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Familial X-Linked Acrogigantism: Postnatal Outcomes and Tumor Pathology in a Prenatally Diagnosed Infant and His Mother

Wise-Oringer, Brittany K; Zanazzi, George J; Gordon, Rebecca J; Wardlaw, Sharon L; William, Christopher; Anyane-Yeboa, Kwame; Chung, Wendy K; Kohn, Brenda; Wisoff, Jeffrey H; David, Raphael; Oberfield, Sharon E
CONTEXT/BACKGROUND:X-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs. CASE DESCRIPTION/METHODS:The patient's mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For over 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During pre-conception planning, X-LAG was diagnosed: single-nucleotide polymorphism (SNP) microarray showed chromosome Xq26.3 microduplication. After conception, SNP microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother's pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and PIT1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and OCT4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index-5.6% (mother) and 8.5% (infant)-the highest reported in X-LAG. CONCLUSIONS:This is the first prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential.
PMID: 31166600
ISSN: 1945-7197
CID: 3922962

Interpretation of androgen and anti-Mullerian hormone profiles in a Hispanic cohort of 5- to 8-year-old girls with premature adrenarche

Brar, Preneet Cheema; Dingle, Elena; Ovadia, Daniela; Pivo, Sarah; Prasad, Veeramac; David, Raphael
PURPOSE/OBJECTIVE:Premature adrenarche (PA) often leads to polycystic ovary syndrome (PCOS). Higher anti-mullerian hormone (AMH) levels are reported in PCOS. We studied the androgen profile and AMH profiles in Hispanic girls with PA (aged 5-8 years) and age and body mass index (BMI) matched controls. METHODS:Retrospective review of electronic medical records of girls who met the inclusion criteria for premature adrenarche were done. RESULTS:PA girls (n=76) were matched to control girls (n=12) for age (mean±standard deviation) (6.7±1 years vs. 6.2±1.3 years) and BMI (20±10 kg/m2 vs. 17.8±2.7 kg/m2). Dehydroepiandrostenedione sulfate (63.3±51.3 μg/dL vs. 29.8±17.3 μg/dL, P<0.001) and testosterone levels (11.4±4.8 ng/dL vs. 8.2±2.9 ng/dL, P=0.001) were significantly higher in the PA group than controls. AMH values (<14 years: reference range, 0.49-3.15 ng/mL) were 3.2±2.2 ng/mL vs. 4.6± 3.2 ng/mL respectively in the PA and control groups and were not different (P=0.4). AMH did not show a correlation with bone age (P=0.1), and testosterone (P=0.9) in the PA group. 17-hydroxyprogesterone levels (17-OHP ng/dL) were 39.5±30.5 ng/dL vs. 36.8±19.8 ng/dL in PA versus control girls. The concentration of 17-OHP was not statistically different between the control and PA groups. CONCLUSION/CONCLUSIONS:Higher AMH was not observed in PA girls and no correlation with BA and androgen levels was observed.
PMID: 30599482
ISSN: 2287-1012
CID: 3562792

Severe metabolic disturbance in an human immunodeficiency virus-exposed newborn: Possible effect of in utero antiretroviral exposure

Eng, L; Raisingani, M; Kaul, A; Mehta, S; Prasad, K; David, R; Shah, B
The use of antiretroviral (ARV) medications has successfully reduced maternal transmission of human immunodeficiency virus (HIV)-1 to newborns, but metabolic and mitochondrial toxicities in newborns continue to be a concern. We report the case of a 10-day-old full-term female infant born to an HIV-positive mother presenting with lethargy and respiratory distress. Maternal ARV medications included nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase strand transcriptase inhibitors (INSTIs). Infant ARV prophylaxis included two NRTIs and a nonnucleoside reverse transcriptase inhibitor. At presentation, laboratory tests were significant for hyponatremia, hyperkalemia, severe metabolic acidosis, and acute kidney injury. She was resuscitated with fluids and a stress dose of hydrocortisone (HC), which resulted in improvement of her condition within 48 h. Adrenal profile on the day of admission revealed elevated levels of 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, aldosterone, and elevated plasma renin activity. HC was tapered and the patient was discharged on the day of life (DOL) 26. Adrenocorticotropic hormone (ACTH) stimulation test off HC for one night that was performed on DOL31 showed a normal cortisol response of 35.8 mcg/dL at 60 min. HC was later discontinued. A repeat ACTH stimulation test off HC for 7 days that was performed on DOL59 yielded a normal cortisol response of 27.6 mcg/dL at 60 min. This report reveals severe metabolic disturbances suggestive of adrenal insufficiency (AI) in a neonate exposed to a combination of ARV medications in utero and postnatally with improvement of symptoms after glucocorticoid treatment. The AI was transient in nature, which resolved after cessation of ARV therapy.
EMBASE:623554987
ISSN: 2249-4847
CID: 3261792

FACTITIOUS HYPERPROLACTINEMIA OR PROLACTINOMA? ROLE OF THE LABORATORY IMMUNOASSAY [Meeting Abstract]

Sodhi, Misha; Carter, Janell; Mcvoy, Lauren; Raisingani, Manish; David, Raphael; Shah, Bina
ISI:000412595405189
ISSN: 1663-2826
CID: 2746112

Salivary Testosterone during the Minipuberty of Infancy

Contreras, Maria; Raisingani, Manish; Chandler, Donald Walt; Curtin, William D; Barillas, Julia; Brar, Preneet Cheema; Prasad, Kris; Shah, Bina; David, Raphael
BACKGROUND: The hypothalamic-pituitary-gonadal axis is transiently activated during the postnatal months in boys, a phenomenon termed "minipuberty" of infancy, when serum testosterone (T) increases to pubertal levels. Despite high circulating T there are no signs of virilization. We hypothesize that free T as measured in saliva is low, which would explain the absence of virilization. METHODS: We measured serum total T and free T in saliva using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 infant boys, aged 1-6 months, and in 12 adolescents, aged 11-17 years. RESULTS: Total serum T in all infants was, as expected, high (172 +/- 78 ng/dL) while salivary T was low (7.7 +/- 4 pg/mL or 0.45 +/- 0.20%). In contrast, salivary T in the adolescents was much higher (41 +/- 18 pg/mL or 1.3 +/- 0.36%) in relation to their total serum T (323 +/- 117 ng/dL). We provide for the first time reference data for salivary T in infants. CONCLUSION: Measurement of salivary T by LC-MS/MS is a promising noninvasive technique to reflect free T in infants. The low free T explains the absence of virilization. The minipuberty of infancy is more likely of intragonadal than peripheral significance..
PMID: 28073108
ISSN: 1663-2826
CID: 2541132

Spiral Fracture in Young Infant Causing a Diagnostic Dilemma: Nutritional Rickets versus Child Abuse

Kaushal, Sonia; Raisingani, Manish; David, Raphael; Shah, Bina
Fractures are uncommon in young, nonambulatory infants. The differential diagnosis includes nonaccidental injury (NAI) and metabolic bone disease, including rickets. While rickets typically present after six months of age, multiple cases have been reported in younger infants. We report a case of an 11-week-old male infant who presented with a spiral fracture of the humerus and no radiologic evidence of rickets. A detailed psychosocial assessment failed to reveal any risk factors for NAI. The patient had elevated alkaline phosphatase and PTH with low 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D levels. Additionally, the mother was noncompliant with prenatal vitamins, exclusively breastfeeding without vitamin D supplementation, and had markedly low vitamin D levels 15 weeks postpartum. The biochemical data and history were consistent with rickets. Given the diagnostic dilemma, the working diagnosis was rickets and the patient was started on ergocalciferol with subsequent normalization of his laboratory values and healing of the fracture. These findings are consistent with nutritional rickets largely due to maternal-fetal hypovitaminosis D. This case highlights that in young infants rickets should be considered even in the absence of positive radiologic findings. Additionally, it illustrates the importance of maintaining adequate vitamin D supplementation during pregnancy and early infancy.
PMCID:5625808
PMID: 29057134
ISSN: 2090-6803
CID: 2756742

Childhood acromegaly due to X-linked acrogigantism: long term follow-up

Gordon, Rebecca J; Bell, Jennifer; Chung, Wendy K; David, Raphael; Oberfield, Sharon E; Wardlaw, Sharon L
PURPOSE: Acromegaly in infancy is extremely rare. We describe a 32 year old woman who presented at 6 months of age with isolated macrocephaly, followed by accelerated linear growth. At 21 months of age, her head circumference was 55 cm (+5.5 SD), height was 97.6 cm (+4.4 SD) and weight was 20.6 kg (+6.2 SD). She had markedly elevated levels of growth hormone (GH) (135 ng/ml), IGF-1 (1540 ng/ml) and prolactin (370 ng/ml). A pituitary macroadenoma was surgically resected. Immunohistochemical staining was positive for GH. Post-operatively, she developed ACTH and TSH deficiency and diabetes insipidus. METHODS: Long term clinical follow-up and genetic testing with chromosomal microarray analysis. RESULTS: Despite GH deficiency, she grew well until 7 (1/2) years old, with subsequent decline in growth velocity, and received GH therapy for 5 years. Puberty was initiated with estrogen therapy. As an adult, she has no stigmata of acromegaly, with a height of 164.5 cm and non-acromegalic features. IGF-1 has remained in the low normal range. Prolactin has been mildly elevated. Serial MRIs have shown no evidence of tumor recurrence. She receives replacement therapy with hydrocortisone, levothyroxine and DDAVP. Chromosomal microarray analysis revealed that she has X-linked acrogigantism (X-LAG) due to a de novo duplication of Xq26.3 (516 kb). She recently became pregnant following ovarian stimulation and chorionic villus sampling revealed that she is carrying a male with the same duplication. CONCLUSION: This report provides detailed long term clinical follow-up of a patient with X-LAG syndrome.
PMCID:5244823
PMID: 27631333
ISSN: 1573-7403
CID: 2247072

Unusual phenotype of congenital adrenal hyperplasia (CAH) with a novel mutation of the CYP21A2 gene

Raisingani, Manish; Contreras, Maria F; Prasad, Kris; Pappas, John G; Kluge, Michelle L; Shah, Bina; David, Raphael
Gonadotropin independent sexual precocity (SP) may be due to congenital adrenal hyperplasia (CAH), and its timing usually depends on the type of mutation in the CYP21A2 gene. Compound heterozygotes are common and express phenotypes of varying severity. The objective of this case report was to investigate the hormonal pattern and unusual genetic profile in a 7-year-old boy who presented with pubic hair, acne, an enlarged phallus, slightly increased testicular volume and advanced bone age. Clinical, hormonal and genetic studies were undertaken in the patient as well as his parents. We found elevated serum 17-hydroxyprogesterone (17-OHP) and androstenedione that were suppressed with dexamethasone, and elevated testosterone that actually rose after giving dexamethasone, indicating activity of the hypothalamic-pituitary-gonadal (HPG) axis. An initial search for common mutations was negative, but a more detailed genetic analysis of the CYP21A2 gene revealed two mutations including R341W, a non-classical mutation inherited from his mother, and g.823G>A, a novel not previously reported consensus donor splice site mutation inherited from his father, which is predicted to be salt wasting. However, the child had a normal plasma renin activity. He was effectively treated with low-dose dexamethasone and a GnRH agonist. His father was an unaffected carrier, but his mother had evidence of mild non-classical CAH. In a male child presenting with gonadotropin independent SP it is important to investigate adrenal function with respect to the androgen profile, and to carry out appropriate genetic studies.
PMID: 27180336
ISSN: 2191-0251
CID: 2188632

Androgen profile and anti-Mullerian hormone levels in girls with premature adrenarche [Meeting Abstract]

Brar, P C; Attaelmannan, M; Prasad, V; Wilkes, M; David, R
Background: Premature adrenarche (PA), the presence of pubic hair before age eight years in girls, is considered a harbinger of polycystic ovary syndrome (PCOS). Anti-Mullerian hormone (AMH), a dimeric glycoprotein, reflects the amount of growing follicles in the ovaries and is considered a robust index of ovarian function. AMH levels are known to be elevated in patients with PCOS and also in pre pubertal daughters of women with PCOS. Objective and hypotheses: The goal of this study was to determine the androgen and AMH profile in a multiethnic cohort of girls with PA. Methods: Girls diagnosed with PA between 2002- 2012 were studied for BMI, bone age (BA), testosterone, dehydroepiandrosterone sulfate (DHEA-S) and 17-hydroxyprogesterone (17-OHP). Age matched girls were identified to serve as a comparison group. AMH levels were measured in stored sera of girls with PA as well in matched controls via the AMH Gen II ELISA assay from Quest Diagnostics, Nichols Institute (reference range< 18 years: 0.3- 11.2ng/ml). Results: Fifty-one patients with PA (58% Hispanic) with an average BMI (mean+/- SD) of 19.4+/- 4.1years, BA of 6.9+/- 3.2 years and chronological age (CA) 6.8+/- 0.8 years were compared to controls (n= 15) with BMI of 16.4+/-1.56 years, BA of 6.2+/-1.6 years and CA of 6.02+/- 1.3 years. Testosterone levels of 11.5+/- 4.1 ng/dl were elevated in 66% (<=10: pre pubertal) of girls of PA. DHEA-S levels of 67+/- 56 ug/dl (>=75: 6-8 yr >=55< 5 yr) were elevated in 21% of girls with PA, and 40% of all girls with PA had an advanced BA (defined as BA>= 1 year of CA). In girls with PA (n=14) AMH levels of 2.16+/-1.7 ng/dl were lower than in controls (n=6) 4.18+/- 2.58 ng/dl, though this difference did not reach statistical significance (p= 0.128). Conclusions: In our investigation we did not find PCOS related abnormalities in serum AMH levels in girls with PA. AMH levels cannot discriminate which girls with PA will go on to develop PCOS in the future
EMBASE:71247323
ISSN: 1663-2818
CID: 688292

Vitamin D intoxication in a toddler due to a dispensing error of an imported vitamin D supplement [Meeting Abstract]

Rusyn, L; Patel, P R; David, R; Kohn, B; Brar, P C
Introduction: Vitamin D intoxication is a rare cause of hypercalcemia. There is a recent increase in reports of pediatric cases of hypercalcemia, secondary to vitamin D intoxication. This trend is attributable to the growing popularity of vitamin D supplements, especially as Vitamin D is being marketed as a "panacea" for a number of medical problems.Immigrant families often travel to their countries of origin, where vitamin supplements are available in formulations different from the US. Parents may not report using supplements to their child's pediatrician, as these supplements are perceived "safe" with no dangerous side effects.Case Presentation: A three year old toddler presented to the emergency room with emesis, polyuria, and lethargy. On inquiry, the family reported use of a multivitamin gel (made in Ecuador) dispensed at 1 tsp bid. Per the manufacturer's label, 5 grams (aD;one teaspoon) contains 0.096 mg (aD;100 IU) of cholecalciferol. A standard conversion of 1mug of cholecalciferol equals 40 IU1, secondary to conversion error this patient received 7,680 IU per day and 108,000 IU total vitamin D3 over 14 days, which is toxic. "Teaspoon" dosage inaccuracies and potentially excessive administration by caretakers compounded vitamin D toxicity.Initial lab values revealed Ca 16 mg/dl, iPTH 2.25 pg/mL (15-65), 25 OH vit D3: >512ng/mL(30-100), and UCa/UCreatinine 1.14mg/mg(<0.2). Hydration, lasix, calcitonin (6 days), and prednisolone (7 days) were used to manage the hypercalcemia. After 15 days of treatment, the 25 OH vitamin D3 was 324 ng/ml and the calcium decreased to 11.2 mg/dL. Conclusion s: In our case, dispensing and labeling errors led the parents to administer high doses of vitamin D to their toddler, leading to hypercalcemia. This highlights several issues regarding vitamin supplement usage.First, physicians should be aware of the dosage conversion of vitamin D in terms of IU, mg and mcg to calculate if the prescribed dose is appropriate for their patients. In addition, as there are no established manufacturing standards for certain vitamin supplement formulations-such as gels-caution should be exercised as more reports are emerging of toxic ingestion from overzealous supplementation. Verification of supplement source and composition is essential. Lastly, educating parents about the safe use of vitamin D supplements-emphasizing the need to report imported supplements to the patient's pediatrician-is important to avoiding erroneous toxic ingestion
EMBASE:70833827
ISSN: 0163-769x
CID: 175829