Current status and its background of Adult Turner Syndrome (TS) are not clarified well. Via a questionnaire survey of 492 adult women with TS, this study investigated the association between menstruation, Kaufmann therapy (menstrual induction therapy), social status (education, employment & marriage), complications, transition from pediatric to adult care, and sex chromosome karyotype using statistical methods. Spontaneous menarche occurred in 22.0% and more frequently among patients with the 45,X/46,XX karyotype. Over 60% of these subjects, menstruation did not persist regularly. Kauffmann therapy was performed in 69.4%; the most common formulation was a conjugated estrogen and progesterone combination. Marriage and higher education advancement rates were low in adults with TS, whereas their employment rate was similar to that of the age-matched general female population. Patients receiving Kauffmann therapy had higher complication rates, greater education length, and higher employment rates. The higher-education advancement rate was observed among patients with 45,X/46,X,Xi and 46,X,Xi karyotypes. Transition from pediatrician to adult specialist was not smooth, subjects were treated in pediatric departments (60.7%), gynecological department (21.4%), internal medicine departments (13.3%), and others. While reason is not clear, the largest number of TS patients are treated in general pediatrics and the percentage of receiving Kauffmann therapy and having complication were significantly lower than in pediatric and adult department of endocrinology (& metabolism). This Study revealed many novel findings of adult TS.

The reported prevalence of complications in Turner Syndrome (TS) was highly variable because of the rarity and the limited numbers analyzed. Again, possible presence of other complications that are not described as specific for TS, is also speculated. To resolve these issues, a questionnaire survey was conducted in hGH treated 492 patients with adult TS (17-42 years). The possible association with these complications and karyotypes were also analyzed. The complications and their prevalence were as follows: chronic thyroiditis (25.2%), inflammatory bowel disease (1.8%), congenital cardiovascular anomaly (11.8%), urinary tract malformation (11.8%), low bone mineral density (BMD) (42.9%), scoliosis (8.4%), hearing loss (6.2%), epilepsy (2.8%) and schizophrenia (0.9%). The majority of prevalence of these diseases in TS was higher than in the general population. In distribution, the most frequent karyotype was 45,X monosomy (28.9%), followed by 45,X/46,X,Xi (16.9%), 46,X,Xi (9.1%), and 45,X/46,XX (6.3%), while other mosaic 45,X was noted in 29.9%. Regarding the karyotype, cardiovascular anomaly was more frequent in the 45,X group and less in the 46,X,Xi group. Urinary tract malformation and epilepsy were frequently associated with the chromosome 45,X. The prevalence of low BMD was noticed more in the chromosome 46,X,Xi and 45,X/46,X,Xi, and less in other mosaic 45,X. In conclusion, the more exact prevalence of diverse complications was clarified and it exceeded the prevalence of the majority of complications in general population. As novel findings, it was observed that the prevalence of epilepsy was significantly high, and epilepsy and low BMD were frequently associated with the specific karyotypes.

This study investigated the factors associated with adult height in Japanese women with Turner syndrome (TS) with and without human growth hormone (hGH) treatment, and the association between obesity and lifestyle-related diseases in TS based on current findings.Adult height in women with untreated TS increased from 139.1 cm to 141.3 cm between 1992 and 2008 in a secular trend. The adult height of women with untreated TS was not significantly different between those with the 45,X and non-45,X karyotypes. The adult height after (low-dose hGH treatment (0.5 IU/kg/week) was significantly lower in women with TS with spontaneous menstruation (mean, 141.9 cm) than in those women without spontaneous menstruation (mean, 145.5 cm). A recent survey reported that the mean adult height in women with TS after high dose hGH treatment (0.35 mg/kg/week) was 149.1 cm. In addition, adult height improved with low-dose estrogen treatment started at age 12-15 years, reaching a height of 140 cm. According to the questionnaire survey administered to women with TS, conducted by the Foundation for Growth Science, the prevalence of obesity (body mass index (BMI) >= 25 kg/m(2)] in women with TS aged 15-39 years (24.7%) was significantly higher than that in the general female population in the same age range (9.4%). The prevalence of complications in women with TS was 5.5% for diabetes mellitus (DM), 7.7% for hypertension, 18.9% for dyslipidemia, and 11.5% for liver dysfunction, all of which were higher than the prevalence in the general female population. BMI was higher in women with TS who were diagnosed with lifestyle-related diseases than in those without lifestyle-related diseases, and the rate of each disease increased with an increase in BMI. In addition, those with multiple complications had substantially higher BMI. These findings indicate that obesity is strongly associated with the development of lifestyle-related diseases. In addition, women with TS who had any one of the complications (except for DM) had significantly lower birth weight compared with those without complications. This is consistent with the fetal programming hypothesis, which proposes that low birth weight may be associated with obese after birth and lifestyle-related diseases in adulthood. The adult height in untreated women with TS increased by 2.2 cm over 16 years. However, adult height in women with TS treated with hGH can be further increased with early high-dose hGH treatment and low dose estrogen replacement therapy. In addition, the rate of lifestyle-related diseases among women with TS was closely associated with their weight gain. In particular, those with a BMI of >= 25 kg/m(2) or higher had a higher rate of lifestyle-related diseases. These findings offer important considerations for clinical treatment of women with TS.

Our current understanding of the phenotypic consequences and the molecular basis of germline complex chromosomal rearrangements remains fragmentary. Here, we report the clinical and molecular characteristics of 2 women with germline complex X-chromosomal rearrangements. Patient 1 presented with nonsyndromic ovarian dysfunction and hyperthyroidism; patient 2 exhibited various Turner syndrome- associated symptoms including ovarian dysfunction, short stature, and autoimmune hypothyroidism. The genomic abnormalities of the patients were characterized by array-based comparative genomic hybridization, high-resolution karyotyping, microsatellite genotyping, X-inactivation analysis, and bisulfite sequencing. Patient 1 carried a rearrangement of unknown parental origin with a 46,X,der(X)(pter→ p22.1::p11.23→q24::q21.3→q24::p11.4→pter) karyotype, indicative of a catastrophic chromosomal reconstruction due to chromothripsis/chromoanasynthesis. Patient 2 had a paternally derived isochromosome with a 46,X,der(X)(pter→ p22.31::q22.1→q10::q10→q22.1::p22.31→pter) karyotype, which likely resulted from 2 independent, sequential events. Both patients showed completely skewed X inactivation. CpG sites at Xp22.3 were hypermethylated in patient 2. The results indicate that germline complex X-chromosomal rearrangements underlie nonsyndromic ovarian dysfunction and Turner syndrome. Disease-causative mechanisms of these rearrangements likely include aberrant DNA methylation, in addition to X-chromosomal mispairing and haploinsufficiency of genes escaping X inactivation. Notably, our data imply that germline complex X-chromosomal rearrangements are created through both chromothripsis/chromoanasynthesis-dependent and -independent processes.

In this study, the prevalence of obesity and complications of lifestyle-related diseases, such as diabetes mellitus, hypertension, dyslipidemia and liver dysfunction, as well as the relationship with karyotypes, were investigated in 492 patients with Turner syndrome (TS) aged 17 years or older. Data were obtained through questionnaire surveys administered by attending physicians throughout Japan. Collected data were compared with data from the National Health and Nutrition Survey. Patient ages ranged from 17.1 to 42.5 years (mean ± standard error, 26.6±0.2). The prevalence of lifestyle-related diseases at age 20 or over was 6.3% for diabetes, 8.7% for hypertension, 20.2% for dyslipidemia and 12.4% for liver dysfunction. These four diseases were clearly associated with severity of obesity. Obesity (BMI ≥25 kg/m(2)) was observed in 106 out of 426 patients with TS aged 15 to 39 years (24.7%) and the prevalence was significantly higher than that of the general female population (9.4%). The mean BMI in age subgroups without any complications ranged from 21.2 to 22.7, which although was within normal ranges was significantly higher than that in the general female population (20.3-21.3). In this study population, patients with TS had more complications related to lifestyle-related diseases that were highly related to obesity. Few associations between complications and karyotypes were found. In the follow-up of patients with TS, the presence of lifestyle-related disease should be considered in the evaluation and treatment of the disease.

Treatment costs for children with growth hormone (GH) deficiency are subsidized by the government in Japan if the children meet clinical criteria, including height limits (boys: 156.4 cm; girls: 145.4 cm). However, several funding programs, such as a subsidy provided by local governments, can be used by those who exceed the height limits. In this study, we explored the impacts of financial support on GH treatment using this natural allocation.

OBJECTIVE:To develop and validate the Adult Hypopituitarism Questionnaire (AHQ) as a disease-specific, self-administered questionnaire for evaluation of quality of life (QOL) in adult patients with hypopituitarism.METHODS:We developed and validated this new questionnaire, using a standardized procedure which included item development, pilot-testing and psychometric validation. Of the patients who participated in psychometric validation, those whose clinical conditions were judged to be stable were asked to answer the survey questionnaire twice, in order to assess test-retest reliability.RESULTS:Content validity of the initial questionnaire was evaluated via two pilot tests. After these tests, we made minor revisions and finalized the initial version of the questionnaire. The questionnaire was constructed with two domains, one psycho-social and the other physical. For psychometric assessment, analyses were performed on the responses of 192 adult patients with various types of hypopituitarism. The intraclass correlations of the respective domains were 0.91 and 0.95, and the Cronbach's alpha coefficients were 0.96 and 0.95, indicating adequate test-retest reliability and internal consistency for each domain. For known-group validity, patients with hypopituitarism due to hypothalamic disorder showed significantly lower scores in 11 out of 13 sub-domains compared to those who had hypopituitarism due to pituitary disorder. Regarding construct validity, the domain structure was found to be almost the same as that initially hypothesized. Exploratory factor analysis (n = 228) demonstrated that each domain consisted of six and seven sub-domains.CONCLUSION:The AHQ showed good reliability and validity for evaluating QOL in adult patients with hypopituitarism.

Growth hormone (GH) therapy was approved in 1999 for only GH-deficient Turner syndrome (TS) in Japan. It was subsequently approved for all cases of TS regardless of GH secretory status since 1999. The dose of GH is 1.0 u (0.35 mg)/kg/wk at present, but it was 0.5 u (0.175 mg)/kg/wk before 1999. The adult height in patients with TS on the dose of 0.5 u/kg/wk was studied from the report on of Foundation for Growth Science in 2000. GH therapy was registered for 920 cases, and 258 cases reached adult height. The mean adult height was 145.7 cm. The adult height in patients with TS without GH therapy was reported to be 138 cm in Japan. Thus, the height gain by GH treatment was 7.7 cm. The mean age at the start of GH therapy was 12.0 yr old. The mean duration of GH therapy was 5.6 yr. The mean age at the start of estrogen therapy was 17.0 yr old. Patients in Japan were older at the start of GH and estrogen therapy than in the US and Europe at that time. The adult height and gain of height SD were not correlated with age at the start GH therapy in this study. This may be the result of the older age at the start of GH therapy and the low dose of the GH therapy. Patients are beginning to start GH therapy at a much earlier age and the dose has been doubled in Japan. We expect that the recent data concerning adult height in the patients with TS after GH therapy will improve better than this report.

It is still in doubt whether the standard-dose growth hormone (GH) used in Japan (0.5 IU/kg/week, 0.167 mg/kg/week) for growth hormone deficiency is effective for achieving significant adult height improvement in non-growth hormone deficient (non-GHD) short children. We compared the growth of GH-treated non-GHD short children with that of untreated short children to examine the effect of standard-dose GH treatment on non-GHD short children. GH treatment with recombinant human growth hormone (rhGH) was started before the age of 11 yr in 64 boys and 76 girls with non-GHD short stature registered at the Foundation for Growth Science who have now reached their adult height. In 119 untreated boys and 127 untreated girls whose height standard deviation score (SDS) was below -2 SD at the age of 6 yr, height growth was followed until 17 yr. Height SDS was significantly lower before GH treatment in the GH-treated group than at the age of 6 yr in the untreated group, in both sexes. Adult height and adult height SDS were significantly greater in the untreated group than in the GH-treated group, in both sexes, although the change in height SDS did not differ significantly. Height SDS was significantly lower before GH treatment in the GH-treated group than at the age of 6 yr in the untreated group, so 57 boys and 57 girls whose height SDS at the age of 6 yr in the untreated group closely matched the height SDS before GH treatment in the GH-treated group were chosen for comparison. Height SDS did not differ significantly between the GH-treated group before GH treatment and the untreated group at the age of 6 yr, nor were there differences between these subgroups in adult height, adult height SDS, or height SDS change, in either sex. The effect of GH treatment is reported to be dose-dependent and doses over 0.23 mg/kg/week are reported to be necessary to improve adult height in non-GHD short children. Currently, the GH dose is fixed at 0.175 mg/kg/week in Japan, and we expected to find, and indeed concluded, that ordinary GH treatment in Japanese, non-GHD short children does not improve adult height.

In this study, we sent questionnaires to doctors treating severe short stature with severe GH deficiency (GHD) (height SDS (HtSDS) below -4 and all peak GH to provocative stimuli below 2 micro/L) (abbreviated as Severe Case), and obtained effective replies of 51 cases. The clinical characteristics, etiologies, and pathophysiology of these patients were examined. Among the 51 Severe Cases no consanguinity was observed, 44 were IGHD (24 males and 20 females), 3 were GH-1 gene deletion, 2 were Pit-1 gene mutation, and 2 were achondroplasia. HtSDS in these Severe Cases was already remarkably low at 12 (-3.0) and 24 months old (-3.9), while their birth weight and birth length were within normal ranges. Among 44 patients with IGHD, 12 were isolated GHD, and the remaining 32 were combined pituitary hormone deficiency (CPHD). Pituitary MRI was undergone in 25 idiopathic GHD, and abnormal findings (pituitary atrophy, interruption of stalk, and ectopic posterior lobe) were observed in 21 patients with CPHD. More than half of these patients had the history of breech delivery. Three patients with GH-1 gene mutation showed normal pituitary MRI, whereas one of two patients with Pit-1 mutation showed pituitary atrophy and narrowing of pituitary stalk. In conclusion, Severe Cases tended to have CPHD, and the incidence of Severe Case was only 0.6% of total IGHD. Although GHD due to genetic disorders is considered to be extremely rare (0.06% of total IGHD), the incidence reaches high levels (9.8%) among Severe Cases. Growth disorders in these Severe Cases seem to occur soon after delivery. Much earlier diagnosis and hGH treatment are desirable to attain better final height in the Severe Cases. GH-1 and Pit-1 gene analyses are crucial, when genetic abnormalities other than achondroplasia are suspected.

The ratio, clinical characteristics, and therapeutic efficacy of hGH treatment in patients with severe short stature (HtSDS below -4SD) with severe GHD (all peak GH values to provocation tests: below 2 mug/L) were studied. From March 1986 to January 1998, 23,110 patients with idiopathic GH deficiency (IGHD) were registered with the Foundation for Growth Science, Japan. These subjects were divided into 5 groups as follows: Group 1 (G1), all subjects; Group 2 (G2), at least one GH peak to provocative test > or = 5 microg/L; Group 3 (G3), 2 microg/L < or = GH peak<5 microg/L; Group 4 (G4), all GH peaks<2 microg/L and HtSDS>-4; Group 5 (G5), all GH peaks<2 microg/L and HtSDS< or = -4. The ratio of G5 was 139 patients (0.6%) out of 23,110 patients with IGHD. In G5, there were no significant differences in birth weight, birth length, gestational age and parental height between G2, G3 and G4. However, asphyxia at delivery was more frequent in G5 and G4 than G2 and G3. Chronological age (CA), bone age (BA) and BA/CA ratio at registration were significantly lower in G5 than G2, G3 and G4. Further, the IGF-I SD score in G5 was significantly lower than those in G2 and G3. After hGH treatment, the final height and final height SDS in G5 remained the lowest, while the DeltaHtSDS value in G5 was the greatest among G2 to G5 groups. In conclusion, the ratio of severe short stature with severe GH deficiency (G5) is only 0.6% of all IGHD cases. Growth failure in G5 seems to occur after birth, and its etiology in G5 seems to be different from that of patients with other forms of IGHD. Early diagnosis and hGH treatment are needed to attain better final height.

We report on PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutation analysis and clinical assessment in 45 patients with Noonan syndrome. Sequence analysis was performed for all of the coding exons 1-15 of PTPN11, revealing a novel 3-bp deletion mutation and 10 recurrent missense mutations in 18 patients. Clinical assessment showed that 1) the growth pattern was similar in mutation-positive and mutation-negative patients, with no significant difference in birth length [-0.6 +/- 2.2 sd (n = 10) vs. -0.6 +/- 1.4 sd (n = 21); P = 0.95], childhood height [-2.6 +/- 1.1 sd (n = 14) vs. -2.1 +/- 1.6 sd (n = 23); P = 0.28], or target height [-0.4 +/- 0.9 sd (n = 14) vs. -0.2 +/- 0.7 sd (n = 17); P = 0.52]; 2) pulmonary valve stenosis was more frequent in mutation-positive patients than in mutation-negative patients (10 of 18 vs. 6 of 27; P = 0.02), as was atrial septal defect (10 of 18 vs. 4 of 27; P = 0.005), whereas hypertrophic cardiomyopathy was present in five mutation-negative patients only; and 3) other features were grossly similar in the prevalence between mutation-positive and mutation-negative patients, but hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, were exclusively present in mutation-positive patients (5 of 18 vs. 0 of 27; P = 0.007). The results suggest that PTPN11 mutations account for approximately 40% of Noonan syndrome patients, as has been reported previously. Furthermore, assessment of clinical features, in conjunction with data reported previously, implies that the type of cardiovascular lesions and the occurrence of hematological abnormalities are different in mutation-positive and mutation-negative patients, whereas the remaining findings are similar in the two groups of patients.

OBJECTIVE: The effects of human leptin fragment(126-140) on pituitary function in eight healthy, non-obese men were studied. METHODS AND DESIGN: The effects of the fragment on spontaneous secretion of pituitary hormones and endogenous leptin, as well as on GHRH-induced GH secretion were examined. RESULTS: After the administration of the fragment (50 microg i.v. for 150 min), the mean nadir value and 45 min value were significantly lower than that of the control study. Endogenous leptin levels did not decrease significantly following the administration of the leptin fragment. Other pituitary hormones were not affected by the fragment. The area under the curve of the GH response to GHRH(1-44)NH(2) (10 microg, i.v. from 0 to 75 min) was also significantly inhibited by the combined administration of the leptin fragment (100 microg i.v. from -30 to 75 min) (P<0.001). Three subjects were re-examined with larger doses of the leptin fragment (200-400 microg), and even greater GH suppression was observed. CONCLUSIONS: These results indicate that human leptin fragment(126-140) has an inhibitory role in GH secretion, since when administered exogenously this fragment significantly suppressed spontaneous and, in a dose-response manner, GHRH-induced GH secretion. Clear effects of the fragment on other pituitary hormones and an inhibitory effect on endogenous leptin secretion were not observed in this study.

OBJECTIVEThe role of endogenous GHRH in arginine-, insulin-, clonidine- and l-dopa-induced GH secretion was studied in man using a GHRH antagonist (GHRH-Ant).DESIGNTen healthy adult males were studied for serum GH responses to arginine or insulin singly, or sequentially 120 min after GHRH injection with or without combined administration of GHRH-Ant. Further, GHRH, clonidine or l-dopa were sequentially administered to these subjects 120 min after the GHRH injection.RESULTSThe combined administration of GHRH-Ant distinctly inhibited the arginine- and insulin-induced GH release. When these four agents were sequentially administered 120 min after GHRH injection, the GH responses to clonidine and l-dopa disappeared completely while clear responses were observed to arginine and insulin administration. These responses to arginine and insulin were also completely inhibited by the combined administration of GHRH-Ant.CONCLUSIONSThese results indicate that clonidine and l-dopa stimulate GH secretion mainly through the release of hypothalamic GHRH, and that arginine- and insulin-induced hypoglycaemia stimulate GH secretion mainly through the inhibition of hypothalamic somatostatin release. However, the presence of endogenous hypothalamic GHRH seems to be essential for the maximal stimulation of GH release induced by arginine and insulin.

It is not clear whether acute and slight elevation of serum IGF-I, which does not affect blood glucose levels, modulates circulating GH levels. To clarify this, small doses of recombinant human IGF-I (rhIGF-I, 5 μg/kg, iv) were administered as a bolus to 10 children with non-endocrine short stature (NESS) (5 males and 5 females, 11.2±0.7 yr old) after an overnight fast. Physiological saline was administered intravenously to sex- and age-matched NESS controls (5 males and 5 females, 10.9±0.7 yr old). The changes of serum GH, TSH, PRL, IGF-I, IGF-II, IGFBP-3, T 4 , T 3 and plasma glucose levels after the administration were compared to those of the control subjects. Serum IGF-I levels increased significantly from 15 to 150 min after injection compared to those in the control group. The peak value was observed at 15 min (Δ increment, 74.6±11.8 μg/l). At 15 min after the injection, serum insulin was suppressed significantly ( p <0.05), although plasma glucose levels were not modified significantly. Serum TSH showed a significant decrease by rhIGF-I at 15 min and 60 min, whereas serum T 4 and T 3 levels were not modified. Serum GH was also significantly suppressed at 60 min ( p <0.02) and showed a rebound increase at 120 min ( p <0.05). Serum IGFBP-3 levels after rhIGF-I were higher than controls at 90 min and 150 min. No significant changes of serum PRL, IGF-II, (IGF-I plus IGF-II)/IGFBP-3 ratios were observed after the IGF-I injection compared to controls. These results indicate that circulating IGF-I is a physiological regulator of GH secretion in normal children, since the changes of IGF-I after the small doses of rhIGF-I administration were within physiological ranges and did not affect plasma glucose levels.

A 16-year-old girl with short stature, short neck, shield chest, and cubitus valgus was studied. FISH analyses of her structurally altered X chromosome showed a der(X)- (wcpX+,TelXp/Yp++,SHOX++,STS++,KAL-, 37A12-,DXZ1+,XIST++,97L7++,300O13-,404F- 18-,417G15-,404F18-,140A-,TelXq/Yq-). These results, together with the high-resolution banding analysis, indicated her karyotype to be 46,X,der(X)(Xpter-->Xp22.3::Xq22.3--> cen-->Xq22.3::Xp22.3-->Xpter). The der(X) was an isochromosome, consisting of duplicated terminal short arms and duplicated proximal long arms. This in turn suggested that the chromosome was formed through pericentric inversion of an X chromosome, followed by isochromosome formation through sister chromatid exchange at Xp, close to the centromere. Replication R-banding analysis showed that the abnormal X chromosome was late replicating. Analysis of digestion patterns with a methylation-sensitive restriction endonuclease of the phosphoglycerate kinase 1 gene, located in Xq13.3, indicated that its inactivation patterns were completely skewed.

The final heights of 2,526 GH-treated short children (1,475 boys and 1,051 girls) who were registered with the Foundation for Growth Science were analyzed. The patients were divided into two groups according to the year of the start of GH treatment: Group P consisted of 1,325 patients (826 boys and 499 girls) who started GH treatment with pituitary derived human GH (phGH) before 1989, when recombinant human GH (rhGH) became available; Group R consisted of 1,201 patients (649 boys and 552 girls) who started GH treatment in or after 1989 and received rhGH. The patients were subdivided into an additional three groups according to gonadal function, and the presence or absence of gonadal suppression treatment (GST): Group A consisted of 1,769 patients (1,089 boys and 680 girls) with isolated growthhormone deficiency (IGHD) who developed spontaneous puberty and did not receive GST; Group B consisted of 508 patients (253 boys and 255 girls) with IGHD who developed spontaneous puberty and did receive GST; and Group C consisted of 251 patients (133 boys and 118 girls) with multiple pituitary hormone deficiency (MPHD) who did not develop spontaneous puberty and who also received gonadal replacement treatment. Mean final height was significantly taller in Group R than in Group P in both boys (P: 157.9 ± 7.4 cm, R: 160.3 ± 6.1 cm, p<0.0001) and girls (P: 145.5 ± 6.8 cm, R: 147.8 ± 5.4 cm, p<0.0001). In Group A, mean final height was taller in Group R-A than in Group P-A in both boys (P: 157.2 ± 7.5 cm, R: 160.5 ± 5.8 cm, p<0.0001) and girls (P: 145.3 ± 6.9 cm, R: 147.8 ± 5.4 cm, p<0.0001). In Group B. mean final height was significantly taller in Group R-B than in Group P-B in girls (P: 144.4 ± 6.8 cm, R: 147.6 ± 4.8 cm, p<0.0001), but showed no significant difference in boys (P: 157.3 ± 7.1 cm, R: 159.0 ± 7.3 cm). In Group C, mean final height was not significantly different in either boys (P: 162.4 ± 6.0 cm, R: 161.2 ± 7.8 cm) or girls (P: 148.3 ± 5.7 cm, R: 147.2 ± 7.0 cm). Mean final height in Group B (boys: 157.8 cm, girls: 145.8 cm) was not taller than Group A (boys: 158.8 cm, girls: 146.8 cm), but pubertal height gain was significantly greater in Group B (boys: 18.4 cm, girls: 14.0 cm) than in Group A (boys: 13.9 cm, girls: 10.3 cm). Mean final height was the tallest in Group C (boys: 162.1 cm, girls: 147.9 cm). The taller final height in Group R than Group P is mainly attributable to the greater height SDS at the start of GH treatment, since the increase in height SDS during GH treatment was not greater in Group R than in Group P. The improved modalities of GH Received: July 28, 2000 Accepted: February 16, 2001 Correspondence: Dr. Toshiaki Tanaka, Division of Endocrinology & Metabolism, National Children's Hospital, 3– 35–31, Taishidoh, Setagaya-ku, Tokyo 154-8509, Japan Tanaka et al. 54 Vol.10 / No.1 treatment, such as increased frequency of subcutaneous injection and higher GH dose also contributed to the improved final height in Group R-A and Group R-B, since the height velocity was significantly greater and height at the onset of puberty was taller in Group R than Group P. Since pubertal height gain was greater in Group B than in Group A, it can be concluded that GST was effective. Although the final height was not greater in Group B than the Group A, the final height in Group B would have been much shorter without GST than it was with it. The taller final height in Group C was caused by bone age delay due to hypogonadism and by delaying the induction of puberty. The optimal treatment is therefore whatever permits the patient to catch up with and reach normal height before the onset of puberty, since total pubertal height gain is not greater in GH-treated short children than in untreated short children. Early diagnosis and treatment is therefore important to permit early catch-up with normal height before puberty.

We report clinical and molecular findings in 15 Japanese mosaic females with r(X) chromosomes, 45,X/46,X,r(X), confirmed by fluorescence in situ hybridization (FISH) analysis for DXZ1 and whole X chromosome painting. Cases 1–3, 5–7, and 11–13 had mental retardation (MR), the remaining cases being free from MR. FISH analysis showed that XIST was absent from the r(X) chromosomes in cases 1–4 and was present on the r(X) chromosomes in cases 5–15. X-inactivation analysis for the methylation status of the AR gene indicated that, of eight cases with XIST-positive r(X) chromosomes in more than 10% (23%–62%) of lymphocytes (cases 5–12), cases 5–10 had selective X-inactivation, whereas cases 11 and 12 had active X disomy. Microsatellite analysis for multiple loci on the pericentromeric region revealed that, of 11 cases with r(X) chromosomes in more than 10% (13%–62%) of lymphocytes (cases 1, 2, and 4–12), cases 1, 2, and 5–10 had heterozygous alleles for at least one locus, whereas cases 4, 11, and 12 had single alleles for all the loci examined. The results suggest that the r(X) and normal X chromosomes could be of biparental or uniparental origin, and that mental status in females with r(X) chromosomes is determined by multiple factors, including the presence or absence of XIST on the r(X) chromosomes and the size and frequency of active r(X) chromosomes, in addition to co-incidental genetic and environmental factors.