Study of bone mineral density in Chinese patients with complete androgen insensitivity syndrome

<正> Objective:To explore the characteristics of bone mineral density(BMD)and treatment inChinese patients with complete androgen insensitivity syndrome(CAIS).Methods:Fourteen cases of CAIS were studied retrospectively through analyzing and compa-ring BMD of pre-and post-gonadectomy with healthy Chinese men and women.BMD at the lum-bar spine and the femur were measured by dual energy X-ray absorptiometry(DXA).Results:There were 10 cases of CAIS having pre-gonadectomy DXA,in which 6 cases hadvery significantly reduced lumbar 2-4 BMD[(0.92±0.08)g/cm~2]comparing with both healthymen and women(P<0.01),5 cases had significantly reduced femur neck BMD[(0.89±0.12)g/cm~2]comparing with healthy men(P<0.05).There were 7 cases having 12 post-gonadectomyDXA,in which all lumbar 2-4 BMD[(0.954-0.06)g/cm~2]were reduced very significantly com-paring with both healthy men and women(P<0.01),femur neck BMD[(0.91±0.08)g/cm~2]were also reduced significantly comparing with healthy men(P<0.01)and women(P<0.05).Conclusion:There were different degrees of osteopenia in patients of CAIS,especially inlumbar vertebra.This suggests that both estrogen and androgen play important roles in the ac-quirement and maintenance of peak bone mass.     

Height and bone mineral density in androgen insensitivity syndrome with mutations in the androgen receptor gene

Introduction and hypothesis Androgen insensitivity syndrome (AIS) constitutes a natural model to study effects of androgens and estrogens on growth and bone density. We evaluated height and bone density in patients with AIS with mutations in the androgen receptor (AR) gene. Methods A retrospective analysis was conducted of eight subjects with complete AIS (CAIS) and four with partial AIS (PAIS) submitted to gonadectomy followed by estrogen replacement, and three with PAIS who did not undergo gonadectomy. Standing height and bone mineral apparent density (BMAD) by DXA were measured and compared with male (z _m) and female (z _f) reference populations. The z-scores were compared with a value of zero using the one-sample t-test. Results Final heights of patients with CAIS and PAIS were intermediate between those predicted for females and males. BMAD of the lumbar spine in CAIS and PAIS after gonadectomy and estrogen replacement (z _f = − 1.56 ± 1.04, P = 0.006, and z _m = − 0.75 ± 0.89, P = 0.04) indicated vertebral bone deficit, whereas BMAD at the femoral neck was normal. No patient reported fractures. Conclusion Subjects with AIS had mean final height intermediate between mean normal male and female, and decreased bone mineral density in the lumbar spine. These data suggest an important role for androgens in normal male growth and bone density not replaced by estrogens.     

Novel androgen receptor gene mutation in patient with complete androgen insensitivity syndrome

To present a rare case of a patient probably with complete androgen insensitivity syndrome (CAIS) and studied its potential genetic cause. A 24-year-old woman with a normal-appearing vulva and vagina presented to us because of primary amenorrhea. Imaging studies showed no uterus or ovary development but inguinal cryptorchism. Histopathologic examination revealed normal testicular structures. Sequencing the CAIS-associated androgen receptor gene revealed a novel missense mutation of T to G (F698L). A novel androgen receptor gene mutation in the ligand binding domain was detected in the present patient with CAIS, supporting the important role of an androgen receptor defect in the etiology of CAIS.     

Tibia and radius bone geometry and volumetric density in obese compared to non-obese adolescents

Childhood obesity is associated with biologic and behavioral characteristics that may impact bone mineral density (BMD) and structure. The objective was to determine the association between obesity and bone outcomes, independent of sexual and skeletal maturity, muscle area and strength, physical activity, calcium intake, biomarkers of inflammation, and vitamin D status. Tibia and radius peripheral quantitative CT scans were obtained in 91 obese (BMI > 97th percentile) and 51 non-obese adolescents (BMI > 5th and < 85th percentiles). Results were converted to sex- and race-specific Z-scores relative to age. Cortical structure, muscle area and muscle strength (by dynamometry) Z-scores were further adjusted for bone length. Obese participants had greater height Z-scores (p < 0.001), and advanced skeletal maturity (p < 0.0001), compared with non-obese participants. Tibia cortical section modulus and calf muscle area Z-scores were greater in obese participants (1.07 and 1.63, respectively, both p < 0.0001). Tibia and radius trabecular and cortical volumetric BMD did not differ significantly between groups. Calf muscle area and strength Z-scores, advanced skeletal maturity, and physical activity (by accelerometry) were positively associated with tibia cortical section modulus Z-scores (all p < 0.01). Adjustment for muscle area Z-score attenuated differences in tibia section modulus Z-scores between obese and non-obese participants from 1.07 to 0.28. After multivariate adjustment for greater calf muscle area and strength Z-scores, advanced maturity, and less moderate to vigorous physical activity, tibia section modulus Z-scores were 0.32 (95% CI − 0.18, 0.43, p = 0.06) greater in obese, vs. non-obese participants. Radius cortical section modulus Z-scores were 0.45 greater (p = 0.08) in obese vs. non-obese participants; this difference was attenuated to 0.14 with adjustment for advanced maturity. These findings suggest that greater tibia cortical section modulus in obese adolescents is attributable to advanced skeletal maturation and greater muscle area and strength, while less moderate to vigorous physical activities offset the positive effects of these covariates. The impact of obesity on cortical structure was greater at weight bearing sites.     

Relationships between bone geometry,volumetric bone mineral density and bone microarchitecture of the distal radius and tibia with alcohol consumption

PurposeChronic heavy alcohol consumption is associated with bone density loss and increased fracture risk, while low levels of alcohol consumption have been reported as beneficial in some studies. However, studies relating alcohol consumption to bone geometry, volumetric bone mineral density (vBMD) and bone microarchitecture, as assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT), are lacking.MethodsHere we report an analysis from the Hertfordshire Cohort Study, in which we studied associations between HR-pQCT measures at the distal radius and tibia and alcohol consumption in 376 participants (198 men and 178 women) aged 72.1–81.4 years.ResultsA total of 30 (15.2%), 90 (45.5%) and 78 (39.4%) men drank minimal/none (< 1 unit/week), low (≥ 1 unit/week and < 11 units/week) and moderate/high (≥ 11 units/week) amounts of alcohol respectively. These figures were 74 (41.8%), 80 (45.2%) and 23 (13.0%) respectively in women for minimal/none (< 1 unit/week), low (≥ 1 unit/week and < 8 units/week) and moderate/high (≥ 8 units/week). At the distal radius, after adjustment for confounding factors (age, BMI, smoking status, dietary calcium intake, physical activity and socioeconomic status and years since menopause and HRT use for women), men that drank low alcohol had lower cortical thickness (p = 0.038), cortical vBMD (p = 0.033), and trabecular vBMD (p = 0.028) and higher trabecular separation (p = 0.043) than those that drank none/minimal alcohol. Similar differences were shown between minimal/none and moderate/high alcohol although these only reached statistical significance for the cortical parameters. Interestingly, after similar adjustment, women showed similar differences in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia. However, women that drank moderate/high alcohol had significantly higher trabecular vBMD (p = 0.007), trabecular thickness (p = 0.026), and trabecular number (p = 0.042) and higher trabecular separation (p = 0.026) at the distal radius than those that drank low alcohol.ConclusionsOur results suggest that alcohol consumption (low and moderate/high) may have a detrimental impact on bone health in men in both the cortical and trabecular compartments at the distal radius with similar results in women in the trabecular compartment between none/minimal alcohol and low alcohol at the distal tibia suggesting that avoidance of alcohol may be beneficial for bone health.     

Effect of parathyroidectomy versus risedronate on volumetric bone mineral density and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism

The objective of the study was to evaluate the effect of parathyroidectomy (PTX) versus 35 mg once-weekly (ow) risedronate administration on volumetric bone mineral density (vBMD) and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism (PHPT). Our open-label prospective observational study included 32 postmenopausal women with PHPT as the study group: 16 underwent PTX and 16 were treated with 35 mg ow risedronate for 2 years. We assessed areal BMD (aBMD) by DXA, and vBMD and bone mineral content (BMC) (cortical and trabecular area) by peripheral quantitative computed tomography (pQCT) at the tibia at baseline and at 2 years. Risedronate did not result in any significant change on vBMD and structural pQCT indices. PTX resulted in significant increase in trabecular (trab) BMC (6.44 %) and vBMD (4.64 %), with percent increase being significantly higher than risedronate (p < 0.05). At cortical sites, there was no significant change following PTX. However, the percent change in cortical (cort) vBMD was higher following PTX versus risedronate (0.39 % vs. ?0.26 %, p < 0.05). In conclusion, in postmenopausal women with PHPT, PTX is superior to ow risedronate, in terms of improvement of trabecular mineralization and vBMD at the tibia, whereas the effect at cortical sites is less pronounced.     

完全性雄激素不敏感综合征家系报告并文献复习

目的报告1家系6例完全性雄激素不敏感综合征(CAIS)并文献复习。方法 3岁患者,社会性别女性,染色体核型46,XY,双侧腹股沟睾丸,右侧斜疝多次嵌顿。家族调查另5人患病。回顾临床特征、诊断与处理。结果腹腔镜探查腹腔未见子宫附件,行改良二孔法18G动静脉留置针腹腔镜辅助右疝囊颈高位结扎及左鞘状突高位结扎。结论 CAIS为X-连锁隐性遗传病,腹腔镜探查有诊治价值,有必要加强心理支持治疗及产前诊断及基因分析。     

A novel androgen receptor mutation resulting in complete androgen insensitivity syndrome and bilateral Leydig cell hyperplasia

Androgens drive male secondary sexual differentiation and maturation. Mutations in the androgen receptor (AR) gene cause a broad spectrum of abnormal phenotypes in humans, ranging from mild through partial to complete androgen insensitivity. We have analyzed the AR gene by using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing and have studied gonads histologically in a familial case of complete androgen insensitivity syndrome. Sequence analysis of the AR gene showed a novel C2578T missense mutation, resulting in the replacement of a highly conserved leucine residue with phenylalanine (L859F) in ligand-binding domain of the receptor. The residue L859, located in helix 10 of the androgen receptor, plays a significant role in overall architecture of ligand-binding pocket. The mutation was absent from the father, normal brother of the patients, and 100 normal males recruited in this study as controls. The inheritance of the mutation in the family clearly shows that C2578T is the underlying mutation for the eventual phenotype in the patients. Histology of patient's gonads showed Leydig cell hyperplasia, with a few or no spermatogonium. It is thought that AR gene mutations result in hormonal imbalance, resulting in the high levels of luteinizing hormone (LH) and ultimately Leydig cell hyperplasia or tumor formation. In the present study, we have reported a rare familial case of Leydig cell hyperplasia despite consistently normal LH levels. The finding will help in giving counseling to this family and prevent the transmission of the mutated X chromosome to the coming generations.     

Reduced bone volumetric density and weak correlation between infection and bone markers in cystic fibrosis adult patients

Summary

In our current adult CF population, low BMD prevalence was only 20 %, lower than that historically described. We found a mild increase of serum RANK-L levels, independent from the bone resorption level. The increased fracture risk in CF may be explained by a lower tibial cortical thickness and total vBMD.

Introduction

Bone disease is now well described in cystic fibrosis (CF) adult patients. CF bone disease is multifactorial but many studies suggested the crucial role of inflammation. The objectives of this study were, in a current adult CF population, to assess the prevalence of bone disease, to examine its relationship with infections and inflammation, and to characterize the bone microarchitecture using high resolution peripheral scanner (HR-pQCT).

Methods

Fifty-six patients (52 % men, 26?±?7 years) were assessed in clinically stable period, during a respiratory infection, and finally 14 days after the end of antibiotic therapy. At each time points, we performed a clinical evaluation, lung function tests, and biochemical tests. Absorptiometry and dorso-lumbar radiographs were also performed. A subgroup of 40 CF patients (63 % men, 29?±?6 years) underwent bone microarchitecture assessment and was age- and gender-matched with 80 healthy controls.

Results

Among the 56 CF patients, the prevalence of low areal BMD (T-score?<??2 at any site), was 20 % (95 % CI: [10.2 %; 32.4 %]). After infections, serum RANK-L (+24 %, p?=?0.08) and OPG (+13 %, p?=?0.04) were increased with a stable ratio. Microarchitectural differences were mostly observed at the distal tibia, with lower total and cortical vBMD and trabecular thickness (respectively ?9.9, ?3.0, and ?5 %, p?<?0.05) in CF patients compared to controls, after adjustment for age, gender, weight, and height.

Conclusions

In this study, bone disease among adult CF patients was less severe than that previously described with only 20 % of CF patients with low BMD. We found a mild increase of biological marker levels and an impaired volumetric density of the tibia that may explain the increased fracture risk in CF population.

     

A novel E153X point mutation in the androgen receptor gene in a patient with complete androgen insensitivity syndrome

AIM: To study a 46, XY newborn patient with a phenotype suggestive of an androgen insensitivity syndrome to confirm an anomaly in the AR gene. METHODS: Genomic DNA from leukocytes was isolated in order to analyze SRY gene by PCR and sequencing of the eight exons of AR gene. Isolation of human Leydig cell mesenchymal precursors from the testis was performed in order to study testosterone production and response to hCG stimulation in culture. RESULTS: Surgical exploration disclosed two testes, no Wolffian structures and important Müllerian derivatives. The SRY gene was present in peripheral blood leukocytes. Sequencing of the AR gene evidenced a previously unreported G to T transversion in exon 1 that changed the normal glutamine 153 codon to a stop codon. Interstitial cell cultures produced sizable amounts of testosterone and were responsive to hCG stimulation. CONCLUSION: This E153X nonsense point mutation has not been described previously in cases of AIS, and could lead to the synthesis of a short truncated (153 vs 919 residues) non functional AR probably responsible for the phenotype of complete androgen insensitivity syndrome (CAIS).     

A novel E153X point mutation in the androgen receptor gene in a patient with complete androgen insensitivity syndrome

Aim: To study a 46, XY newborn patient with a phenotype suggestive of an androgen insensitivity syndrome toconfirn an anomaly in the AR gene. Methods: Genomic DNA from leukocytes was isolated in order to analyze SRYgene by PCR and sequencing of the eight exons of AR gene. Isolation of human Leydig cell mesenchymal precursorsfrom the testis was performed in order to study testosterone production and response to hCG stimulation in culture.Results: Surgical exploration disclosed two testes, no Wolffian structures and important Mullerian derivatives. TheSRY gene was present in peripheral blood leukocytes. Sequencing of the AR gene evidenced a previously unreported Gto T transversion in exon 1 that changed the normal glutamine 153 codon to a stop codon. Interstitial cell culturesproduced sizable amounts of testosterone and were responsive to hCG stimulation. Conclusion: This E153X nonsensepoint mutation has not been described previously in cases of AIS, and could lead to the synthesis of a short truncated(15     

A 19 year old with complete androgen insensitivity syndrome and juvenile fibroadenoma of the breast

We report a case of a 19-year-old female with complete androgen insensitivity syndrome (CAIS) who was diagnosed with a juvenile fibdroadenoma of the breast. The patient presented at age 18 with primary amenorrhea. She had been raised as a female and went through thelarche at age 13 and adrenarche at age 14. She had two sisters and three maternal aunts with androgen insensitivity syndrome. Physical exam revealed that the patient had no cervix, and a pelvic sonogram confirmed that the uterus was absent. Genetic analysis revealed a 46 XY karyotype. Bilateral intra-abdominal testes were noted on ultrasound and subsequently removed. She was placed on synthetic estrogen replacement therapy. Roughly 1 year following orchiectomy, the patient noticed an enlarging mass in her right breast. Physical exam revealed a roughly 5 cm mobile mass in the upper portion of the nipple-areolar complex. Ultrasound showed a solid mass consistent with a fibroadenoma. Because of the size of the lesion and the patient's hormonal make-up, a fine needle aspirate was obtained. Cytopathology showed large cohesive sheets of ductal epithelial cells, scattered histiocytes, numerous bare nuclei, fragments of fibrous tissue and metachromatic stroma. Some of the stroma was noted to be cellular. The tumor was subsequently excised. Microscopically, the lesion had epithelial and stromal hyperplasia consistent with a fibroadenoma. Phyllodes-like qualities of large size, increased stromal cellularity, and intracanalicular growth ("leaf-like projections") were noted; however, the pathologist found that the florid epithelial hyperplasia and the patient's young age were more compatible with a juvenile fibroadenoma. We describe what we believe to be the first report of a patient with CAIS and a fibroadenoma of the breast. The hormonal imbalance typically found in these patients, combined with the fact that most individuals with CAIS receive exogenous estrogen therapy, suggests that there may be a relatively high incidence of fibroadenoma in these patients.     

The volumetric bone density and cortical thickness in adult patients affected by osteogenesis imperfecta.

In patients with osteogenesis imperfecta (OI), a disease characterized by abnormal bone fragility, bone mineral density (BMD) was found to be relatively preserved. Quantitative computed tomography (QCT) is the only available method for directly measuring in vivo both volumetric density and the cross-sectional area. Here we report the data from dual-energy X-ray absorptiometry DXA (spine and hip) and peripheral (pQCT) (ultradistal and proximal radius) measurement of 27 adult patients affected by OI, mostly of type I, compared with a group of healthy persons. In the patients with OI, areal BMD values at both femoral neck and lumbar spine were considerably lower than in control subjects (-32 and -36%, respectively; p<0.001 for body weight and height adjusted values). pQCT volumetric density at the ultradistal radius was 19% lower than in control subjects and this difference rose to 32% for purely cancellous bone tissue. The whole bone cross-sectional area of ultradistal radius, as measured by pQCT, was superimposable to normal. At the proximal radius, both cross-sectional area and cortical area, together with Bending Breaking Resistance Index (BBRI), were significantly lower in OI (-23; -22; -32% respectively; p<0.001 for body weight and height adjusted values), but cortical volumetric density was even slightly higher in the OI group than in control subjects. In conclusion, it appears that the most obvious defect in adults with OI is the inability to acquire an adequate thickness of the cortices of long bone and to achieve or maintain normal trabecular density.     

Structural analysis of the impact of a novel androgen receptor gene mutation in two adult patients with mild androgen insensitivity syndrome

Androgen receptor gene (AR) mutations are responsible for androgen insensitivity syndrome (AIS) presenting with a clinical phenotype that ranges from gynaecomastia and/ or infertility in mild AIS (MAIS) to complete testicular feminisation in complete AIS. We report a novel AR gene mutation in two unrelated adult patients with MAIS and we studied its functional impact using 3D modelling. Patient 1, referred for infertility, presented with gynaecomastia, mild hypospadias and bilateral testicular hypotrophy contrasting with high testosterone levels, an elevated FSH, an elevated androgen sensitivity index (ASI) and oligoasthenoteratospermia. In vitro fertilisation and intracytoplasmic sperm injection resulted in a successful twin pregnancy. Patient 2 referred for a decrease in athletic performance had surgically treated gynaecomastia, oligoasthenospermia, high testosterone levels and an elevated ASI. Despite his impaired spermogram, he fathered two children without assisted reproductive technology. AR gene sequencing in the two patients revealed a common novel missense mutation, Ala699Thr, in exon 4 within the ligand-binding domain. 3D modelling studies showed that this mutation may impact dimer stability upon ligand binding or may affect allosteric changes upon dimerisation. This study illustrates the value of structural analysis for the functional study of mutations and expands the database of AR gene mutations.     

The incidence of complete androgen insensitivity in girls with inguinal hernias and assessment of screening by vaginal length measurement

Background/Purpose

Complete androgen insensitivity syndrome (CAIS) is a rare disorder; however, surgeons have noted a higher rate in girls with inguinal hernias. A few retrospective studies have estimated the incidence of CAIS to be 0.8% to 2.4% in girls with inguinal hernias. An inexpensive, quick screening method for this population has not been established. Because CAIS is associated with a short vagina, measuring vaginal length could serve this purpose if normal standards were known. The authors endeavored to (1) prospectively confirm the incidence of CAIS, (2) identify normal standards of vaginal length, and (3) assess the usefulness of measuring vaginal length to screen for CAIS in girls with inguinal hernias.

Methods

Vaginal lengths were measured in 270 girls with inguinal hernias at a university hospital from 1991 to 2003. A fallopian tube was identified to exclude CAIS. If CAIS was suspected, gonadal tissue was sampled and karyotyping was performed. Linear regression analysis was performed, and 95% confidence intervals were calculated for individual values.

Results

Normal vaginal length for age was established. Three patients were found to have significantly short vaginas: 2 were confirmed to have CAIS, 1 did not (false-positive). One other infant was proved to have CAIS despite having a normal vaginal length (false-negative). The incidence of CAIS in our study was 1.1% (3/270).

Conclusions

This is the largest prospective study of the incidence of CAIS in girls with hernias. The authors found that 1.1% of premenstrual girls with inguinal hernias have this syndrome. The authors also provide standards for normal vaginal length in the pediatric population. Vaginal length increases predictably with age, and some patients with CAIS have significantly shorter vaginas. Vaginal length is not a perfect predictor of this disorder, but can be a useful adjunctive screening tool.     

Novel mutation in the ligand-binding domain of the androgen receptor gene (l790p) associated with complete androgen insensitivity syndrome.

Mutations in the X-linked androgen receptor (AR) gene cause androgen insensitivity syndrome (AIS), resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity (CAIS) produces a female external phenotype, whereas cases with partial androgen insensitivity (PAIS) have various ambiguities of the genitalia. Mild androgen insensitivity (MAIS) is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone (T) and dihydrotestosterone (DHT) synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.     

Gender differences in volumetric bone density: a study of opposite-sex twins

Gender difference in bone size is a potential confounder when comparing bone density between males and females. A comparison of volumetric BMD (vBMD) between men and women, which is a measure of bone mass relative to three-dimensional bone volume (g/cm³) as opposed to areal bone density (g/cm²), may be a more accurate reflection of gender differences in bone density. The aims of this study were to examine gender differences in bone mass (BMC), areal BMD (aBMD), volumetric BMD (vBMD) by comparing twins of opposite sex in whom the effects of age, genes and environment are partially controlled for. DEXA derived BMC, aBMD, vBMD at the third lumbar vertebra (L3), femoral neck (FN) and forearm (1/3 radius) were compared between 82 opposite sex pairs aged 18–80. BMC was significantly higher in males at all three sites (26–45.5%). For aBMD the gender differences remained significant at all sites except the spine. The average differences in aBMD were not as great as the differences in BMC (2.2–20.5%). The differences in vBMD, however, followed a different pattern. FN and L3 vBMD were significantly higher in females (4.8 and 0.6%, respectively), while radial BMD was not significantly different between the sexes. Comparing aBMD values between males and females, when females in general have a smaller skeleton than males may not be a true indication of gender differences in bone density. A comparison of vBMD between men and women shows only small differences in bone density between the sexes.