All PRKAR1A and PDE4D patients present similar bone dysplasia characterizing acrodysostosis. Phenotypic differences, including the presence of resistance to GPCR-cAMP signaling hormones in PRKAR1A but not PDE4D patients, indicate phenotype-genotype correlations and highlight the specific contributions of PRKAR1A and PDE4D in cAMP signaling in different tissues.

No abstract

Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.steroid hormones | missense mutations | classic CAH | ambiguous genitalia C ongenital adrenal hyperplasia (CAH) is a Mendelian disorder transmitted as an autosomal recessive trait. The most prevalent form of CAH arises from steroid 21-hydroxylase enzyme deficiency, accounting for ∼90-95% of all cases (1, 2). In contrast, CAH caused by steroid 11β-hydroxylase deficiency is considerably rare, with a prevalence of 5-8% (3), from which we estimate an overall frequency of 1 in 100,000 live births.Two homologous enzymes, 11β-hydroxylase and aldosterone synthase, are encoded by the CYP11B1 and CYP11B2 genes, respectively. The two genes are 40-kb apart, each comprising nine exons and mapped to chromosome 8q21-22 (3, 4) (Fig. 1A). In contrast to CYP21A2 and its CYP21A1P pseudogene, CYP11B1 and CYP11B2 are both active and do not have a pseudogene. The two encoded homologs, however, have distinct functions in cortisol and aldosterone synthesis, respectively (3). In the zona fasciculata, 11β-hydroxylase converts 11-deoxycortisol and 11-deoxycorticosterone to cortisol and corticosterone, respectively, and is regulated by adrenocorticotropic hormone secreted by the pituitary. In contrast, in the zona glomerulosa aldosterone synthase converts corticosterone to aldosterone with the intermediate production of 18-hydroxycorticosterone. These latter conversions are controlled mainly by the renin angiotensin II system and serum potassium concentration (3).Deficiency of 11β-hydroxylase prevents the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. This results in high levels of 11-deoxycortisol and 11-deoxycorticosterone, respectively, which are shunted into the androgen synthesis pathway, resulting in high levels of the androgenic steroid, androstenedione. Female newborns are thus profoundly virilized and exhibit significant masculinization of the ex...

Premature stop codons of the human androgen receptor (AR) gene are usually associated with a complete androgen insensitivity syndrome. We, however, identified an adult patient with a 46,XY karyotype carrying a premature stop codon in exon 1 of the AR gene presenting with signs of partial virilization: pubic hair Tanner stage 4 and clitoral enlargement. No other family members were affected. A point mutation at codon position 172 of the AR gene was detected that replaced the original TTA (Leu) with a premature stop codon TGA (opal). Careful examination of the sequencing gel, however, also identified a wild-type allele, indicating a mosaicism. In addition, elimination of the unique AflII recognition site induced by the mutation was incomplete, thus confirming the coexistence of mutant and wild-type AR alleles in the patient. Normal R1881 binding and a normal 110/112-kDa AR doublet in Western immunoblots consolidated the molecular genetic data by demonstrating the expression of the wild-type AR in the patient's genital skin fibroblasts. Transfection analysis revealed that only relatively high plasmid concentrations carrying the mutated AR complementary DNA lead to expression of a shortened AR due to downstream reinitiation at methionine 189. Thus, reinitiation does not play a role in the presentation of the phenotype; rather, the partial virilization is caused by the expression of the wild-type AR due to a somatic mosaic. We conclude that somatic mosaicism of the AR gene can represent a substantial factor for the individual phenotype by shifting it to a higher degree of virilization than expected from the genotype of the mutant allele alone.

<b><i>Introduction:</i></b> Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. <b><i>Methods:</i></b> A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. <b><i>Results:</i></b> National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. <b><i>Conclusions:</i></b> GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence.

Study Type – Therapy (case series)Level of Evidence 4What's known on the subject? and What does the study add?In some individuals with disorders of sex development (DSD), gonadal tumour risk is increased. The individual risk is estimated based on the molecular diagnosis and the age and approaches 30% in the high‐risk group. In the past, early gonadectomy has been advised for all individuals with 46XY DSD. Gonadectomy clearly represents an overtreatment for many individuals with 46XY DSD. Thus, further clinical indicators of individual tumour risk are urgently needed.The present study provides a comprehensive description of gonadal morphology, as seen during laparoscopy. For the first time, laparoscopic features, molecular diagnosis and histopathological findings are presented in a comprehensive context. The present study adds a detailed morphological description of the variability found in different subgroups of 46XY DSD. As three of four detected tumours were microscopic, early diagnosis by inspection appears unfeasible. Biopsy, gonadopexy and precise localisation of the gonad will potentially allow for gonadal preservation in well‐defined clinical situations.OBJECTIVE To investigate the role of laparoscopy for the early detection of gonadal tumours, with emphasis on gonadal preservation, in patients with 46XY disorders of sex development (DSD). In patients with DSD, gonadectomy is frequently recommended and depending on the age and the molecular diagnosis, an increased gonadal tumour risk exists and undesired hormone effects may arise. However, gonadectomy is irreversible and impacts considerably on body image. It represents an overtreatment for some patients and should be considered after a comprehensive diagnostic evaluation. Laparoscopy is an important technique, because it is able to retrieve small gonads and allows guided biopsies. PATIENTS AND METHODS We performed laparoscopic assessment of the gonads in 40 patients with various 46XY DSD. In all, 77 gonads were evaluated, images were analysed and compared with histological findings. Laparoscopic procedures included gonadectomy, biopsy, laparoscopic orchidolysis or the Fowler–Stephens procedure as well as the removal or splitting of uterine remnants. RESULTS In all, 19 patients underwent gonadectomy and tumours were discovered in four. Three patients had only microscopic evidence of tumour, in one the tumour was diagnosed intraoperatively. In 21 patients, biopsies were taken and the gonads preserved. Laparoscopic biopsy and gonadopexy was performed in six patients with complete androgen insensitivity syndrome (CAIS). CONCLUSION Laparoscopy and biopsy detected three microscopic tumours, one tumour was macroscopically evident. In CAIS, gonadopexy improved the visibility of the gonads on postoperative ultrasonography. This procedure facilitated the examination of the gonad at follow‐up. In complete gonadal dysgenesis, a highly variable morphology of the gonads was found. Laparoscopy improved exposure of gonads and Müllerian structures, and facilitated biopsies and organ‐preserving procedures.

Context Larger studies on outcomes in males with 45,X/46,XY mosaicism are rare. Objective To compare health outcomes in males with 45,X/46,XY diagnosed as a result of either genital abnormalities at birth or nongenital reasons later in life. Design A retrospective, multicenter study. Setting Sixteen tertiary centers. Patients or Other Participants Sixty-three males older than 13 years with 45,X/46,XY mosaicism. Main Outcome Measures Health outcomes, such as genital phenotype, gonadal function, growth, comorbidities, fertility, and gonadal histology, including risk of neoplasia. Results Thirty-five patients were in the genital group and 28 in the nongenital. Eighty percent of all patients experienced spontaneous pubertal onset, significantly more in the nongenital group (P = 0.023). Patients were significantly shorter in the genital group with median adult heights of 156.7 cm and 164.5 cm, respectively (P = 0.016). Twenty-seven percent of patients received recombinant human GH. Forty-four patients had gonadal histology evaluated. Germ cells were detected in 42%. Neoplasia in situ was found in five patients. Twenty-five percent had focal spermatogenesis, and another 25.0% had arrested spermatogenesis. Fourteen out of 17 (82%) with semen analyses were azoospermic; three had motile sperm. Conclusion Patients diagnosed as a result of genital abnormalities have poorer health outcomes than those diagnosed as a result of nongenital reasons. Most patients, however, have relatively good endocrine gonadal function, but most are also short statured. Patients have a risk of gonadal neoplasia, and most are azoospermic, but almost one-half of patients has germ cells present histologically and up to one-quarter has focal spermatogenesis, providing hope for fertility treatment options.

This study analyzed whether area deprivation is associated with disparities in health care of pediatric type 1 diabetes in Germany. RESEARCH DESIGN AND METHODS We selected patients <20 years of age with type 1 diabetes and German residence documented in the "diabetes patient follow-up" (Diabetes-Patienten-Verlaufsdokumentation [DPV]) registry for 2015/2016. Area deprivation was assessed by quintiles of the German Index of Multiple Deprivation (GIMD 2010) at the district level and was assigned to patients. To investigate associations between GIMD 2010 and indicators of diabetes care, we used multivariable regression models (linear, logistic, and Poisson) adjusting for sex, age, migration background, diabetes duration, and German federal state. RESULTS We analyzed data from 29,284 patients. From the least to the most deprived quintile, use of continuous glucose monitoring systems (CGMS) decreased from 6.3 to 3.4% and use of long-acting insulin analogs from 80.8 to 64.3%, whereas use of rapid-acting insulin analogs increased from 74.7 to 79.0%; average HbA 1c increased from 7.84 to 8.07% (62 to 65 mmol/mol), and the prevalence of overweight from 11.8 to 15.5%, but the rate of severe hypoglycemia decreased from 12.1 to 6.9 events/100 patient-years. Associations with other parameters showed a more complex pattern (use of continuous subcutaneous insulin infusion [CSII]) or were not significant. CONCLUSIONS Area deprivation was associated not only with key outcomes in pediatric type 1 diabetes but also with treatment modalities. Our results show, in particular, that the access to CGMS and CSII could be improved in the most deprived regions in Germany.