Ian Marshall

A Novel Dominant Negative Mutation of OTX2 Associated with Combined Pituitary Hormone Deficiency

CONTEXT Combined pituitary hormone deficiency (CPHD) is characterized by deficiencies in more than one anterior pituitary hormone. Mutations in developmental factors responsible for pituitary cell specification and gene expression have been found in CPHD patients. OTX2, a bicoid class homeodomain protein, is necessary for both forebrain development and transactivation of the HESX1 promoter, but as of yet, has not been associated with CPHD. OBJECTIVE The goal of this study was to identify and characterize novel mutations in pituitary specific transcription factors from CPHD patients. DESIGN Genomic DNA was isolated from patients with hypopituitarism to amplify and sequence eight pituitary specific transcription factors (HESX1, LHX3, LHX4, OTX2, PITX2, POU1F1, PROP1, and SIX6). Characterization of novel mutations is based on structural and functional studies. RESULTS We describe two unrelated children with CPHD who presented with neonatal hypoglycemia, and deficiencies of GH, TSH, LH, FSH, and ACTH. Magnetic resonance imaging revealed anterior pituitary hypoplasia with an ectopic posterior pituitary. A novel heterozygous OTX2 mutation (N233S) was identified. Wild-type and mutant OTX2 proteins bind equivalently to bicoid binding sites, whereas mutant OTX2 revealed decreased transactivation. CONCLUSIONS A novel mutation in OTX2 binds normally to target genes and acts as a dominant negative inhibitor of HESX1 gene expression. This suggests that the expression of HESX1, required for spaciotemporal development of anterior pituitary cell types, when disrupted, results in an absent or underdeveloped anterior pituitary with diminished hormonal expression. These results demonstrate a novel mechanism for CPHD and extend our knowledge of the spectrum of gene mutations causing CPHD.

Urinary mycoestrogens, body size and breast development in New Jersey girls.

BACKGROUND Despite extensive research and interest in endocrine disruptors, there are essentially no epidemiologic studies of estrogenic mycotoxins, such as zeranol and zearalenone (ZEA). ZEA mycoestrogens are present in grains and other plant foods through fungal contamination, and in animal products (e.g., meat, eggs, dairy products) through deliberate introduction of zeranol into livestock to enhance meat production, or by indirect contamination of animals through consumption of contaminated feedstuff. Zeranol is banned for use in animal husbandry in the European Union and other countries, but is still widely used in the US. Surprisingly, little is known about the health effects of these mycoestrogens, including their impact on puberty in girls, a period highly sensitive to estrogenic stimulation. OBJECTIVES AND METHODS We conducted a cross-sectional analysis among 163 girls, aged 9 and 10 years, participating in the Jersey Girl Study to measure urinary mycoestrogens and their possible relationship to body size and development. RESULTS We found that mycoestrogens were detectable in urine in 78.5% of the girls, and that urinary levels were predominantly associated with beef and popcorn intake. Furthermore, girls with detectable urinary ZEA mycoestrogen levels tended to be shorter and less likely to have reached the onset of breast development. CONCLUSIONS Our findings suggest that ZEA mycoestrogens may exert anti-estrogenic effects similar to those reported for isoflavones. To our knowledge, this was the first evaluation of urinary mycoestrogens and their potential health effects in healthy girls. However, our findings need replication in larger studies with more heterogeneous populations, using a longitudinal approach.

Vitamin D in the maternal-fetal-neonatal interface: clinical implications and requirements for supplementation.

Abstract Identification of the current evidence regarding the pathophysiological and clinical facets of vitamin D in the maternal–fetal–neonatal interface is of value because of the significance of the vitamin D endocrine system in human health and high prevalence of vitamin D deficiency in mothers and their infants. Although many questions have still not been answered by the existing literature, we found evidence that: (i) during pregnancy vitamin D participates in fetal skeletal mineralization and growth, (ii) neonatal vitamin D levels are dependent on the maternal vitamin D status at delivery, (iii) a vitamin D sufficient status at birth may decrease the risk for the development of asthma and type 1 diabetes mellitus in later life, (iv) recommendations for maintaining serum 25-hydroxyvitamin D [25(OH)D] levels ≥32 ng/mL to avoid secondary hyperparathyroidism in adults have not been applied to mothers and their infants, (v) American Academy of Pediatrics recommended supplementation of 400 IU of vitamin D per day is sufficient only for infants who are born with normal vitamin D levels and (vii) supplementation of lactating mothers with high doses of vitamin D (4000 IU/d) allows the achievement of optimal 25(OH)D concentrations (>32 ng/mL) in the maternal and infant serum without any risk of hypervitaminosis D in the mother. We believe that inconsistency in the recognition of sufficient levels of vitamin D in mothers and their infants affects the identification of adequate doses for vitamin D supplementation during pregnancy, lactation and infancy.

Youngest Reported Patient Presenting with an Androgen Producing Sclerosing Stromal Ovarian Tumor

BACKGROUND Sclerosing stromal tumors are extremely rare sex cord stromal tumors of the ovary, with approximately 100 cases reported since first described in 1973. These tumors present predominantly in the 2nd and 3rd decades of life, typically present with pelvic/abdominal pain and tenderness, mass, and/or abnormal menses, and with hormonal activity reported predominantly in postmenarchal females. Only 5 cases of these tumors have been reported in premenarchal girls, with age ranging from 7 months to 12 years. Only 2 demonstrated hormonal manifestations, with vaginal bleeding due to hyperestrogenism in the 7 month old, and virilization in an 11-year-old female. CASE We report a 9-year-old female who was diagnosed with this ovarian tumor, and who presented with virilization. SUMMARY AND CONCLUSION This report is remarkable as our patient not only was diagnosed with an ovarian tumor that is extremely rare in this age group but is the youngest reported patient with this tumor who presented with virilization.

Prevalence and risk factors for vitamin D insufficiency and deficiency at birth and associated outcome.

BackgroundOccurrence and consequence of cord blood (CB) vitamin D insufficiency/deficiency has not been adequately explored despite rising concern regarding this topic in pediatrics. This study was designed to determine the rate, maternal risk factors, and clinical outcomes in infants in association with vitamin D insufficient/deficient status at birth.MethodsAmerican Academy of Pediatrics (AAP) defined levels (ng/mL) were utilized to categorize the vitamin D status in CB samples as deficient (5–15), insufficient (16–20), and sufficient (21–100). We used descriptive statistics and multiple regression models to identify the rate and factors associated with vitamin D deficiency/insufficiency and related outcomes in the enrolled mother-infant pairs.ResultsThis prospective study was conducted at a single center on postpartum women and their infants. Vitamin D deficiency and insufficiency was recorded in 38.9 and 29.8% respectively of the 265 CB samples. Deficient CB vitamin D levels in infants were associated with maternal Black, Hispanic, or Asian race/ethnicity, younger age, and increased number of pregnancies. The likelihood for infants to be born with an insufficient vitamin D level increases with younger maternal age and the number of pregnancies as well as Asian ethnicity. We did not find an association between the vitamin D status at birth and pre-discharge clinical characteristics of the neonates.ConclusionsThe likelihood for an infant to be born with vitamin D deficiency/insufficiency is relatively high and is related mainly to younger maternal age, gravidity, and non-White race/ethnicity. Our findings raise a question regarding the adequacy of the AAP recommended vitamin D supplementation requirements without knowing the infant’s vitamin D status at birth.

Rare presentation of neurofibromatosis and Turner syndrome in a pediatric patient

Neurofibromatosis type 1 (NF1) is classically defined by the presence of multiple café-au-lait macules as one of the diagnostic criteria. Turner syndrome (TS) can also present with café-au-lait macules along with short stature. Our patient is the fifth reported with both NF1 and TS and the first who has been on growth hormone for short stature associated with TS.