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Biomedical subjects

C A Stratakis

Publications and source records attributed to C A Stratakis.

At least 109 records · Page 6Linked to original sources
PubMed1996

Dideoxyfingerprinting (ddF) analysis of the type X collagen gene (COL10A1) and identification of a novel mutation (S671P) in a kindred with Schmid metaphyseal chondrodysplasia.

Schmid metaphyseal chondrodysplasia (SMCD; MIM 156500) is an autosomal dominant disorder of the skeleton that is manifested in early childhood by short stature, coxa vara, and a waddling gait. Patients with SMCD have mutations in the gene that codes for the alpha-1 chain of collagen X (COL10A1); however, mutation analysis of this gene is hampered by its size. We studied a family with SMCD: the mother, a 36-year-old woman with a height of 149 cm, had mild bilateral coxa vara. Her two sons presented with short stature, bowed legs, and coxa vara in early childhood. DNA was extracted from peripheral lymphocytes from the three patients and subjected to PCR amplification by COL10A1 gene-specific primers. In addition to single-strand conformational polymorphism (SSCP) analysis of the COL10A1 gene, we used a novel method, dideoxy fingerprinting (ddF). The genetic defect in this family was found to be a previously unreported missense mutation (T-to-C transition) at nucleotide 2011. This change resulted in a Ser-to-Pro substitution at position 671 of the carboxy-terminus of the COL10A1 protein. In addition, the two boys, but not the mother, were found to carry a trinucleotide (CCC) deletion at position 2048 of the 3' untranslated region, a polymorphism of the COL10A1 gene. We conclude that ddF can be used in the analysis of the COL10A1 gene along with SSCP. The S671P substitution is novel, but located in the same region with the other reported COL10A1 mutations, confirming type X collagen as the locus for this disease.

Adult↗
PubMed1996

Transient elevation of serum thyroid hormone levels following lithium discontinuation.

UNLABELLED: Lithium therapy has been associated with altered thyroid function and even goiter in as many as half of chronically treated patients. We describe the case of a 16-year-old boy who developed transient hyperthyroxinemia after discontinuation of chronic lithium therapy. The lack of clinical hyperthyroidism and the gradual resolution of the biochemical abnormalities in this patient pointed to the benign character of his condition known as "euthyroid hyperthyroxinemia". CONCLUSION: Euthyroid hyperthyroxinemia may be a benign, transient complication of lithium-therapy discontinuation and should be considered in the diagnostic evaluation of lithium-related thyroid abnormalities.

Adolescent↗
PubMed1996

Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gs alpha gene.

Cardiac myxomas are rare tumors that may be encountered sporadically or in the context of the Carney complex. The molecular basis for the development of cardiac myxomas and Carney complex tumors is unclear. Pathological myocardial function and myocardial hypertrophy have been associated with alterations in the heterotrimeric GTP-binding proteins. The postulated proto-oncogenic character of the gene encoding the alpha sub-unit of the stimulatory GTP-binding protein Gs alpha (gsp) in pituitary and thyroid tumors, the finding of identical somatic gsp mutations in the myocardium of patients with McCune-Albright syndrome, and the associated endocrine anomalies of the Carney complex prompted us to investigate the occurrence of activating missense mutations in the Gs alpha gene in 10 sporadically occurring atrial myxomas and in 8 tumors from 7 patients with Carney complex. No gsp mutations could be demonstrated by using the polymerase chain reaction and denaturing gradient gel electrophoresis complemented by direct DNA sequencing. Thus, activating Gs alpha mutations neither are associated with the development of atrial myxomas, nor can be demonstrated in other tumors from patients with Carney complex. The significance of these mutations in the myocardium of asymptomatic patients with McCune-Albright syndrome remains to be determined.

Adult↗
PubMed1996

Nelson's syndrome associated with a somatic frame shift mutation in the glucocorticoid receptor gene.

Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for Cushing's disease. Extremely high plasma ACTH levels and aggressive neoplastic growth might be explained by the lack of appropriate glucocorticoid negative feedback due to defective glucocorticoid signal transduction. To study the glucocorticoid receptor (GR) gene in Nelson's syndrome, DNA was extracted from pituitary adenomas and leukocytes of four patients with this condition and amplified by PCR for direct sequence analysis. In one of the tumors, a heterozygous mutation, consisting of an insertion of a thymine between complementary DNA nucleotides 1188 and 1189, was found in exon 2. This frame-shift mutation led to premature termination at amino acid residue 366 of the wild-type coding sequence, excluding the expression of a functioning receptor protein from the defective allele. The mutation was not detected in the sequence of the GR gene in the patient's leukocyte DNA, indicating a somatic origin. By lowering the receptor number in tumorous cells, this defect might have caused local resistance to negative glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistance syndrome. P53 protein accumulation, previously reported in 60% of corticotropinomas, could not be detected in any of the four pituitary tumors examined by immunohistochemistry. We suggest that a somatic GR defect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation.

Adrenocorticotropic Hormone↗
PubMed1996

Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex).

Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known and includes endocrine neoplasms causing Cushing's syndrome [primary pigmented nodular adrenocortical disease (PPNAD)] and acromegaly (GH-producing adenoma). The molecular defect leading to CC remains unknown, but was recently mapped to chromosome 2p16 by linkage analysis. This region has exhibited cytogenetic aberrations in atrial myxomas from patients with CC and harbors the hMSH2 and hMSH6 genes, which are involved in the preservation of microsatellite length stability of replicating human cells. In the present study, we examined 15 tumor and normal tissue specimens from 13 patients with CC [GH-producing adenoma (n = 1), adrenal tumors (PPNAD, n = 8), thyroid cancer (n = 1), normal adrenal gland (n = 1)] and 4 cultured cell lines [heart myxoma (n = 3) and eyelid myxoma (n = 1)]. Chromosome analysis was obtained by standard cytogenetic techniques. One of the myxoma cell lines and 3 PPNAD specimens contained multiple telomeric associations (tas). The normal adrenocortical tissue from a patient with PPNAD contained no apparent chromosomal anomalies, whereas the neighboring PPNAD tissue demonstrated tas. DNA was extracted from peripheral blood, tumor cell lines, and frozen or paraffin-embedded tissues and subjected to PCR amplification with primers from 64 microsatellite locations covering chromosomes 1 and 3-22 and 14 loci covering chromosome 2. The alterations detected were loss and gain of heterozygosity (LOH and GOH; 49% and 26%, respectively), deletions of both alleles (DEL; 10%), and microsatellite length instability (15%). GOH and LOH were the most frequent changes, with telomeric markers significantly over-represented (P < 0.05). Chromosomes 6, 11, 22, 10, and 19 demonstrated mostly LOH, GOH, or DEL in over 40% of the informative loci tested (73%, 59%, 47%, 46%, and 44%, respectively), whereas markers on chromosome 2 showed only microsatellite length instability (10%). The degree of genomic instability and its type were independent of tumor type (P > 0.1). We conclude that tumors and tumor cell lines from patients with CC demonstrate significant genomic, but not microsatellite length, instability. Thus, the CC gene(s) on chromosome 2p16 is different from the hMSH2 and hMSH6 genes and has dominant, rather than recessive, tumorigenic function. This gene(s) appears to be involved in the regulation of genomic stability of dividing cells, in particular the structure of telomeres in replicating chromosomes and/or the function of the mitotic apparatus.

Acromegaly↗
PubMed1996

24-hour secretion of growth hormone (GH), insulin-like growth factors-I and -II (IGF-I, -II), prolactin (PRL) and thyrotropin (TSH) in young adults of normal and tall stature.

Studies of the growth hormone (GH) secretory dynamics of children with normal and idiopathic short stature (ISS) have revealed that the regulation of the GH-somatomedin (GHS) axis can differ significantly among normal individuals. Information on the GH secretion in idiopathic tall stature (ITS) is scarce. We previously showed that the GH response to stimulation with GH-releasing hormone (GHRH) in male, late adolescents and young adults with ITS is significantly greater than that of their sex and age-matched controls of average height. In the present study, we studied the 24-hour (hr) GH, insulin-like growth factor-I and -II (IGF-I and -II), prolactin (PRL) and thyroid-stimulating hormone (TSH) secretion by every 30 minutes (min) sampling in 12 young, healthy male Greek army recruits. Group I [n = 6, age 22 + 1.4 years (y.), mean + standard deviation (SD)] had a height of 198.5 + 4.2cm, at least 3 SD's above the mean of the Greek male population. Group II (n = 6, age 20.5 + 1.05 y.) had a height of 169.2 + 3.4cm, within 2SD's of the normal mean. Serum IGF-I levels were determined in both unextracted and extracted samples. Our results indicated that the number of secretory bursts and the circadian panel of GH, IGF-I and -II, PRL and TSH were similar in the two groups. Both the amplitude of the secretory GH peaks (5.08 + 3.07 vs. 3.3 + 0.8 ng/ml, p = 0.19,) and the area under the curve (AUC) of the 24-hour GH secretion (9.8 + 5.5 vs. 6.6 + 1.3 ng/ml/hr, p = 0.2) were higher in group I than in group II, but the difference was not significant. A significant nocturnal increase of both IGF-I and -II levels was found only in extracted human plasma (p < 0.001), whereas measurements of IGF-I in unextracted samples failed to reveal circadian variation (p < 0.1). We conclude that no significant differences were found in this pilot study of the neurosecretory regulation of the GHS axis between individuals of tall and normal stature. A tendency for greater amount of GH secretion per secretory peak was found in persons with tall stature; however, this finding needs to be confirmed in a larger study. IGF-I and -II levels had a significant circadian variation with a large nocturnal surge, when measured in extracted plasma. The latter, might be explained by circadian variation of the circulating IGF-binding proteins and its detection appears to be method of extraction-dependent.

Adult↗
PubMed1995

Neuroendocrinology and pathophysiology of the stress system.

The human organism is in a state of dynamic equilibrium, homeostasis. The stress system is activated when homeostasis is challenged by extrinsic or intrinsic forces, the stressors. This system, whose central component is the central nervous system (CNS) and includes corticotropin-releasing hormone (CRH) and noradrenergic neurons, respectively, in the hypothalamus and the brain stem, has as its peripheral limbs the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic (sympathetic) nervous system. Normal development and preservation of life and species are dependent on a normally functioning stress system. Maladaptive neuroendocrine responses, i.e., dysregulation of the stress system, may lead to disturbances in growth and development, and cause psychiatric, endocrine/metabolic, and/or autoimmune diseases or vulnerability to such diseases.

Affect↗
PubMed1995

Recurring oral giant cell lesion in a child with X-linked hypophosphatemic rickets: clinical manifestation of occult parathyroidism?

A 9-year-old boy with X-linked hypophosphatemic rickets had a recurring oral giant cell lesion. These lesions are relatively uncommon in children and represent a potentially aggressive disorder that is microscopically indistinguishable from the brown tumors of hyperparathyroidism. Subclinical hyperparathyroidism is not uncommon in X-linked hypophosphatemic rickets and may account for the giant cell lesion in this patient.

Biopsy↗
PubMed1995

Neuroendocrinology of stress: implications for growth and development.

A stressor above a threshold magnitude, or multiple stressors applied simultaneously, cause an organism to alter its behaviour and physiology, with the aim of maintaining homeostasis. The adaptive changes that occur are coordinated and mediated by the stress system in the central nervous system (which includes corticotrophin-releasing hormone and noradrenergic neurons in the hypothalamus and brainstem, respectively), and its peripheral limbs, the hypothalamic-pituitary-adrenal axis and the autonomic (sympathetic) system. Controlled or self-driven challenges to homeostasis and a normally functioning stress system are crucial for normal development and preservation of self and species. In childhood and adolescence, appropriately functioning neuroendocrine responses to stressors are necessary to allow growth and psychosexual maturation to progress normally. Maladaptive neuroendocrine responses, i.e. dysregulation of the stress system, may lead to disturbances in growth and development and cause psychiatric, endocrine/metabolic and/or autoimmune diseases or vulnerability to such diseases, not only during childhood and adolescence, but also in adulthood.

Animals↗
PubMed1995

Molecular genetics in pediatric training: how much do we really know?

A questionnaire was designed to assess the degree of knowledge among 44 residents and medical students in a pediatric residency program about recent advances in medical genetics. The mean score was 40% (4 correct answers per individual). There were no significant differences among the groups. The mean number of correct responses to each question was 13, but topics that had been highly publicized, especially in the lay press, were associated with more correct answers. Among residents and medical students, knowledge of the exact genetic defects of inherited diseases and their implications at the molecular and clinical levels may be limited.

District of Columbia↗
PubMed1994

Glucocorticosteroid resistance in humans. Elucidation of the molecular mechanisms and implications for pathophysiology.

Familial glucocorticoid resistance (FGR) is a rare hereditary disorder characterized by hypercortisolism and the absence of stigmata of Cushing's syndrome. The inability of glucocorticoids to exert their effects on target tissues is compensated for by increases in circulating corticotropin (ACTH) and cortisol, the former causing excess secretion of both adrenal androgens and adrenal steroid-biosynthesis intermediates with salt-retaining activity. There is considerable variability in the clinical presentations of FGR ranging from asymptomatic, to isolated chronic fatigue and to hypertension with or without hypokalemic alkalosis or to hyperandrogenism, or both. In women, hyperandrogenism can result in acne, hirsutism, menstrual irregularities, oligoanovulation, and infertility; in men it may lead to infertility and in children to precocious puberty. The reported molecular defects in FGR, such as point mutations and a microdeletion of the glucocorticoid receptor (GR) gene, cause partial resistance by, respectively, compromising the function of the GR or decreasing its intracellular concentration in glucocorticoid target tissues. Complete glucocorticoid resistance is believed to be incompatible with life in humans. Hence, the glucocorticoid resistance cases reported have been partial and of variable degree. The extreme variability in the clinical manifestations of the disorder can, additionally, be explained by differing sensitivity of target tissues to mineralocorticoids or androgens or both, and perhaps by different biochemical defects of the glucocorticoid receptor, causing selective resistance of certain glucocorticoid responses in specific tissues. Isolated tissue-resistance from a somatic mutation of the GR in a corticotropinoma from a patient with Nelson's syndrome was also found, suggesting that this may be a mechanism of tumorigenesis. There is additional evidence that defects of GR function can appear surreptitiously in a variety of clinical conditions, suggesting that glucocorticoid resistance in humans may be involved in the pathogenesis and/or clinical picture of a plethora of disease states, of which FGR is the archetype.

Adrenocorticotropic Hormone↗