Hypothalamic-pituitary lesions in pediatric patients: endocrine symptoms often precede neuro-ophthalmic presenting symptoms.

OBJECTIVE: To evaluate whether analyses of clinical and endocrine presenting symptoms could help to shorten the time to diagnosis of hypothalamic-pituitary lesions in children. STUDY DESIGN: A retrospective, single-center, cohort study of 176 patients (93 boys), aged 6 years (range, 0.2-18 years), with hypothalamic-pituitary lesions was performed. RESULTS: The lesions were craniopharyngioma (n = 56), optic pathway glioma (n = 54), suprasellar arachnoid cyst (n = 25), hamartoma (n = 22), germ cell tumor (n = 12), and hypothalamic-pituitary astrocytoma (n = 7). The most common presenting symptoms were neurologic (50%) and/or visual complaints (38%), followed by solitary endocrine symptoms (28%). Precocious puberty led to diagnosis in 19% of prepubertal patients (n = 131), occurring earlier in patients with hamartoma than in patients with optic-pathway glioma (P < .02). Isolated diabetes insipidus led to diagnosis for all germ-cell tumors. For 122 patients with neuro-ophthalmic presenting symptoms, the mean symptom interval was 0.5 year (95% CI, 0.4-0.6 year), although 66% of patients had abnormal body mass index or growth velocity, which preceded the presenting symptom interval onset by 1.9 years (95% CI, 1.5-2.4 years) (P < .0001) and 1.4 years (95% CI, 1-1.8 years) (P < .0001), respectively. Among them, 41 patients were obese before diagnosis (median 2.2 years [IQR, 1-3 years] prior to diagnosis) and 35 of them had normal growth velocity at the onset of obesity. The sensitivity of current guidelines for management of childhood obesity failed to identify 61%-85% of obese children with an underlying hypothalamic-pituitary lesion in our series. CONCLUSIONS: Endocrine disorders occurred in two-thirds of patients prior to the onset of the neuro-ophthalmic presenting symptom but were missed. Identifying them may help to diagnose hypothalamic-pituitary lesions earlier.

Inhibin B and anti-Müllerian hormone as markers of gonadal function after treatment for medulloblastoma or posterior fossa ependymoma during childhood.

OBJECTIVE: To evaluate the roles of hypothalamic-pituitary and spinal irradiations and chemotherapy in gonadal deficiency after treatment for medulloblastoma or posterior fossa ependymoma by measuring levels of plasma inhibin B and antimüllerian hormone (AMH). STUDY DESIGN: A total of 34 boys and 22 girls were classified as having normal levels of plasma follicle-stimulating hormone (FSH; <9 IU/L), or abnormal levels of FSH (>9 IU/L) and luteinizing hormone (LH; <5 or >5 IUL). RESULTS: Two boys had partial gonadotropin deficiency, combined with testicular deficiency in one boy. Six boys had increased levels of FSH, indicating tubular deficiency, combined with Leydig cell deficiency in 5 boys. The 7 boys with inhibin B levels <100 ng/mL included the one with combined deficiencies and the 6 with testicular deficiency. Puberty did not progress in 7 girls; 3 had gonadotropin deficiency, combined with ovarian deficiency in one, and 4 had increased FSH levels, indicating ovarian deficiency. Inhibin B and AMH levels were low in the girl with combined deficiencies, in the 4 girls with ovarian deficiency, and in 4 girls with normal clinical-biological ovarian function, including 2 who underwent ovarian transposition before irradiation. CONCLUSION: The plasma concentrations of inhibin B and AMH are useful means of detecting primary gonad deficiency in patients with no increase in their plasma gonadotropin levels because of radiation-induced gonadotropin deficiency.

Predicting the adult height of girls with central precocious puberty.

BACKGROUND: There are no absolute criteria for identifying those girls with idiopathic central precocious puberty (CPP) who will benefit from gonadotropin-releasing hormone analog (GnRHa) treatment. Our objective was to predict at initial evaluation the differences between adult height (AH) and target height (TH) and (for untreated girls) the time between puberty onset and first menstruation. MATERIAL/METHODS: The 122 girls with CPP who reached their AH included 70 who were given GnRHa because their predicted AH was <155 cm (n=24), their luteinising hormone (LH)/follicle-stimulating hormone peaks (FSH) ratio was >0.66 (n=41) and/or their estradiol was >15 pg/ml (n=40). The other 52 were untreated because their predicted AH was >155 cm. Multiple linear regressions were performed on several subsets of variables. RESULTS: Treated: the difference between AH and TH (-0.6±5.4 cm) was predicted by (using SDS) =3.68 (height at initial evaluation - TH) - 1.94 (height at initial evaluation-predicted AH) - 4.23; R2=0.73. Untreated: the difference between AH and TH (1.7±4.3 cm) was predicted by =2.76 (height at initial evaluation - TH) - 3.68 LH/FSH peaks ratio - 3.49; R2=0.77. Time between puberty onset and first menstruation (years) was predicted by =12.2 - 1.06 age CPP - 0.4 (height at initial evaluation - TH); R2=0.75. CONCLUSIONS: A greater difference between height at initial evaluation and TH (SDS) is associated with a greater AH in treated and untreated girls, as are smaller differences between height at initial evaluation and predicted AH in treated and lower LH/FSH peaks ratios in untreated girls.

Inhibin B and anti-Müllerian hormone as markers of gonadal function after hematopoietic cell transplantation during childhood.

BACKGROUND: It is difficult to predict the reproductive capacity of children given hematopoietic cell transplantation (HCT) before pubertal age because the plasma concentrations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are not informative and no spermogram can be done. METHODS: We classified the gonadal function of 38 boys and 34 girls given HCT during childhood who had reached pubertal age according to their pubertal development and FSH and LH and compared this to their plasma inhibin B and anti-Müllerian hormone (AMH). RESULTS: Ten (26%) boys had normal testicular function, 16 (42%) had isolated tubular failure and 12 (32%) also had Leydig cell failure. All 16 boys given melphalan had tubular failure. AMH were normal in 25 patients and decreased in 6, all of whom had increased FSH and low inhibin B.Seven (21%) girls had normal ovarian function, 11 (32%) had partial and 16 (47%) complete ovarian failure. 7/8 girls given busulfan had increased FSH and LH and 7/8 had low inhibin B. AMH indicated that ovarian function was impaired in all girls.FSH and inhibin B were negatively correlated in boys (P < 0.0001) and girls (P = 0.0006). Neither the age at HCT nor the interval between HCT and evaluation influenced gonadal function. CONCLUSION: The concordance between FSH and inhibin B suggests that inhibin B may help in counselling at pubertal age. In boys, AMH were difficult to use as they normally decrease when testosterone increases at puberty. In girls, low AMH suggest that there is major loss of primordial follicles.

Plasma inhibin B and antimüllerian hormone concentrations in boys: discriminating between congenital hypogonadotropic hypogonadism and constitutional pubertal delay.

BACKGROUND: Inhibin B and antimüllerian hormone (AMH) are secreted by the Sertoli cells, stimulated by gonadotropins. We evaluated their use for discriminating between congenital hypogonadotropic hypogonadism (HH) and constitutional pubertal delay. MATERIAL/METHODS: Group 1 (n=39) was diagnosed with constitutional pubertal delay; group 2 (n=15), isolated HH; and group 3, pituitary stalk interruption syndrome (3a with [n=5] and 3b [n=8] without HH). RESULTS: At pubertal age, mean plasma inhibin B concentrations were similar in the groups having the same gonadotropin status. Individual concentrations were normal in groups 1 and 3b, but low in 6 group 2, and 3 group 3a patients. Four group 2, and 1 group 3a, also had low AMH. Among these 9 with low inhibin B, 1 in each group evaluated before puberty had had normal inhibin B and AMH. In contrast, inhibin B increased (P<.03) and AMH decreased (P<.02) in 7 group 3b patients from before to after puberty. There were 20 patients with inhibin B below 100 pg/mL including 4 group 1, 13 group 2, and 3 group 3a. The basal plasma follicle stimulating (FSH) and luteinizing (LH) hormone concentrations were < 1 IU/L in 18%, 36% in group 1, and in 56% and 100% in group 2. CONCLUSIONS: Before puberty, plasma inhibin B and AMH concentrations may be normal despite HH. At pubertal age, both are low in some patients with HH. These hormone values may help discriminate between HH and constitutional pubertal delay together with plasma FSH and LH.

Improved screening for growth hormone deficiency using logical analysis data.

BACKGROUND: The growth hormone (GH) Research Society proposed criteria based on auxological parameters (height, difference between target and actual heights, growth rate) to predict GH deficiency (GHD) followed by GH stimulation tests. These criteria are very sensitive but not specific enough. The objective of this study was to improve screening for GHD, so reducing the need for stimulation tests. MATERIAL/METHODS: The patients were divided into three groups: Group 1 (n=54) with GHD and pituitary stalk interruption syndrome; Group 2 (n=104) with a normal GH peak after pharmacological and sleep tests; Group 3 (n=19) with transient GHD. The GHD diagnosis was based on the parameters proposed by the GH Research Society to evaluate the GH secretion, first alone and then plus plasma insulin-like growth factor (IGF) I concentrations. Data were analysed using the logical analysis of data framework. RESULTS: Screening can be achieved using a simple graph based on IGF I and the growth rate (GR): (1) all patients below a given line (GR < or =-7.3 - 1.3xIGF (SDS)) had GHD; (2) all but two patients above another given line (GR >-4.5 + 6.4/(IGF + 4.5) (SDS)) did not have GHD; (3) in-between, patients in a "gray area" cannot be diagnosed using only growth rate and IGF I. Most of the transient GHD were in or near the "gray area". CONCLUSIONS: Short children can be screened for GHD using growth rate and IGF I. Magnetic resonance imaging can then be used to detect pituitary stalk interruption syndrome or a tumor.

Diagnosis of growth hormone (GH) deficiency: comparison of pituitary stalk interruption syndrome and transient GH deficiency.

BACKGROUND: Most patients with childhood non-organic growth hormone (GH) deficiency (GHD) produce a normal GH peak as young adults. Our objectives were to better define this transient GHD and evaluate the factors influencing the growth response of patients with pituitary stalk interruption syndrome (PSIS). METHODS: We studied 72 prepubertal patients with a GH peak < 6.7 ng/ml after 2 stimulation tests, treated with 0.2 mg GH/kg/w for at least 3 years. Group 1 (n = 53, 4.7 +/- 4.0 years) had PSIS and Group 2 (n = 19, 9.2 +/- 3.0 years) had transient GHD and normal pituitary. RESULTS: At diagnosis, 64% of Group 1 and one Group 2 were < 5 years old. The growth rate of 59% Group 1 and two Group 2 patients was < or = -2 SDS. The GH peak of 64% Group 1 patients and no Group 2 patients was < 3 ng/ml. The plasma insulin-like growth factor-1 of all Group 1 and all but one Group 2 patients was < or = -2 z scores.During the first year of GH treatment, the growth rate was > or = 2 SDS in 81% Group 1 and 37% Group 2 patients. In Group 1, it was negatively correlated with the GH peak before treatment (P < 0.03), and with the difference between the target and adult heights (P < 0.01).The height gain SDSs between diagnosis and adult height were 1.7 +/- 1.2 in Group 1 (n = 30) and 1.08 +/- 0.8 in Group 2 (n = 12, P = 0.05). CONCLUSION: The factors of the growth response to GH treatment should be analysed separately for each population: with and without PSIS or other markers.

Childhood craniopharyngioma: greater hypothalamic involvement before surgery is associated with higher homeostasis model insulin resistance index.

BACKGROUND: Obesity seems to be linked to the hypothalamic involvement in craniopharyngioma. We evaluated the pre-surgery relationship between the degree of this involvement on magnetic resonance imaging and insulin resistance, as evaluated by the homeostasis model insulin resistance index (HOMA). As insulin-like growth factor 1, leptin, soluble leptin receptor (sOB-R) and ghrelin may also be involved, we compared their plasma concentrations and their link to weight change. METHODS: 27 children with craniopharyngioma were classified as either grade 0 (n = 7, no hypothalamic involvement), grade 1 (n = 8, compression without involvement), or grade 2 (n = 12, severe involvement). RESULTS: Despite having similar body mass indexes (BMI), the grade 2 patients had higher glucose, insulin and HOMA before surgery than the grade 0 (P = 0.02, <0.05 and 0.02 respectively) and 1 patients (P < 0.02 and <0.03 for both insulin and HOMA). The grade 0 (5.8 +/- 4.9) and 1 (7.2 +/- 5.3) patients gained significantly less weight (kg) during the year after surgery than did the grade 2 (16.3 +/- 7.4) patients. The pre-surgery HOMA was positively correlated with these weight changes (P < 0.03). The data for the whole population before and 6-18 months after surgery showed increases in BMI (P < 0.0001), insulin (P < 0.005), and leptin (P = 0.0005), and decreases in sOB-R (P < 0.04) and ghrelin (P < 0.03). CONCLUSION: The hypothalamic involvement by the craniopharyngioma before surgery seems to determine the degree of insulin resistance, regardless of the BMI. The pre-surgery HOMA values were correlated with the post-surgery weight gain. This suggests that obesity should be prevented by reducing inn secretion in those cases with hypothalamic involvement.

Factors influencing the growth hormone peak and plasma insulin-like growth factor I in young adults with pituitary stalk interruption syndrome.

BACKGROUND: The diagnostic criteria for growth hormone (GH) deficiency (GHD) in adolescents and young adults are not yet clearly established.We evaluated the factors influencing the GH peak and plasma insulin-like growth factor (IGF) I in order to determine the cut-off limits for the diagnosis of GHD during the transition period. METHODS: 21 patients treated for GHD due to pituitary stalk interruption syndrome at 5.7 +/- 4.1 years were reevaluated at 16.0 +/- 1.8 years, 0.6 +/- 0.6 years after the end of GH treatment. Group 1 had isolated GHD (n = 9) and group 2 had multiple pituitary deficiencies (n = 12), including deficiencies of thyroid stimulating (n = 12), adrenocorticotropin (n = 8) and gonadotropin (n = 9) hormones. RESULTS: At diagnosis, group 1 had a greater pituitary height (2.8 +/- 1.2 vs 1.6 +/- 1.1 mm, P = 0.03) and GH peak (3.8 +/- 1.9 vs 1.6 +/- 1.5 ng/ml, P < 0.02) than did group 2.At last evaluation, group 1 had greater GH peak (3.9 +/- 1.9 vs 0.2 +/- 0.4 ng/ml, P = 0.0001) and plasma IGF I (211 +/- 88 vs 78 +/- 69 ng/ml, P < 0.002) than did group 2. No group 1 and 9 group 2 patients had an undetectable GH peak, while the 3 others had GH peak below 1 ng/ml.The GH peak decreased between diagnosis and last evaluation only in group 2 (P < 0.008). CONCLUSION: The GH peak response to pharmacological stimulation and the plasma IGF I concentration in young adults with GHD of childhood onset depend on the presence of additional pituitary deficiencies, reflecting a more severe defect of the hypothalamic-pituitary axis. The sex steroids cannot increase the IGF I if the GH secretion is zero.

Idiopathic central precocious puberty in girls: presentation factors.

BACKGROUND: It is sometimes difficult to distinguish between premature thelarche and precocious puberty in girls who develop breasts before the age of 8 years. We evaluated the frequencies of the signs associated with breast development and the factors influencing the presentation of girls with idiopathic central precocious puberty (CPP). METHODS: 353 girls monitored 0.9 +/- 0.7 year after the onset of CPP. RESULTS: The age at CPP was < 3 years in 2%, 3-7 years in 38% and 7-8 years in 60% of cases. Pubic hair was present in 67%, growth rate greater than 2 SDS in 46% and bone age advance greater than 2 years in 33% of cases. Breast development was clinically isolated in 70 (20%) cases. However, only 31 of these (8.8% of the population) had a prepubertal length uterus and gonadotropin responses to gonadotropin releasing hormone and plasma estradiol. The clinical picture of CPP became complete during the year following the initial evaluation.25% of cases were obese. The increase in weight during the previous year (3.7 +/- 1.4 kg) and body mass index were positively correlated with the statural growth and bone age advance (P < 0.0001). There was no relationship between the clinical-biological presentation and the age at puberty, the interval between the onset of puberty and evaluation, or the presence of familial CPP. CONCLUSION: The variation in presentation of girls with CPP does not depend on their age, interval between the onset and evaluation, or familial factors. This suggests that there are degrees of hypothalamic-pituitary-ovarian activation that are not explained by these factors.

Selecting short-statured children needing growth hormone testing: derivation and validation of a clinical decision rule.

BACKGROUND: Numerous short-statured children are evaluated for growth hormone (GH) deficiency (GHD). In most patients, GH provocative tests are normal and are thus in retrospect unnecessary. METHODS: A retrospective cohort study was conducted to identify predictors of growth hormone (GH) deficiency (GHD) in children seen for short stature, and to construct a very sensitive and fairly specific predictive tool to avoid unnecessary GH provocative tests. GHD was defined by the presence of 2 GH concentration peaks < 10 ng/ml. Certain GHD was defined as GHD and viewing pituitary stalk interruption syndrome on magnetic resonance imaging. Independent predictors were identified with uni- and multi-variate analyses and then combined in a decision rule that was validated in another population. RESULTS: The initial study included 167 patients, 36 (22%) of whom had GHD, including 5 (3%) with certain GHD. Independent predictors of GHD were: growth rate < -1 DS (adjusted odds ratio: 3.2; 95% confidence interval [1.3-7.9]), IGF-I concentration < -2 DS (2.8 [1.1-7.3]) and BMI z-score > or = 0 (2.8 [1.2-6.5]). A clinical decision rule suggesting that patients be tested only if they had a growth rate < -1 DS and a IGF-I concentration < -2 DS achieved 100% sensitivity [48-100] for certain GHD and 63% [47-79] for GHD, and a specificity of 68% [60-76]. Applying this rule to the validation population (n = 40, including 13 patients with certain GHD), the sensitivity for certain GHD was 92% [76-100] and the specificity 70% [53-88]. CONCLUSION: We have derived and performed an internal validation of a highly sensitive decision rule that could safely help to avoid more than 2/3 of the unnecessary GH tests. External validation of this rule is needed before any application.

Factors and markers of growth hormone secretion and gonadal function in Fanconi anemia.

UNLABELLED: Many factors may be involved in the growth and gonadal dysfunction of Fanconi anemia (FA). OBJECTIVE: To evaluate the (1) relationship between FA presentation, including genital abnormalities and pituitary stalk interruption syndrome (PSIS), (2) markers of growth hormone (GH) deficiency and gonadal function, and (3) factors influencing final height and gonadal function. PATIENTS: Twenty five patients with FA were included, 17 of them were given bone marrow transplantation. RESULTS: Six patients were diagnosed with GH deficiency and PSIS (group A), whereas 19 had no evidence of GH deficiency (group B). In group A, all patients had more than 3 FA malformations and all 5 boys had cryptorchidism associated with microphallus in 4. All patients had heights and plasma insulin-like growth factor I < -3SD. Final height was reached in 15 patients and was < or = -2SD in 12 of them, all but 3 were born small for gestational age and/or given norethandrolone and/or corticosteroids. Gonadal function was abnormal in 5/7 boys and 4/5 girls evaluated at pubertal age. The plasma concentrations were low in 4/9 for antimüllerian hormone and in 3/9 for inhibin B, 3 of them had been given bone marrow transplantation. CONCLUSIONS: PSIS can be part of a severe FA phenotype. It seems to occur mainly in boys, with more than 3 malformations, microphallus and cryptorchidism. This phenotype is associated with normal blood counts, defining a new clinical subgroup of patients.

Diencephalic syndrome due to hypothalamic tumor: a model of the relationship between weight and puberty onset.

CONTEXT: Changes in body weight, statural growth rate, and puberty may be the presenting symptoms of hypothalamic-pituitary tumors. OBJECTIVE: The objective of the study was to assess the relationship between the tumor and its treatment and the weight, growth rate, and onset of puberty, using the diencephalic syndrome of emaciation as model. PATIENTS: Eleven patients seen before 1 yr of age, except one aged 9 yr, for diencephalic syndrome of emaciation due to hypothalamic pilocytic astrocytoma, were treated by surgical resection (n = 9), cranial irradiation (n = 7), and/or chemotherapy (n = 10). RESULTS: At diagnosis, growth rate was normal, despite the emaciation, and there was no hypothalamic-pituitary deficiency, except in the oldest patient. After tumor treatment, all had GH and thyroid-stimulating hormone deficiencies, but only three, who underwent major surgical resection, also had ACTH deficiency and diabetes insipidus. Eight became obese, and all but the oldest had transient precocious puberty. Plasma leptin concentrations were very low at diagnosis, increased after tumor treatment, and decreased transiently in one boy when the testosterone increased. The plasma soluble leptin receptor concentrations changed in the opposite direction, leading to an increase in the free leptin index, including in the three patients whose tumor was reduced without surgery. The body mass index was correlated positively with plasma leptin (rho = 0.73, P = 0.0004) and free leptin index (rho = 0.63, P < 0.004) and negatively with ghrelin (rho = -0.49, P < 0.03) concentrations. CONCLUSIONS: The obesity that occurs after treatment of hypothalamic tumors is not due to dysregulation of leptin secretion because it and plasma soluble leptin receptor remain regulated by factors like testosterone. This study also shows the influence of weight, possibly via leptin secretion, on the transient hypothalamic-pituitary-gonadal activation that occurs during the first year of life.

Diagnosis of idiopathic growth hormone deficiency: contributions of data on the acid-labile subunit, insulin-like growth factor (IGF)-I and-II, and IGF binding protein-3.

UNLABELLED: The diagnosis of non-organic growth hormone (GH) deficiency (GHD) remains difficult. OBJECTIVE: To evaluate the value of measuring plasma insulin-like growth factor (IGF)-I and -II, IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS) as criteria for diagnosing GHD. PATIENTS: 120 prepubertal patients having at least one of the main auxological criteria defined by the GH Research Society for initiating GH exploration were classified as (1) certain GHD (n = 40), (2) transient GHD (n = 18), (3) idiopathic short stature (n = 27), or (4) extreme short stature (n = 35). RESULTS: All the patients with certain GHD had low (< or = -2 z-score) plasma concentrations of IGF-I and ALS, but only 35.1% had low IGF-II, and 48.6% had low IGFBP-3. All the patients but three (83.3%) with transient GHD had low IGF-I, but only 44.4% had low ALS, and only one had low IGF-II or IGFBP-3. The data for patients with idiopathic and extreme short stature and normal GH peak were similar to each other and to those for patients with transient GHD, except that IGF-I was less frequently low (49.2%, p <0.05). CONCLUSIONS: All the patients with certain GHD had both IGF-I and ALS z-scores < or = -2, unlike those with transient GHD, and idiopathic or extreme short stature. Almost all the patients with short stature and normal GH peak had normal serum IGF-II and IGFBP-3 concentrations.

Influence of tumor location on the presentation and evolution of craniopharyngiomas.

OBJECT: This study was performed to optimize the management of craniopharyngiomas, particularly by identifying factors predicting weight changes to prevent obesity. METHODS: A series of 35 patients who had undergone surgery at a mean age of 7.4 +/- 3.7 years (standard deviation [SD]) and had been followed up until 14.9 +/- 5 years of age by the same endocrinologist were assigned to one of three groups according to their hypothalamic involvement: Group 1 (10 patients) had no involvement, Group 2 (eight patients) had compression without involvement, and Group 3 (17 patients) had severe involvement. Abnormal height and/or weight evolution indicated the craniopharyngioma in only 17% of the patients, although these elements were present at diagnosis in 85%. Before surgery, 85% of the patients lacked growth hormone, 24% lacked thyroid-stimulating hormone, 15% lacked adrenocorticotropin hormone, and 12% lacked antidiuretic hormone. All had complete hypothalamic-pituitary deficiencies after surgery. The body mass index (BMI) before surgery (mean SD 1.1 +/- 1.6) was positively correlated with BMI 1 year after surgery (mean SD 3.1 +/- 2), which correlated with the BMI at the last evaluation (mean SD 3.1 +/- 1.9; p < 0.0001 for both). Before surgery, patients in Group 3 had a greater BMI than did Group 1 (p < 0.02). The BMI of Group 1 patients did not change, but those of Groups 2 and 3 patients increased during the 1st year after surgery (p < 0.02 and p = 0.0003, respectively), with no further change. The changes occurred mainly during the first 3 months after surgery in Group 1, during the first 6 months in Group 2, and throughout the year in Group 3. CONCLUSIONS: The degree of hypothalamic involvement by the craniopharyngioma determines the presentation and predicts weight changes after surgery.

An analysis of the genetic factors involved in testicular descent in a cohort of 14 male patients with anorchia.

Anorchia, or the "vanishing testis syndrome," is characterized by the absence of testis in a 46,XY individual with a male phenotype. The etiology is unknown; however, the familial occurrence of the disease and the association of this phenotype with 46,XY gonadal dysgenesis has led to the suggestion that genetic factors, which play a role in testicular determination, may be involved. Alternatively, exploratory laparoscopy has suggested that anorchia may be caused by a prenatal testicular vascular accident associated with torsion during testicular descent. We screened a cohort of 14 boys with bilateral anorchia for mutations in the Y chromosome-linked testis-determining gene SRY (sex-determining region, Y chromosome); in the gene necessary for correct testicular descent, INSL3; and in the gene of its receptor (LGR8). Mutations in the INSL3 gene and the LGR8 T222P mutation are known to cause cryptorchidism. We confirmed previous reports that mutations in the SRY gene are not associated with anorchia. Although a common polymorphism was identified in the INSL3 gene, no mutations were observed. The recurrent T222P mutation in the LGR8 gene was not found in any of the patients. These data show for the first time a lack of association between genetic factors necessary for correct testicular descent and anorchia.

High prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus despite different hormonal profiles.

OBJECTIVES: To compare the pubertal development, the hormonal profiles and the prevalence of hirsutism and menstrual disorders in obese adolescent girls and adolescent girls with type 1 diabetes mellitus (T1DM). METHODS: Data were collected from 96 obese adolescent girls and 78 adolescent girls with T1DM at Tanner stage IV or V, whose ages ranged between 11.9 and 17.9 years. RESULTS: High prevalence of hirsutism and menstrual disorder was found in the obese adolescent girls (36.5 and 42% respectively) and the adolescent girls with T1DM (21 and 44% respectively). The obese girls were significantly younger at pubarche, thelarche and menarche than the girls with T1DM. Hirsutism in the obese girls and those with T1DM was associated with hyperandrogenaemia and a raised free androgen index (FAI). When the cause of the raised FAI was investigated in both the groups of girls with hirsutism, the raised FAI in the obese girls was due to low serum sex hormone-binding globulin (SHBG) levels. In contrast, the raised FAI of the girls with T1DM and hirsutism was due to hyperandrogenaemia. Menstrual disorders in the T1DM girls were associated also with hyperandrogenaemia unlike obese girls. CONCLUSIONS: Hirsutism and menstrual disorders are common in obese adolescent girls and adolescent girls with T1DM. Although hyperandrogenaemia is present in both groups of girls, the androgenic profiles of the two groups differ. The hyperandrogenaemia in the obese girls is primarily due to their decreased serum SHBG levels, whereas the hyperandrogenaemia in the girls with T1DM is due to their increased androgen production.

Clinical, biological and genetic analysis of anorchia in 26 boys.

BACKGROUND: Anorchia is defined as the absence of testes in a 46,XY individual with a male phenotype. The cause is unknown. METHODS: We evaluated the clinical and biological presentation, and family histories of 26 boys with anorchia, and sequenced their SRY, NR5A1, INSL3, MAMLD1 genes and the T222P variant for LGR8. RESULTS: No patient had any associated congenital anomaly. At birth, testes were palpable bilaterally or unilaterally in 13 cases and not in 7; one patient presented with bilateral testicular torsion immediately after birth. The basal plasma concentrations of anti-Müllerian hormone (AMH, n = 15), inhibin B (n = 7) and testosterone (n = 19) were very low or undetectable in all the patients evaluated, as were the increases in testosterone after human chorionic gonadotropin (hCG, n = 12). The basal plasma concentrations of follicle stimulating hormone (FSH) were increased in 20/25, as was that of luteinising hormone in 10/22 cases. Family members of 7/26 cases had histories of primary ovarian failure in the mother (n = 2), or sister 46,XX, together with fetal malformations of the only boy with microphallus and secondary foot edema (n = 1), secondary infertility in the father (n = 2), or cryptorchidism in first cousins (n = 2). The sequences of all the genes studied were normal. CONCLUSION: Undetectable plasma concentrations of AMH and inhibin B and an elevated plasma FSH, together with 46,XY complement are sufficient for diagnosis of anorchia. The hCG test is unnecessary. NR5A1 and other genes implicated in gonadal development and testicle descent were not mutated, which suggests that other genes involved in these developments contribute to the phenotypes.

Mutation analysis of NR5A1 encoding steroidogenic factor 1 in 77 patients with 46, XY disorders of sex development (DSD) including hypospadias.

BACKGROUND: Mutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum of 46,XY DSD (Disorder of Sex Development) phenotypes including severe forms of hypospadias. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the frequency of NR5A1 gene mutations in a large series of patients presenting with 46,XY DSD and hypospadias. Based on their clinical presentation 77 patients were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external genitalia without uterus (n = 33) or hypospadias (n = 33). We identified heterozygous NR5A1 mutations in 4 cases of ambiguous external genitalia without uterus (12.1%; p.Trp279Arg, pArg39Pro, c.390delG, c140_141insCACG) and a de novo missense mutation in one case with distal hypospadias (3%; p.Arg313Cys). Mutant proteins showed reduced transactivation activity and mutants p.Arg39Pro and p.Arg313Cys did not synergize with the GATA4 cofactor to stimulate reporter gene activity, although they retained their ability to physically interact with the GATA4 protein. CONCLUSIONS/SIGNIFICANCE: Mutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias. Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo heterozygous missense mutation, thus extending the range of phenotypes associated with NR5A1 mutations and suggesting that this group of patients should be screened for NR5A1 mutations.

Clinical, biological and genetic analysis of prepubertal isolated ovarian cyst in 11 girls.

BACKGROUND: The cause of isolated gonadotropin-independent precocious puberty (PP) with an ovarian cyst is unknown in the majority of cases. Here, we describe 11 new cases of peripheral PP and, based on phenotypes observed in mouse models, we tested the hypothesis that mutations in the GNAS1, NR5A1, LHCGR, FSHR, NR5A1, StAR, DMRT4 and NOBOX may be associated with this phenotype. METHODOLOGY/PRINCIPAL FINDINGS: 11 girls with gonadotropin-independent PP were included in this study. Three girls were seen for a history of prenatal ovarian cyst, 6 girls for breast development, and 2 girls for vaginal bleeding. With one exception, all girls were seen before 8 years of age. In 8 cases, an ovarian cyst was detected, and in one case, suspected. One other case has polycystic ovaries, and the remaining case was referred for vaginal bleeding. Four patients had a familial history of ovarian anomalies and/or infertility. Mutations in the coding sequences of the candidate genes GNAS1, NR5A1, LHCGR, FSHR, NR5A1, StAR, DMRT4 and NOBOX were not observed. CONCLUSIONS/SIGNIFICANCE: Ovarian PP shows markedly different clinical features from central PP. Our data suggest that mutations in the GNAS1, NR5A1, LHCGR, FSHR StAR, DMRT4 and NOBOX genes are not responsible for ovarian PP. Further research, including the identification of familial cases, is needed to understand the etiology of ovarian PP.