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 detection of growth disorders with the CrescNet system at the Leipzig treatment center.

BACKGROUND: Growth hormone replacement therapy is more effective the earlier it is begun. This article adresses the question whether children with growth hormone deficiency (GHD) were able to begin treatment earlier through the use of the CrescNet system in the Department of Pediatrics at the Leipzig University Hospital. CrescNet is a network of pediatricians and endocrinological treatment centers, established in Leipzig in 1998, whose aim is to improve the early detection of growth disorders. METHODS: Pediatricians participating in CrescNet provided anonymized data on their patients' height and weight to the CrescNet database. Each participating pediatrician received a quarterly screening report with recommendations for the work-up of children with abnormal growth. Some patients with GHD who were treated in the Leipzig treatment center were referred in response to these recommendations, while others came spontaneously from the practices of pediatricians participating or not participating in CrescNet. We determined the age at the onset of treatment for the 139 patients treated for GHD in the University Children's Hospital Leipzig from 1999 to 2005 and compared the findings with data from other treatment centers in Germany. RESULTS: Patients from CrescNet practices began treatment at a younger age than those from non-CrescNet practices (8.77 ± 3.40 versus 9.50 ± 3.78 years, p = 0.26). Patients from CrescNet practices whose GHD was detected by screening began treatment earlier than those for whom no data had been sent (7.67 ± 3.21 versus 9.28 ± 3.39 years, p = 0.031). In the center in Leipzig, but not in other German GHD treatment centers, the age at onset of treatment dropped significantly over the period of the study and then remained steady till 2009 in the range of 7.61 ± 3.0 years. CONCLUSION: These descriptive results imply that the linking of pediatricians' practices with the CrescNet system resulted in earlier treatment of children with GHD.

Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency can achieve their target height: the Leipzig experience.

BACKGROUND: Despite treatment, the mean final height (FH) of patients with classic congenital adrenal hyperplasia (CAH) is below the mean height of a normal population. AIMS: To show that CAH patients can achieve their target height (TH), 39 adult subjects, whose therapy had started in infancy, were studied in a retrospective analysis. All height SDS were corrected so that they related to TH SDS. PATIENTS: Group 1: patients born before 1975 (n = 13) had received prednisolone, at doses equivalent to hydrocortisone 39.4 +/- 15.6 mg/m2 BSA daily, together with DOCA in the first 2 years of life. Group 2: patients born from 1975 to 1986 (n = 26) received at this age lower hydrocortisone doses (16.4 +/- 6.9 mg/m2 BSA daily, divided 8 hourly; p < 0.001) combined with fludrocortisone, had outpatient visits every 3 months and bone age (BA) estimation every 6 months. RESULTS: Patients of group 1 (FH SDS -1.2 +/- 1.0) had a poor outcome, whereas patients of group 2 (FH SDS 0.1 +/- 0.9; p = 0.01) achieved their TH. CONCLUSION: Combined corticoid administration adjusted quarterly to keep height, BMI, blood pressure and BA within normal limits resulted in FH close to TH in patients with classic CAH.

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.

Pregnancies in patients with congenital adrenal hyperplasia with complete or almost complete impairment of 21-hydroxylase activity.

OBJECTIVE: To show that, with appropriate therapy, women with classic congenital adrenal hyperplasia (CAH) can become pregnant. DESIGN: Observational clinical study. SETTING: University hospital. PATIENT(S): Adult young women with CAH: three with the salt-wasting form and four patients with simple virilizing CAH due to severe homozygous or compound heterozygous mutations of the CYP21B gene (deletions, I172N in exon 4 and nt656A/C-->G in intron 2) who wished to become pregnant. INTERVENTION(S): After confirmation in the first patient of the beneficial effect of additional treatment with fludrocortisone in lowering 17alpha-hydroxyprogesterone (17-OHP) levels, five other patients were treated with hydrocortisone as three daily doses at 8-hour intervals and fludrocortisone 0.1-0.2 mg daily divided into two to three doses. One patient received glucocorticoid alone. MAIN OUTCOME MEASURE(S): Treatment was controlled on the basis of morning salivary 17-OHP estimates and plasma renin concentrations. RESULT(S): Nine pregnancies occurred in six women. The course of the pregnancies (except one spontaneous abortion) was normal without any other modification of therapy. Only the women treated with hydrocortisone alone did not become pregnant. CONCLUSION(S): When treated with a combination of glucocorticoids and mineralocorticoids, sexually active patients with the classic phenotype of CAH can become pregnant.