Long-Term Outcomes of Paediatric-Onset Craniopharyngioma: A Retrospective Analysis from a Tertiary Care Centre in North India.

Background: Craniopharyngiomas are associated with long-term morbidity in the form of hormone deficiencies, visual deficits, and hypothalamic obesity. Objective: To study the long-term outcomes, including cure rates, endocrine dysfunction, visual dysfunction, hypothalamic obesity, and mortality in pediatric-onset craniopharyngiomas. Methods: A retrospective data analysis of pediatric (onset <18 years) craniopharyngioma diagnosed between 2003 and 2018. Data were collected from electronic hospital records, case files, and direct patient interviews. Results: The mean age at presentation was 10.4 ± 4.5 years (n = 62). The median duration of symptoms at diagnosis was 6 months (3-13 months). At presentation, central diabetes insipidus was present in four (6.5%), central hypothyroidism in 27 (43.5%), secondary adrenal insufficiency in 20 (32%) and delayed puberty in 15 (24%) patients. Hypothalamus was involved in 59/60 patients (98%). At last visit, 22.6% were obese in comparison to 4.6% at presentation, and anterior pituitary deficiency was present in 90% of the patients. Sixty-one percent patients (n = 62) had delayed puberty and 67% (n = 53) had short-stature. Out of 35 short children, nine (14%) children who received growth hormone had significant increase in height SD score (-3.8 (1.4) at start vs. -2.9 (1.2) at last follow-up; P = 0.008). Tumor progression was significantly less in the group that received RT compared to those who did not (8% vs. 39%; P = 0.002). Conclusion: Childhood-onset craniopharyngioma results in significant morbidity. The prevalence of pituitary hormones deficiency, visual deficits, and obesity are high at long-term follow-up. Incomplete tumor removal is also frequent. Thus, long-term monitoring is necessary for the timely management of the morbidities associated with craniopharyngioma.

Disorders of Puberty in Girls.

Puberty is the process through which reproductive competence is achieved and comprises gonadarche and adrenarche. Breast development is the initial physical finding of pubertal onset in girls and typically occurs between 8 and 13 years. Menarche normally occurs 2 to 3 years after the onset of breast development. Pubertal onset is controlled by the gonadotropin-releasing hormone pulse generator in the hypothalamus; however, environmental factors such as alterations in energy balance and exposure to endocrine-disrupting chemicals can alter the timing of pubertal onset. Improvement in nutritional and socioeconomic conditions over the past two centuries has been associated with a secular trend in earlier pubertal onset. Precocious puberty is defined as onset of breast development prior to 8 years and can be central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic and is defined as lack of breast development by 13 years or lack of menarche by 16 years. Both precocious and delayed puberty may have negative effects on self-esteem, potentially leading to psychosocial stress. Patients who present with pubertal differences require a comprehensive assessment to determine the underlying etiology and to devise an effective treatment plan.

Long-Term Follow-Up and Treatment of a Female With Complete Estrogen Insensitivity.

CONTEXT: We previously reported the first female with a causative ESR1 gene variant, who exhibited absent puberty and high estrogens. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown. OBJECTIVE: The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment. DESIGN: We have characterized gonadotropin pulsatility and followed this patient's endocrine profile and bone density over 8 years. Seventy-five different compounds were tested for transactivation of the variant receptor. A personalized medicine approach was tailored to our patient. SETTING: Academic medical center. PATIENT OR OTHER PARTICIPANTS: A 24-year-old adopted white female with CEI. INTERVENTION(S): The patient was treated with diethylstilbestrol (DES) for approximately 2.5 years. MAIN OUTCOME MEASURE(S): Induction of secondary sexual characteristics. RESULTS: Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH, and mildly elevated mean follicle-stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the variant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient. CONCLUSIONS: Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.

Blue Rubber Bleb Nevus Syndrome: A Possible Cause for Growth Retardation and Pubertal Delay.

OBJECTIVE: The aim of this paper was to describe a rare case of blue rubber bleb nevus (BRBNS) with growth retardation and pubertal delay. CLINICAL PRESENTATION AND INTERVENTION: A 16-year-old boy with severe iron deficiency anemia was diagnosed with BRBNS, showing growth retardation and pubertal delay simultaneously. The patient was treated conservatively with intravenous iron therapy, and his puberty advanced gradually. CONCLUSION: Given that growth retardation and pubertal delay are rare in BRBNS patients, this case reminds us to include BRBNS in the differential diagnosis of growth retardation.

Ultrasonographic assessment of pubertal breast development in obese children: compliance with the clinic.

BACKGROUND: The aim of the study was to determine the compliance with the clinical and ultrasonographic staging of pubertal breast development in obese children. METHODS: Fifty-two obese children with Tanner stage 2 and stage 3 breast development accompanied by at least one pubertal clinical finding were included in the study. The staging of breast development was also performed according to the ultrasonographic morphostructural appearance. The subjects were then divided into subgroups according to their clinical and ultrasonographic breast stages. The stages given by both methods were compared for consistency with the hormonal values and other radiological (uterus long diameter, ovary sizes) findings. RESULTS: The correlation between the clinical and ultrasonographic staging of pubertal breast development was determined to be weak (r=0.19). Estradiol levels, uterus long diameter and ovary sizes were significantly increased when the ultrasonographic stage increased among the subjects with clinically similar breast development stage. However, no statistical difference was determined in these parameters among the subjects with ultrasonographically similar but clinically different breast development. CONCLUSIONS: It was shown that the ultrasonographic staging of breast development could provide more accurate and objective data due to the possible mistakes caused in the breast development staging of obese children by their adipose tissue.

Adult Consequences of Self-Limited Delayed Puberty.

Delayed puberty is a common condition defined as the lack of sexual maturation by an age ≥2 SD above the population mean. In the absence of an identified underlying cause, the condition is usually self-limited. Although self-limited delayed puberty is largely believed to be a benign developmental variant with no long-term consequences, several studies have suggested that delayed puberty may in fact have both harmful and protective effects on various adult health outcomes. In particular, height and bone mineral density have been shown to be compromised in some studies of adults with a history of delayed puberty. Delayed puberty may also negatively affect adult psychosocial functioning and educational achievement, and individuals with a history of delayed puberty carry a higher risk for metabolic and cardiovascular disorders. In contrast, a history of delayed puberty appears to be protective for breast and endometrial cancer in women and for testicular cancer in men. Most studies on adult outcomes of self-limited delayed puberty have been in small series with significant variability in outcome measures and study criteria. In this article, we review potential medical and psychosocial issues for adults with a history of self-limited delayed puberty, discuss potential mechanisms underlying these issues, and identify gaps in knowledge and directions for future research.

Growth hormone treatment in a patient with Hurler-Scheie syndrome.

A female patient with known Hurler-Scheie syndrome, who underwent hematopoietic cell transplantation, presented with growth retardation and delayed puberty. She started growth hormone (GH) treatment at age 12.33 years, resulting in significantly improved linear growth and predicted adult height. We describe details of her clinical course and literature review of growth pattern as well as GH use in patients with mucopolysaccharidosis I.

Pathological fractures in paediatric patients with inflammatory bowel disease.

UNLABELLED: Paediatric inflammatory bowel disease (IBD), especially Crohn's disease (CD), is commonly associated with poor skeletal health, related to the direct effects of chronic inflammation, prolonged use of glucocorticoid (GC), poor nutrition, delayed puberty and low muscle mass. Low bone mineral density is commonly reported, although the prevalence of long bone fractures may not be increased in these patients. Emerging evidence however suggests that there may be an increased risk of vertebral fractures (VFs) in this group. VFs presenting at diagnosis of paediatric CD, prior to any GC exposure, have been reported, highlighting the deleterious effect of inflammation on skeletal health. This paper reviews the published literature on pathophysiology of skeletal morbidity and fractures in paediatric IBD, illustrated with a new case report of multiple VFs in a prepubertal girl with CD, soon after diagnosis, who received minimal amounts of oral GC. Optimising control of disease, addressing vitamin D deficiency, encouraging physical activity and ensuring normal growth and pubertal progression are paramount to management of bone health in these patients. Despite the lack of evidence, there may be a place for bisphosphonate treatment, especially in the presence of symptomatic pathological fractures, but this requires close monitoring by clinicians with expertise in paediatric bone health. CONCLUSION: Chronic inflammation mediated by pro-inflammatory cytokines may have adverse effects on skeletal health in paediatric patients with IBD. The risk of vertebral fractures may be increased, even without exposure to glucocorticoid. Clinical monitoring of these patients requires careful attention to the various factors that impact on bone health.

[Puberty, fertility and chronic diseases]. / Puberté, fertilité et maladies chroniques.

The onset of puberty is the sum of complex and multifactorial mechanisms resulting from the action of both activating and inhibiting factors, leading to the maturation of the gonads and the ability to reproduce. Many contributors to pubertal development are involved in fat mass acquisition and their action is relayed through the hypothalamus. It is therefore easy to understand how chronic diseases can affect the development of puberty and fertility apart from the specific impact of their molecular alteration. We have chosen cystic fibrosis and chronic renal disease as examples of chronic disorders affecting puberty through distinct mechanisms. As drugs are undistinguishable from chronic diseases, we also describe the impact of corticosteroids and chemotherapy on reproductive function. Last, we describe the surveillance and care of pubertal delay and its consequences (growth and bone mineralization) of patients affected with chronic disorders during adolescence.

Pubertal disorders and bone maturation.

Bone age (BA) indicates more clearly than chronologic age how far an individual has progressed toward full maturity, and predicts the potential for further growth. Single or serial skeletal age estimations help to confirm the diagnosis of normal puberty and normal pubertal variants such as constitutional delay of growth and puberty, premature therlache, and precocious adrenarche. BA can aid in the clinical workup of children whose sexual maturation is early or delayed. Although BA is considered a qualitative rather than quantitative measure, it serves to round out the clinical picture, providing information without which diagnosis could not be achieved.

Intracranial hypertension with delayed puberty: a rare presentation of juvenile onset systemic lupus erythematosus.

An adolescent boy presented with headache, bilateral papilloedema, growth retardation and absent secondary sexual characteristics. The diagnosis of intracranial hypertension was confirmed by increased intracranial pressure and normal neuroimaging of the brain except for partial empty sella and prominent perioptic cerebrospinal fluid (CSF) spaces. Evaluation showed an erythrocyte sedimentation rate of 150 mm/hr, positive antinuclear antibody, anti-dsDNA and antiribosomal P protein. Renal biopsy revealed diffuse segmental proliferative lupus nephritis (LN) class IV-S (A), which confirmed the diagnosis of systemic lupus erythematosus (SLE). Treatment of LN with intravenous pulse methylprednisolone and cyclophosphamide normalised the patient's CSF pressure and symptoms. In cases of intracranial hypertension, SLE must be considered. Growth retardation and absence of secondary sexual characteristics could coexist and may be presenting features of SLE. These manifestations point to advanced grades of LN, which could be asymptomatic and may be missed without a renal biopsy.

High prevalence of primary ovarian insufficiency in girls and young women with Nijmegen breakage syndrome: evidence from a longitudinal study.

CONTEXT: Nijmegen breakage syndrome (NBS) is a severe chromosomal instability disorder characterized by microcephaly, growth retardation, immune deficiency, and predisposition for malignancy. It is caused by hypomorphic mutations in the NBN gene, which product belongs to the protein complex critical for processing DNA double-strand breaks during mitotic and meiotic recombination. Data on gonadal function in patients with NBS are limited. OBJECTIVE: Growth and sexual development, along with hormonal assays, were evaluated in girls and young women with NBS homozygous for c.657_661del5 mutation. STUDY DESIGN AND PATIENTS: The group comprised 37 girls and young women with NBS (ages, 0.17-24.25 yr), followed between 1993 and 2008. Patients were divided into three age groups: 1) 1-3 yr; 2) 4-9 yr; and 3) 10 yr and older. Growth, puberty, concentrations of gonadotropins and 17-beta-estradiol, bone age, and pelvic ultrasound were assessed. RESULTS: None of the patients presented a typical growth spurt; the adult height ranged between the 3rd and 25th centiles. Median bone age was delayed by 4.05 yr. Pubarche reached stadium P2 in eight patients and P3 in two patients. In all but one girl, thelarche did not exceed Th2, with low 17beta-estradiol levels. Gonadotropin levels showed a biphasic pattern, with median FSH values of 55.0, 10.9, and 81.9 IU/liter, and LH of 3.2, 0.8, and 21.0 IU/liter in consecutive age groups. Ultrasound visualized small ovaries or solid streaks and the hypoplastic uterus. CONCLUSIONS: Primary ovarian insufficiency and the associated hypergonadotropic hypogonadism are hallmark manifestations in girls and young women with NBS. Our findings emphasize the need for long-term endocrinological and interdisciplinary supervision of these patients.

Assessment of puberty in relation to L-carnitine and hormonal replacement therapy in beta-thalassemic patients.

OBJECTIVE: To investigate puberty in a group of thalassemic patients with delayed or arrested pubertal development and to compare the effects of hormonal and L-carnitine therapy on puberty in those patients. PATIENTS: Thirty-two -thalassemic patients with arrested or failure of puberty were enrolled for 1 year in this study. METHOD: Clinical pubertal assessment and laboratory investigations were done for all patients at the beginning, 6 months later clinical pubertal assessment was done. Patients were divided into two groups (16 each): first group received L-carnitine therapy, while the second group received hormonal therapy. Pubertal and laboratory assessment were done 6 months after hormonal and L-carnitine therapy. RESULTS: Failure of puberty was confirmed in 71.4% of boys and 33.3% of girls, while arrested puberty was observed in 28.6% of boys and 66.7% of girls. All girls had amenorrhea, primary amenorrhea in 88.9% and secondary amenorrhea in 11.1%. Menses occurred in 20% of female patients after L-carnitine therapy and in 37.5% of them after hormonal therapy. Improvement of pubertal staging was observed in 50% of males after L-carnitine therapy compared to 75% of them after hormonal therapy. While improvement of pubertal staging was seen in 90% of females after L-carnitine therapy compared to 100% of females after hormonal treatment. However, these results showed no significant difference between both groups. CONCLUSION: Delayed puberty in beta-thalassemia major is either due to failure of gonads or failure of the whole hypothalamic pituitary gonadal axis. L-carnitine as well as hormonal replacement therapy had a positive effect on puberty in the thalassemic patients. Further studies are needed to clarify the role of L-carnitine on puberty in these patients.

Growth hormone normalizes pubertal onset in children with cystic fibrosis.

UNLABELLED: Children with cystic fibrosis (CF) have a high incidence of delayed puberty and poor growth. We retrospectively reviewed pubertal maturation data from 105 children with CF who had participated in studies on growth hormone (GH). As part of the GH study, participants were randomized into two cohorts, one of which was treated with GH for 1 year, and then followed off GH, and the other group was first followed off GH, and then treated with GH for 1 year. Pubertal staging was obtained throughout these studies and we have retrospectively analyzed the data. RESULTS: In prepubertal females, GH treatment resulted in a normalized onset of breast development as compared to delayed onset in non-treated females. Females treated during puberty had a normal tempo of breast development. In prepubertal males, GH treatment resulted in a normalized onset of testicular volume compared to non-treated males. Testicular size progression was not accelerated in pubertal boys treated with GH. CONCLUSION: GH treatment normalizes pubertal onset in prepubertal children with CF.

Multiple pituitary hormone deficiency (MPHD) associated with normal height, absent puberty and obesity.

We present a 22-year old girl with MPHD and a normal pituitary imaging (MRI) who grew to normal size without GH. She was very obese. At age 19 years replacement therapy with hydrocortisone, L-thyroxine and sex steroids was started. Despite severe growth hormone deficiency according to the provocative tests and decreased IGF I level our patient grew normally. On follow up at age 22 she is 174cm tall.

Subtotal splenectomy for treatment of retarted growth and sexual development associated with splenomegaly.

This communication presents a new alternative for the treatment of retarded growth and sexual development associated with spleno- megaly: subtotal splenectomy, preserving the upper splenic pole supplied only by the splenogastric vessels, to avoid adverse effects of total splenectomy. We performed this procedure associated with central splenorenal shunt or portal-variceal disconnection in 3 teenagers with portal hypertension due to Schistosomia-sis Mansoni, complicated by variceal bleedings. All of them presented retarded growth and sexual development. All patients had uneventful postoperative follow-up, and normal growth and sexual development after the surgery. Subtotal splenectomy should be considered for treatment dwarfism associated with splenomegaly.

Delayed puberty and primary amenorrhea associated with a novel mutation of the human follicle-stimulating hormone receptor: clinical, histological, and molecular studies.

Inactivating mutations of the FSH receptor have been described in rare cases of premature ovarian failure. Only one mutation was associated with a complete phenotype, including delayed puberty, primary amenorrhea, and small ovaries. We describe here a new patient presenting a similar complete phenotype of premature ovarian failure, with high plasma FSH levels associated with very low estrogen and inhibin B levels. No biological response to high doses of recombinant FSH was detected. A novel homozygous Pro(519)Thr mutation was found in this patient. This mutation is located in the second extracellular loop of the FSH receptor, within a motif highly conserved in gonadotropin and TSH receptors. The mutation totally impairs adenylate cyclase stimulation in vitro. FSH binding experiments and confocal microscopy showed that this mutation alters the cell surface targeting of the mutated receptor, which remains trapped intracellularly. Histological studies of the ovaries of the patient showed an increase in the density of small follicles compared with age-matched normal women. A complete block in follicular maturation after the primary stage was also observed. Immunocytochemical studies allowed detection of the expression of c-Kit and proliferation cellular nuclear antigen, whereas no apoptosis was shown by the 3'-end-labeling method. This observation supports the concept that in humans FSH seems mandatory for the initiation of follicular growth only after the primary stage. In our patient complete FSH resistance yields infertility, which is remarkably associated with the persistence of a high number of small follicles.

Pitfall in diagnosing growth hormone deficiency in a hypochondroplastic patient with a delayed puberty.

Hypochondroplasia is a clinically and genetically heterogeneous skeletal dysplasia with less obvious disproportion in childhood and a reduced pubertal growth spurt. We report on a young hypochondroplastic man who had been misdiagnosed and treated as being growth hormone (GH) deficient in the early phase of puberty. The delay of his puberty which is unusual in hypochondroplasia might have confused the results of provocative GH testing. At the age of 17 years measurement of body proportions revealed an increased upper to lower body segment ratio. Skeletal radiographs showed a lack of increase in the interpedicular distance from the first to the fifth lumbar vertebra, anteroposterior shortening of the lumbar pedicles, short femoral necks, a fibula longer than the tibia, and short tubular bones. As the clinical and radiographic features suggested the diagnosis of a skeletal dysplasia, a DNA sequence analysis of the fibroblast growth factor receptor 3 gene on chromosome 4 p16.3 was performed, which identified the missense mutation C1620 G in the tyrosine kinase domain resulting in an Asn540Lys substitution. Hypochondroplastic children with this common mutation (N540K) were previously found to respond to GH treatment with an increase in sitting height compared to leg length, which accentuated the existing disproportion. We want to emphasise that in children with normal serum IGF-I and IGFBP-3 levels accurate measurements of body proportions and skeletal radiographs in disproportionate cases are more important than reiterative GH stimulation tests, which prepubertally and in the early phase of puberty often show subnormal responses.

Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study.

Few longitudinal studies have investigated the effects of amenorrhea and amenorrhea plus exercise on bone mineral density (BMD) of young women. We carried out a 2-yr comparison of dancers and nondancers, both amenorrheic and normal, that investigated the role of hypothalamic amenorrhea on bone in this context. We studied 111 subjects (mean age, 22.4 +/- 4.6 yr; age of menarche, 14.1 +/- 2.2 yr), including 54 dancers, 22 with hypothalamic amenorrhea, and 57 nondancers, 22 with hypothalamic amenorrhea. Detailed hormonal and nutritional data were obtained in all groups to determine possible causal relationship to osteoporosis. The amenorrheic groups, dancers and nondancers, both showed reduced BMD in the spine, wrist, and foot, which remained below controls throughout the 2 yr. Only amenorrheic dancers showed significant changes in spine BMD (12.1%; P < 0.05) but still remained below controls, and within this subgroup, only those with delayed menarche showed a significant increase. The seven amenorrheic subjects (three dancers and four nondancers) who resumed menses during the study showed an increase in spine and wrist BMD (17%; P < 0.001) without achieving normalization. Delayed menarche was the only variable that predicted stress fractures (P < 0.005), which we used as a measure of bone functional strength. Analysis of dieting and nutritional patterns showed higher incidence of dieting behavior in this group, as manifested by higher Eating Attitudes Test scores (16.3 +/- 2.00 vs. 11.5 +/- 1.45; P < 0.05) and higher fiber intakes (30.7 +/- 3.00 vs. 17.5 +/- 2.01 g/24 h; P < 0.001). We concluded that low bone mass occurs in young women with amenorrhea and delayed menarche, both exercisers and nonexercisers. Crucial bone mass accretion may be compromised by their reproductive and nutritional health.