Catastrophic cellular events leading to complex chromosomal rearrangements in the germline.

Although complex chromosomal rearrangements were thought to reflect the accumulation of DNA damage over time, recent studies have shown that such rearrangements frequently arise from 'all-at-once' catastrophic cellular events. These events, designated chromothripsis, chromoanasynthesis, and chromoanagenesis, were first documented in the cancer genome and subsequently observed in the germline. These events likely result from micronucleus-mediated chromosomal shattering and subsequent random reassembly of DNA fragments, although several other mechanisms have also been proposed. Typically, only one or a few chromosomes of paternal origin are affected per event. These events can produce intrachromosomal deletions, duplications, inversions, and translocations, as well as interchromosomal translocations. Germline complex rearrangements of autosomes often result in developmental delay and dysmorphic features, whereas X chromosomal rearrangements are usually associated with relatively mild clinical manifestations. The concept of these catastrophic events provides novel insights into the etiology of human genomic disorders. This review introduces the molecular characteristics and phenotypic outcomes of catastrophic cellular events in the germline.

Testicular volume in Japanese boys up to the age of 15 years.

UNLABELLED: Previous studies have indicated that Japanese children grow and mature significantly faster than Caucasian children, thus calling for a separate reference standard for each skeletal and sexual maturity index. To establish normal reference values for testicular volume in Japanese boys, we studied from 1985 to 1995, 900 healthy male children of 0 to 15 years of age for medical history, physical examination, height, weight, sitting height, and head circumference measurements, Tanner sex maturity stage, and testicular size. The testicular volume was determined using a Prader orchidometer by the same observer (N.M.). Based on these data, we established the cross-sectional percentile growth curves (90th, 50th, 10th percentiles) for testicular volume of Japanese boys. The testicular volume of 3 ml was attained at 9.3 years of age (90th percentile), 11.0 years of age (50th percentile), and 12.1 years of age (10th percentile), respectively. CONCLUSION: Swelling of the testis in Japanese children begins approximately 1 year earlier than in Swiss children in accordance with the earlier skeletal maturation in Japanese children.

Absent circadian variation of blood pressure in patients with anorexia nervosa.

OBJECTIVE: To examine whether circadian rhythm of blood pressure (BP) is altered in patients with anorexia nervosa (AN), and if so, to determine whether it is reversible after refeeding. STUDY DESIGN: Ambulatory BP monitoring was performed on 17 female inpatients with AN (mean age, 13.3 +/- 1.9 years) at the time of admission and serially during refeeding; 17 age-matched normal weight, normotensive female inpatients served as control subjects. RESULTS: Patients with AN had lost an average of 23.4% +/- 11.5% of body weight before the illness. Weight after refeeding was 105.6% +/- 9. 2% of that before illness. Mean 24-hour systolic BP (SBP) (96.5 +/- 8.6 mm Hg) and diastolic BP (DBP) (53.4 +/- 5.8 mm Hg) were significantly lower in patients with AN compared with those of control subjects (SBP, 106.1 +/- 6.5 mm Hg; DBP, 60.2 +/- 5.8 mm Hg). Although awake SBP and DBP were also lower in patients with AN, asleep SBP and DBP were not statistically different from those of control subjects. Night/day BP ratio in the control group was 0.93 +/- 0.06 in systolic and 0.92 +/- 0.09 in diastolic. Those values were significantly elevated in patients with AN (systolic 1.00 +/- 0. 09 and diastolic 1.00 +/- 0.09). After refeeding, the ratio decreased to 0.88 +/- 0.09 and 0.90 +/- 0.08,respectively (both P <. 05 vs baseline). CONCLUSIONS: In patients with AN, circadian variation of BP is absent. This reverts to normal after refeeding.

Deletion mapping and X inactivation analysis of a non-specific mental retardation gene at Xp21.3-Xp22.11.

We report on deletion mapping and X inactivation analysis of a gene for X linked non-specific mental retardation (MRX) at Xp21.3-Xp22.11, on the basis of molecular studies in two families with Xp microdeletions involving the DAX-1 gene. In family A, mental retardation (MR) was profound in the older brother with an episode of adrenal crisis, severe in the younger brother with no episode of adrenal crisis, and mild to moderate in the sister and the mother with no signs of adrenal hypoplasia. In family B, MR was absent in the male patient with adrenal hypoplasia. Polymerase chain reaction for 16 loci in the middle of Xp showed that the brothers of family A had a small Xp deletion between DXS7182 and DXS1022, and that the patient of family B had a tiny Xp deletion between DXS319 and DXS1022. Microsatellite analysis for tetranucleotide repeats in the promoter region of the DAX-1 gene and Southern blotting for DAX-1 and DXS28 showed that the sister and the mother of family A were heterozygous for the interstitial deletion. X inactivation analysis for the methylation status of the AR gene and the HPRT gene indicated that the normal X and the deleted X chromosome underwent random X inactivation in both the sister and the mother. The results imply that an MRX gene subject to X inactivation is present in a roughly 4 Mb region between DXS7182 and DAX-1, and that reduced expression of the normal MRX gene caused by random X inactivation results in MR in carrier females.