Nadine G. Haddad

Hypopituitarism and neurodevelopmental abnormalities in relation to central nervous system structural defects in children with optic nerve hypoplasia.

OBJECTIVE Optic nerve hypoplasia (ONH) is a heterogeneous disease with variable findings of pituitary insufficiency, CNS and neurodevelopmental abnormalities. We characterized the spectrum of endocrinopathy in a cohort of children with ONH and attempted to correlate the presence of different midline CNS findings with the degree of hypopituitarism. The correlation of variable CNS abnormalities with the presence of a seizure disorder and neurodevelopmental delay was also examined. METHODS Charts of 56 patients with ONH referred to our endocrine clinics between 1990 and 2000 were reviewed. Neurodevelopmental assessment was based on questionnaires sent to families during the study period. RESULTS Forty-six patients (82%) had hypopituitarism, with growth hormone deficiency being the most common endocrinopathy. All patients with diabetes insipidus, hypocortisolism, and hypogonadotropin hypogonadism also had combined pituitary hormone deficiency. Evolving pituitary hormone deficiency was observed in two of 37 patients diagnosed with hypopituitarism in the first 3 years of life. No single midline CNS finding correlated with the presence of hypopituitarism or a seizure disorder. However, hydrocephalus or a seizure disorder was more commonly seen in patients with developmental delay. CONCLUSION ONH is a heterogeneous disorder with possible multifactorial etiologies. All patients with this diagnosis deserve a comprehensive endocrine and neurodevelopmental evaluation.

An Update on the Treatment of Precocious Puberty in McCune-Albright Syndrome and Testotoxicosis

McCune-Albright syndrome and testotoxicosis are rare forms of peripheral precocious puberty. Our understanding of the pathophysiology and mechanism of these diseases has significantly increased following identification of their underlying molecular etiology. However, their treatment remains challenging. We provide a review of the various treatment modalities used in both conditions with an update on recent trials using novel and promising pharmacological agents.

Phytoestrogens: Effects on the reproductive system

Phytoestrogens are ubiquitous compounds in nature. They are found largely in soy but are also abundant in legumes and vegetables. They include a wide variety of chemicals with diverse estrogenic and antiestrogenic activities. Different phytoestrogens have different mechanisms of action based on estr

Seminoma and a gonadoblastoma in an infant with mixed gonadal dysgenesis

The genital examination of a newborn with ambiguous genitaliarevealedanenlargedphallicstructure,asingleanterior perineal opening, and fused labioscrotal folds with no palpable gonads (Fig 1). No Turner syndrome stigmata were present. The testosterone level was 29 ng/dL (normal range for female newborns, 20-64 ng/dL; males, 75-400 ng/dL), and a mullerian inhibitory substance was undetectable. Chromosome analysis revealed a 45,X/46,XY mosaic karyotype. A normal uterus and kidneys were identified by ultrasonogram, and a urogenital sinus was present on cystourethrogram. The family selected a female gender for the baby. At9monthsofage,theinfanthadbilateralgonadectomy and feminizing genital surgery. Intraoperative findings confirmed a low confluence urogenital sinus with a well-formed vagina. A streak gonad with a normal fallopian tube and hemiuterus were present on the right. The left gonad was torsed and free-floating in the abdomen without identifiable ductal structures. Pathologic examination of the right gonad showed a testis-streak with seminiferous tubules containing placental alkaline phosphatase-positive (PLAP) cells, consistent with intratubular germ cell neoplasia, and peripheral streak gonadal tissue with multifocal areas of gonadoblastoma (Fig 2, B). The left gonad consisted of an encapsulated 2.0 3 1.8 3 0.6 cm soft tissue mass with diffuse coagulative necrosis and dystrophic calcifications consistent with torsion. Sheets of monomorphic large round cells surrounded by fibrous septae (Fig 2, A) were identified, consistent with a seminoma. A computed tomography scan of the abdomen, pelvis, and chest showed no evidence of metastasis. Beta-human chorionic gonadatropin and a-fetoprotein levels were normal. We describe a unique case of bilateral gonadal tumors occurring in an infant with mixed gonadal dysgenesis (MGD). MGD is an intersex disorder characterized by asymmetric dysgenetic gonads, ambiguous genitalia, persistent mullerian structures, and a Y cell line. Patients with MGD are at high risk of developing gonadal tumors, the majority being identified in the second and third decade of life. The most common tumor is a gonadoblastoma, a benign lesion composed of dysplastic germ and sex cord cells. However, the germ cell element can give rise to malignant germinomas such as seminomas, as in our case. 1,2 Prophylactic gonadectomy is indicated, but there are no clear recommendations as to when this should occur. The young age of this child emphasizes the importance of very early gonadectomy in patients with MGD that are to be raised in the female gender, and careful monitoring of male infants after early orchiopexy.

Hypothalamic Obesity Syndrome: Rare Presentation of CNS+ B-Cell Lymphoblastic Lymphoma

Hypothalamic obesity syndrome can affect brain tumor patients following surgical intervention and irradiation. This syndrome is rare at diagnosis in childhood cancer, but has been reported with relapse of acute lymphoblastic leukemia. Here we present a case of hypothalamic obesity syndrome as the primary presentation of a toddler found to have CNS+ B‐cell lymphoblastic lymphoma. Cytogenetic studies on diagnostic cerebrospinal fluid revealed MLL gene rearrangement (11q23). Hyperphagia and obesity dramatically improved following induction and consolidation chemotherapy. We describe a novel presentation of hypothalamic obesity syndrome in CNS B‐cell lymphoblastic lymphoma, responsive to chemotherapy. Pediatr Blood Cancer 2012; 59: 930–933.

INCIDENCE OF CENTRAL DIABETES INSIPIDUS IN CHILDREN PRESENTING WITH POLYDIPSIA AND POLYURIA

OBJECTIVE Polydipsia and polyuria are common reasons for referral to the Pediatric Endocrine clinic. In the absence of hyperglycemia, diabetes insipidus (DI) should be considered. The objectives of the study were to determine the prevalence of central DI (CDI) in a group of children presenting for evaluation of polydipsia and polyuria, and to determine if predictive features were present in patients in whom the diagnosis of DI was made. METHODS The study was a retrospective chart review of children presenting to the endocrine clinic with complaints of polydipsia and polyuria over a 5-year period. RESULTS The charts of 41 patients (mean age 4.9 ± 3.7 years, 28 males) were reviewed. CDI was diagnosed in 8 (20%) children based on abnormal water deprivation test (WDT) results. All but one patient had abnormal magnetic resonance imaging (MRI) findings, the most common being pituitary stalk thickening. Children with DI were older (7.86 ± 4.40 vs. 4.18 ± 3.20 years, P = .01) and had a higher propensity for cold beverages intake and unusual water-seeking behaviors compared to those without DI. Baseline WDT also revealed higher serum sodium (Na) and osmolality. CONCLUSION The incidence of CDI in children presenting with polydipsia and polyuria is low. Factors associated with higher likelihood of pathology include older age, propensity for cold beverage intake, and higher baseline serum Na and osmolality on a WDT. ABBREVIATIONS BMI = body mass index CDI = central diabetes insipidus DI = diabetes insipidus Na = sodium WDT = water deprivation test.

Peripheral Precocious Puberty: Interventions to Improve Growth

Precocious puberty is usually defined as the onset of secondary sexual characteristics prior to age 7 1/2–8 in girls and prior to age 9 in boys. Although sex steroids cause growth acceleration and tall stature in the short term, the potential for a significant loss of ultimate adult height is a central concern in all children with pathologic forms of early puberty. Unlike central precocious puberty (CPP), which refers to early activation of the hypothalamic-pituitary-gonadal axis, peripheral precocious puberty (PPP) arises from abnormal sex steroid exposure from other sources. These may be endogenous or exogenous, congenital, or acquired. The clinical presentation will depend on the underlying process and on the class of sex steroids (estrogens or androgens) involved. Although many different causes of PPP exist, the most common are congenital adrenal hyperplasia (CAH), familial male-limited precocious puberty (FMPP), and McCune Albright syndrome (MAS). The pathophysiology and clinical characteristics of each of these will be described. A variety of factors are known to influence growth in these disorders. The impact of primary and adjuvant treatment on growth and ultimate height in children with these conditions will be discussed. Data regarding the long-term outcome of established clinical management as well as preliminary findings from investigational approaches will also be summarized.

Gonadal and Adrenal Tumors

Ovarian and adrenal tumors are rare causes of precocious puberty. The pubertal progression is typically more rapid than is observed in central precocious puberty. Juvenile granulosa cell tumors are the most common ovarian tumors associated with premature sexual development, whereas Leydig cell tumors are the most common hormone-producing tumors of the testis. A variety of other sex cord tumors and less commonly germ cell tumors can be associated with premature pubertal development. These tumors can secrete androgens, estrogens, and a multitude of other hormones. Adrenocortical tumors (ACTs) are characteristically functional in children. Virilizing signs are the most common feature, although a mixed hormonal syndrome is often present. The association of ACT with several genetic syndromes has increased our understanding of the molecular mechanism of these tumors. Genetic abnormalities of chromosomes 11 and 17 are the most common finding. Complete surgical resection is potentially curative. Advances in therapy are still needed to improve outcome.