A Phenotypic Female Adolescent with Primary Amenorrhea and Dysmorphic Features.

We report on a case of a 14-year-old phenotypic female with a microdeletion at 13q31.1-q31.3, dysmorphic facial and limb features, and neurologic symptoms. She presented to her pediatrician with concerns for delayed puberty, and laboratory analysis revealed hypergonadotropic hypogonadism. She was found to have an XY karyotype and streak gonads. Further genetic studies did not reveal another cause for her gonadal dysgenesis and, to our knowledge, an association with her known 13q-microdeletion has not yet been reported. Given the risk of malignancy with XY gonadal dysgenesis, the patient had surgery to remove the gonads and had no postoperative complications after a 6-month follow-up visit. We also discuss the role of the pediatrician in cases of delayed puberty, from initial diagnosis to definitive management. [Pediatr Ann. 2019;48(12):e495-e500.].

Delayed Puberty-Phenotypic Diversity, Molecular Genetic Mechanisms, and Recent Discoveries.

This review presents a comprehensive discussion of the clinical condition of delayed puberty, a common presentation to the pediatric endocrinologist, which may present both diagnostic and prognostic challenges. Our understanding of the genetic control of pubertal timing has advanced thanks to active investigation in this field over the last two decades, but it remains in large part a fascinating and mysterious conundrum. The phenotype of delayed puberty is associated with adult health risks and common etiologies, and there is evidence for polygenic control of pubertal timing in the general population, sex-specificity, and epigenetic modulation. Moreover, much has been learned from comprehension of monogenic and digenic etiologies of pubertal delay and associated disorders and, in recent years, knowledge of oligogenic inheritance in conditions of GnRH deficiency. Recently there have been several novel discoveries in the field of self-limited delayed puberty, encompassing exciting developments linking this condition to both GnRH neuronal biology and metabolism and body mass. These data together highlight the fascinating heterogeneity of disorders underlying this phenotype and point to areas of future research where impactful developments can be made.

Being Reproductive.

Women's reproductive health maintenance begins in the early years of growth and development. Routine care is the basis for early detection of menstrual dysfunction and delays or acceleration of physical development. Patients and their families may not address menstruation concerns because of the sensitive nature of the topic, the patient's self-conscious attitudes, and the parent's apprehension. Providers should be able to provide early detection of menstrual abnormalities, which may uncover underlying health concerns and structural abnormalities. Early intervention and treatment may accelerate or decelerate physical growth, preserve fertility, and promote healthy behaviors with decreased psychological stress for patients and families.

Transition in Pediatric and Adolescent Hypogonadal Girls: Gynecological Aspects, Estrogen Replacement Therapy, and Contraception.

Hypogonadism may be suspected if puberty is delayed. Pubertal delay may be caused by a normal physiological variant, by primary ovarian insufficiency (Turner syndrome), or reflect congenital hypogonadotropic hypogonadism (HH; genetic) or acquired HH (brain lesions). Any underlying chronic disease like inflammatory bowel disease, celiac disease, malnutrition (anorexia or orthorexia), or excessive physical activity may also result in functional HH. Thus, girls with delayed puberty should be evaluated for an underlying pathology before any treatment, including oral contraception, is initiated. Estrogen replacement is important and natural 17ß-estradiol, preferably transdermally, is the preferred choice, whereas the oral route can be used as an alternative depending on patient preference and compliance. Sexual activity is often delayed in the hypogonadal adolescent girl. In the adolescent hypogonadal girl, hormone replacement therapy (HRT) most likely has been initiated at the time she becomes sexually active. If a risk of unwanted pregnancy cannot be ruled out, there is a need to consider contraception. This consideration does not contradict the principles of HRT but can be included as a part of the substitution, e.g. oral contraceptives containing 17ß-estradiol or a progestogen intrauterine device combined with continuous 17ß-estradiol (transdermal or oral).

The investigation of children and adolescents with abnormalities of pubertal timing.

Concerns with pubertal development are common and can cause considerable distress to patients and their carers. Many presentations reflect normal variations of pubertal timing and primarily require reassurance, although patients may opt for interventions. Other presentations need active management to avoid significant adverse effects on growth and psychosocial development. All should undergo careful assessment, particularly as some children or adolescents presenting with abnormalities in pubertal timing may have serious pathology which requires urgent investigations and treatment. This review describes the appropriate investigations and their interpretation for young people presenting with disorders in pubertal timing.

RASopathies Are Associated With Delayed Puberty; Are They Associated With Precocious Puberty Too?

RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic-pituitary-gonadal axis and the timing of puberty by the rat sarcoma-mitogen-activated protein kinase pathway. Additional study of the timing of puberty among patients with RASopathies is warranted to ascertain the incidence of delayed and precocious puberty in these conditions and to examine genotype-phenotype correlations, which may provide insight into pathways that regulate the timing of puberty.

The measurement of urinary gonadotropins for assessment and management of pubertal disorder.

OBJECTIVE: Measurement of urinary LH (uLH) and FSH (uFSH) may facilitate non-invasive pubertal assessment but there is a need for further validation by studying children and adolescents with disorders of puberty. DESIGN: 65 cases (Male: 25) with a median age of 12 years (2.9-18.1) supplied at least one non-timed urine sample for uLH and uFSH measurement by immunoassay and corrected for creatinine excretion. 25 cases were receiving GnRH-agonist (GnRH-a) at the time of sample collection. In 41 cases, urine samples were collected prior to a LHRH test and in 12 cases matched serum samples for basal LH (sLH) and FSH (sFSH) were also available. RESULTS: There was a significant correlation between sLH and uLH:uCr (r=0.82; p-value <0.001) and sFSH and uFSH:uCr (r=0.93; p-value <0.001). Based on receiver operator characteristics analysis, a uLH:uCr value of 0.05 IU/mmol as a cut-off would detect a LH peak >5U I/L with a sensitivity of 86% and a specificity of 72% with a positive predictive value of 93%. In pubertal boys (6) and girls (22) with a sLH peak >5UI/L, median uLH:uCr was 0.27 IU/mmol (0.27-0.28) and 0.17 IU/mmol (0.09-0.43), respectively. The median uFSH:uCr was 0.51 IU/mmol (0.41-0.60) for boys and 1.1 IU/mmol (0.21-2.44) for girls. In the 25 cases on GnRH-a, the median uLH:uCr for boys and girls was 0.02 IU/mmol (0.01-0.02) and 0.02 IU/mmol (0.004-0.07), respectively, and the median uFSH:uCr was 0.07 IU/mmol (0.05-0.09) and 0.27 IU/mmol (0.09-0.54), respectively. CONCLUSION: Urinary gonadotrophins reflect serum gonadotrophin concentration and may represent a reliable non-invasive method of assessing pubertal progress.

IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.

Early or late pubertal onset affects up to 5% of adolescents and is associated with adverse health and psychosocial outcomes. Self-limited delayed puberty (DP) segregates predominantly in an autosomal dominant pattern, but the underlying genetic background is unknown. Using exome and candidate gene sequencing, we have identified rare mutations in IGSF10 in 6 unrelated families, which resulted in intracellular retention with failure in the secretion of mutant proteins. IGSF10 mRNA was strongly expressed in embryonic nasal mesenchyme, during gonadotropin-releasing hormone (GnRH) neuronal migration to the hypothalamus. IGSF10 knockdown caused a reduced migration of immature GnRH neurons in vitro, and perturbed migration and extension of GnRH neurons in a gnrh3:EGFP zebrafish model. Additionally, loss-of-function mutations in IGSF10 were identified in hypothalamic amenorrhea patients. Our evidence strongly suggests that mutations in IGSF10 cause DP in humans, and points to a common genetic basis for conditions of functional hypogonadotropic hypogonadism (HH). While dysregulation of GnRH neuronal migration is known to cause permanent HH, this is the first time that this has been demonstrated as a causal mechanism in DP‡.

Coexisting diseases modifying each other's presentation - lack of growth failure in Turner syndrome due to the associated pituitary gigantism.

Introduction: Turner syndrome presents with one of the most frequent chromosomal aberrations in female, typically presented with growth retardation, ovarian insufficiency, facial dysmorphism, and numerous other somatic stigmata. Gigantism is an extremely rare condition resulting from an excessive growth hormone (GH) secretion that occurs during childhood before the fusion of epiphyseal growth plates. The major clinical feature of gigantism is growth acceleration, although these patients also suffer from hypogonadism and soft tissue hypertrophy. Case report: We presented a girl with mosaic Turner syndrome, delayed puberty and normal linear growth for the sex and age, due to the simultaneous GH hypersecretion by pituitary tumor. In the presented case all the typical phenotypic stigmata related to Turner syndrome were missing. Due to excessive pituitary GH secretion during the period while the epiphyseal growth plates of the long bones are still open, characteristic stagnation in longitudinal growth has not been demonstrated. The patient presented with delayed puberty and primary amenorrhea along with a sudden appearance of clinical signs of hypersomatotropinism, which were the reasons for seeking medical help at the age of 16. Conclusion: Physical examination of children presenting with delayed puberty but without growth arrest must include an overall hormonal and genetic testing even in the cases when typical clinical presentations of genetic disorder are absent. To the best of our knowledge, this is the first reported case of simultaneous presence of Turner syndrome and gigantism in the literature.

Hypothalamic obesity.

Hypothalamic obesity represents a rare diagnosis applicable to only a small subset of obese patients. It is important to identify, diagnose, and treat these patients. This article reviews the physiology of the hypothalamus, focusing on its role in regulation of hunger, feeding, and metabolism. The causes of hypothalamic obesity are discussed including genetic, anatomic, and iatrogenic etiologies. The complex hormonal environment leading to obesity is explored for each etiology and treatment strategies are discussed. Reproductive consequences are also reviewed.

Associations between early alcohol and tobacco use and prolonged time to puberty in boys.

BACKGROUND: Previous research has demonstrated a relationship between prepubertal alcohol and tobacco use and delayed pubertal characteristics in girls. Although, laboratory research indicates that alcohol and tobacco use inhibits sexual maturation in male rats, human research in this area is lacking. To address this question among boys, we conducted a study to explore the association between early use of alcohol and tobacco and time to development of secondary sexual characteristics. METHODS: The study population included 3199 boys interviewed between the ages of 11 and 21. Participants reported the ages at which they first experienced body hair growth, deepening of the voice and facial hair growth. Early alcohol and tobacco use were defined as first use preceding the age of pubertal development among those reporting regular consumption patterns. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazard models. RESULTS: Early alcohol use was associated with longer time to body hair growth (HR 0.77; 95% CI 0.69-0.87), voice changes (HR 0.72; 95% CI 0.64-0.82) and facial hair growth (HR 0.77; 95% CI 0.68-0.86), after adjusting for tobacco use and age at interview. Tobacco use was not independently associated with the puberty indicators after controlling for alcohol use and age at interview. CONCLUSIONS: Our findings are consistent with the hypothesis that alcohol may inhibit puberty onset in boys, an association that has been previously observed among young girls. Thus, alcohol may be an exposure deserving more scrutiny as a disruptor to normal pubertal development.

Crohn's disease and growth deficiency in children and adolescents.

Nutritional concerns, linear growth deficiency, and delayed puberty are currently detected in up to 85% of patients with Crohn's disease (CD) diagnosed at childhood. To provide advice on how to assess and manage nutritional concerns in these patients, a Medline search was conducted using "pediatric inflammatory bowel disease", "pediatric Crohn's disease", "linear growth", "pubertal growth", "bone health", and "vitamin D" as key words. Clinical trials, systematic reviews, and meta-analyses published between 2008 and 2013 were selected to produce this narrative review. Studies referring to earlier periods were also considered if the data was relevant to our review. Although current treatment strategies for CD that include anti-tumor necrosis factor-α therapy have been shown to improve patients' growth rate, linear growth deficiencies are still common. In pediatric CD patients, prolonged diagnostic delay, high initial activity index, and stricturing/penetrating type of behavior may cause growth deficiencies (in weight and height) and delayed puberty, with several studies reporting that these patients may not reach an optimal bone mass. Glucocorticoids and inflammation inhibit bone formation, though their impact on skeletal modeling remains unclear. Long-term control of active inflammation and an adequate intake of nutrients are both fundamental in promoting normal puberty. Recent evidence suggests that recombinant growth factor therapy is effective in improving short-term linear growth in selected patients, but is of limited benefit for ameliorating mucosal disease and reducing clinical disease activity. The authors conclude that an intense initial treatment (taking a "top-down" approach, with the early introduction of immunomodulatory treatment) may be justified to induce and maintain remission so that the growth of children with CD can catch up, ideally before puberty. Exclusive enteral nutrition has a key role in inducing remission and improving patients' nutritional status.

Pubertal gynecomastia coincides with peak height velocity.

OBJECTIVE: Pubertal gynecomastia (PG) occurs in up to 65% of adolescent boys. In this study, we investigated the relationship between the ages at which PG and peak height velocity occur in pubertal boys. METHODS: This was a prospective study that was designed to detect PG within three months of its emergence. We examined one hundred and six boys who were followed for short stature and/or delayed puberty at three month intervals, and gynecomastia was observed in 43 of these boys (40.5%). RESULTS: PG occurred in the 43 boys within a year of their peak height velocity, and most of these boys were at Tanner stage 3 for pubic hair and had testicular volumes between 8-10 mL. CONCLUSION: It is recommended that evaluation of height growth be included in the diagnostic approach to PG in boys with short stature and/or delayed puberty. The coincidence of age of peak height velocity and PG suggests a causal relationship between the two events and a role of insulin-like growth factor-1.

Delayed puberty but normal fertility in mice with selective deletion of insulin receptors from Kiss1 cells.

Pubertal onset only occurs in a favorable, anabolic hormonal environment. The neuropeptide kisspeptin, encoded by the Kiss1 gene, modifies GnRH neuronal activity to initiate puberty and maintain fertility, but the factors that regulate Kiss1 neurons and permit pubertal maturation remain to be clarified. The anabolic factor insulin may signal nutritional status to these neurons. To determine whether insulin sensing plays an important role in Kiss1 neuron function, we generated mice lacking insulin receptors in Kiss1 neurons (IR(ΔKiss) mice). IR(ΔKiss) females showed a delay in vaginal opening and in first estrus, whereas IR(ΔKiss) males also exhibited late sexual maturation. Correspondingly, LH levels in IR(ΔKiss) mice were reduced in early puberty in both sexes. Adult reproductive capacity, body weight, fat composition, food intake, and glucose regulation were comparable between the 2 groups. These data suggest that impaired insulin sensing by Kiss1 neurons delays the initiation of puberty but does not affect adult fertility. These studies provide insight into the mechanisms regulating pubertal timing in anabolic states.

Social and emotional predictors of the tempo of puberty in female rhesus monkeys.

A cascade of neuroendocrine events regulates the initiation and progression of female puberty. However, the factors that determine the timing of these events across individuals are still uncertain. While the consequences of puberty on subsequent emotional development and adult behavior have received significant attention, what is less understood are the social and environmental factors that actually alter the initiation and progression of puberty. In order to more fully understand what factors influence pubertal timing in females, the present study quantified social and emotional behavior; stress physiology; and growth and activity measures in juvenile female rhesus monkeys to determine what best predicts eventual puberty. Based on previous reports, we hypothesized that increased agonistic behavior resulting from subordinate status in their natal group, in combination with slowed growth, reduced prosocial behavior, and increased emotional reactivity would predict delayed puberty. The analyses were restricted to behavioral and physiological measures obtained prior to the onset of puberty, defined as menarche. Together, our findings indicate that higher rates of aggression but lower rates of submission received from group mates; slower weight gain; and greater emotional reactivity, evidenced by higher anxiety, distress and appeasing behaviors, and lower cortisol responsivity in response to a potentially threatening situation, predicts delayed puberty. Together the combination of these variables accounted for 58% of the variance in the age of menarche, 71% in age at first ovulation, and 45% in the duration of adolescent sterility. While early puberty may be more advantageous for the individual from a fertility standpoint, it presents significant health risks, including increased risk for a number of estrogen dependent cancers and as well as the emergence of mood disorders during adulthood. On the other hand, it is possible that increased emotional reactivity associated with delayed puberty could persist, increasing the risk for emotional dysregulation to socially challenging situations. The data argue for prospective studies that will determine how emotional reactivity shown to be important for pubertal timing is affected by early social experience and temperament, and how these stress-related variables contribute to body weight accumulation, affecting the neuroendocrine regulation of puberty.

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.

A comprehensive approach to the spectrum of abnormal pubertal development.

Puberty is the biological transition from childhood to adulthood. The process involves the coordination of hormonal, physical, psychosocial, and cognitive systems to result in physiologic change. Precocious puberty is defined as pubertal development beginning earlier than expected based on normal standards. Gonadotropin dependent precocious puberty is caused by premature activation of the hypothalamus resulting in pulsatile secretion of GnRH. Gonadotropin independent precocious puberty is caused by excess sex hormones from peripheral or external sources. Treatment with GnRH agonists should be offered to prevent early fusion of the epiphyseal plates to avoid unnecessary short stature and should not be based on perceived psychosocial consequences of early puberty. Delayed puberty is the absence of or incomplete development of secondary sexual characteristics. Hypergonadotropic hypogonadism or primary hypogonadism may result from genetic mutation syndromes or can be acquired from antiovarian antibodies, exposure to radiation or chemotherapy, inflammatory insult, or surgical removal of the gonads. Hypogonadotropic hypogonadism or secondary hypogonadism is due to hypothalamic dysfunction resulting in impaired secretion of GnRH. The long-term goal for patients with inadequate estrogen stimulation is to maintain the serum concentration of sex steroids within the normal adult range to promote the development of secondary sexual characteristics, prevent premature bone loss, and ultimately to induce fertility when indicated.

The physiology of puberty and its disorders.

Puberty is a complex process of developmental change regulated by multiple genetic and endocrine controls. Abnormal pubertal development (both precocious and delayed puberty) can cause significant distress to the patient and may in some instances be a sign of life-threatening pathology. Delayed puberty is often due to constitutional delay of growth and puberty, but will also occur in cases of primary gonadal failure and in patients with disorders leading to diminished gonadotropin levels (ie, central nervous system [CNS] tumors). Precocious puberty may occur due to CNS disorders, certain genetic disorders, ectopic gonadotropin secretion or autonomous sex steroid secretion. Treatment is directed toward the underlying pathology, and may include agents to either stimulate or block pubertal development. Health care providers require knowledge of the normal onset of timing and rate of progression of puberty, and must be able to identify patients with abnormal pubertal development, as well as initiate the appropriate laboratory workup.

Adult height in girls with delayed pubertal growth.

BACKGROUND/AIMS: Boys with constitutional delay of growth and puberty (CDGP) with early reduction in relative height before the onset of puberty will have adult height (AH) clearly below their target height (TH). Characteristics of growth in girls with CDGP are poorly known. We examined whether girls with CDGP attain their TH and whether early reduction in height SDS influences their AH. We also investigated effects of low-dose estrogen on AH. METHODS: We investigated growth of 39 women (7 treated with low-dose estrogen) with CDGP history. We compared AH between estrogen-treated and untreated subjects, and used multiple linear regression to investigate the influence of various growth characteristics, e.g. height SDS changes between different ages in childhood, on AH. RESULTS: AH was similar in estrogen-treated and untreated subjects. Reduction of height SDS between 3 and 8 years was significantly associated with the difference between AH and TH (regression coefficient 0.8, 95% confidence interval 0.1-1.5). Overall, 49% of subjects had AH >0.50 SDS below TH. CONCLUSION: A proportion of CDGP girls do not attain AH consistent with their TH. Reduction in height SDS in childhood predicts smaller AH. Low-dose estrogen treatment does not seem to influence AH in girls with CDGP.