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C A Stratakis

Publications and source records attributed to C A Stratakis.

122 records · Page 7Linked to original sources
PubMed1994

Ulerythema ophryogenes and keratosis pilaris in a child with monosomy 18p.

We report a 13-year-old boy with deletion of the short arm of chromosome 18 and follicular, partially inflammatory, keratotic papules of the eyebrows, foreskin, and cheeks (ulerythema ophryogenes) as well as the shoulders, upper back, upper arms, and thighs (keratosis pilaris), initially diagnosed as atopic dermatitis. Over 100 patients with this genetic defect have been reported, and the 18p- syndrome is considered one of the most frequently occurring deletion syndromes. However, ulerythema ophryogenes and keratosis pilaris have not been described in any of these patients, although the association of the latter with other genetic abnormalities is well known. Keratosis pilaris is a relatively common genodermatosis of ectodermal origin, frequently occurring with ichthyosis or atopy; concomitance with ulerythema ophryogenes has also been reported. The association of chromosome 18p deletion defect and ulerythema ophryogenes may be helpful in future attempts to localize the gene defect responsible for follicular genokeratoses.

Child↗
PubMed1993

Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene.

The clinical syndrome of generalized, compensated glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hyper- or hypocortisolism, and manifestations of androgen and/or mineralocorticoid excess. This condition results from partial failure of the glucocorticoid receptor (GR) to modulate transcription of its target genes. We studied the molecular mechanisms of this syndrome in a Dutch kindred, whose affected members had hypercortisolism and approximately half of normal GRs, and whose proband was a young woman with manifestations of hyperandrogenism. Using the polymerase chain reaction to amplify and sequence each of the nine exons of the GR gene alpha, along with their 5'- and 3'-flanking regions, we identified a 4-base deletion at the 3'-boundary of exon 6 in one GR allele (delta 4), which removed a donor splice site in all three affected members studied. In contrast, the sequence of exon 6 in the two unaffected siblings was normal. A single nucleotide substitution causing an amino acid substitution in the amino terminal domain of the GR (asparagine to serine, codon 363) was also discovered in exon 2 of the other allele (G1220) in the proband, in one of her affected brothers and in her unaffected sister. The functional importance of this mutation was tested in a cotransfection study using the recombinant expression vector pRShGR-Ser363 and the glucocorticoid responsive vector mouse mammary tumor virus-chloramphenicol transferase. This amino acid substitution did not alter the function of the glucocorticoid receptor. Using reverse transcription-polymerase chain reaction we could only identify messenger RNA transcripts of the G1220-allele but not of the delta 4-allele in the affected members of this family who were heterozygous for the G1220 mutation. This deletion in the glucocorticoid receptor gene was, thus, associated with the expression of only one allele and a decrease of GR protein by 50% in affected members of this glucocorticoid resistant family. The mutation identified in exon 2 did not segregate with the disease and appears to be of no functional significance. The presence of the null allele was apparently compensated for by increased cortisol production at the expense of concurrent hyperandrogenism.

Adult↗
PubMed1991

Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance.

Familial glucocorticoid resistance is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations in the absence of stigmata of Cushing's syndrome. Our previous studies of the first reported kindred showed a two- to threefold reduction in glucocorticoid receptor-ligand binding affinity in the propositus, and a lesser reduction in affinity in his mildly affected son and nephew. Glucocorticoid receptor cDNA from these three patients was amplified by polymerase chain reaction and sequenced. The cDNA nucleotide sequence was normal, except for nucleotide 2054, which substituted valine for aspartic acid at amino acid residue 641. The propositus was homozygous while the other relatives were heterozygous for the mutation. COS-7 monkey kidney cells were cotransfected with expression vectors for either wild type or Val 641-mutant receptors, together with the reporter plasmid pMMTV-CAT. Dexamethasone increased chloramphenicol acetyltransferase activity in cells expressing wild type receptor, but had no effect in cells expressing Val 641-mutant receptors, despite similar receptor concentrations, as indicated by Western blotting. The binding affinity for dexamethasone of the Val 641-mutant receptor was threefold lower than that of the wild type receptor. These results suggest that glucocorticoid resistance in this family is due to a point mutation in the steroid-binding domain of the glucocorticoid receptor.

Amino Acids↗
PubMed1990

Structural analysis of the regulatory region of the human corticotropin releasing hormone gene.

A DNA fragment containing the human corticotropin releasing hormone (CRH) gene, along with 9 kb of upstream and 4 kb of downstream sequences, was isolated from a human genomic DNA library. Nucleotide sequence analysis of the proximal 918 nucleotides 5' flanking the putative major mRNA start site of the human gene and comparison to the 866 nucleotide long homologous ovine sequence, revealed that this region of the CRH gene consists of two distinct areas with different degrees of homology, varying from 72% to 94%. The putative functional features of the human sequence were identified. Many, but not all, features were conserved in the ovine sequence. The highly conserved nature of the regulatory region of this gene makes it a good candidate for tracing possible related genetic defects of the hypothalamic-pituitary-adrenal (HPA) axis.

Animals↗
PubMed1990

Effect of hypertonic saline infusion on the level of immunoreactive dynorphin in extracted human plasma.

Dynorphin-A and its related peptides are derived from prodynorphin, one of the three known endogenous opioid precursors. The prodynorphin gene is expressed in the vasopressinergic magnocellular neurons of the hypothalamus, while its peptide products are present in the vasopressin (AVP) neurosecretory vesicles of the neurohypophysis. The concentration of immunoreactive (IR) dynorphin is orders of magnitude higher in the neurohypophysis than in any other tissue, suggesting that perhaps the prodynorphin-derived peptides are secreted from the hypothalamic-neurohypophyseal unit into the general circulation. Experiments in rats have shown that osmotic stimuli increase both AVP and prodynorphin in the hypothalamus. To determine whether human hypothalamic prodynorphin is also under osmotic regulation, we measured plasma IR-dynorphin, plasma IR-AVP, and serum sodium immediately before and during the infusion of normal or hypertonic saline in normal human volunteers. Because of the unusual susceptibility of the prodynorphin-derived peptides to cleavage by endopeptidases, we also developed an appropriate plasma dynorphin extraction technique. We found that the IR-dynorphin present in human plasma was composed of 6K- and 4K-sized peptides and that no larger than 6K or smaller than 4K dynorphins were present. The infusion of normal saline did not have any significant effect on plasma IR-dynorphin, while 3% hypertonic saline increased its plasma levels. Thus, the mean IR-dynorphin level in the plasma of the volunteers infused with normal saline was 40.3 +/- 6.4 fmol/mL (mean +/- SE; n = 6) at zero time; after 30 min of infusion, plasma IR-dynorphin was 36.0 +/- 6.3, after 60 min it was 29.9 +/- 5, after 90 min it was 36.0 +/- 4.7, after 120 min it was 36.8 +/- 3.2, and after 150 min it was 36.0 +/- 6.1. The plasma IR-dynorphin level in the volunteers infused with hypertonic saline was 31.7 +/- 3.5 fmol/mL (mean +/- SE; n = 10) at zero time. After 30 min of infusion it increased to 37.4 +/- 3.8, after 60 min to 46.4 +/- 7.7, after 90 min to 56.2 +/- 9.1, after 120 min to 53.6 +/- 8.7, and after 150 min to 99.0 +/- 14.2. The increase in plasma IR-dynorphin with time was significant (P less than 0.0001) and correlated positively with serum sodium and plasma AVP. The physiological role of the prodynorphin-derived peptides of the hypothalamic-neurohypophyseal unit is not yet known.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromatography, Affinity↗
PubMedDate not supplied

Lack of linkage between the corticotropin-releasing hormone (CRH) gene and bipolar affective disorder.

Corticotropin-releasing hormone (CRH) plays a key role in the regulation of the stress response. Abnormalities in CRH secretion have been documented in both the depression and manic phases of bipolar disorder (BPD). In the present study, we investigated genetic linkage between the CRH gene and BPD in 22 pedigrees. A highly informative, short tandem repeat (STR) polymorphism adjacent to the CRH gene on human chromosomal region 8q13 was used to examine linkage. Affected sibling pair (ASP) and the likelihood-based disequilibrium tests revealed nonsignificant values. We conclude that the CRH gene is not linked to BPD; if genes involved in the regulation of stress response are indeed linked to BPD, the search should be directed towards those that regulate CRH secretion or its effects on target tissues.

Bipolar Disorder↗
PubMedDate not supplied

Ovarian tumors associated with multiple endocrine neoplasias and related syndromes (Carney complex, Peutz-Jeghers syndrome, von Hippel-Lindau disease, Cowden's disease).

Despite the relatively high prevalence of ovarian cancer (1% of American women will develop this disease in their lifetime) and recent developments in its molecular genetic understanding (several proto-oncogenes, such as AKT2 and cKRAS, and tumor suppressor genes, such as BRCA1 and BRCA2, have been implicated), little is known about the presence of ovarian tumors and cancer in women already diagnosed with other familial multiple tumor syndromes. In this review, we focus on the possible association of ovarian tumors with multiple endocrine neoplasias (MENs) and their related syndromes, such as Carney complex (CNC), Peutz-Jeghers syndrome (PJS), von Hippel-Lindau disease (VHLD), and Cowden's disease (CD). These conditions recently have been molecularly elucidated, and some of the genes responsible for them (including STK11/LKB1 and PTEN, the genes responsible for PJS and CD, respectively) have already been investigated in series of sporadic ovarian lesions, mostly carcinomas. A brief description of each disease is followed by a literature search for affected patients with ovarian tumors; we review our own experience with CNC patients and ovarian tumors. An association between PJS and CNC and ovarian neoplasms seems likely; carcinoids of the ovary may occur in patients with MEN 1. Only few patients with CD and VHLD have any ovarian pathology, but PTEN, the CD gene has been investigated in sporadic ovarian tumors. The aim of the present report is to alert clinicians who care for patients with MENs, CNC, PJS, VHLD, CD, and other syndromes for possible associations between various types of ovarian tumors and these conditions.

Female↗
PubMedDate not supplied

Skin manifestations of Cushing disease in children and adolescents before and after the resolution of hypercortisolemia.

Cushing disease (CD) is a common cause of endogenous hypercortisolism in childhood. Its skin manifestations include striae, facial acne, hirsutism, acanthosis nigricans, fungal infections, hyperpigmentation and easy bruisability. We followed 36 children and adolescents with CD (14 boys and 22 girls), to define the natural history of skin disease in endogenous hypercortisolism. Physical examination and 24 hour urinary free cortisol (UFC) and 17-hydroxycorticosteroid (17-OHS) excretion values were obtained preoperatively and quarterly for 18 months. Preoperatively our patients exhibited purple subcutaneous striae (77.7%), steroid-induced acne (58.3%), hirsutism (63.7% of the 22 girls), acanthosis nigricans (27.7%), ecchymoses (27.7%), hyperpigmentation (16.6%), and fungal infections (11.1%). The levels of UFC and 17-OHS preoperatively were 351.84+/-243.85 microg/m2/day (mean+/-SD) and 17.92+/-7.86 mg/g creatinine/day, respectively. No correlation was found between these levels and the severity of the lesions. All patients were cured. Symptoms decreased dramatically within the 3 postoperative months and progressively disappeared within the first year of the follow-up period with the exception of light-colored striae; they were present in 5.6% of the patients at 18 months postoperatively. No acanthosis nigricans or hyperpigmentation were observed at 3 months postoperatively. Hirsutism was not present at 9 months postoperatively. We conclude that in children with CD the skin is affected at multiple sites; however, the severity of the manifestations does not correlate with the biochemical indices of the disease. With the exception of striae, cutaneous effects of endogenous hypercortisolism completely heal within the first year after surgical cure of the disease.

Adolescent↗
PubMedDate not supplied

Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome.

Primary bilateral adrenocortical diseases are rare entities that have recently been appreciated as potential causes of Cushing syndrome. They include (i) primary pigmented adrenocortical disease (PPNAD), also known as "micronodular adrenal disease", which is a genetic disorder that is often associated with Carney complex, and (ii) massive macronodular adrenocortical disease (MMAD), a rare disorder of unknown etiology that affects older adults. Carney complex is a multiple endocrine neoplasia (MEN) syndrome that affects not only the adrenal cortex, but also the pituitary, thyroid, and gonads. It is associated with pigmentation abnormalities as well as myxomas and other mesenchymal and neural crest neoplasms. The inheritance of the complex is autosomal dominant, and genetic mapping has shown that at least two loci are involved in its pathogenesis. MMAD appears to be an isolated finding in most cases, and a genetic defect has not yet been defined. Ectopic expression of hormone receptors has been implicated in several cases of MMAD, but an underlying deficit has not been detected. Bilateral adrenocortical hyperplasia has also been described in McCune-Albright syndrome and MEN type-1, but this finding is not always associated with hypercortisolism. The genetic defects for these diseases are known, but their role in adrenal cortex pathophysiology has not been fully elucidated. Identification of the molecular defects responsible for bilateral adrenocortical disorders is expected to shed light on many aspects of early adrenal gland differentiation and tumorigenesis.

Adrenal Cortex Diseases↗
PubMedDate not supplied

Pituitary adenoma in Carney complex: an immunohistochemical, ultrastructural, and immunoelectron microscopic study.

First described in 1985, Carney complex is a rare, heritable disorder featuring abnormal skin pigmentation, cardiac and cutaneous myxoma, melanotic schwannoma of psammomatous type, and endocrine abnormalities, including pituitary adenomas. Patients with the latter present with elevated growth hormone (GH) levels and acromegaly or gigantism. Prolactin (PRL) elevation may also be seen. The authors have investigated 2 resected pituitary adenomas from patients with Carney complex. One, a 19-year-old female acromegalic with elevated GH, IgF-1, and PRL levels, had a mammosomatotroph adenoma immunoreactive for GH and PRL. Ultrastructurally, GH and PRL were present in the same secretory granules. The second patient, a 27-year-old acromegalic, had a sparsely granulated GH cell adenoma that by immuno-electron microscopy revealed GH immunoreactivity only. The lack of morphologic similarity between the 2 adenomas indicatesthat pituitary tumors in patients with Carney complex may not exhibit the same phenotype.

Abnormalities, Multiple↗
PubMedDate not supplied

Dysregulation of the hypothalamic-pituitary-adrenal axis in short children with and without growth hormone deficiency.

The effects of L-dopamine (LD) administration and insulin-induced hypoglycemia in adrenocorticotropin (ACTH) and cortisol secretion were studied in 14 short boys. LD caused moderate changes in both hormones. The four boys with isolated, idiopathic growth hormone (GH) deficiency (IGD) demonstrated a greater cortisol increase in response to hypoglycemia than the 10 boys with normal GH secretion. In at least some short children with IGD, abnormal regulation of the hypothalamic-pituitary-adrenal axis may be present.

Adolescent↗