Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity.

CONTEXT: Only approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene. OBJECTIVE: The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls. DESIGN: Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus. SETTING: The study was conducted at a university hospital endocrine research laboratory. PATIENTS: GFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46). INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured. RESULTS: The APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling. CONCLUSIONS: AR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance.

Pseudoautosomal inheritance of Léri-Weill syndrome: what does it mean?

The short stature homeobox (SHOX) gene is located in the pseudoautosomal region 1 of both sex chromosomes. Haploinsufficiency of SHOX leads to different phenotypes ranging from isolated short stature to Léri-Weill syndrome characterized by short stature, mesomelia and Madelung deformity. We describe a family with a SHOX deletion originally located on the Y chromosome and transmitted from father to daughter by crossover during meiosis. The male index patient presented with short stature, mesomelia and mild Madelung deformity. His father had a normal height but slightly disproportionate short legs. The sister of the index patient presented with marked Madelung deformity and normal height. A deletion of the SHOX gene was identified in the male index patient, his father and his sister. Metaphase fluorescence in situ hybridization (FISH) analyses showed a deletion of the SHOX gene on the Y chromosomes of the index patient and his father, and on the X chromosome of his sister, indicating that a meiotic crossover of the SHOX gene region between the X and Y chromosomes had occurred. The pseudoautosomal region 1 is a known recombination 'hot spot' in male meiosis. Published genetic maps indicate high recombination frequency of ∼40% for SHOX in male meiosis leading to pseudoautosomal inheritance.

Bilateral deficit during short-term, high-intensity cycle ergometry in girls and boys.

Peak torque during an isokinetic bilateral knee extension or flexion is usually lower than the summed peak torque of two unilateral contractions, and this phenomenon is designated as bilateral deficit (BD). The objectives of this study were to determine whether a BD also exists for more complex, alternating movements (e.g., short-term, high-intensity cycling), and to assess the possible effects of gender and maturity. Forty children and adolescents performed two unilateral (ULWAnT) and one bilateral Wingate anaerobic test (BLWAnT). The highest power reached in any 3-s interval (peak power; PP), and the total mechanical work (TMW) performed during the test was determined. Individual BD for PP (BDpp, %) was calculated by dividing the PP in the BLWAnT by the sum of the PP values of both ULWAnTs. The BD for TMW (BDTMw) was calculated in the same way. The sum of PP generated during the two ULWAnTs was larger than the PP measured in the BLWAnT (P<0.000001). The same difference was observed for TMW (P<0.0001). Maturity did not affect the BDpp or BDTMW (P=0.34). However, the BD was more pronounced in females compared to males (P= 0.03). In conclusion, a BD is evident during cycling exercise.

Single-leg Wingate Test in children: reliability and optimal braking force.

PURPOSE: Single-leg cycle ergometry employing the protocol of the Wingate Test (WAnT) has been used to assess unilateral muscle power and leg-dominance. The objectives of this study were to determine the reliability of the single-leg WAnT (SLWAnT) and to establish optimal braking force for the SLWAnT. METHODS: Twenty female and 19 male subjects (prepubertals: 6.0-9.9 yr, 7 female and 6 male; midpubertals: 11.0-14.9 yr, 7 female and 7 male; and postpubertals: 17.0-20.9 yr, 6 female and 6 male) came to the laboratory on three occasions. On each visit, they first performed two SLWAnT after a standardized warm-up, one with each leg. Braking force for these tests was kept constant throughout all visits. On each of the following visits, subjects performed four additional SLWAnT, two with each leg, with braking force varying from test to test to determine the braking force associated with the highest performance over 30 s. RESULTS: Although a significant increase in performance was observed from visit to visit in some groups, intraclass correlation coefficients (which included trial-to-trial differences) of peak power and total work generated during the first two SLWAnT of each visit ranged from 0.89 to 0.98. Optimal braking force (J x rev(-1)) could be estimated from 0.4052 x body mass(1.4662) for all subjects irrespective of gender or maturity. The standard error of estimate was lowest in the prepubertals and highest in postpubertals (8.3-31.4 J x rev(-1)). CONCLUSIONS: SLWAnT is a highly reliable method to measure single-leg power. The above equation provides good estimates of optimal braking force. The SLWAnT can, therefore, be used to monitor changes in single-leg power and to assess leg-dominance.