Embryonic Testicular Regression Syndrome Presenting as Primary Amenorrhea: A Case Report and Review of Disorders of Sexual Development.

BACKGROUND: Sex development depends on the synchronous interaction of complicated genetic and hormonal events. Sex differentiation begins with sex determination, which is the assignment of the embryonic bipotential gonads as either testes or ovaries on the basis of transcriptional regulation. Hormonal regulation then directs the development of the male or female phenotype. Disruptions of this intricate cascade of events result in disorders of sexual development. CASE: A 16-year-old female adolescent presented with primary amenorrhea. Evaluation revealed female external genitalia, XY karyotype, absent gonadal tissue, and rudimentary Müllerian structures. On the basis of her constellation of findings, the most logical diagnosis was the rare embryonic testicular regression syndrome. SUMMARY AND CONCLUSION: A careful understanding of embryonic sexual development is critical to the evaluation of patients with disorders of sexual development.

Relationship of low vitamin D status with positive, negative and cognitive symptom domains in people with first-episode schizophrenia.

AIM: Deficient vitamin D levels are very common among Americans of all ages and ethnicities, but little is known about its prevalence or associated problems among those with schizophrenia. METHODS: Stored plasma from 20 recent onset schizophrenia subjects and 20 matched healthy comparison subjects were analysed for 25 OH vitamin D, and related to measures of symptom severity and neurocognition. RESULTS: There was no significant difference in mean 25 OH vitamin D between the schizophrenia and the healthy comparison subjects (28.2 standard deviation (SD) 12.6 ng mL(-1) vs. 29.9 SD 14.3 ng mL(-1) ), and about half the subjects in each group had insufficient levels (<30 ng mL(-1) ). Among psychosis subjects, greater severity of negative symptoms was correlated with lower vitamin D status (r = -0.55, P = 0.012); the correlations of overall symptom severity and positive symptom severity with 25 OH vitamin D levels approached significance (r = -0.42, P = 0.07 and r = -0.36, P = 0.12, respectively). There was no relationship of vitamin D with depressive symptoms. Among the schizophrenia subjects, lower 25 OH vitamin D levels were associated with more severe overall cognitive deficits (r = 0.56, P = 0.019). CONCLUSION: This study found that lower vitamin D levels in schizophrenia subjects were associated with more severe negative symptoms and overall cognitive deficits. However, the cross-sectional design precludes any conclusions about whether low vitamin D status in fact causes more severe negative symptoms and cognitive impairments. No relationship was found between lower vitamin D levels and depressive symptoms.

Adolescents with Type 1 diabetes mellitus experience psychosensorial symptoms during hypoglycaemia.

AIM: To describe mood and psychosensorial symptoms of hypoglycaemia in adolescents with Type 1 diabetes mellitus in two countries with different cultures, Turkey and the USA. METHODS: We developed a 68-item questionnaire assessing physical, behavioural, mood and psychosensorial symptom frequency and ratings ['good', 'bad', or 'both' (sometimes good, sometimes bad)]. Adolescents with Type 1 diabetes were recruited from paediatric diabetes clinics at the University of North Carolina at Chapel Hill in the USA and Kocaeli University in Turkey. The percentages of participants at each clinic who endorsed individual symptoms, symptom categories and symptom ratings were calculated and compared. RESULTS: Cronbach's α values were > 0.7 for each real symptom category. No symptom items were excluded from the questionnaire analysis based on item-total correlation results which were all > 0.2. Data were collected from 132 participants (69 from University of North Carolina, 63 from Kocaeli University, 54% male). The mean (SD) age of the participants was 14.9 (1.9) years, HbA1c level was 8.7 (1.8) % and duration of Type 1 diabetes was 5.8 (3.7) years. On average, each physical symptom was experienced by 65.2% of participants, each behavioural symptom by 46.5%, each mood symptom by 42.8%, and each psychosensorial symptom by 48.9%. On average, each physical, behavioral, mood and psychosensorial symptom was rated as 'good' or 'both' by 23.0, 29.1, 36.9 and 37.2% of participants, respectively. There were no symptom differences between the groups in each country. CONCLUSIONS: In addition to the classic physical symptoms experienced during hypoglycaemia, adolescents with Type 1 diabetes report psychosensorial, mood and behavioral symptoms, and some describe them as positive experiences. Symptom experiences were similar in these two countries with different cultures.

Type I diabetes mellitus in a patient with chromosome 22q11.2 deletion syndrome.

We describe a patient with type I diabetes, clinical findings consistent with velocardiofacial syndrome, and a chromosome 22q11.2 deletion. A nine-year-old boy presented with a history of polyuria, polydipsia, weight loss, hyperglycemia, ketosis, serum insulin antibodies, and a low C-peptide level. He had distinctive facial features, learning disabilities, short stature, and a history of glottic web and clubfoot. Although a normal karyotype was obtained, fluorescence in situ hybridization (FISH) revealed a submicroscopic deletion in the DiGeorge/velocardiofacial syndrome critical region at 22q11.2. His maternal half-brother also carried a chromosome 22q11.2 deletion. His mother has similar facial features and hypoparathyroidism. Autoimmune problems associated with chromosome 22q11.2 deletions have been reported. We suggest that the defects in immune regulation due to T-cell deficiency in chromosome 22q11.2 deletion syndrome may predispose to autoimmune disorders, including type I diabetes mellitus.

Androgen-accelerated bone maturation in mice is not attenuated by Faslodex, an estrogen receptor blocker.

Androgens accelerate bone maturation, but it is unclear to what extent this process may be mediated by estrogens derived from aromatization of androgens. In this study, we investigated whether an estrogen-blocking agent, Faslodex (ICI 182,780), can attenuate testosterone-accelerated skeletal maturation in immature mice. On days of life 2-8, mouse pups received either testosterone propionate (50 microg/100 g body weight), Faslodex (100 microg/100 g body weight), a combination of Faslodex + testosterone, or vehicle alone. Skeletal maturation was assessed in the forepaw and the lumbar spine. Testosterone caused acceleration of bone maturation (p < 0.05, compared with vehicle), predominantly of axial bones. Faslodex, however, failed to block the effect of testosterone, such that the mice receiving Faslodex + testosterone had skeletal maturation scores similar to those treated with testosterone alone. These results suggest that androgens have the capacity to stimulate bone maturation directly, probably via their own receptors.

Insulin-like growth factor-I overexpression attenuates cerebellar apoptosis by altering the expression of Bcl family proteins in a developmentally specific manner.

In studies of transgenic (Tg) mice that overexpress insulin-like growth factor-I (IGF-I) exclusively in the CNS, we demonstrated a dramatic increase in cerebellar granule cell number that appeared to be attributable predominantly to enhanced survival. IGF-I anti-apoptotic actions are well established in cultured neurons, but comparable studies in vivo are few. Using the same Tg mice, therefore, we set out to document IGF-I anti-apoptotic effects during cerebellar development and to probe IGF-I signaling mechanisms. Compared with cerebella (CBs) of non-Tg littermates, those of Tg mice had fewer apoptotic cells at postnatal day 7 (P7) and showed a similar tendency at P14 and P21. At each age studied, procaspase-3 and caspase-3 were decreased in CBs of Tg mice. The caspase-3 decline was accompanied by decreases in the 85 kDa fragment of Poly(ADP-ribose) polymerase, a known product of caspase cleavage, suggesting decreased caspase activity. At P7 decreased apoptosis in Tg mice was associated with increased expression of the anti-apoptotic Bcl genes, Bcl-x(L) and Bcl-2. The mRNA expression of the proapoptotic Bcl genes, Bax and Bad, also was increased, but no changes were observed in the abundance of their proteins. At P14 Bcl-xL and Bcl-2 expression were similar in normal and Tg mice; Bax mRNA was unchanged in Tg mice, but its protein abundance was decreased, and both Bad mRNA and protein abundance were decreased. At P21 Bcl-xL and Bcl-2 expression were unchanged, but Bax and Bad expression were decreased. Our data show that IGF-I exerts anti-apoptotic actions during cerebellar development, and thereby alters the magnitude of naturally occurring apoptosis. IGF-I appears to affect multiple steps in the apoptotic pathway in a developmentally specific manner. IGF-I decreases caspase-3 availability and activity, increases the expression of anti-apoptotic Bcl-x(L) and Bcl-2 during early postnatal development, and decreases proapoptotic Bax and Bad expression at later developmental stages.

Effects of hypothyroidism on insulin-like growth factor-I expression during brain development in mice.

Hypothyroidism has devastating consequences on brain development. While the mechanisms that mediate these effects are not known, several lines of evidence suggest that a reduction in insulin-like growth factor-I (IGF-I) expression and/or action has a role. To assess whether reduced IGF-I expression and/or actions mediates the brain pathology of congenital hypothyroidism, we induced hypothyroidism by treating pregnant mice and lactating dams with 0. 1% propylthiouracil (PTU) in drinking water. Control and PTU-treated pups were sacrificed on postnatal day (P) 7, 10 and 14, and IGF-I mRNA expression was assessed in the cerebral cortex and cerebellum by ribonuclease protection assay. To control for mRNA loading, the signal of IGF-I protected bands was normalized to those for cyclophillin. IGF-I mRNA expression in hypothyroid animals was decreased significantly in cortex at P10 and P14 (42 and 60%, respectively). In the cerebellum, IGF-I mRNA expression was down-regulated at all ages studied, but the decrease was only statistically significant at P7 (31% decreased). We conclude that hypothyroidism alters IGF-I expression in the developing brain. Furthermore, we speculate that IGF-I plays a role in mediating some thyroid hormone actions during brain development.

Nutritional rickets in African American breast-fed infants.

OBJECTIVE: To analyze the characteristics of infants and children diagnosed with nutritional rickets at two medical centers in North Carolina in the 1990s. STUDY DESIGN: The physical and radiographic findings, calcium, phosphorus, alkaline phosphatase, and 25-hydroxyvitamin D levels of infants and children diagnosed with nutritional rickets at two medical centers were reviewed. Breast-feeding data were obtained from the North Carolina Women, Infants and Children Program (WIC). RESULTS: Thirty patients with nutritional rickets were first seen between 1990 and June of 1999. Over half of the cases occurred in 1998 and the first half of 1999. All patients were African American children who were breast fed without receiving supplemental vitamin D. The average duration of breast-feeding was 12.5 months. The age at diagnosis was 5 to 25 months, with a median age of 15.5 months. Growth failure was common: length was <5th percentile in 65% of cases, and weight was <5th percentile in 43%. CONCLUSION: Factors that may have contributed to the increase in referrals of children with nutritional rickets include more African American women breast-feeding, fewer infants receiving vitamin D supplements, and mothers and children exposed to less sunlight. We recommend that all dark-skinned breast-fed infants and children receive vitamin D supplementation.

The effects of the estrogen receptor blocker, Faslodex (ICI 182,780), on estrogen-accelerated bone maturation in mice.

Sex steroids accelerate bone maturation, but it is believed that estrogen action is needed for terminal epiphyseal fusion. In this study, we investigated the effects of a new estrogen-blocking agent, Faslodex (ICI 182,780), on estrogen-accelerated skeletal maturation in immature mice. On day-of-life 2 through 8, mice pups received either estradiol (5 microg/100 g body weight), Faslodex (100 microg/100 g body weight), a combination of Faslodex + estradiol, or vehicle alone. Skeletal maturation was assessed with a scoring system based on the size and appearance of epiphyseal plates in the forepaw and the lumbar spine. Estradiol caused acceleration of bone maturation in our mouse model (p < 0.05). Faslodex blocked the effect of estrogen, such that the mice receiving Faslodex + estradiol did not vary significantly from controls. Faslodex may prove useful in the treatment of patients with diseases causing rapid skeletal maturation, such as precocious puberty.

Insulin-like growth factor-I (IGF-I) ameliorates and IGF binding protein-1 (IGFBP-1) exacerbates the effects of undernutrition on brain growth during early postnatal life: studies in IGF-I and IGFBP-1 transgenic mice.

Insulin-like growth factor-I (IGF-I) plays an important role in the stimulation of postnatal brain growth. In transgenic (Tg) mice, IGF-I overexpression stimulates postnatal brain growth, whereas decreased IGF-I availability caused by ectopic brain expression of IGF binding protein-1 [(IGFBP-1), an inhibitor of IGF-I action] retards postnatal brain growth. Because undernutrition during early postnatal development profoundly retards growth and maturation of the brain in rodents, we sought to determine the influence of IGF-I on undernutrition-induced brain growth retardation. Caloric restriction was imposed on IGF-I Tg mice, IGFBP-1 Tg mice, and their non-Tg littermates by separating half of each litter from their dams during the suckling period, postnatal d 1 to 21. Undernutrition reduced the brain growth of each group of mice, but the growth of undernourished IGF-I Tg mice was comparable to that of well-fed control mice (increased 4.13- and 4.22-fold, respectively) and greater than that of undernourished control mice (increased 3.45-fold), whereas undernourished IGFBP-1 Tg mice exhibited less growth (increased 3.15-fold) than undernourished control mice. When the effects of undernutrition were examined in specific brain regions of each group, the same pattern was observed, and IGF-I was found to be more effective in preserving the growth of the regions with the highest transgene expression (cerebral cortex, hippocampus, and diencephalon). Despite undernutrition, IGF-I transgene expression stimulated overgrowth of these regions as well as that of the posterior medial barrel subfield, a somatosensory area of the cerebral cortex in which IGF-I may be especially important in development. These data indicate that IGF-I can ameliorate the brain growth retardation caused by undernutrition imposed during development, although it is unclear whether IGF-I directly opposes the impact of undernutrition or acts independently of nutritional status. Nonetheless, these findings raise the possibility that the relatively high IGF-I expression during early postnatal life may be responsible for sparing the brain from the full impact of undernutrition during this time in development.

Increased neural activity in transgenic mice with brain IGF-I overexpression: a [3H]2DG study.

To evaluate whether insulin-like growth factor-I (IGF-I) modulates neural activity in vivo, relative levels of brain [3H]2-deoxyglucose (2DG) uptake were compared in adult behaving and anesthetized wild type (wt) mice, and transgenic (Tg) mice with either brain IGF-I overexpression or ectopic brain expression of IGF binding protein-1 (IGFBP-1). Overall, awake behaving IGF-I Tg mice showed significant increases in brain 2DG uptake compared with wt and IGFBP-1 Tg mice. These differences were eliminated after anesthesia. 2DG uptake was similar in awake behaving, and anesthetized wt and IGFBP-1 Tg mice. Our observations thus suggest that IGF-I increases neural activity levels in vivo, and that it is not involved in regulating glucose consumption in the adult brain.

In vivo effects of insulin-like growth factor-I on the development of sensory pathways: analysis of the primary somatic sensory cortex (S1) of transgenic mice.

In the rodent brain, insulin-like growth factor I (IGF-I) messenger RNA is transiently expressed in sensory projection neurons during periods of synaptogenesis and neuronal growth. Transgenic (Tg) mice with brain IGF-I overexpression and ectopic brain expression of IGF-binding protein-1 (IGFBP-1), an inhibitor of IGF-I actions, show changes in brain size and myelination. We used these mouse models to evaluate in vivo IGF-I effects on sensory pathway development by conducting anatomical studies in the S1 barrel field. Brain size, cortical area, and barrel field dimensions were increased in IGF-I and reduced in IGFBP-1 Tg mice compared with those in wild-type (wt) mice. The brain and cerebral cortex of Tg mice with the highest transgene expression were the most altered in size. Cortex and barrel field size changes were not precisely proportional, because in some Tg mice barrels were relatively more affected than the cortex, whereas in others the opposite was observed. Brain IGF-I overexpression increased the average number of neurons per barrel, neuronal cell body cross-sectional area, and barrel neuropil volume, whereas brain expression of IGFBP-1 reduced each. Neuronal density was greatly reduced in IGF-I Tg mice and increased in IGFBP-1 Tg mice. No differences in body weight, whisker pad and follicle areas, and whisker pad innervation density were found among Tg and wt mice. These observations indicate that IGF-I enhances neuronal growth in developing sensory pathways and support the concept that modified availability of local trophic factors, such as IGF-I, changes brain, neocortical, and S1 relative dimensions by altering neuronal survival and neuropil elaboration. Study of the S1 cortex provides an excellent model to probe the in vivo mechanisms of IGF actions.

The role of the insulin-like growth factors in the central nervous system.

Increasing evidence strongly supports a role for insulin-like growth factor-I (IGF-I) in central nervous system (CNS) development. IGF-I, IGF-II, the type IIGF receptor (the cell surface tyrosine kinase receptor that mediates IGF signals), and some IGF binding proteins (IGFBPs; secreted proteins that modulate IGF actions) are expressed in many regions of the CNS beginning in utero. The expression pattern of IGF system proteins during brain growth suggests highly regulated and developmentally timed IGF actions on specific neural cell populations. IGF-I expression is predominantly in neurons and, in many brain regions, peaks in a fashion temporally coincident with periods in development when neuron progenitor proliferation and/or neuritic outgrowth occurs. In contrast, IGF-II expression is confined mainly to cells of mesenchymal and neural crest origin. While expression of type I IGF receptors appears ubiquitous, that of IGFBPs is characterized by regional and developmental specificity, and often occurs coordinately with peaks of IGF expression. In vitro IGF-I has been shown to stimulate the proliferation of neuron progenitors and/or the survival of neurons and oligodendrocytes, and in some cultured neurons, to stimulate function. Transgenic (Tg) mice that overexpress IGF-I in the brain exhibit postnatal brain overgrowth without anatomic abnormality (20-85% increases in weight, depending on the magnitude of expression). In contrast, Tg mice that exhibit ectopic brain expression of IGFBP-1, an inhibitor of IGF action when present in molar excess, manifest postnatal brain growth retardation, and mice with ablated IGF-I gene expression, accomplished by homologous recombination, have brains that are 60% of normal size as adults. Taken together, these in vivo studies indicate that IGF-I can influence the development of most, if not all, brain regions, and suggest that the cerebral cortex and cerebellum are especially sensitive to IGF-I actions. IGF-I's growth-promoting in vivo actions result from its capacity to increase neuron number, at least in certain populations, and from its potent stimulation of myelination. These IGF-I actions, taken together with its neuroprotective effects following CNS and peripheral nerve injury, suggest that it may be of therapeutic benefit in a wide variety of disorders affecting the nervous system.

Congenital hypothyroidism delays the formation and retards the growth of the mouse primary somatic sensory cortex (S1).

Intrinsic neural factors are thought to regulate the growth and formation of specific regions of the neocortex. To determine whether factors extrinsic to the brain are also involved in shaping the cytoarchitecture of the mammalian neocortex, we evaluated the effects of thyroid hormone (TH) on the formation and postnatal growth of the mouse S1 postero-medial barrel subfield (PMBSF). Congenital deficiency of TH, induced by propylthiouracil administration from day 12 of gestation, did not disrupt S1 specification, because no alterations in barrel number or configuration were observed in congenital hypothyroid mice. Barrel formation, however, was delayed by 3 days. In control mice, barrels were first seen at postnatal day (PN) 4, whereas in congenital hypothyroid mice they appeared at PN7. TH deficiency led to reduced adult brain, cortical, and S1 barrel dimensions. Barrel size, however, was relatively more affected than brain and cortical size. Our observations indicate, therefore, that TH does not participate in S1 specification, but in timing its formation. Our findings also indicate that TH regulates the relative size of the S1 barrel field by modulating the developmental timing of areal specification and brain growth.

Screening for congenital hypothyroidism in Turkey.

UNLABELLED: A pilot study was performed to determine the incidence of congenital hypothyroidism (CH) in Turkey and to build a model for nationwide screening. From December 1991 to December 1992, 30,097 newborns were screened for CH using a primary measurement of thyroid stimulating hormone in capillary blood on days 3-5 of life. Samples were obtained in collaboration with the ongoing nationwide phenylketonuria screening programme. Eleven cases of primary CH were detected giving the incidence of 1:2736. Recall rate was 2.3%. Replacement therapy with L-thyroxine was started after the confirmation of diagnosis. The median age at the initiation of replacement therapy was 23 days (range 7-35 days). CONCLUSION: The incidence of CH is notably higher in Turkey than reported in most other countries. Iodine deficiency and/or dyshormonogenesis might contribute to this high incidence. This result emphasizes the necessity of a nationwide screening programme.

Serum 3 alpha-androstanediol glucuronide measurements in children with congenital adrenal hyperplasia.

To determine the value of 3 alpha-androstanediol glucuronide (3-AG) measurements in children with congenital adrenal hyperplasia, we compared serum 3AG, 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T) and dihydrotestosterone (DHT) levels and 24-h urinary 17-ketosteroid (17-KS) excretion in 42 female children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, including 27 with the simple virilizing and 15 with the salt-losing form. Their mean age was 74.5 +/- 48.5 months (range, 6-194 months). Twenty-four-hour urinary 17-KS excretion and serum 3-AG, A, T, DHT and 17-OHP levels were measured in the patients. The values were less than the mean + 2 SD of the control group in 63%, 74%, 67%, 69%, 60% and 31% of the patients, respectively. Serum 3-AG levels correlated with 24-h urinary 17-KS excretion (r = 0.66) and plasma A (r = 0.80), 17-OHP (r = 0.56), T (r = 0.79) and DHT (r = 0.62) levels. We conclude that serum 3-AG is a useful metabolic index in the management of children with congenital adrenal hyperplasia.

Growth response to growth hormone-releasing hormone(1-29)-NH2 compared with growth hormone.

To assess the growth-promoting effect of different doses of growth hormone-releasing hormone(1-29)-NH2 (GHRH(1-29)-NH2) in GH deficiency (GHD) of hypothalamic origin, 43 prepubertal children aged between 4.3 and 18.9 years (mean 10.4 +/- 2.9 years) were randomly assigned to three treatment regimens: low-dose GHRH(1-29)-NH2 (LD group; n = 15), high-dose GHRH(1-29)-NH2 (HD group; n = 12) and GH (GH group; n = 16). The LD group received GHRH(1-29)-NH2 at 30 micrograms/kg/day s.c. in three daily doses, the HD group received 60 micrograms/kg/day s.c. in three daily doses and the GH group received GH, 0.1 IU/kg/day s.c. once daily. All children were treated for a period of 6 months. Evaluation included anthropometry, bone age, intravenous and subcutaneous GHRH(1-29)-NH2 tests and determination of insulin-like growth factor I (IGF-I) levels. An increase in height velocity of 2 cm/year or more was observed in all except two children. Height velocity during treatment was lowest in the LD group, but comparable in the HD and GH groups. An increase in height SDS for bone age occurred only in the GH-treated group. GH responses to intravenous GHRH(1-29)-NH2 showed a priming effect of the LD GHRH(1-29)-NH2 treatment, while a decrease in response occurred in the GH-treated group. Following a subcutaneous test dose of one-third of the daily dose of GHRH(1-29)-NH2, GH levels remained unchanged in both the LD and HD groups. There was accumulation of GHRH immunoreactivity over time in the HD group, but there was no correlation between measured GHRH and GH levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulbactam/ampicillin in the treatment of pediatric infections.

Seventy eight pediatric patients (43 males, 35 females) aged 34 days to 17 years were treated with intravenous or intramuscular sulbactam/ampicillin 3 or 4 times daily for skeletal system infection (10 cases), systemic salmonellosis (2 cases), intrathoracic infection (12 cases), and soft tissue or miscellaneous infections (54 cases). The dose used to treat the majority of patients was 200 mg of ampicillin plus 100 mg of sulbactam per kg/day. The duration of treatment ranged from 8 to 23 days. Sulbactam/ampicillin alone was used in 68 patients. Ten patients were treated with an additional antibacterial agent. The overall cure rate was 98.7% for all 78 study patients. One patient with an abscess in the neck was shown to be infected with a strain of Escherichia coli resistant to sulbactam/ampicillin. Only one patient experienced a rash, but it did not necessitate discontinuation of therapy. This study shows that sulbactam/ampicillin is a safe and effective agent in the treatment of various pediatric infections.