Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty.

CONTEXT: The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE: This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS: We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS: MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION: We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.

Prevalence of delayed puberty and low bone density in patients with epidermolysis bullosa: Insight from a large single center's experience.

BACKGROUND: Epidermolysis bullosa (EB) is a group of rare genetic skin conditions that result in skin fragility. EB can be quite severe with chronic inflammation and malnutrition impairing growth and pubertal development. These factors have potential consequences for skeletal health. We aimed to determine the prevalence of delayed puberty and low bone mineral density (BMD) for age in children and young adults with EB. METHODS: Electronic medical records (EMR) of patients with confirmed EB <30 years of age at time of initial encounter at Cincinnati Children's Hospital Medical Center between January 1, 2010 and September 30, 2020 were reviewed. Natural language processing software was used to categorize pubertal status of patients with EB as early, normal or delayed. BMD was measured by dual energy x-ray absorptiometry and categorized as low if height adjusted Z-score was <-2.0 using age, sex and race specific reference ranges. RESULTS: 29% of individuals with EB had low BMD with most cases occurring prior to 10 years of age. Of patients who reached adolescence, 23% failed to develop any signs of puberty in the normal range (before age 13 in females or 14 in males) and BMD Z-scores further declined in these individuals. CONCLUSION: Delayed puberty is an under-recognized comorbidity of individuals with EB, especially in those with recessive dystrophic EB, and can have a significant impact on BMD.

Increased androgen-related comorbidity in adolescents and adults born with hypospadias: A population-based study.

BACKGROUND: Hypospadias is a common congenital malformation often related to the effect of androgens in utero. While hypogonadism is associated with many potential health risks including metabolic and cardiovascular disease, the risk of clinical hypogonadism and comorbidities in men with hypospadias later in life has not been studied. OBJECTIVES: Investigate the risk of hypogonadism and somatic comorbidities in adolescents and men born with hypospadias. MATERIALS AND METHODS: We conducted a population-based cohort study using Swedish registers. Associations between hypospadias and hypogonadism, delayed puberty, metabolic, and cardiovascular disease respectively were estimated using Cox proportional hazards regression. Body measurements from military conscription were analysed in a subpopulation as indicators of growth and cardiometabolic risk. We used sibling comparison analyses to control for familial confounding. RESULTS: Using register data, a total of 2,165,255 men including 9,714 men born with hypospadias were followed from the age of 10 to a maximum of 60 years. We found an association between hypospadias and hypogonadism (Hazard ratio (HR) 3.27, 95% confidence interval (CI) 2.33-4.59) which was more pronounced in proximal hypospadias. Men with hypospadias had shorter average height than their brothers and the general population. We further found an increased risk of delayed puberty (HR 1.49, 95% CI 1.08-2.07), diabetes mellitus type 2 (HR 1.57, 95% CI 1.18-2.09) and cardiovascular disease (HR 1.47, 95% CI 1.27-1.71). DISCUSSION: We found an increased risk of hypogonadism, metabolic and cardiovascular disease in men born with hypospadias, increasing with severity of phenotype, as well as impacted growth. These results indicate discruptions in androgen function past childhood, although some of the associations may be due to other underlying aetiologies. CONCLUSION: Hypospadias is associated with an increased risk of androgen-related comorbidity in adolescence and adulthood. We suggest that this can be considered clinically, while further research is needed, especially in older populations.

Clinical profile and aetiologies of delayed puberty: a 15 years' experience from a tertiary centre in Sudan.

OBJECTIVES: Delayed puberty is a common presentation to endocrine clinics, with adult height, sexual capability and fertility being the main concerns for the child and his/her family. Presentation is variable including short stature and/or absence of secondary sexual characteristics. The aetiology can either be constitutional, functional or permanent hypogonadotropic hypogonadism, permanent hypergonadotropic hypogonadism or unclassified. Despite the importance of this subject, there are no publications from Sudan. METHODS: A retrospective hospital-based study. Records of all patients who were seen in the endocrinology unit at Gaffar Ibn Auf Children's Hospital and were diagnosed as having delayed puberty were reviewed and demographic, clinical, and investigations data were obtained. RESULTS: A total of 136 patients were included in this study. Presentation includes short stature in 52.2%, both short stature and delayed puberty in 27.2%, and delayed puberty in 20.6%. The most common aetiologies were permanent hypogonadotropic hypogonadism and functional hypogonadotropic hypogonadism presented in 37.5% and 36% respectively, while constitutional delay of growth and puberty was found in only 14.7%. Type 1 diabetes mellitus (T1DM) was the most frequent chronic illness followed by coeliac disease. Hypergonadotropic hypogonadism was diagnosed in 11.7%, the majority of which were females. CONCLUSIONS: The aetiological pattern reported in this series highlights the role of nutrition and general well-being in pubertal development, as well as the major impact of genetics and consanguinity on disease patterns. Data from African countries are limited and this is the first reported cohort on delayed puberty from Sudan.

Accelerated pubertal onset in short children with delayed bone age.

OBJECTIVES: Constitutional delay of growth (CDG) is usually associated with a delay in pubertal onset (CDGP) and a catch-up growth after puberty. Some individuals, however, have earlier-than-expected pubertal onset resulting in a shorter adult height. We investigated the current incidence of such individuals and that of 30 years ago. METHODS: The study subjects are 1,312 consecutive Japanese children referred to Osaka City General Hospital (OCGH) for short stature during 2010-2018, and a cohort of 11,256 individuals in the Ogi Growth Research (OGR, 1979-1992). Individuals with the height standard deviation score <-1.0, the bone age (BA)/chronological age (CA) ratio <0.8 at first visits, and without other identifiable causes of short stature were extracted from the record of OCGH. Similarly, individuals meeting the height and bone age criteria were extracted from the OGR record. The pubertal growth onset was auxologically determined as the upward shift from the prepubertal growth curve fitted to a quadratic function. Earlier-than-expected onset was defined as the onset earlier than the population average +1 year. RESULTS: From the OCGH cohort, 55 children (38 boys, 17 girls) met the criteria, and earlier-than-expected onset was observed in 34.2% of boys and 29.4% of girls. In the 73 short individuals with delayed bone age in the OGR cohort, earlier-than-expected onset was less common (13.0% for boys and 14.8% for girls). There was no significant association between the timing of pubertal growth onset and the BA/CA ratio, IGF-1, and midparental height. CONCLUSIONS: Earlier-than-expected pubertal growth onset is common in CDG and possibly increasing.

Timing of Pubertal Onset in Girls and Boys With Constitutional Delay.

CONTEXT: The decision whether to treat a child with delayed puberty with sex steroids is primarily based on patient, family, and provider preference. Knowing when children with constitutional delay eventually enter puberty would inform this decision. OBJECTIVE, DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES: To estimate and compare rates of pubertal entry, we conducted a retrospective cohort study by reviewing medical records of children evaluated for delayed puberty at a large academic medical center between 2000 and 2015, extracting data on pubertal status for all clinical visits, then conducting time-to-event analyses. RESULTS: Of 392 girls and 683 boys with delayed puberty, constitutional delay was the most common cause, found in 32% of girls and 70% of boys. In a subcohort of 97 girls and 243 boys who were prepubertal at one or more visits, we observed a broad age range for pubertal entry, up to >16 years for girls and >17 years for boys. The probability of entering puberty within the next year for 12- to 15.5-year-old girls and 13.5- to 16.5-year-old boys with delayed puberty ranged between 38% and 74%. No differences in the rates of pubertal entry were seen between girls and boys after data harmonization. CONCLUSION: The broad range of ages at pubertal entry for children with constitutional delay challenges the concept that constitutional delay is merely an extreme of normal variation. Discussions with patients and families about management should consider the possibility that some children may need to wait years after presentation until puberty starts.

Exposure to non-persistent pesticides and puberty timing: a systematic review of the epidemiological evidence.

BACKGROUND: Numerous modern non-persistent pesticides have demonstrated estrogenic/anti-androgenic activity and have been classified as endocrine-disrupting chemicals (EDCs). Processes involved in puberty development are vulnerable to EDCs, such as compounds that interfere with the metabolism or activity of sex steroids. OBJECTIVE: To conduct a systematic review of epidemiological studies on the relationship between early-life exposure to non-persistent pesticides and puberty timing and/or sexual maturation in girls and boys. METHODS: A systematic search was carried out using MEDLINE and SCOPUS databases, including original articles published up to November 2020. RESULTS: Thirteen studies were selected after excluding non-original and non-human studies. Exposure to different types of pesticides has been associated with altered puberty timing in girls and/or boys in eight studies. In utero exposure to atrazine has been related to earlier age of menarche in girls; exposure to organophosphate (OP) pesticides has been related to delayed sexual development in boys and girls; childhood pyrethroid exposure has been associated with pubertal delay in girls and pubertal advancement in boys; and prenatal/childhood exposure to multiple pesticides has been linked to earlier puberty onset in girls and pubertal delay in boys. CONCLUSIONS: Most of the reviewed studies describe a relationship between pesticide exposure and changes in the age of puberty onset or sex hormone levels, although the quality of the evidence is generally low. Further well-designed longitudinal studies are warranted on specific classes of pesticides and on possible interactions between different types of compounds.

Growth hormone deficiency and other endocrinopathies after childhood brain tumors: results from a close follow-up in a cohort of 242 patients.

PURPOSE: Brain tumors are the most common solid tumor in children. The prevalence of survivors from these cancers has been increasing, presenting endocrine sequelae in more than 40% of the cases. Our aim was to characterize the endocrinopathies diagnosed in this population, exploring the outcomes of growth hormone treatment. METHODS: We have performed a retrospective analysis of the survivors that were followed-up through a close protocol at our endocrine late-effects clinic. RESULTS: 242 survivors, followed during 6.4 (0-23.4) years, were considered. The median age at tumor diagnosis was 6.7 (0-18) years and pilocytic astrocytoma was the most frequent neoplasm (33.5%). The prevalence of endocrinopathies was of 71.5%, with growth hormone deficiency being the most frequent (52.9%). An indirect correlation between the age at the beginning of somatropin and growth velocity in the first year of treatment was observed. Those treated with craniospinal radiotherapy presented a smaller final upper/lower segments ratio comparing with those that only received cranial radiotherapy. However, their final height was not compromised when compared to their family height target. We found pubertal delay in 12%; accelerated/precocious puberty in 13.2%; central and primary hypogonadism in 21.9% and 3.3%, respectively; primary and central hypothyroidism in 23.6% and 14.5%, respectively; thyroid nodules in 7.4%; ACTH deficiency in 10.3% and diabetes insipidus in 12%. CONCLUSION: This study reveals a higher prevalence of endocrinopathies in brain tumors survivors and explores the influence of craniospinal irradiation in the adult body proportions. It reinforces the importance of routine follow-up among survivors.

Hypogonadotrophic hypogonadism, delayed puberty and risk for neurodevelopmental disorders.

Hypogonadotrophic hypogonadism (HH) is a rare disorder that manifests absent puberty and infertility. Genetic syndromes with hypogonadism, such as Klinefelter syndrome, are associated with an increased risk of neurodevelopmental disorders (NDDs). However, it is not clear whether patients with HH or transient delayed puberty in general, have an increased risk of NDDs. We performed a register-based study on a national cohort of 264 patients with HH and 7447 patients diagnosed with delayed puberty that was matched with 2640 and 74 470 controls, respectively. The outcome was defined as having any of the following NDD diagnoses: (i) autism spectrum disorder (ASD); (ii) attention deficit hyperactivity disorder (ADHD); or (iii) intellectual disability (ID). Additional sensitivity analyses were performed to control for different parental and birth variables, as well as diagnosed malformation syndromes and chromosomal anomalies (ie, Down's and Turner syndromes). Patients with HH had increased risk for being diagnosed with ASD (odds ratio [OR] = 5.7; 95% confidence interval [CI] = 2.6-12.6), ADHD (OR = 3.0; 95% CI = 1.8-5.1) and ID (OR = 18.0; 95% CI = 8.9-36.3) compared to controls. Patients with delayed puberty also had a significantly increased risk of being diagnosed with an NDD. These associations remained significant after adjustments. This is the first study to demonstrate a significant association between HH, delayed puberty and NDDs in a population-based cohort. Clinicians should be aware of the overlap between these disorders. Further studies should explore the mechanisms behind these associations.

Long-term implications of structured transition of adolescents with inflammatory bowel disease into adult health care: a retrospective study.

BACKGROUND: We aimed to evaluate the long-term clinical and socioeconomic outcome of structured transition care in adolescents with inflammatory bowel disease (IBD). METHODS: We compared the clinical long-term course of 24 patients with and 11 patients without structured transition care within 24 months before and 24 months after transfer from paediatric to adult health care. Socio-economic parameters and quality of life were assessed by IBD Questionnaire (IBDQ-32) and additional items. Treatment costs were calculated for medication, surgery and hospitalisation. RESULTS: The percentage of transfer group patients with an IBD-related intestinal complication was higher compared to the transition group (64% vs. 21%, p = 0.022). We also found a tendency towards a higher number of IBD-related surgery in the transfer group compared to the transition group (46% vs. 13%, p = 0.077). Transfer group patients received higher mean cumulated doses of radiation compared with the transition group (4.2 ± 5.3 mSv vs. 0.01 ± 0.01 mSv, p = 0.036). Delayed puberty was only noted in the transfer group (27%, p = 0.025). Mean expenditures for surgeries and hospitalisation tended to be lower in the transition group compared to transfer group patients (744 ± 630€ vs. 2,691 ± 4,150€, p = 0.050). Sexual life satisfaction was significantly higher (p = 0.023) and rates of loose bowel movements tended to be lower (p = 0.053) in the transition group. CONCLUSIONS: Structured transition of adolescents with IBD from paediatric into adult health care can lead to important clinical and economic benefits.

Influence of sexual maturation status on the relationship between body adiposity indicators and age: a cross-sectional study.

OBJECTIVES: To determine the influence of sexual maturation status on adiposity indicators of children and adolescents. RESULTS: 2412 individuals participated, 1285 (47.4%) males and 1408 (52.6%) females. There was moderate to weak correlation between age and adiposity indicators for both sexes. By analyzing the relationship between age and body fat indexes adjusted for Sexual Maturation Status, several changes were observed, mainly in girls. Precocious maturation was associated with increased adiposity indicators in girls, whereas late maturation was associated with decreased adiposity indicators in both sexes. Precocious maturation was associated with increased adiposity indicators in girls, whereas late maturation was associated with decreased adiposity indicators in both sexes.

Single-Centre Experience of Testosterone Therapy for Boys with Hypogonadism.

BACKGROUND: Hypogonadism in boys is one of the commonest conditions encountered in paediatric endocrinology. AIMS: To study variations in management in a contemporary group of boys at a single specialist centre. METHODS: Retrospective review of case records of all boys treated with testosterone at a tertiary endocrine service from 2012 to 2017. RESULTS: Of the 358 boys reviewed for hypogonadism, 46 (13%) were initiated on testosterone therapy at a median age (range) of 14.2 years (12.1, 17.7). Indications for therapy included a functional delay of puberty that was constitutional in 17 (37%) or related to chronic disease in 10 (22%) or organic hypogonadism due to primary gonadal failure in 7 (15%), multiple pituitary hormone deficiency in 6 (13%), and isolated hypogonadotropic hypogonadism in 6 (13%). Of the 46 boys, 40 (89%) were started on intramuscular testosterone, 4 (9%) on oral testosterone, and 1 (2%) on transdermal gel. Of the 19 boys (40%) with organic hypogonadism re-quiring long-term therapy, 12 (63%) had assessment of liver function, 6 (32%) had a haematocrit, and 2 (11%) had a DXA scan in the year of commencing treatment. CONCLUSIONS: Testosterone therapy is administered in about 13% of boys reviewed for hypogonadism and its monitoring requires standardisation.

Trends in the use of puberty blockers among transgender children in the United States.

BACKGROUND: The objective of the study was to identify national trends in the utilization of histrelin acetate implants among transgender children in the United States. METHODS: We analyzed demographic, diagnostic and treatment data from 2004 to 2016 on the use of histrelin acetate reported to the Pediatric Health Information System (PHIS) to determine the temporal trends in its use for transgender-related billing diagnoses, e.g. "gender identity disorder". Demographic and payer status data on this patient population were also collected. RESULTS: Between 2004 and 2016, the annual number of implants placed for a transgender-related diagnosis increased from 0 to 63. The average age for placement was 14 years. Compared to natal females, natal males were more likely to receive implants (57 vs. 46) and more likely to have implants placed at an older age (62% of natal males vs. 50% of natal females were ≥;13 years; p<0.04). The majority of children were White non-Hispanic (White: 60, minority: 21). When compared to the distribution of patients treated for precocious puberty (White: 1428, minority: 1421), White non-Hispanic patients were more likely to be treated with a histrelin acetate implant for a transgender-related diagnosis than minority patients (p<0.001). This disparity was present even among minority patients with commercial insurance (p<0.001). CONCLUSIONS: Utilization of histrelin acetate implants among transgender children has increased dramatically. Compared to natal females, natal males are more likely to receive implants and also more likely to receive implants at an older age. Treated transgender patients are more likely to be White when compared to the larger cohort of patients being treated with histrelin acetate for central precocious puberty (CPP), thus identifying a potential racial disparity in access to medically appropriate transgender care.

Low digit ratio (2D:4D) and late pubertal onset indicate prenatal hyperandrogenziation in alcohol binge drinking.

BACKGROUND: Alcohol binge drinking behavior is an important public health issue. Causal rodent and human associational studies show that reinforcement of prenatal androgen signaling increases alcohol consumption in adulthood. However, the effects of prenatal androgen exposure on adult binge drinking patterns have not been investigated yet. METHOD: We analyzed data from 2225 participants of an online survey (conducted 06-07/2016) to evaluate biomarkers for prenatal androgen exposure (second-to-fourth finger length ratio [2D:4D], age at spermarche or menarche as hallmark for pubertal onset) in binge drinking (≥1 episode of 15+, 10+, and/or 5+ standard drinks of ~13 g of alcohol within 2 h during the 24 month- and 2 week-recall periods). RESULTS: Men reported binge drinking more often than women (ORs > 1.4, P < .001). For the 24 month-recall period, binge drinkers showed lower 2D:4D (P = .006) and reported later pubertal onset (P = .022) than non-binge drinkers. These findings consistently suggest excess prenatal androgen exposure in adult binge drinkers. Moreover, 2D:4D was negatively associated with severity (15+/10+/5+/non-binge drinking, P = .005) and frequency of binge drinking episodes (P = .044). All of these effects were stronger in men than in women. For the 2 week-recall period, the biomarkers were not significantly related to binge drinking behavior. CONCLUSION: Our results indicate that increased prenatal androgen exposure is involved in the development of alcohol binge drinking behavior in adults.

Congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty have distinct genetic architectures.

OBJECTIVE: Congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) represent rare and common forms of GnRH deficiency, respectively. Both CDGP and CHH present with delayed puberty, and the distinction between these two entities during early adolescence is challenging. More than 30 genes have been implicated in CHH, while the genetic basis of CDGP is poorly understood. DESIGN: We characterized and compared the genetic architectures of CHH and CDGP, to test the hypothesis of a shared genetic basis between these disorders. METHODS: Exome sequencing data were used to identify rare variants in known genes in CHH (n = 116), CDGP (n = 72) and control cohorts (n = 36 874 ExAC and n = 405 CoLaus). RESULTS: Mutations in at least one CHH gene were found in 51% of CHH probands, which is significantly higher than in CDGP (7%, P = 7.6 × 10-11) or controls (18%, P = 5.5 × 10-12). Similarly, oligogenicity (defined as mutations in more than one gene) was common in CHH patients (15%) relative to CDGP (1.4%, P = 0.002) and controls (2%, P = 6.4 × 10-7). CONCLUSIONS: Our data suggest that CDGP and CHH have distinct genetic profiles, and this finding may facilitate the differential diagnosis in patients presenting with delayed puberty.

Etiologies of short stature in a pediatric endocrine clinic in Southern Thailand.

BACKGROUND: Short stature is one of the common disorders referred for investigation of an endocrine disorder. The etiologies of short stature vary and are commonly grouped into pathological and non-pathological disorders. The objective of the study was to determine the etiologies and describe the characteristics of short stature patients who attended the Pediatric Endocrinology Clinic and to compare factors between normal variant short stature (NVSS) and growth hormone deficiency (GHD). METHODS: This was a retrospective review of 572 patients referred for evaluation of short stature between January 2004 and December 2015. Short stature was defined as height below -2 standard deviation score (SDS) by gender and age based on population data of Thai children. RESULTS: In total, 521 patients were identified as having short stature. NVSS was the most common etiology (44.9%) and pathological short stature was found in 35.3% of the cases, of which 21.2% had GHD. The median age at presentation of NVSS patients was 8.6 years while that of pathological short stature patients was 2.1 years (p<0.001). Patients with NVSS had significantly higher median height SDS (HSDS) than patients with pathological diseases. The common etiologies in severe short patients, defined by HSDS ≤-3, were syndromic short stature (16.2%) and GHD (14.1%). In the moderate short stature group (HSDS between -2 and -3), constitutional delay of growth and puberty (CDGP) was the most common etiology (34.1%). CONCLUSIONS: NVSS was the most common etiology of short stature, followed by syndromic short stature and GHD. Physical examination is crucial to identify GHD from syndromic short patients.

Elite athletes and pubertal delay.

Intensive physical training and participation in competitive sports during childhood and early adolescence may affect athletes' pubertal development. On the other hand, pubertal timing, early or late, may impact on an athlete selection for a particular sport. Genetic predisposition, training load, nutritional status and psychological stress determine athletes' pubertal timing. Athletes that practice esthetic sports, especially gymnasts, are predisposed to a delay in pubertal development. The growing evidence indicates that energy deficiency, not a systemic training per se, plays a crucial role in the pathogenesis of functional hypothalamic hypogonadism in female athletes. Metabolic and psychologic stress activate hypothalamic-pituitary-adrenal axis and suppress hypothalamic-pituitary-ovarian axis. Female athletes who do not begin secondary sexual development by the age of 14 or menstruation by the age of 16 warrant a comprehensive evaluation and a targeted treatment. Somatic growth and sexual maturation of elite female athletes are largely sport-specific since each sport favors a particular somatotype and requires a specific training. Chronic negative energy balance resulting from a systemic physical training and inadequate energy intake may delay pubertal development in elite athletes. Youth athletes, especially those engaged in competitive sports that emphasize prepubertal or lean appearance, are at risk of developing relative energy deficiency in sport associated with disordered eating or eating disorders. Management strategies should address the complex conditions underlying functional hypothalamic hypogonadism.

Juvenile idiopathic arthritis in multiplex families: longitudinal follow-up.

OBJECTIVE: To describe the physical, social, educational and employment status and clinical outcomes of patients with juvenile idiopathic arthritis (JIA) from multiplex families. METHODS: All familial JIA patients were treated and had regular follow-up between 1990 and 2015 at King Faisal Specialist Hospital and Research Center (KFSH-RC), Riyadh, were included. Demographic data, disease duration, active arthritis and articular and extra-articular damage at last follow-up visit were reviewed. Additionally, social, educational and employment history were obtained via personal or phone interviews. RESULTS: Twenty-three patients (20 females) belonging to 10 families were included. The mean age was 14.6 (±9) years with mean disease duration of 11.4 (±9) years and mean follow-up duration of 10.5 (±6). Fourteen patients had systemic JIA while eight patients had polyarticular subtype, and one patient had psoriatic arthritis. All patients received concomitant treatment. Twenty-one patients commenced biologic agents; treatment switched to another agent in all of them because of inadequate response. Most patients had progressive disease course. Twelve patients had active polyarthritis and 22 patients showed evidence of articular damage. All patients had raised inflammatory markers. Eighteen patients had short stature and 11 patients had delayed puberty. Two patients had lower limb lymphedema and one patient had a single kidney with refractory hypertension. Three patients underwent hip arthroplasty. Seventeen patients had satisfactory educational achievement and four patients were in employment. Two patients died due to infection. CONCLUSION: Our results showed the largest familial clusters of JIA in the Middle East. Patients with familial JIA had refractory disease with progressive disease course.

Delayed puberty in the female patient.

PURPOSE OF REVIEW: The purpose is to review current recommendations for the evaluation and management of delayed puberty in the female patient. RECENT FINDINGS: Kisspeptin activation has emerged as an important factor for initiation of pubertal development. Causes of delayed puberty can be considered in four main categories: constitutional delay of growth and puberty, hypergonadotropic hypogonadism, permanent hypogonadotropic hypogonadism, and transient/functional hypogonadism. The most common cause of delayed puberty is constitutional delay of growth and puberty; however, consistent differentiation from idiopathic hypogonadotropic hypogonadism remains challenging. Initial assessment with broad spectrum testing in an otherwise healthy adolescent is often of low clinical value. Treatment is aimed at the underlying cause of delayed puberty whenever possible and individualized to the patient. SUMMARY: Understanding the factors that contribute to delayed puberty and a thoughtful evaluation, structured to the patient, is important to identify the cause of delayed puberty and prevent unnecessary and often expensive investigations. Insuring appropriate pubertal progression, optimizing height and bone health, as well as preservation of psychosocial well-being are the ultimate goals of management of delayed puberty.

Maternal fish oil supplementation during lactation is associated with reduced height at 13 years of age and higher blood pressure in boys only.

Dietary long-chain n-3 PUFA (n-3 LCPUFA) in infancy may have long-term effects on lifestyle disease risk. The present follow-up study investigated whether maternal fish oil (FO) supplementation during lactation affected growth and blood pressure in adolescents and whether the effects differed between boys and girls. Mother-infant pairs (n 103) completed a randomised controlled trial with FO (1·5 g/d n-3 LCPUFA) or olive oil (OO) supplements during the first 4 months of lactation; forty-seven mother-infant pairs with high fish intake were followed-up for 4 months as the reference group. We also followed-up 100 children with assessment of growth, blood pressure, diet by FFQ and physical activity by 7-d accelerometry at 13·5 (sd 0·4) years of age. Dried whole-blood fatty acid composition was analysed in a subgroup (n 49). At 13 years of age, whole-blood n-3 LCPUFA, diet, physical activity and body composition did not differ between the three groups. The children from the FO group were 3·4 (95 % CI 0·2, 6·6) cm shorter (P=0·035) than those from the OO group, and tended to have less advanced puberty (P=0·068), which explained the difference in height. There was a sex-specific effect on diastolic blood pressure (P sex×group=0·020), which was driven by a 3·9 (95 % CI 0·2, 7·5) mmHg higher diastolic blood pressure in the FO compared with the OO group among boys only (P=0·041). Our results indicate that early n-3 LCPUFA intake may reduce height in early adolescence due to a delay in pubertal maturation and increase blood pressure specifically in boys, thereby tending to counteract existing sex differences.