The Prader-Willi Syndrome

When I was asked to write an editorial to comment on the article by Simon et al (1) in this issue of the Journal, I felt it would be a real challenge. The use of GH therapy in children has provoked more discussion in the last few years from a legal, journalistic, economical, and even political point of view than from medical and scientific perspectives. I decided to take the challenge and to comment on the facts as I perceive them. An impact of recombinant human GH (rhGH) on muscle strength is controversial. As physicians, we are essentially warned about rhGH doping in professional and Olympic athletics, with the presumption that it has a beneficial effect on muscle strength. This is despite the fact that there appears to be no evidence that rhGH enhances muscle strength, power, or aerobic capacity in trained adult athletes. However, rhGH does increase modestly anaerobic exercise capacity when administered alone and to a greater extent when combined with testosterone (2). Thus, despite the abuse of rhGH by athletes, there is little support of performance benefit except for an effect on anaerobic exercise capacity (2). In GH-deficient patients, replacement of rhGH improves aerobic exercise capacity, although it remains to be elucidated whether this is due to the direct effect on muscle function or on other factors influencing cardiovascular function, well-being, and motivation. Long-term rhGH replacement in excess of 12 months seems to be required for improved muscle strength to take place in GH-deficient adult subjects (2). It has been reported that 10 years of rhGH replacement therapy in GH-deficient adults increased muscle strength during the first half of the study and then protected partly against the normal decline withage inmusclestrength,resulting inapproximatelynormalized muscle strength after 10 years (3). Even fewerdataareavailable inchildren,with theexception of data gathered from children affected with Prader-Willi syndrome(PWS),araregenetic formofobesitywithhypothalamic involvement that leads to GH deficiency. One group assessed the impact of rhGH therapy begun early in life on the natural history of PWS and compared height, body composition, and strength in similar-age children with PWS naive to rhGH with those treated with hGH for 6 years (4). Motor strength testing included broad jump, agility run, sit-ups, and upper arm strength assessments. The evaluator of motor strength testing was blinded to the treatment status of each child. PWS children treated with rhGH demonstrated greater motor strength (increased standing broad jump 22.9 2.1 vs 14.6 1.9 inches (P .001) and sit-ups 12.4 0.9 vs 7.1 0.7 repetitions in 30 seconds; P .001). Clear trends were seen in the 2 other areas of the testing, including improved agility run and weight-lift repetitions, although these did not reach statistical significance. Thus, thisnonrandomizedstudysuggestedabeneficialeffecton muscle strength in children affected by PWS. However, these few reports on young active adults, on GH-deficient adults, and on children affected by PWS may not be relevant to the chronically ill and less active children included in the study of Simon et al (1). In this study, the authors evaluated the effects of rhGH on muscle strength in children receiving long-term glucocorticoid therapy. Expected effects of growth hormone on height and body composition were assessed and confirmed, but those will not be commented upon here. This was a pilot study, randomized and controlled, with a delayed-start of rhGH for 12 months. rhGH was started after randomization (month 0) or 6 months later (month 6). A total of 30 children with various diagnoses, on glucocorticoid therapy for a chronic disease, startedat least1year earlierwithheight1SDorat2SDscore (SDS) below and bone age 15 years in boys and 13 years in girls. rhGH was administered at a dose of 0.065 mg/kg/d for 6monthsandtheninthedosagemaintainingserumIGF-1levels

Prader-Willi syndrome (PWS) is primarily caused by a paternal microdeletion of the 15q11-q13 region, maternal uniparental disomy (mUPD) or unbalanced translocations. The MKRN3 gene, located within 15q11-q13, is a master regulator of pubertal initiation. We aimed to compare variant pubertal onset and progression with recent normative data and to correlate it with abnormal MKRN3 gene status. Age at pubarche, gonadarche, subsequent pubertal progression and bone age (BA) at gonadarche were investigated in 37 PWS patients (18 females) who already entered pubarche and/or gonadarche with median age 11.1 (95% CI: 6.4 - 18.8) years. All patients were re-tested to confirm genetic subtypes of PWS. The MKRN3 gene was analyzed using single gene sequencing. Out of 37 subjects, 22 had microdeletion and 15 mUPD. Regardless of genetic subtypes and MKRN3 gene status, no correlation between genotypes and the pubertal pattern was found. They initiated pubarche early - girls at 7.4 (95%CI:6.4-8.4), and boys at 9.2 (8.2-10.2) years. The subsequent progression from PH2 to PH4 (pubic hair development) was prolonged to 3.7 years in girls (1.5-5.9;p<0.05), and 2.9 in boys (2.2-3.6;p<0.001). The age at gonadarche was adequate - 10.0 years in girls (8.8-11.2), and 11.0 in boys (9.8-12.1). Progression rate of breast development from B2 to B4 was 3.9 (0.2-7.5) years in girls and of testicular volume from 4 ml to 15ml was 3.8 (0.0-8.1) years in boys. The BA at gonadarche is advanced by 0.6 ± 1.1 years (p<0.001). Children with PWS, regardless of the genetic subtype and/or MKRN3 status, had an early pubarche and normally timed gonadarche. Pubarche progression was slower. Advanced BA was significantly correlated with gonadarche.

Longitudinal data on bone mineral density (BMD) in children and adolescents with Prader-Willi Syndrome (PWS) during long-term GH treatment are not available. This study aimed to determine effects of long-term GH treatment and puberty on BMD of total body (BMDTB), lumbar spine (BMDLS), and bone mineral apparent density of the lumbar spine (BMADLS) in children with PWS. This was a prospective longitudinal study of a Dutch PWS cohort. Seventy-seven children with PWS who remained prepubertal during GH treatment for 4 years and 64 children with PWS who received GH treatment for 9 years participated in the study. The children received GH treatment, 1 mg/m(2)/day (≅ 0.035 mg/kg/d). BMDTB, BMDLS, and BMADLS was measured by using the same dual-energy x-ray absorptiometry machine for all annual measurements. In the prepubertal group, BMDTB standard deviation score (SDS) and BMDLSSDS significantly increased during 4 years of GH treatment whereas BMADLSSDS remained stable. During adolescence, BMDTBSDS and BMADLSSDS decreased significantly, in girls from the age of 11 years and in boys from the ages of 14 and 16 years, respectively, but all BMD parameters remained within the normal range. Higher Tanner stages tended to be associated with lower BMDTBSDS (P = .083) and a significantly lower BMADLSSDS (P = .016). After 9 years of GH treatment, lean body mass SDS was the most powerful predictor of BMDTBSDS and BMDLSSDS in adolescents with PWS. This long-term GH study demonstrates that BMDTB, BMDLS, and BMADLS remain stable in prepubertal children with PWS but decreases during adolescence, parallel to incomplete pubertal development. Based on our findings, clinicians should start sex hormone therapy from the age of 11 years in girls and 14 years in boys unless there is a normal progression of puberty.

BackgroundThe “Assessment of Motor Repertoire—3 to 5 Months”, which is a part of Prechtl's General Movements Assessment (GMA), has been gradually applied to infants with genetic metabolic disorders. However, there have been no studies on the application of the GMA for infants with Prader-Willi syndrome (PWS).AimsThe purpose of this study was to determine the inter- and intra-observer reliability of the assessment tool in a population of infants with PWS.Study designThis was a reliability and agreement study.SubjectsThis was a cross-sectional study with15 infants with PWS born at an average gestational age of 38 weeks.Outcome measuresStandardized video recordings of 15 infants with PWS (corrected ages of 3 to 5 months) were independently assessed by three observers. Kappa and ICC statistics were applied in inter- and intra- observer reliability analyses.ResultsThe overall reliability ICC values of the “Motor Optimality Score” (MOS) ranged from 0.84 to 0.98, and the pairwise agreement ranged between 0.86 and 0.95 for inter- observe reliability. In addition, ICC values for the MOS ranged between 0.95 and 0.98 for tester agreement in intra-observer reliability.Complete agreement reliability (100%) was achieved in the subcategories of “Fidgety Movements” and “Movement Character” for the inter- and intra-observer reliability. Moderate to high inter- and intra-observer reliability were found in the subcategories of “Repertoire of Co-Existent Other Movements”, “Quality of Other Movements” and “Posture”, with kappa values ranging between 0.63 and 1.00.ConclusionThere were high levels of inter-and intra-observer agreement in the “Assessment of Motor Repertoire—3 to 5 Months” for infants with PWS. It is possible to carry out standardized quantitative assessments of the motor performance of infants with PWS.

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.

Effects of growth hormone treatment in adults with Prader–Willi syndrome

Prader-Willi Syndrome (PWS) is a chromosome 15 disorder characterized by hypotonia, hypogonadism, hyperphagia, and obesity. Musculoskeletal manifestations, including scoliosis, hip dysplasia, and lower limb alignment abnormalities, are well described in the orthopaedic literature. However, care of this patient population from the orthopaedic surgeon's perspective is complicated by other clinical manifestations of PWS. Osteopenia, psychiatric disorders, and diminished pain sensitivity are frequently noted in PWS but are not discussed in the orthopaedic literature. The authors present a clinical review of an 8-year experience of caring for 31 patients with PWS to highlight all clinical concerns that influence orthopaedic management. Thirty-one institutionalized patients diagnosed with PWS were examined and all past medical records were reviewed. Patient demographics, genetic testing, musculoskeletal diagnoses, psychiatric diagnoses, and clinical behaviors were recorded. Radiological studies performed in the course of routine clinical care were evaluated. Twenty-three men and 8 women, with an average age of 22 years (range, 8-39 years), were studied. A chromosome 15q abnormality was confirmed in 18 patients. Scoliosis was clinically detected in 21 of 30 patients and confirmed by radiographs in 14 of these 24 patients (overall with scoliosis, 45%) with an average primary curve of 27 degrees; 3 were braced, and 2 underwent spinal fusion. Radiographs also revealed diminished cervical lordosis and increased cervicothoracic kyphosis in 16 patients, a previously undescribed finding. Hip radiographs of 26 patients revealed dysplasia in 2 patients (13%); no slipped capital femoral epiphysis were identified. Fourteen patients had sustained a total of 58 fractures, with 6 patients sustaining multiple fractures (range, 2-7). Six patients have undergone orthopaedic surgical procedures with one major complication (spinal infection). Fracture management was associated with frequent minor complications. Bone densitometry was performed on 14 patients; 8 patients had osteopenia, and 4 had osteoporosis based on lumbar spine z scores. Twenty-six patients had Axis I psychiatric diagnoses including impulse control disorder (7), organic personality disorder (6), oppositional defiant disorder (5), dysthymic disorder (4), depressive disorder not otherwise specified (3), attention-deficit/hyperactivity disorder (2), and obsessive-compulsive disorder (2). Nine patients exhibited self-mutilating behaviors. Osteopenia, poor impulse control and defiant behaviors, and diminished pain sensitivity are aspects of PWS that may complicate all facets of orthopaedic nonsurgical and surgical management in this patient population. The treating orthopaedic surgeon must plan carefully and proceed with caution when treating children and adults with PWS.

Prader-Willi syndrome (PWS) is a rare genetic syndrome, with a prevalence of infantile scoliosis of ~23%. These curves are likely related to severe hypotonia. Approximately 15% of children with PWS will need surgical intervention for their scoliosis. The purpose of this study was to evaluate the effectiveness of curing or controlling moderate and severe infantile scoliosis curves in children with PWS. This single institution, retrospective study of patients with PWS and infantile scoliosis reviewed 34 consecutive children with >24 months follow-up from initiation of serial spinal casting. Cobb angle comparison measurements of radiographs taken precasting, during treatment, and at follow-up were performed. Rib-vertebral angle difference, Nash-Moe rotation, and space available for lung measurements were followed. Outcomes were stratified as "Cured," "Braced," and "Surgery." Average age for first cast for the entire study was 32 months (range, 14 to 64), undergoing 8 casts (range, 3 to 18) over 25 months (range, 9 to 57) for an initial curve of 54 degrees (range, 27 to 106 degrees), which improved to 27 degrees (range, 11 to 78 degrees). In total, 12 patients (35%) were in the Cured group, following 6 casts over 17 months, with an initial curve of 44±14 degrees improving to 17±5 degrees at the end of treatment, and 20±18 degrees at 68-month follow-up. In total, 18 patients were in the Braced group, with curves initially improving from 55±14 degrees to 35±14 degrees, but at 47±20 degrees at 51-month follow-up. Four patients needed surgery, with initial curves 85 degrees (range, 54 to 106 degrees), but surgery could be postponed 56 months (range, 40 to 73) by casting. Rib-vertebral angle difference was not prognostic. Serial spinal casting is effective in for treating infantile scoliosis in children with PWS. One third of patients had their curve resolved, at least temporarily, where they were braced and cast free. The others were able to delay surgery for a number of years. Initial curves <50 degrees in children <3 years of age seem to have the best prognosis. Level IV.

To investigate craniofacial characteristics in pediatric patients with Prader-Willi syndrome (PWS). A retrospective sample of 20 consecutive patients with PWS who had lateral and antero-posterior (AP) cephalograms (14 males and six females; average age 10.2 ± 3 years) was compared to 20 controls matched for age and sex (14 males and six females; average age 10.5 ± 3.7 years). Cephalometric skeletal measurements were performed twice at a 1-week interval by one calibrated operator, and random error was calculated using Dahlberg's formula. Mean values and standard deviations were computed for all variables. Student's t-test for independent samples was used to determine significant differences between PWS and controls. The level of significance was set at p < 0.05. Cephalometric values for the length of the maxilla (p < 0.01), mandibular length (p < 0.05) at both the ramus (p < 0.05) and the mandibular body (p < 0.01), and posterior and anterior facial height (p < 0.01) were significantly lower in patients with PWS compared to controls. The AP cephalometric analysis revealed a significant reduction (p < 0.01) in maxillary skeletal width, mandibular skeletal width, and interzygomatic distance. Pediatric patients with PWS seem to have a general reduction in certain craniofacial skeletal parameters (i.e., maxillary and mandibular length) compared to controls, but this study did not assess the overall craniofacial characteristics.

The consequences of hyperphagia in people with Prader-Willi Syndrome: A systematic review of studies of morbidity and mortality

Incidence of strabismus and amblyopia in preverbal children previously diagnosed with pseudoesotropia

Prader-Willi syndrome (PWS) is a complex genetic disorder with errors in genomic imprinting, generally due to a paternal deletion of chromosome 15q11-q13 region. Maternal disomy 15 (both 15s from the mother) is the second most common form of PWS resulting from a trisomic zygote followed by trisomy rescue in early pregnancy and loss of the paternal chromosome 15. However, trisomy 15 or mosaicism for trisomy 15 may be present in the placenta possibly leading to placental abnormalities affecting gestational age and delivery. We examined growth and gestational data from 167 PWS infants (93 males and 74 females; 105 infants with 15q11-q13 deletion and 62 infants with maternal disomy 15) to determine if there are differences in gestation between the two genetic subtypes. No significant differences in growth data (birth weight, length, head circumference) or average gestational ages were found between the two genetic subgroups. However, post-term deliveries (> 42 weeks gestation) were more common in the maternal disomy group (i.e., 12 of 62 infants) compared with the deletion group (i.e., 7 of 105 infants) (chi-square test = 6.22; p < 0.02). The distribution of gestational ages in the 15q11-q13 deletion group was more bell-shaped or normal while the distribution in the maternal disomy group suggested a bimodal pattern. Maternal disomy 15 in PWS may contribute to disturbances in gestational age and delivery by impacting on placental structure or function secondary to the abnormal chromosomal number in the placental cells or in mechanisms leading to the maternal disomy status in PWS infants.

Cutaneous blood flow and thermoregulation in prader-willi syndrome patients

This study examined sensitivity of eye tracking measures to hyperphagia severity in Prader-Willi syndrome (PWS). Gaze data were collected in 57 children with PWS, age 3-11 years, and 47 typically developing peers at two study sites during free visual exploration of complex stimulus arrays that included images of food, animals, and household objects. Analysis of the number and duration of fixations as well as gaze perseverations revealed that food items are not exceptionally salient for children with PWS. Instead, increased attention to food in the context of other high-interest items (e.g., animals) was associated with caregiver reports of more severe hyperphagia and more advanced nutritional phase. The study also provided preliminary evidence of possible genetic subtype and sex differences as well as demonstrated that multiple investigators in a wide range of settings can effectively implement the eye tracking protocol. The results indicate that gaze characteristics derived from eye tracking may be a promising objective marker of hyperphagia in PWS for use in research and clinical trials.

Objectives After completing this article, readers should be able to: Development and maturation of the reproductive system begins in fetal life and is a surprisingly active process throughout the first postnatal months. The reproductive system becomes quiescent during childhood until its reactivation triggers pubertal development. Puberty begins with increased pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, increased pituitary responsiveness to GnRH, increased secretion of gonadotropins,gonadal maturation, and increasing production of sex steroids. Increased concentrations of sex steroids induce the development of secondary sexual characteristics, acceleration of growth, and ultimate fertility. Factors that determine the timing of pubertal onset remain poorly understood and the subject of intense investigation, but general health, nutrition, and genetic factors all are known to contribute.The diagnostic criteria for pubertal delay are based roughly on statistical norms (ie, delay of more than 2 to 3 standard deviations from the mean age of pubertal onset), but in fact they are somewhat arbitrary. Puberty is considered to be clinically delayed if sexual maturation has not become apparent by age 14 years in boys or age 13 years in girls. This clinical diagnosis also is made in the absence of menarche by age 16 years or in the absence of menarche within 5 years of pubertal onset. Using these criteria, approximately 2.5% of healthy adolescents will be identified as having pubertal delay. Most are boys. After evaluation, the majority of these adolescents will be found to have no pathology; rather, onset of their otherwise normal puberty simply is sufficiently late or slow relative to that of their peers to have triggered concern and evaluation. When puberty does begin, it is entirely normal. Some adolescents have a variety of other causes to explain pubertal delay(TableT1), and with careful evaluation, most are diagnosed accurately. In constitutional delay of puberty, the normal prepubertal growth nadir is protracted. Presumably, the pubertal increase of pulsatile GnRH secretion is slow to develop, which delays pubertal levels of sex steroid secretion and their developmental effects on secondary sexual characteristics and growth hormone production. The prototypic patient who has constitutional delay of puberty is a 14- or 15-year-old boy who presents after most of his peers have begun puberty. Boys present far more often than girls because short stature and sexual immaturity extract a higher psychosocial price in males than in females. In many cases, delay of puberty is superimposed on constitutional short stature, exaggerating the effects of the delay. History may reveal similarly delayed puberty in the patient's parents or siblings. Findings on physical examination are unremarkable except possibly for early signs of puberty unnoticed by the patient. Laboratory evaluation results are normal, although bone age is delayed and consistent with the extent of pubertal maturation.The outcome of isolated constitutional delay of puberty is excellent;neither sexual maturity nor final adult height is affected by the timing of pubertal onset. However, when constitutional delay of puberty is superimposed on constitutional short stature, final height will be short. Resolving the relative effects of these factors in final height has been difficult in the studies performed to date.Chronic illness may affect pubertal onset, tempo, and potential. The pathophysiology of pubertal delay in chronic illness is variable,frequently multifactorial, and in some cases, not well-established. Chronic illness may affect underlying genetic potential, disturb physiologic function, or limit adequate nutrition. Chronic use of glucocorticoids, cancer chemotherapy, other medications, or radiation therapy may have short- or long-term consequences for growth or sexual maturation.Adolescents who have chronic conditions, about which they already are acutely self-conscious, deserve particularly close monitoring of their pubertal course to allow early detection of pubertal difficulties. Often, only reassurance that puberty ultimately will proceed and eventual development will be normal is all that is required. However,when more pathologic pubertal derangements are detected, they should be treated early to maximize the potential for catch-up. Nutrition should be a priority, especially in those conditions where it frequently is compromised (eg, inflammatory bowel disease, cystic fibrosis), with supplementation used where appropriate. The risks and benefits of proposed medications and therapies, especially their effects on growth and maturation, always should be considered. Other explanations for pubertal delay should be investigated when the disease process does not explain maturational insufficiency or delay adequately. Finally,hormone replacement or augmentation with exogenous sex steroids is appropriate in some settings, but it is not a substitute for aggressive management of the underlying condition.Delayed puberty is not a common presentation of panhypopituitarism;affected children typically present with short stature earlier in childhood. Panhypopituitarism presenting in adolescence is usually due to idiopathic hypothalamic failure. However, other unusual central nervous system etiologies (eg, tumor, Langerhans cell histiocytosis)should be ruled out.The syndromes of isolated gonadotropin deficiency (IGD) are heterogeneous in clinical presentation. They occur more frequently in boys than in girls and often are difficult to distinguish from constitutional delay. IGD in association with hyposmia or anosmia is known as Kallman syndrome. The KAL-1 gene encodes a protein that allows fetal GnRH neurons to migrate from the olfactory placode through the cribiform plate and into the hypothalmus. Deletion of the KAL-1 gene is associated with sensorineural deafness, kidney malformations, and pes cavus. Boys who have GnRH deficiency often have a small phallus and testes, but findings on history and physical examination may be entirely normal except for sexual immaturity. Delayed bone age is the only consistent laboratory finding.Thyroid hormone is required for normal puberty. Its absence may delay the onset or retard the progress of pubertal maturation by interfering with gonadotropin secretion. Thyroid replacement therapy usually normalizes gonadotropin secretion and allows puberty to proceed normally.Hyperprolactinemia may cause primary or secondary amenorrhea, but it is an otherwise rare cause of delayed puberty. Elevated prolactin levels interfere with gonadotropin production and may be due to a functioning pituitary adenoma (prolactinoma) or related to use of prescribed or illicit drugs (eg, phenothiazines, cocaine). Measurement of serum prolactin is a useful part of the evaluation for amenorrhea or delayed puberty, even in the absence of galactorrhea, and always should be obtained in the presence of galactorrhea. Prolactinomas may not be visible on imaging studies of the brain,making diagnosis more difficult.Bilateral gonadal failure is uncommon and is characterized by markedly elevated concentrations of serum gonadotropins. The most common causes of gonadal failure are congenital: Turner syndrome(gonadal dysgenesis) and Klinefelter syndrome. Other congenital causes of gonadal failure and acquired bilateral gonadal failure are rare.Girls who have Turner syndrome have short stature, variable but incomplete puberty, primary amenorrhea, and characteristic congenital anomalies. Growth retardation is the most consistent characteristic and begins in utero. Rarely is a pubertal growth spurt seen. For some girls, the diagnosis will not be made until they present with pubertal insufficiency. Most girls who have Turner syndrome have primary ovarian failure that gives rise to markedly elevated levels of gonadotropins by adolescence, although variable sexual development still occurs. More than 50% of patients in one study had some breast development, and some pubic and axillary hair is typical for most patients. A minority of affected girls experience spontaneous menarche at an average age of 13.4 years, but most girls who have Turner syndrome require long-term estrogen replacement therapy.Klinefelter syndrome is relatively common. The genotype is typically 46,XXY, but genetic variability and mosaicism occur. Many affected boys are not identified until puberty or early adulthood. Often, some spontaneous pubertal development occurs, but testes become fibrotic and smaller as boys become older. Males who have Klinefelter syndrome present with small testicles and external genitalia and often have gynecomastia. Affected boys tend to be tall in childhood, and their tall stature sometimes delays diagnosis despite their pubertal immaturity. Borderline intellectual abilities or behavioral difficulties sometimes lead to diagnosis in childhood or may be appreciated in retrospect. In adolescence, young men who have Klinefelter syndrome present with small testicles and hypogonadism. Testosterone production is abnormally low, follicle-stimulating hormone values are high, and oligospermia or azospermia is seen.Iatrogenic gonadal failure may occur in the aftermath of chemotherapy,radiation therapy, or surgery. Acquired gonadal failure also may have traumatic, postinfectious, autoimmune, or metabolic causes. Mumps orchitis is the most common infectious cause of gonadal failure. Autoimmune oophritis, a rare cause of ovarian failure, often is associated with Addison disease and other autoimmune endocrinopathies. In galactosemia, the effects of galactose or its metabolites on the prenatal or neonatal ovary may cause delayed or deficient puberty in girls or may be a cause of menstrual dysfunction.Among patients who have complete androgen insensitivity, phenotypic females have the XY genotype and present with primary amenorrhea and sparse or absent pubic and axillary hair despite normal thelarche. Prader-Willi syndrome is associated with hypogonadism, short stature,and obesity in both males and females. Micropenis and bilateral cryptorchidism are characteristic of boys; hypoplasia of the labia majora and clitoris are seen in girls, who also frequently have delayed or absent menarche. Hypogonadotropic hypogonadism occurs in both the Laurence-Moon syndrome and the Bardet-Biedl syndrome. Boys who have Noonan syndrome have abnormal testes (cryptorchidism, atrophy,anorchia), and their sexual maturation is consistently delayed. Many have primary gonadal failure with no spontaneous puberty, and infertility is common.In the "vanishing testes syndrome," 46,XY karyotype and masculine-appearing genitalia are associated with absent testes and failure of puberty. Presumably, testicular atrophy or destruction occurred some time after fetal differentiation of the external genitalia. Patients who have "resistant ovaries syndrome" have a 46,XX karyotype and typically present with sexual immaturity and primary amenorrhea. Further evaluation reveals small ovaries with primordial follicles despite elevated gonadotropin concentrations. The pathophysiology is believed to be due to abnormalities in gonadotropin receptors or antibodies to these receptors.A long list of other congenital disorders and syndromes may be associated with pubertal delay or failure. These include Bloom syndrome, LEOPARD syndrome, ataxia telangectasia syndrome, and the cerebrohepatorenal syndrome. Enzyme defects in steroid synthesis(eg, cholesterol desmolase complex, 3-beta-hydroxysteroid dehydrogenase) also can lead to pubertal failure. Genetic males who have these disorders are born with ambiguous genitalia.Other conditions, including eating disorders, malnutrition, and excessive exercise, may cause hypogonadotropic hypogonadism that results in pubertal delay or insufficiency. Girls are affected more often than boys and typically present with primary or secondary amenorrhea. Girls who are competitive athletes have significantly later pubarche and menarche than their peers, with the delays proportional to the intensity of their training. Similarly, eating disorders can disrupt normal pubertal progress profoundly. Weight gain usually corrects these abnormalities, although women who have eating disorders are at higher risk for menstrual irregularity independent of weight.Congenital anomalies of the female reproductive tract usually present with delayed onset of menses despite normal development of secondary sexual characteristics. Congenital anomalies associated with the apparent absence of menses include imperforate hymen, vaginal atresia, or vaginal aplasia. Other girls present in the early teen years with cyclic abdominal pain as a result of a normally responsive endometrium and spillage of menstrual fluid into the pelvis("concealed menarche").The extensive differential diagnosis of delayed puberty requires a systematic and focused approach to evaluation. Anosmia, galactorrhea,or symptoms of hypothyroidism may suggest a specific diagnosis. A careful history can identify excessive exercise or symptoms of chronic illness or psychiatric disease. A positive family history for pubertal delay would support the diagnosis of constitutional delay of puberty. Careful measurement of growth and determination of sexual maturity are the initial steps in physical assessment. Early signs of sexual development, unnoticed by the patient, may eliminate the need for a costly evaluation. A careful physical examination can help to identify stigmata of unsuspected congenital syndromes.Determination of serum gondotropin levels will distinguish disorders of congenital or acquired gonadal failure from other causes of delayed puberty. By adolescence (bone age 10 to 12 y), gonadal failure consistently produces markedly elevated levels of serum gonadotropins. When these are present, findings from the history and physical examination will often point to the specific diagnosis. Chromosomal analysis is indicated to confirm clinical suspicion of gonadal dysgenesis or Klinefelter syndrome. On the other hand, when serum gonadotropins are normal or low, constitutional delay of puberty is the most frequent diagnosis. However, further laboratory evaluation may be required to exclude the possibility of occult chronic illness or endocrinopathy. Reasonable screening studies include a complete blood count, erythrocyte sedimentation rate, and measurement of serum prolactin and serum thyrotropin-stimulating hormone. Even when results of these studies are normal, IGD remains a possible diagnosis because no studies reliably distinguish IGD from constitutional delay(Figs. 1and 2). Measurement of first morning urinary testosterone or stimulation testing using a GnRH agonist eventually may help to differentiate these conditions, but neither study currently is in broad general use.Ideally, management of pubertal delay should address the underlying cause if one can be identified. For patients whose hypothalamic hypogonadism is related to exercise, eating disorder, or chronic illness, every effort should be made to effect changes in overall health and nutrition that will allow spontaneous puberty to proceed. Constitutional delay of puberty may be managed by reassurance alone, given our understanding that even striking delays will have no effect on final adult height or development (Fig. 1). Expectant management is more acceptable to families when clinicians can point out early signs of puberty that were not obvious to the patient. However,short-term hormonal therapy to "jump start" puberty may be appropriate when severe delay has led to psychosocial dysfunction.Testosterone injections (eg, testosterone enanthate 100 mg intramuscularly administered monthly for 6 mo) are used for boys whose pubertal development already has begun. For boys who have not yet begun puberty, oral oxandrolone can be used at a starting dose of 1.25 mg daily. Such treatment should be monitored by specialists familiar with the potential side effects, including hepatic peliosis and premature epiphyseal closure. All boys treated with sex steroids should be monitored at 3- to 6-month intervals to assess response to treatment and skeletal maturation. Treatment is discontinued when it is expected that endogenous hormone production is established.Patients who have gonadotropin deficiency or hypogonadism require lifelong replacement with sex steroids and should be managed in consultation with a pediatric endocrinologist. Testosterone supplementation is begun in boys at approximately age 12 years. It may be administered by injection, transdermal patch, or topical gel. Doses initially are small and are increased based on careful follow-up of secondary sexual characteristics and growth to achieve a relatively normal puberty. Once puberty is complete, lifelong testosterone replacement is continued.For girls who have hypogonadism, replacement hormone therapy is begun to coincide with puberty in peers. Estrogen replacement may be started with a transdermal estradiol patch or small daily doses of conjugated estrogens or ethinyl estradiol that are increased gradually to adult replacement levels. As with boys, careful monitoring of secondary sexual characteristics and growth is required. Cyclic hormonal replacement, typically with low-dose oral contraceptives, should be instituted after 1 to 2 years of estrogen replacement or once breakthrough bleeding has occurred.Adolescents who have marked pubertal delay are at risk for psychosocial difficulties that should be sought actively in the initial evaluation. Delayed or absent puberty is more troublesome for boys than for girls. Significant delay may lead to poor body image, low self-esteem, teasing, bullying, parental overprotection, social withdrawal and isolation, declining academic performance, and school avoidance. Boys who look younger than their chronologic age have fewer opportunities for age-appropriate activities and social interaction,date less, and report feelings of unpopularity.Girls who have pubertal delay present with fewer psychosocial concerns. Indeed, some value their immature body habitus. For girls who have eating disorders, for example, early puberty consistently is associated with increasing dissatisfaction with weight or body image. The psychosocial burden imposed on the adolescent by delayed puberty should help to determine the extent of intervention. Simple reassurance may suffice when puberty is expected to proceed and psychosocial effects are few. Some form of hormonal therapy to accelerate puberty may be appropriate in cases of substantial psychosocial distress, even in cases of constitutional delay in which puberty is expected to progress spontaneously.