Long-term follow-up of females with unbalanced X;Y translocations-reproductive and nonreproductive consequences.

BACKGROUND: Females with Xp;Yq translocations manifest short stature and normal fertility, but rarely have follow-up. The study purpose was to define the phenotype of a family with t(X;Y)(p22.3;q11.2), determine long-term reproductive function, and compare to all reported female cases. METHODS: Comprehensive clinical and molecular analyses were performed on the female proband, who had regular menses, normal endocrine function, and three pregnancies spanning seven years--a normal liveborn male and two with unbalanced translocations (liveborn female and stillborn male). RESULTS: The translocation truncated KAL1 and deleted 44 genes on der(X). Our report constitutes the longest follow-up of an X;Y translocation female. She had no evidence of Kallmann syndrome, gonadoblastoma, or cardiovascular disease. Detailed analysis of 50 published female cases indicated a uniform lack of follow-up and significant morbidity-intellectual disability (10%), facial dysmorphism (28%), eye abnormalities (14%), and skeletal defects (28%). CONCLUSIONS: Our findings indicate normal ovarian function to date in a woman with an t(X;Y)(p22.3;q11.2). However, additional published studies in the literature suggest careful follow-up is necessary and contradict the generalization that females with Xp;Yq translocations are usually normal except for short stature.

Familial 46,XY sex reversal without campomelic dysplasia caused by a deletion upstream of the SOX9 gene.

BACKGROUND: 46,XY sex reversal is a rare disorder and familial cases are even more rare. The purpose of the present study was to determine the molecular basis for a family with three affected siblings who had 46,XY sex reversal. METHODS: DNA was extracted from three females with 46,XY sex reversal, two normal sisters, and both unaffected parents. All protein coding exons of the SRY and NR5A1 genes were subjected to PCR-based DNA sequencing. In addition, array comparative genomic hybridization was performed on DNA from all seven family members. A deletion was confirmed using quantitative polymerase chain reaction. Expression of SOX9 gene was quantified using reverse transcriptase polymerase chain reaction. RESULTS: A 349kb heterozygous deletion located 353kb upstream of the SOX9 gene on the long arm of chromosome 17 was discovered in the father and three affected siblings, but not in the mother. The expression of SOX9 was significantly decreased in the affected siblings. Two of three affected sisters had gonadoblastomas. CONCLUSION: This is the first report of 46,XY sex reversal in three siblings who have a paternally inherited deletion upstream of SOX9 associated with reduced SOX9 mRNA expression.

Plasticity of microvascular oxygenation control in rat fast-twitch muscle: effects of experimental creatine depletion.

Aging, heart failure and diabetes each compromise the matching of O2 delivery (Q˙O2)-to-metabolic requirements (O2 uptake, V˙O2) in skeletal muscle such that the O2 pressure driving blood-myocyte O2 flux (microvascular PO2, PmvO2) is reduced and contractile function impaired. In contrast, ß-guanidinopropionic acid (ß-GPA) treatment improves muscle contractile function, primarily in fast-twitch muscle (Moerland and Kushmerick, 1994). We tested the hypothesis that ß-GPA (2% wt/BW in rat chow, 8 weeks; n=14) would improve Q˙O2-to-V˙O2 matching (elevated PmvO2) during contractions (4.5V @ 1Hz) in mixed (MG) and white (WG) portions of the gastrocnemius, both predominantly fast-twitch). Compared with control (CON), during contractions PmvO2 fell less following ß-GPA (MG -54%, WG -26%, P<0.05), elevating steady-state PmvO2 (CON, MG: 10±2, WG: 9±1; ß-GPA, MG 16±2, WG 18±2 mmHg, P<0.05). This reflected an increased Q˙O2/V˙O2 ratio due primarily to a reduced V˙O2 in ß-GPA muscles. It is likely that this adaptation helps facilitate the ß-GPA-induced enhancement of contractile function in fast-twitch muscles.

Long-term post-pneumonectomy pulmonary adaptation following all-trans-retinoic acid supplementation.

In adult dogs following right pneumonectomy (PNX) and receiving all-trans-retinoic acid (RA) supplementation for 4 mo, we found modestly enhanced alveolar-capillary growth in the remaining lung without enhanced resting lung function (J Appl Physiol 96: 1080-1089 and 96: 1090-1096, 2004). Since alveolar remodeling progresses beyond this period and the lipid-soluble RA continues to be released from tissue stores, we hypothesized that RA supplementation may exert additional long-term effects. To examine this issue, adult male litter-matched foxhounds underwent right PNX followed by RA supplementation (2 mg/kg po 4 days/wk, n = 6) or placebo (n = 4) for 4 mo. Cardiopulmonary function was measured at rest and during exercise at 4 and 20 mo post-PNX. The remaining lung was fixed under a constant airway pressure for morphometric analysis. Comparing RA treatment to placebo controls, there were no differences in aerobic capacity, cardiopulmonary function, or lung volume at rest or exercise. Alveolar-capillary basal lamina thickness and mean harmonic thickness of air-blood diffusion barrier were 23-29% higher. The prevalence of double-capillary profiles remained 82% higher. Absolute volumes of septal interstitium, collagen fibers, cells, and matrix were 32% higher; the relative volumes of other septal components and alveolar-capillary surface areas expressed as ratios to control values were up to 24% higher. Thus RA supplementation following right PNX modestly and persistently enhanced long-term alveolar-capillary structural dimensions, especially the deposition of interstitial and connective tissue elements, in such a way that caused a net increase in barrier resistance to diffusion without improving lung mechanics or gas exchange.

Management of transverse vaginal septum using the Olbert balloon catheter to mobilize the proximal vaginal mucosa and facilitate low anastomosis.

OBJECTIVE: To mobilize and make available for anastomosis the maximal amount of mucosa from the expanded upper vaginal tissue and avoid postoperative narrowing of the vagina. DESIGN: Technique paper. SETTING: Tertiary care medical center. PATIENT(S): Patients with a hematocolpos due to transverse vaginal septum. INTERVENTION(S): Pull through of proximal distended vagina using an Olbert balloon catheter. MAIN OUTCOME MEASURE(S): To avoid midvaginal narrowing due to retraction of the suture line in the surgical management of transverse vaginal septum with hematocolpos. RESULT(S): High-pressure balloon expansion of the proximal hematocolpos optimizes the vaginal mucosa available for final anastomosis. CONCLUSION(S): The use of a high-pressure dilatation balloon permits high intraballoon pressures that facilitate the surgical management of transverse vaginal septum and limit postoperative narrowing of the vagina.

Phenotypic spectrum of 45,X/46,XY males with a ring Y chromosome and bilaterally descended testes.

OBJECTIVE: To characterize the phenotypic spectrum of males with bilaterally descended testes and a 45,X/46,X,(r)Y karyotype. DESIGN: Retrospective review of patient records; cytogenetic and molecular analysis. SETTING: Tertiary medical center setting. PARTICIPANT(S): Five males, two prepubertal and three postpubertal, with a 45,X/46,X(r)Y karyotype and bilaterally descended testes. INTERVENTION(S): Linear growth evaluation, testicular endocrine and exocrine studies, cytogenetic and molecular analysis on each patient. MAIN OUTCOME MEASURE(S): Clinical phenotype versus genotype. RESULT(S): Both prepubertal males had short stature and low testosterone. All three adults had normal puberty and normal testosterone levels. Two of the adults (one with short stature and one with normal stature) had elevated gonadotropins and azoospermia. The third adult had normal stature, severe oligospermia, normal gonadotropins, and normal serum testosterone. CONCLUSION(S): The phenotypic spectrum of males with a 45,X/46,X(r)Y karyotype and bilaterally descended testes varies greatly from males with short stature and spermatogenic failure to males without short stature and less severely affected spermatogenesis. This broad spectrum of phenotypic findings needs to be taken into account when the clinical geneticist encounters a prenatal diagnosis of a 45,X/46,X(r)Y karyotype. This information will also be helpful for pediatric and reproductive endocrinologists in counseling males with bilaterally descended testes and a 45,X/46,X(r)Y karyotype.

Control of oxygen uptake during exercise.

Other than during sleep and contrived laboratory testing protocols, humans rarely exist in prolonged metabolic steady states; rather, they transition among different metabolic rates (V O2). The dynamic transition of V O2 (V O2 kinetics), initiated, for example, at exercise onset, provides a unique window into understanding metabolic control. This brief review presents the state-of-the art regarding control of V O2 kinetics within the context of a simple model that helps explain the work rate dependence of V O2 kinetics as well as the effects of environmental perturbations and disease. Insights emerging from application of novel approaches and technologies are integrated into established concepts to assess in what circumstances O2 supply might exert a commanding role over V O2 kinetics, and where it probably does not. The common presumption that capillary blood flow dynamics can be extrapolated accurately from upstream arterial measurements is challenged. From this challenge, new complexities emerge with respect to the relationships between O2 supply and flux across the capillary-myocyte interface and the marked dependence of these processes on muscle fiber type. Indeed, because of interfiber type differences in O2 supply relative to V O2, the presence of much lower O2 levels in the microcirculation supplying fast-twitch muscle fibers, and the demonstrated metabolic sensitivity of muscle to O2, it is possible that fiber type recruitment profiles (and changes thereof) might help explain the slowing of V O2 kinetics at higher work rates and in chronic diseases such as heart failure and diabetes.

Long-term follow-up and analysis of monozygotic twins concordant for 45,X/46,XY peripheral blood karyotype but discordant for phenotypic sex.

We report on the follow-up of a set of monozygotic (MZ) twins who were concordant for peripheral blood karyotype 45,X/46,XY but discordant for phenotypic sex. One twin is a phenotypically normal male and the other twin has asymetrical gonadal dysgenesis. The female twin has the mos45,X/46,XY karyotype in all four tissues: left testis, right streak, vas deferens, and clitoral skin. The normal male twin has the normal 46,XY karyotype in all three tissues tested: foreskin, scrotal skin, and testis. Follow-up of the twins at age 21, revealed persistence of mos45,X/46,XY karyotype in peripheral blood into adult life. However, the male grew up with normal male stature, reaching an adult height of 182 cm. The female twin received low dose estrogen replacement with complete breast development at age 14 years. She reached an adult height of 156 cm. At 21 years of age the male twin had normal testicular endocrine function, but severe oligospermia. The long-term follow-up of this set of MZ twins indicate that the male twin has the mosaicism confined to peripheral blood and has the normal 46,XY male constitution. This was further confirmed by his normal male stature and normal testicular endocrine function. The 45X cell line is likely due to his receiving these cells passively from his twin sister via placental anastomoses in utero. The exposure to these 45,X cells during development may have had an impact on his spermatogenesis.

Control of microvascular oxygen pressures during recovery in rat fast-twitch muscle of differing oxidative capacity.

Whether the speed of recovery of microvascular O(2) pressures (Pmvo(2) ) differs within muscles composed primarily of type II fibres with contrasting oxidative capacity has not been determined. We tested the hypothesis that, following contractions, the recovery of Pmvo(2) would be slower in the white (WG; low oxidative capacity) versus the mixed gastrocnemius (MG; comparatively high oxidative capacity). Radiolabelled microsphere and phosphorescence quenching techniques were used to measure muscle blood flow ( Q, hence O(2) delivery, Q(O2)) and during contractions (1 Hz twitch) at low (LO, 2.5 V) and high intensities (HI, 4.5 V) in rat (n = 15) MG and WG muscle and during subsequent recovery. Following the LO protocol, end-contraction Pmvo(2) was lower in WG (11.6 +/- 0.5 mmHg) than in MG (16.2 +/- 0.6 mmHg; P < 0.05) while, contrary to our hypothesis, the initial rate of change in during recovery ( d P(O2)/dt; MG 0.11 +/- 0.01 mmHg s(-1) and WG 0.06 +/- 0.03 mmHg s(-1)) and mean response time (MRT; MG 110.3 +/- 5.1 s and WG 113.5 +/- 8.4 s, P > 0.05) were not different. In contrast, end-contraction baseline Pmvo(2) was not different following the HI protocol (MG 10.3 +/- 0.6 mmHg and WG 9.2 +/- 0.6 mmHg; P > 0.05) but, in agreement with our hypothesis, d P(O2)/dt was slower (MG 0.07 +/- 0.01 mmHg s(-1) and WG 0.03 +/- 0.003 mmHg s(-1); P < 0.05) and MRT longer (WG 180.8 +/- 4.5 s and MG 115.4 +/- 6.7 s; P < 0.05) in WG versus MG following the HI protocol. These data suggest that following high-intensity, though submaximal, muscle contractions, Pmvo(2) recovers much faster in the more oxidative mixed gastrocnemius than in the less oxidative white gastrocnemius.

A mutation in the fibroblast growth factor receptor 1 gene causes fully penetrant normosmic isolated hypogonadotropic hypogonadism.

CONTEXT: Kallmann syndrome (KS) consists of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia/hyposmia. Currently, the fibroblast growth factor receptor 1 (FGFR1) gene is the only known autosomal dominant cause of KS, which is also associated with synkinesia, midfacial defects, and dental agenesis. OBJECTIVE: Mutations in FGFR1 typically demonstrate reduced penetrance, variable expressivity, and until recently have been exclusively identified in families with anosmia. The purpose of this study was to determine whether FGFR1 mutations were present in a unique family with autosomal dominant, fully penetrant, normosmic IHH. DESIGN: The study is a review of detailed clinical findings, dynamic endocrine studies, and performance of a molecular analysis of the FGFR1 gene. SETTING: The study was carried out in an academic medical center. PATIENTS: All four affected individuals have complete IHH with full penetrance but no anosmia/hyposmia, and they have none of the FGFR1-associated anomalies. In addition, no other family member has anosmia. Inverventions: Interventions included detailed phenotype characterization including history, physical exam, smell testing, dynamic pituitary testing, brain imaging, and molecular analysis. MAIN OUTCOME MEASURES: Outcome was measured by the determination of the severity of IHH, olfactory function, and sequence of the FGFR1 gene. RESULTS: The same heterozygous nonsense mutation, Arg622X, was present in all four affected members, but not in three unaffected members or 100 controls. The mutation is predicted to encode a truncated protein or result in nonsense-mediated decay. CONCLUSIONS: Our findings indicate that mutations in the FGFR1 gene can cause normosmic, fully penetrant, complete IHH with little or no variable expressivity, and without the other FGFR1-associated anomalies typically found in KS.

Residence at 3,800-m altitude for 5 mo in growing dogs enhances lung diffusing capacity for oxygen that persists at least 2.5 years.

Mammals native to high altitude (HA) exhibit larger lung volumes than their lowland counterparts. To test the hypothesis that adaptation induced by HA residence during somatic maturation improves pulmonary gas exchange in adulthood, male foxhounds born at sea level (SL) were raised at HA (3,800 m) from 2.5 to 7.5 mo of age and then returned to SL prior to somatic maturity while their littermates were simultaneously raised at SL. Following return to SL, all animals were trained to run on a treadmill; gas exchange and hemodynamics were measured 2.5 years later at rest and during exercise while breathing 21% and 13% O(2). The multiple inert gas elimination technique was employed to estimate ventilation-perfusion (Va/Q) distributions and lung diffusing capacity for O(2) (Dl(O(2))). There were no significant intergroup differences during exercise breathing 21% O(2). During exercise breathing 13% O(2), peak O(2) uptake and Va/Q distributions were similar between groups but arterial pH, base excess, and O(2) saturation were higher while peak lactate concentration was lower in animals raised at HA than at SL. At a given exercise intensity, alveolar-arterial O(2) tension gradient (A-aDo(2)) attributable to diffusion limitation was lower while Dlo(2) was 12-25% higher in HA-raised animals. Mean systemic arterial blood pressure was also lower in HA-raised animals; mean pulmonary arterial pressures were similar. We conclude that 5 mo of HA residence during maturation enhances long-term gas exchange efficiency and Dl(O(2)) without impacting Va/Q inequality during hypoxic exercise at SL.

Effects of Type II diabetes on muscle microvascular oxygen pressures.

We tested the hypothesis that muscle microvascular O2 pressure (PmvO2; reflecting the O2 delivery (QO2) to O2 uptake (VO2) ratio) would be lowered in the spinotrapezius muscle of Goto-Kakizaki (GK) Type II diabetic rats (n=7) at rest and during twitch contractions when compared to control (CON; n=5) rats. At rest, PmvO2 was lower in GK versus CON rats (CON: 29+/-2; GK: 18+/-2Torr; P<0.05). At the onset of contractions, GK rats evidenced a faster change in PmvO2 than CON (i.e., time constant (tau); CON: 16+/-4; GK: 6+/-2s; P<0.05). In contrast to the monoexponential fall in PmvO2 to the steady-state level seen in CON, GK rats exhibited a biphasic PmvO2 response that included a blunted (or non-existent) PmvO2 decrease followed by recovery to a steady-state PmvO2 that was at, or slightly above, resting values. Compared with CON, this decreased PmvO2 across the transition to a higher metabolic rate in Type II diabetes would be expected to impair blood-muscle O2 exchange and contractile function.