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Nongerminomatous germ cell tumor of the pineal gland causing gonadotropin-independent precocious puberty in a child with 47, XYY karyotype - A clinical and radiographic case review

Khan, A; Price, D; Castro-Magana, M; Angulo, M; Canas, JA
A 3-year and 11-months-old boy presented with a 9-month history of increasing penile enlargement, pubic hair, deepening of the voice, and rapid growth. The erect penile length was 14 cm, with bilateral testicular volume of 3 mL. Laboratory evaluation revealed suppressed follicle-stimulating hormone and luteinizing hormone, elevated total testosterone (259 ng/dL), elevated alpha feto-protein (AFP 79 ng/mL), rapidly increasing beta-human chorionic gonadotropin (beta-hCG 14-399 mIU/mL) over 2 weeks, and a karyotype revealed 47, XYY. Radiographic evaluation revealed a 1.5-cm mixed solid/cystic mass in the pineal gland. Chemotherapy was initiated to attempt to normalize the tumor markers (AFP and beta-hCG). This is the first report of a nongerminomatous germ cell tumor (NGGCT) in a 47, XYY karyotype male. Tumor markers (hCG and AFP) should be included in the workup of adult males with 47, XYY as they are in children with precocious puberty.
ISSN: 1051-2144
CID: 3488192


Accacha, SD; Niu, QT; Castro-Magana, M; Aloia, JF; Yeh, JK
ISSN: 0171-967x
CID: 2600942

Influence of growth hormone on bone marrow adipogenesis in hypophysectomized rats

Appiagyei-Dankah, Yaw; Tapiador, Carmen D; Evans, Jodi F; Castro-Magana, Mariano; Aloia, John F; Yeh, James K
The hypophysectomized rat has been used as a model to study the effects of growth hormone deficiency on bone. Here, we have investigated the influence of growth hormone administration to hypophysectomized rats (HX) for 6 wk on accumulation of triglycerides in bone marrow and on the differentiation of primary marrow stromal cells into adipocytes under in vitro conditions. We found that hypophysectomy significantly increased triglyceride concentration in bone marrow, which was attenuated by growth hormone administration. Primary bone marrow stromal cells derived from HX rats also had more adipocytes at confluence compared with growth hormone-treated hypophysectomized (GH) rats. When stimulated with 3-isobutyl-1-methylxanthine plus dexamethasone (IBMX-Dex), preadipocyte colony counts increased more significantly in GH rats. Markers of adipocyte differentiation were higher in HX than in control or GH rats at confluence. However, after stimulation with IBMX-Dex, increased expression of markers was seen in GH compared with HX rats. In conclusion, growth hormone administration to hypophysectomized rats attenuated triglyceride accumulation in bone marrow and inhibited the differentiation of stromal cells into adipocytes in vitro.
PMID: 12453825
ISSN: 0193-1849
CID: 2599322

Newly proposed hormonal criteria via genotypic proof for type II 3beta-hydroxysteroid dehydrogenase deficiency

Lutfallah, Chantal; Wang, Weihua; Mason, J Ian; Chang, Ying Tai; Haider, Anzar; Rich, Barry; Castro-Magana, Mariano; Copeland, Kenneth C; David, Raphael; Pang, Songya
To define the hormonal criteria via genotypic proof for 3beta-hydroxysteroid dehydrogenase (3beta-HSD) deficiency in the adrenals and gonads, we investigated the type II 3beta-HSD genotype in 55 patients with clinical and/or hormonal presentation suggesting compromised adrenal with or without gonadal 3beta-HSD activity. Fourteen patients (11 males and 3 females) had ambiguous genitalia with or without salt wasting and with or without premature pubarche. One female neonate had salt wasting only. Twenty-five children (4 males and 21 females) had premature pubarche only. Fifteen adolescent and adult females had hirsutism with or without menstrual disorder. The type II 3beta-HSD gene, including the promoter region up to -1053 base, all exons I, II, III, IV, and exon and intron boundaries, was sequenced in all subjects. Eight patients had a proven or predictably deleterious mutation in both alleles of the type II 3beta-HSD gene, and 47 patients had no apparent mutation in the gene. ACTH-stimulated (1 h post iv bolus of 250 microg Cortrosyn) serum 17-hydroxypregnenolone (Delta5-17P) levels and basal and ACTH-stimulated ratios of Delta5-17P to cortisol (F) in the genotypic proven patients were unequivocally higher than those of age-matched or pubic hair stage matched genotype-normal patients or control subjects (n = 7-30 for each group). All other baseline and ACTH-stimulated hormone parameters, including dehydroepiandrosterone (DHEA) levels, ratios of Delta5-17P to 17-OHP and DHEA to androstenedione in the genotype-proven patients, overlapped with the genotype-normal patients or control subjects. The hormonal findings in the genotype-proven patients suggest that the following hormonal criteria are compatible with 3beta-HSD deficiency congenital adrenal hyperplasia (numeric and graphic reference standards from infancy to adulthood are provided): ACTH-stimulated Delta5-17P levels in 1) neonatal infants with ambiguous genitalia at or greater than 378 nmol/liter equivalent to or greater than 5.3 SD above the control mean level [95 +/- 53 (SD) nmol/liter]; 2) Tanner I children with ambiguous genitalia at or greater than 165 nmol/liter equivalent to or greater than 35 SD above the control mean level [12 +/- 4.3 (SD) nmol/liter]; 3) children with premature pubarche at or greater than 294 nmol/liter equivalent to or greater than 54 SD above Tanner II pubic hair stage matched control mean level [17 +/- 5 (SD) nmol/liter]; and 4) adults with at or greater than 289 nmol/liter equivalent to or greater than 21 SD above the normal mean level [25 +/- 12 (SD) nmol/liter]. ACTH-stimulated ratio of Delta5-17P to F in 1) neonatal infants at or greater than 434 equivalent to or greater than 6.4 SD above the control mean ratio [88 +/- 54 (SD)]; 2) Tanner I children at or greater than 216 equivalent to or greater than 23 SD above the control mean ratio [12 +/- 9 (SD)]; 3) children with premature pubarche at or greater than 363 equivalent to or greater than 38 SD above the control mean ratio [20 +/- 9 (SD)]; and 4) adults at or greater than 4010 equivalent to or greater than 221 SD above the normal mean ratio [29 +/- 18 (SD)]. Conversely, the hormonal data in the genotype-normal patients suggest the following hormonal criteria are not consistent with 3beta-HSD deficiency congenital adrenal hyperplasia: ACTH-stimulated Delta5-17P levels in children with premature pubarche up to 72 nmol/liter equivalent to up to 11 SD above the control mean level, and in hirsute females up to 150 nmol/liter equivalent to up to 12 SD above the normal female mean level [28 +/- 10 (SD) nmol/liter]; and ACTH-stimulated Delta5-17P to F ratio in children with premature pubarche up to 67 equivalent to up to 5 SD above the control mean ratio, and in hirsute females up to 151 equivalent to up to 10 SD above the normal mean ratio [32 +/- 12 (SD)]. These findings help define newly proposed hormonal criteria to accurately predict inherited 3beta-HSD deficiency
PMID: 12050224
ISSN: 0021-972x
CID: 71768

TSH-induced ovarian hyperstimulation syndrome associated with massive ovarian enlargement and suppressed LH [Meeting Abstract]

Tapiador, CD; Appiagyei-Dankah, Y; Idris, M; Accacha, S; Lamerson, M; Castro-Magana, M
ISSN: 0031-3998
CID: 3488172

Consensus statement - Prader-Willi syndrome: Growth hormone (GH)/insulin-like growth factor axis deficiency and GH treatment

Lee, PDK; Allen, DB; Angulo, MA; Cappa, M; Carrel, AL; Castro-Magana, M; Chiumello, G; Davies, PSW; Eiholzer, U; Grugni, G; Hauffa, BP; Hintz, RL; Lammer, C; Mogul, HR; Myers, SE; Partsch, CJ; Pescovitz, OH; Ritzen, EM; Rosenfeld, RG; Sipila, I; Wilson, DM
Prader-Willi syndrome (PWS) is a disabling condition characterized by hypotonia, hyperphagia, obesity, short stature, delayed or absent puberty, and mental retardation. The syndrome complex was first described in 1956 by Dr. Andrea Prader and colleagues [1]. In the 1980s, a characteristic genetic defect was identified involving deletion of paternal alleles at chromosome 15q11-13 [2-6]. This occurs by deletion of alleles on the paternal copy of chromosome 15q, an absent paternal chromosome 15q with maternal disomy, or, rarely, by mutations of the imprinting center of chromosome 15q. The estimated population prevalence of PWS is 1 in 15,000 live births.
ISSN: 1051-2144
CID: 3488162

Melanocortin 5-receptor expression in bone. A possible involvement in the overgrowth phenomenon of Familial Glucocorticoid Deficiency (FGD) [Meeting Abstract]

Canas, JA; Evans, J; Tapiador, C; Appiagyei, Y; Lamerson, M; Arguello, R; Angulo, M; Castro-Magana, M
ISSN: 0031-3998
CID: 3488142

Final height in Prader-Willi syndrome (PWS) children treated with recombinant growth hormone (rhGH) [Meeting Abstract]

Angulo, MA; Castro-Magana, MS; Canas, JA; Arguello, R; Lamerson, M; Tapiador, C; Appiagyei, Y
ISSN: 0031-3998
CID: 3487622

Progressive deterioration of thyrotrope function associated with increased growth velocity in a child with deletion of the PROP-1 gene [Meeting Abstract]

Tapiador, CD; Appiagyei-Danka, Y; Lamerson, M; Canas, JA; Angulo, MA; Baumbach-Reardon, L; Arguello, R; Castro-Magana, MS
ISSN: 0031-3998
CID: 3487612

Characterization of two novel homozygous missense mutations involving codon 6 and 259 of type II 3beta-hydroxysteroid dehydrogenase (3betaHSD) gene causing, respectively, nonsalt-wasting and salt-wasting 3betaHSD deficiency disorder [Case Report]

Zhang, L; Mason, J I; Naiki, Y; Copeland, K C; Castro-Magana, M; Gordon-Walker, T T; Chang, Y T; Pang, S
We identified two homozygous missense mutations in the human type II 3beta-hydroxysteroid dehydrogenase (3/betaHSD) gene, the first in codon 6 of exon II [CTT (Leu) to TTT (Phe)] in a male infant with hyperpigmented scrotum and hypospadias, raised as a male and no apparent salt-wasting since neonatal age, and the second in codon 259 of exon IV [ACG (Thr) to ATG (Met)] in a male pseudohermaphrodite with labial scrotal folds, microphallus, chordee, and fourth degree hypospadias, raised as a female and with salt-wasting disorder since neonatal age. In vitro transient expression of mutant type II 3betaHSD complementary DNAs of L6F, T259M, as well as T259R for comparison was examined by a site-directed mutagenesis and transfection of construct into COS-1 and COS-7 cells. Northern blot analysis revealed expression of similar amounts of type II 3betaHSD messenger ribonucleic acid from the COS-1 cells transfected by L6F, T259M, T259R, and wild-type (WT) complementary DNAs. Western immunoblot analysis revealed a similar amount of L6F mutant protein compared to WT enzyme from COS-1 cells, but neither L6F from COS-7 cells nor T259M or T259R mutant protein in COS-1 or COS-7 cells was detectable. Enzyme activity in intact COS-1 cells using 1 micromol/L pregnenolone as substrate in the medium after 6 h revealed relative conversion rates of pregnenolone to progesterone of 46% by WT enzyme, 22% by L6F enzyme, and 8% by T259M enzyme and less than 4% activity by T259R enzyme. Using 1 micromol/L dehydroepiandrosterone as substrate, the relative conversion rate of dehydroepiandrosterone to androstenedione after 6 was 89% by WT enzyme, 35% by L6F enzyme, 5.1% by T259M enzyme and no activity by T259R enzyme. However, the L6F mutant 3betaHSD activity, despite its demonstration in the intact cells, was not detected in homogenates of COS-1 cells or in immunoblots of COS-7 cells, suggestive of the relatively unstable nature of this protein in vitro, possibly attributable to the decreased 3betaHSD activity. In the case of T259M and T259R mutations, consistently undetectable proteins in both COS cells despite detectable messenger ribonucleic acids indicate severely labile proteins resulting in either no or very little enzyme activity, and these data further substantiate the deleterious effect of a structural change in this predicted putative steroid-binding domain of the gene. In conclusion, the findings of the in vitro study of mutant type II 3betaHSD enzyme activities correlated with a less severe clinical phenotype of nonsalt-wasting and a lesser degree of genital ambiguity in the patient with homozygous L6F mutation compared to a more severe clinical phenotype of salt-wasting and severe degree of genital ambiguity in the patient with homozygous T259M mutation in the gene.
PMID: 10770215
ISSN: 0021-972x
CID: 3487772