Faculty Bibliography

OBJECTIVE: The purpose of this report is to describe 7 infants conceived by assisted reproductive technology (ART) who presented with breast development and/or pubic hair. The clinical presentation in these infants raises awareness that an altered intrauterine hormonal milieu may impact the fetal and infant stages of children conceived by ART. METHODS: Between May 2001 and April 2004, 7 children between the ages of 5 and 21 months conceived by ART were referred by their pediatricians to the Division of Pediatric Endocrinology at the New York University School of Medicine for evaluation of possible precocious puberty. Patients were evaluated for the possibility of centrally mediated precocious puberty and pseudoprecocious puberty, with a possible ovarian or adrenal origin. RESULTS: Endocrine evaluation in all patients indicated sex-steroid and hormone levels in the prepubertal range; pelvic sonography confirmed prepubertal ovaries with unstimulated uteri. Clinical follow-up of our patients thus far has not revealed progression of breast development, pubarche, or elevation in sex steroids. CONCLUSIONS: It is well established that the developing endocrine system in the fetus and maturation of endocrine-control systems are influenced by hormone concentrations in the fetus. Whether ART alters the intrauterine hormonal milieu for the growing fetus conceived by ART is as yet unknown and is an area of ongoing investigation. Patients conceived through ART, including our patients who presented with hormonal manifestations, will need to be monitored throughout childhood and into adolescence and adulthood to determine if any perturbation exists on the timing of puberty and later fertility

Pituitary apoplexy is an acute clinical event usually caused by hemorrhage or infarction in a pituitary adenoma. We report the unusual case of hemorrhagic pituitary apoplexy in an 18 year-old male with previously undiagnosed type 2 diabetes mellitus who presented with unexplained hyperglycemia (glucose 49.2 mmol/l [887 mg/dl]) and obtundation and in whom an initial diagnosis of non-ketotic hyperglycemic coma (NKHC) was made. MRI revealed a heterogeneous mass arising from an expanded sella turcica into the suprasellar cistern. Despite well-controlled glucose levels on continuous insulin infusion, dexamethasone, and initiation of bromoergocriptine (parlodel) therapy, the patient's vision and pupillary responses deteriorated acutely. Following emergency transphenoidal surgery, the patient's vision and mental status improved. Data confirmed preoperative panhypopituitarism; serum prolactin was 396 ng/ml (microg/l). Immunostudies demonstrated tumoral labeling for prolactin, but not for ACTH, GH, TSH, LH, FSH, or P53

Clinical experience with using an aromatase inhibitor to suppress estrogen production during puberty for improvement of growth potential in adolescents with short stature is limited. This report documents treatment of such a patient with a combination of growth hormone and letrozole, a third-generation aromatase inhibitor. Our case demonstrates a favorable outcome on a short-term basis

OBJECTIVE: To assess experience with growth hormone (GH) therapy in patients with familial dysautonomia (FD).Study design Of 580 patients with FD registered at the Dysautonomia Center at New York University Medical Center, 13 patients (8 males, 5 females) aged 1.10 to 15.10 years received GH treatment. GH doses ranged from 0.2 to 0.3 mg/kg/wk; one patient received 0.14 mg/kg/wk. Information regarding auxologic data, skeletal age, pubertal status, and spinal deformity before and after GH therapy was obtained from center records and treating endocrinologists. Growth velocity was analyzed before and during GH treatment at 0 to 6 months, 6 to 12 months, 1 to 2 years, and >2 years. RESULTS: Before GH therapy, growth velocity was <5 cm/y in 10 patients and 5 to 6 cm/y in three patients. In the first six months of GH therapy, growth velocity exceeded pretreatment rates in all but one patient; 10 patients achieved an annualized growth rate >7 cm/y. Six of nine patients treated for more than one year grew >5 cm/y. Less than optimal treatment responses were attributed to poor compliance, intercurrent illness, scoliosis, or advanced puberty. CONCLUSION: The data demonstrate that GH treatment in patients with FD may increase growth velocity, at least in the short term. This experiential data supports a future prospective study

BACKGROUND: Adenoid cystic carcinoma (ACC) is a malignant tumor of salivary gland origin, which is characterized by a high rate of local recurrence and distant hematogenous metastasis. Despite aggressive surgical treatment and radiotherapy, the patient's long-term prognosis is dismal. Prompted by recent studies on the amplification of the oncogene HER2/neu in salivary gland tumors, we analyzed the immunohistochemical overexpression of HER2/neu in salivary glands ACC. If the tumor exhibits overexpression of HER2/neu, then treating it with the anti-HER2/neu therapeutic agent, Herceptin (Trastuzumab, Genentech, CA), could be considered. METHODS: The study comprised of 32 samples of formalin-fixed, paraffin-embedded specimens. All laboratory procedures and scoring criteria were performed according to currently approved FDA methods. RESULTS: HER2/neu overexpression was found in only five (16%) cases. Four cases (13%) scored 1+ and one case (3%) scored 2+. CONCLUSIONS: The low prevalence of HER2/neu overexpression in ACC limits the clinical utility of Herceptin therapy for salivary gland ACC

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

We investigated two novel point mutations in the human type II 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene causing a mild and a severe form of 3beta-HSD deficiency congenital adrenal hyperplasia. The first is a nonstop mutation in the normal stop codon 373 of the gene in exon IV [TGA (Stop) --> TGC (Cys) = Stop373C) identified from one allele of a female child with premature pubarche whose second allele had an E142K mutation. The Stop373C mutation predictably results in an open reading frame and a mutant-type (MT) II 3beta-HSD protein containing 467 amino acid residues, compared with the 372 amino acid residues of wild-type (WT) protein. The second is a homozygous missense mutation in codon 222 [CCA (Pro) --> ACT (Thr) = P222T] in the gene identified from a female neonate with salt-wasting disorder. The pcDNA vectors containing the constructs of WT II 3beta-HSD cDNA, WT cDNA with the open reading frame (WT cDNA(+)), MT Stop373C with the open reading frame (Stop373C(+)) and MT P222T cDNA were transfected in COS-I and 293T cells and expressed a similar amount of 3beta-HSD mRNA. The enzyme activity in intact cells using pregnenolone and dehydroepiandrosterone as substrate in the medium (1 micromol/liter) was identical between the WT cDNA and the WT cDNA(+), but was decreased to 27% of the WT enzymes at 6 h by MT Stop373C(+) enzyme, and was undetectable by P222T enzyme. In the homogenates of the cells, both MT Stop373C(+) and P222T enzyme activities and enzymes were undetectable despite clear detection of WT enzyme activities and WT enzymes. LH response to an LHRH analog stimulation in the pubertal female with the Stop373C/E142K genotypes and in a pubertal female with compound 273/318 frameshift genotypes were comparable to and higher than control females, respectively. In conclusion, a structurally lengthy MT II 3beta-HSD enzyme due to a nonstop mutation was relatively detrimental in intact cells causing the nonclassic phenotype of 3beta-HSD deficiency. A missense P222T mutation was seriously detrimental, causing the classic phenotype of 3beta-HSD deficiency. The undetectable Stop373C and P222T enzymes on Western blottings, together with the respective in vivo and in vitro data, suggest that a relative instability of Stop373C enzyme and a profound instability of the P222T enzyme are likely the detrimental molecular mechanisms. The increased LH in the female with the frameshift genotype and the appropriate LH response in the female with the nonstop genotype correlated with predictably severe and mild ovarian type II 3beta-HSD deficiency, respectively