of activated charcoal and sodium sulphate (0.25 g/kg) were performed in the outpatient department. Until the middle of 1988, all patients were subsequently admitted to the hospital for a minimum of 24 h. Thereafter, patients were admitted only if symptoms of intoxication were present or if the calculated dose exceeded 500 lg of T4. Those children not admitted to the hospital were seen again on the following 1 or 2 days. The time when the first blood was taken varied considerably. Usually the first blood was taken 2–6 h after ingestion. Further estimations of T4 and T3 were undertaken only if the patients exhibited symptoms of intoxication or when very large doses had been ingested. The concentrations of T3 and T4 in serum were estimated using commercial radioimmunoassays. Despite alterations during the 17 years of the study, the results of the assays varied only in very narrow limits because of the continuous use of external and internal standards. To evaluate the influence of thyroid hormones on the myocardium, the systolic time intervals (STI) were estimated in six children. The measured and calculated values for the pre-ejection period (PEP) and left ventricular ejection time (LVET) were compared with normal values. The PEP/LVET ratio, which does not depend on age and frequency, provides the most reliable estimate of myocardial function [1]. As shown in Table 1, most of the children were younger than 4 years of age. 20 children had taken a mixture of four parts T4 and one of T3 (Thyreotom). A total of 23 children were admitted to hospital and seven were observed as outpatients. Despite extremely high T3 levels in some patients, only eight patients presented mild clinical symptoms such as a pulse rate of more than 120/min and raised blood pressure. There were no cases with unconsciousness, seizures or other symptoms of disturbance of the central nervous system. As reported by other authors [4,5], the initial levels of T3 and T4 in serum showed no close correlation with clinical symptoms of intoxication. Only three of six children in whom the STI was estimated showed a reduced PEP/LVET ratio as found in thyrotoxicosis. Surprisingly the index was normal in those children with the Eur J Pediatr (2003) 162: 639–641 DOI 10.1007/s00431-003-1263-2

Gezielte primäre Adipositasprävention bei Kindern

BACKGROUND AND OBJECTIVE Obesity in children is characterized by a rapid gain of weight starting at an age of 4 to 5 years. We investigated whether low threshold prevention prevented a further increase of the Standard-Deviation-Score of the BMI (BMI SDS) in children with impending obesity. PATIENTS AND METHODS The network CrescNet collected data from more than 300,000 children. We selected 365 children with impending obesity (age 4 to 7 years). After randomisation the study population was divided into an intervention group (180 children) and a control group (185 not informed children). The paediatrician carried out a low threshold intervention consisted of an age-adapted nutrition and exercise program to inspire the awareness of the adequate nourishment and motion. RESULTS 59 children of the intervention group opted for a participation and 49 of them took part to the end of the study. This study population stabilized their BMI SDS (p < 0.025). The children randomised in the intervention group who were not interested to participate, and the children of the control group increased their BMI SDS within the observation period of one year (p < 0.001, p = 0.002). According to nutrition diaries a decrease energy intake of the participants of the intervention group was detected. The percentage of protein intake was particularly remarkable, amounting to 363 % fulfillment of demand at the beginning of the study and 274 % at the end. A regression analysis suggests that an intervention and also the approval to take part in the study had a significant influence on changes in BMI SDS. CONCLUSION A low threshold intervention in early childhood could successfully prevent an increase of obesity.

Gezielte primäreAdipositasprävention bei Kindern

BACKGROUND AND OBJECTIVE Obesity in children is characterized by a rapid gain of weight starting at an age of 4 to 5 years. We investigated whether low threshold prevention prevented a further increase of the Standard-Deviation-Score of the BMI (BMI SDS) in children with impending obesity. PATIENTS AND METHODS The network CrescNet collected data from more than 300,000 children. We selected 365 children with impending obesity (age 4 to 7 years). After randomisation the study population was divided into an intervention group (180 children) and a control group (185 not informed children). The paediatrician carried out a low threshold intervention consisted of an age-adapted nutrition and exercise program to inspire the awareness of the adequate nourishment and motion. RESULTS 59 children of the intervention group opted for a participation and 49 of them took part to the end of the study. This study population stabilized their BMI SDS (p < 0.025). The children randomised in the intervention group who were not interested to participate, and the children of the control group increased their BMI SDS within the observation period of one year (p < 0.001, p = 0.002). According to nutrition diaries a decrease energy intake of the participants of the intervention group was detected. The percentage of protein intake was particularly remarkable, amounting to 363 % fulfillment of demand at the beginning of the study and 274 % at the end. A regression analysis suggests that an intervention and also the approval to take part in the study had a significant influence on changes in BMI SDS. CONCLUSION A low threshold intervention in early childhood could successfully prevent an increase of obesity.