Daniel F. Gunther

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.

A Gender Assessment Team: experience with 250 patients over a period of 25 years.

Purpose: To describe a Gender Assessment Team that has provided a multidisciplinary approach to the diagnosis, medical and surgical treatment, genetic counseling, and psychosocial support of patients with ambiguous genitalia, intersex disorders, and other genital anomalies, collectively termed disorders of sex development; and to determine the major diagnostic categories and approach.Methods: A retrospective review of 250 patients evaluated by the Team at Childrens Hospital and Regional Medical Center in Seattle, WA, from January 1981 through December 2005. The Team included the following specialties: medical genetics, cytogenetics, gynecology, pediatric urology, endocrinology, and psychiatry.Results: Of the subjects, 177 were infants, 46 were children or adolescents, and 27 had a multisystem genetic condition. The most common diagnoses were congenital adrenal hyperplasia (14%), androgen insensitivity syndrome (10%), mixed gonadal dysgenesis (8%), clitoral/labial anomalies (7%), hypogonadotropic hypogonadism (6%), and 46,XY small-for-gestational-age males with hypospadias (6%).Conclusion: The six most common diagnoses comprised 50% of the cohort. The expertise of a multidisciplinary team allowed for integrated care for patients with disorders of sex development and identification of novel conditions. Geneticists play an important role in a team approach through knowledge of genetic testing options and diagnosis of patients with karyotypic abnormalities and syndromes with genital anomalies.

Ascertainment Bias in Turner Syndrome: New Insights From Girls Who Were Diagnosed Incidentally in Prenatal Life

Objective. To evaluate differences in phenotype and other clinical features between patients who have Turner syndrome diagnosed incidentally (on the basis of a prenatal karyotype performed for reasons unrelated to suspicion of Turner syndrome, eg, advanced maternal age) or traditionally (on the basis of either a prenatal karyotype performed for abnormal ultrasound findings or a postnatal karyotype performed for clinical findings suggesting Turner syndrome). Methods. Analysis was performed on baseline data from 88 girls, aged 9 months to 4 years, who were randomized into a multicenter growth hormone intervention trial. Baseline information included a detailed medical history (especially of cardiac and renal anomalies), examination for presence of phenotypic features characteristic of Turner syndrome, length or height (depending on age) expressed as a standard deviation score, and weight standard deviation score. Patients were classified to either the “incidental” (N = 16) or the “traditional” (N = 72) diagnosis group as described above. Results. The incidental group had significantly fewer total phenotypic features of Turner syndrome than the traditional group (3.6 ± 2.9 vs 6.7 ± 2.9). When subgrouped by karyotype, the proportion of patients who manifested phenotypic features was greatest in patients with a 45,X nonmosaic karyotype, lowest in the patients with 45,X/46,XX mosaicism, and intermediate in those with “other” karyotypes. Fewer congenital cardiac defects were observed in the incidental group (31%) compared with the traditional group (64%), but there was no difference between the groups in the prevalence of renal defects. Karyotype distribution differed significantly between the traditional and incidental groups: 74% versus 19% had the nonmosaic 45,X karyotype in the traditional group and 7% versus 56% had the mosaic 45,X/46,XX karyotype. Conclusions. Patients whose Turner syndrome was diagnosed incidentally had significantly fewer phenotypic features and cardiac defects, as well as a greater proportion of mosaic karyotypes, compared with patients whose Turner syndrome was diagnosed clinically. These results support the theory that significant ascertainment bias exists in our understanding Turner syndrome, with important implications for prenatal counseling.

Turner syndrome: A pattern of early growth failure

The purpose of this study was to determine the pattern of early growth in girls with Turner syndrome. Analysis was performed on a total of 464 longitudinal measurements of height, obtained from birth to 8 years of age from 37 girls with Turner syndrome who did not have significant cardiac disease or autosomal abnormalities. All data were obtained prior to the initiation of any hormonal therapy. Mean height SDS fell from ‐0.5 at birth to ‐1.5 at age 1 year and ‐1.8 at age 1.5 years. Growth curves fitted using the first two components of the infancy‐childhood‐puberty model of growth revealed that growth failure was due to (a) mild growth retardation in utero, (b) slow growth during infancy, (c) delayed onset of the childhood component of growth and (d) slow growth during childhood. Physicians should consider the diagnosis of Turner syndrome in any girl with an unexplained failure to thrive or with short stature, even during the first 2 years of life.

A case of true hermaphroditism reveals an unusual mechanism of twinning

Traditionally twins are classified as dizygous or fraternal and monozygous or identical (Hall Twinning, 362, 2003 and 735–743). We report a rare case of 46,XX/46,XY twins: Twin A presented with ambiguous genitalia and Twin B was a phenotypically normal male. These twins demonstrate a third, previously unreported mechanism for twinning. The twins underwent initial investigation with 17-hydroxyprogesterone and testosterone levels, pelvic ultrasound and diagnostic laparoscopy. Cytogenetic analysis was performed on peripheral blood cells and skin fibroblasts. Histological examination and Fluorescence in situ hybridization studies on touch imprints were performed on gonadal biopsies. DNA analysis using more than 6,000 DNA markers was performed on skin fibroblast samples from the twins and on peripheral blood samples from both parents. Twin A was determined to be a true hermaphrodite and Twin B an apparently normal male. Both twins had a 46,XX/46,XY chromosome complement in peripheral lymphocytes, skin fibroblasts, and gonadal biopsies. The proportion of XX to XY cells varied between the twins and the tissues evaluated. Most significantly the twins shared 100% of maternal alleles and approximately 50% of paternal alleles in DNA analysis of skin fibroblasts. The twins are chimeric and share a single genetic contribution from their mother but have two genetic contributions from their father thus supporting the existence of a third, previously unreported type of twinning.

Osseous fragility in Marshall-Smith syndrome.

Marshall–Smith syndrome is characterized by accelerated osseous maturation, craniofacial anomalies, failure to thrive, psychomotor delay, hypotonia, pulmonary dysfunction, and limited life expectancy. We describe a 7‐year‐old girl who, in addition to meeting these criteria for Marshall–Smith syndrome, had multiple fractures and skeletal anomalies. The purpose of this report is to draw attention to Marshall–Smith syndrome as one of the skeletal dysplasias characterized by osseous fragility.

Contents Index Vol. 57, 2002

10 Inverse Correlation between Insulin-Like Growth Factor (IGF)-Binding Protein-5 and IGF-I and II during Postnatal Development of the Anterior Pituitary Gland González-Parra, S. (Rotterdam/Madrid); Rosato, R.R. (Rotterdam); Chowen, J.A.; Argente, J. (Madrid); Groffen, C.; Dits, N.; Drop, S.L.S. (Rotterdam) 15 Differential Regulation of Insulin-Like Growth Factor-(IGF) I and IGF-Binding Protein (IGFBP) Secretion by Human Peripheral Blood Mononuclear Cells Auernhammer, C.J.; Fottner, C.; Engelhardt, D. (München); Bidlingmaier, M.; Strasburger, C.J. (Cologne); Weber, M.M. (München) 22 Longitudinal Assessment of Pituitary-Thyroid Axis and Adrenal Function in Preterm Infants Raised by ‘Kangaroo Mother Care’ Weller, A.; Rozin, A.; Goldstein, A. (Ramat Gan); Charpak, N.; Ruiz-Pelaez, J.G.; Figueroa de Calume, Z. (Santa Fe de Bogotá); Charpak, Y. (Paris); Sack, J. (Tel Hashomer) 27 Suppression of Puberty in Girls with Short-Acting Intranasal versus Subcutaneous Depot GnRH Agonist Tuvemo, T.; Gustafsson, J.; Proos, L.A.; Swedish Growth Hormone Group (Uppsala) 32 Pulsatile Gonadotropin-Releasing Hormone Treatment of Men with Idiopathic Hypogonadotropic Hypogonadism Christiansen, P.; Skakkebæk, N.E. (Copenhagen) 37 Assessing Insulin Resistance: Application of a Fasting Glucose to Insulin Ratio in Growth Hormone-Treated Children Burgert, T.S.; Vuguin, P.M.; DiMartino-Nardi, J. (Bronx, N.Y.); Attie, K.M. (San Francisco, Calif.); Saenger, P. (Bronx, N.Y.) 43 Expression of the Gene for the Alpha-Subunit of Inhibin in Human Adrenocortical Tumours Rich, N.; Gaston, V.; Le Bouc, Y.; Gicquel, C. (Paris) 48 Effects of Thyroid Hormone on mRNAs of Phosphoglycerate Mutase Subunits in Rat Muscle during Development González-Cinca, N.; Gonzalo, S.; Ascaso, C.; Carreras, J.; Climent, F. (Barcelona)