Radiological signs of Leri-Weill dyschondrosteosis in Turner syndrome

BACKGROUND/AIMS: Leri-Weill dyschondrosteosis (LWD), a mesomelic short stature syndrome with Madelung deformity, was recently reported to be caused by SHOX (short stature homeobox-containing gene) haploinsufficiency. The loss of SHOX on Xp22.32, also called PHOG (pseudoautosomal homeobox-containing osteogenic gene), through structural aberrations of the X chromosome was also implicated in the short stature phenotype and some additional stigmata of Turner syndrome. The aim of this study was to systematically examine left-hand radiographs from Turner girls for the presence of signs of LWD. METHODS: We retrospectively studied 168 left-hand radiographs from 54 patients with Turner syndrome (bone age >10.5 years) who were treated with rhGH and seen during the last 10 years in our clinic. For comparison, we analyzed 7 radiographs from 5 patients with LWD and 52 radiographs from 20 patients with GH deficiency. The shape of the distal radial epiphysis (triangularisation index = TI) and the carpal angle were quantitatively measured. In addition, we screened for the presence of a premature cleft fusion or an ulnar deviation of the articular surface of the distal radial epiphysis and for fourth metacarpal shortening. One of 54 Turner girls (2%) was affected with LWD and presented with Madelung deformity. RESULTS: No milder forms of Madelung deformity were detected. However, there was a significant trend to a triangular shape of the distal radial epiphysis in Turner syndrome: the median TI was 2.7 in normal controls (range 1.8-3.7), 3.1 in Turner girls (range 2.0-6.3) (p < 0.001 against controls), and 6.0 in patients with LWD (range 3.5-11.0) (p < 0.001 against controls). CONCLUSIONS: The triangularisation index did not correlate with the carpal angle (median 122.5 Copyright 2001 S. Karger AG, Basel     

Growth failure in early life: an important manifestation of Turner syndrome

The goals of this study were to test the hypothesis that girls with Turner syndrome (TS) experience growth failure early in life and to establish model-based normative growth charts for 0- to 8-year-old American girls with TS. Full-term girls with TS who had 5 or more measurements of height obtained during their first 10 years of life prior to initiation of growth hormone, estrogen and/or androgen therapy were eligible for this study. A nonlinear mixed-effects model comprising the first two components of the infancy-childhood-puberty (ICP) model of growth was fitted to the longitudinal height measurements and compared with those of healthy American girls. Height measurements (n = 1,146) from 112 girls with TS (45,X: 57.1%; 45,X/46,XX: 12.5%; 46,X, iso(X): 4.5%, and other: 25.9%) were analyzed. Mean height SDS fell from -0.68 at birth to -1.60 at 1 year, -1.80 at 2 years and -1.95 at 3 years. When compared to controls (676 girls, 4,537 measurements), girls with TS grew more slowly due to three principal factors: a slow growth rate of the infancy component, a slow growth rate at the onset of the childhood component, and delayed onset of the childhood component. Traditional concepts of growth failure in TS should be revised. Physicians should consider the diagnosis of TS in any girl with unexplained failure to thrive or short stature, even in the first 3 years of life.     

Different chromosome Y abnormalities in Turner syndrome.

A 17-year-old phenotypically female girl was referred for evaluation because of short stature and primary amenorrhea. Cytogenetic analysis showed a mosaic 46,XY/45,X/47,XYY/46,X,idic(Yq)/47,XY,idic(Yq)/48,XXY,idic(Yq)/46,X,t(C;Y) karyotype. Conventional cytogenetic results were supplemented with fluorescence in situ hybridization (FISH) techniques to ensure a better characterization of abnormalities. By using FISH, a supernumerary marker chromosome derived from chromosome Y which could not be detected by conventional cytogenetics was revealed. Furthermore, additional abnormalities and their frequencies were highlighted by the application of DNA probes specific for X and Y chromosomes. Thus, FISH proved useful in determining low frequency cell lines which would need analysis of a large number of good quality metaphase spreads by conventional cytogenetic techniques: it helped in identifying the nature and the origin of unknown markers and rearrangements which have important implication in sexual differentiation and development of gonadal tumours.     

Fertility and genetic counseling in Turner syndrome

We report three cases of Turner syndrome 45,X/46,XX with spontaneous menstruations. Two patients had together four pregnancies with a normal girl, a malformed boy and two miscarriages. The outcome of the pregnancy in such a women is discussed with a review of the literature.     

Reevaluation of a sensitive indicator of early lead exposure

A principal target for the environmental toxin lead (Pb) is porphobilinogen synthase (PBGS), a Zn-metalloenzyme necessary for heme biosynthesis. Measurement of blood Pb inhibited PBGS is the most sensitive indicator of subclinical Pb intoxication, but problems with the assay have diminished its use. This report identifies Pb as a slow acting inhibitor of PBGS. The activity of PBGS could change up to sixfold during an hourlong clinical assay of Pb contaminated blood, and activity is profoundly effected by the presence of serum proteins, such as albumin. When PBGS catalyzed PBG production is allowed to reach a steady state rate, kinetic data on purified PBGS support the hypothesis that Pb inhibition of PBGS results from direct substitution for Zn.     

Molecular detection of XO - Turner syndrome

Turner syndrome is caused by haploinsufficiency of the short arm of X-chromosome, and is usually diagnosed by karyotyping. This procedure is time-consuming, expensive and unfeasible for population screening. We propose molecular detection of 45XO Turner patients based on the ability of HpaII, a methylation sensitive endonuclease, to induce the cleavage of non-methylated DNA in the active X-allele. Genomic DNA was obtained from 22 patients with Turner syndrome confirmed by karyotype (45XO, N = 18; 45XO/46XX, N = 4). After digestion, DNA was amplified with primers directed to exon 1 of the androgen receptor (AR) gene and to the GAPDH control gene. Normal control females or mosaic patients, with a second methylated X-chromosome, escaped from HpaII digestion and produced a band corresponding to AR gene amplification. 45XO patients have just one active non-methylated X-chromosome, completely digested by HpaII, thus preventing the amplification of the AR gene. Three of the 45XO cases gave amplified bands, suggesting low-frequency mosaicisms that are not detected by karyotyping. Compared to classical karyotype studies for the detection of 45XO Turner patients, this new molecular method is simpler, faster and less expensive.     

GH assessment and three years' hGH therapy in girls with Turner syndrome.

Fifteen girls with Turner syndrome (TS) were submitted to GH secretion assessment before undergoing hGH therapy. In the first 9 months, hGH was given at a dose of 0.5 IU/kg/week s.c. daily; afterward, the dose was increased to 1 IU/kg/week s.c. daily. The girls were prepubertal, with a mean (SD) chronological age (CA) of 12.5 (2.6) years, and a mean (SD) bone age of 10.5 (1.8) years. A clonidine stimulation test, 1-29 GHRH test and GH spontaneous nocturnal secretion assessment were performed in all patients. Results showed a variable pattern of GH secretion in 10 patients, in only 2 did we find all values definitely normal, and in 3 we found a total GH deficiency. Height velocity, expressed as standard deviation scores (SDS) for CA according to Turner references, during the first year of treatment increased significantly: 0.36 (1.15) -3.30 (2.87) (p < 0.001), and the increment remained quite unchanged during both the second and third years: 3.16 (2.96) and 2.55 (3.87), respectively (n.s.). Height, expressed in SDS for CA for Turner references, increased significantly throughout the whole period of treatment and reached the highest value at the end of the third year of therapy. GH secretion parameters poorly correlated with pretreatment auxological data or response to treatment. Our long-term study confirms that in TS GH measurement is not useful in indicating hGH therapy or in predicting the response.     

Turner syndrome: a study of chromosomal mosaicism

We report the results of a molecular investigation of 25 patients who had Turner syndrome and who had previously been subject to analysis using cytogenetic techniques. When in situ hybridization and polymerase chain reaction (PCR) techniques were applied, a larger number of mosaic individuals were observed than were detected by cytogenetic methods. This was mainly because of the presence of the cell line 46,XX. The most frequent mosaics were 45,X/46,XX (36%); the presence of isochromosomes comprised 24% and fragments 12%. The patients who had been previously diagnosed with mosaicism displayed a higher complexity in their karyotypes because of the presence of new cellular lines. The isodicentric X chromosome for the long arm, idic(Xq), gave rise to complex mosaics of up to nine cell lines. The application of fluorescence in situ hybridization and PCR led to a clearer definition of alterations at the centromeric level and the identification of the nature of chromosome fragments. Received: 2 August 1995 / Revised: 5 February 1996     

PCR-based detection of mosaicism in Turner syndrome patients

To study the possible role of cryptic mosaicism in phenotypical variations of 45,X Turner syndrome, we analyzed low-level mosaicism by methods based on the polymerase chain reaction. For the detection of Y-chromosome-derived fragments, we used three Y-specific primer pairs representing the centromere, Yp11.3, and Yq12. None of the 18 patients with 45,X had Y-derived chromosomes. For the detection of X chromosome mosaicism, we employed a novel modified HUMARA (human androgen receptor) assay, which proved to be a sensitive method with a detection limit as low as 1 in 960 cells. Using this assay, we detected low frequency cryptic X chromosome mosaicism in 2 of 18 cytogenetically 45,X patients. Received: 24 April 1996 / Revised: 19 August 1996     

Turner syndrome, insulin sensitivity and growth hormone treatment

Mild insulin resistance appears to be an early metabolic defect in girls with Turner syndrome (TS). Impaired glucose tolerance has been reported in 10-34% of patients with TS, and type 2 diabetes mellitus is 2-4 times more common and occurs at a younger age in girls with TS than in the general population. In a mixed longitudinal and cross-sectional study, we analysed carbohydrate tolerance and insulin sensitivity in 46 children and adolescents with TS who reached their final height after long-term treatment (mean 6.3 +/- 2.5 years) with growth hormone (GH: 0.33 mg/kg/week [0.05 mg/kg/day]), and in 36 of these patients who were followed-up after the cessation of GH therapy (mean follow-up, 2.6 +/- 2.5 years; range, 1-9.5 years). Patients with TS were compared with an age-matched female control group. Insulin sensitivity appeared to be lower in patients with TS than in controls, even before the start of GH therapy. As in controls, insulin sensitivity decreased with age in patients with TS, and levels were lower in those aged >12 years than in those aged <12 years. GH therapy resulted in good catch-up growth in patients with TS, with final height significantly higher than projected height evaluated before the initiation of GH therapy. Insulin sensitivity increased after 7-8 years of therapy and, on the cessation of GH therapy, returned to pre-treatment levels. The increase in insulin sensitivity seen on the cessation of GH therapy appeared to be influenced negatively by body mass index and triglyceride levels, and correlated positively with the number of years since cessation of GH therapy. As in the general population, excess weight and an abnormal lipid profile, in particular excess triglyceride levels, worsened insulin sensitivity. In conclusion, our study confirms that GH therapy reduces insulin sensitivity, but at its cessation there is a return to pre-therapy values. We therefore report a progressive improvement in carbohydrate tolerance and insulin function in patients with TS, despite an increase in age.     

A case of Kartagener's syndrome: Importance of early diagnosis and treatment

Kartagener''s syndrome is a very rare congenital malformation comprising of a classic triad of sinusitis, situs inversus and bronchiectasis. Primary ciliary dyskinesia is a genetic disorder with manifestations present from early life and this distinguishes it from acquired mucociliary disorders. Approximately one half of patients with primary ciliary dyskinesia have situs inversus and, thus are having Kartagener syndrome. We present a case of 12 year old boy with sinusitis, situs inversus and bronchiectasis. The correct diagnosis of this rare congenital autosomal recessive disorder in early life is important in the overall prognosis of the syndrome, as many of the complications can be prevented if timely management is instituted, as was done in this in this case.     

Melanoma: prevention and early diagnosis.

Over the past two decades there has been a rapid rise in the numbers of people developing and dying from malignant melanoma. Sunlight is the main aetiological factor linked with melanoma. Exposure to the sun is a risk factor that can be modified provided that people are aware of the dangers. Health promotion campaigns can play a part in producing such change. General practitioners and practice nurses have an important part to play in providing those most at risk with information and advice about sensible sun exposure and sun protection measures. Campaigns to reduce delay in diagnosis by a combination of professional and public education have been reported from several centres around the world. The effects of these campaigns in reducing the depth distribution of cutaneous malignant melanoma have sometimes been encouraging, but in other instances have shown little effect. Until there is clear evidence that early detection reduces mortality from melanoma, the opportunistic promotion of early detection may not be cost effective and will fail to reach all sections of the community at risk. At the present time, therefore, the emphasis should be on the primary prevention of skin cancer.