Pituitary-adrenal axis in Prader Willi syndrome

Purpose: Prader Willi syndrome (PWS) is a rare genetic condition that has concurrent endocrinological insufficiencies. The presence of growth hormone deficiency has been well documented, but adrenal insufficiency (AI) is not widely reported. A review was conducted to investigate its prevalence and relevance in PWS in both adults and children. Methodology: A literature review was performed with the search terms “Prader-Willi syndrome” and “adrenal insufficiency”. Results: The review found studies disagree on the prevalence and method of investigation of AI in PWS. Case studies demonstrate that patients with PWS are at risk of premature death, often secondary to respiratory infections. The possibility that this may be the result of the inability to mount an effective cortisol response has been studied, with some evidence confirming AI in PWS patients. Most reports agreed AI is present in PWS, however, Farholt et al. showed no HPA axis dysfunction in adults, suggesting that perhaps it is rare in adults, and children should be the focus of further studies. Conclusion: AI is present in some patients with PWS. Further research is required to ensure optimal treatment can be implemented and to prevent premature deaths related to adrenal insufficiency. Clinicians should have a low threshold for testing the adrenal axis and considering treatment for adrenal insufficiency in PWS patients

Severe hypertension in pediatric diabetic ketoacidosis – a case report and review of literature

Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes mellitus in children. Despite the presence of dehydration, hypertension occurs in a significant proportion of children with DKA. There is a lack of clarity in the literature regarding the management of hypertension in patients with paediatric DKA. Herein, we report the case of an adolescent boy who presented with DKA and severe hypertension. His neurological status was closely monitored. There was a gradual decline in his blood pressure with an improvement in the pH over the next 72 hours. The combination of severe DKA and hypertension can be a challenging clinical dilemma, especially regarding fluid management. Studies on severe DKA in children are exacting, given the rarity of this condition. A multi-centre study is suggested to provide a meaningful analysis of this aspect of DKA

Longitudinal changes in bone parameters in young girls with anorexia nervosa

Background: Anorexia nervosa (AN) during childhood and adolescence has been reported to adversely affect bone health, but few studies have investigated longitudinal changes. Method: DXA-derived bone parameters and body composition were retrospectively assessed in 111 young girls with AN with a median age of 15.4 years (10.9, 19.8). In 68 (61%) vertebral fracture assessment (VFA) was performed and in 31 (28%), a follow-up DXA was performed. Correlations with growth, changes in body composition and effects of illness duration and menstruation were examined. Size adjusted DXA standard deviation scores were calculated for total body (TB) less head bone mineral content (TBLH-BMC) and lumbar spine bone mineral apparent density (LS-BMAD). Results: Mean (range) bone area (BA) for height centile was 27.1 (0–97), and mean lean mass for height centile was 28.8 (0–95) at baseline. Mean (range) LS BMAD was −1.0 (−2.6, 0.8) SDS at first and − 1.2 (−3.0, −0.2) at second DXA (p = 0.023). On follow up, lean mass for height increased from 27th centile (0, 75) to 40th centile (0, 70) (p = 0.006), and fat mass for height increased from 55 g/cm to 67 g/cm (11.3, 124.2) (p < 0.001). Duration of illness was the only negative predictor of LS BMAD (p < 0.0001). Change in height SDS was the only positive predictor of change in TBLH-BMC (r = 0.384, p = 0.037), and change in LS BMAD (r-0.934, p < 0.0001). Of 68 patients who had VFA, 4 (5.9%) had a mild vertebral fracture. Conclusion: Bones are smaller and less dense in childhood/adolescent AN compared to healthy adolescents. Although there are significant gains in lean mass and fat mass, over time, BMAD SDS decreases slightly. Improvement in BMAD SDS is related to improvement in height SDS

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 LH RH 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

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 re­quiring 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

Neonatal features of the Prader-Willi syndrome; the case for making the diagnosis during the first week of life

Early diagnosis is of proven benefit in Prader-Willi syndrome (PWS). We therefore examined key perinatal features to aid early recognition. Data were collected from case records of subjects attending a multi-disciplinary clinic and from a retrospective birth questionnaire. Ninety patients (54 male: 36 female) were seen between 1991-2015, most with paternal deletion (n=56) or maternal isodisomy (n=26). Features included cryptorchidism in 94% males, preterm birth (26%), birthweight <2500g (24%), polyhydramnios (23%), breech presentation (23%) and need for nasogastric feeding (83%). Reduced fetal movements (FM) occurred in 82.5% patients compared with 4% healthy siblings. Of 35 children born since 1999, 23 were diagnosed clinically within 28 days while diagnosis in 12 was > 28 days: 1-12 months in 7; and 3.75-10.5 years in 5. Typical PWS features in these 12 infants included hypotonia (100%), feeding difficulties (75%), cryptorchidism (83% males) and reduced FM (66%). Causes other than PWS including neuromuscular disease were considered in nine patients. Neonatal hypotonia, reduced FM, feeding difficulties and cryptorchidism should immediately suggest PWS, yet late diagnosis continues in some cases. Awareness of the typical features of PWS in newborn units is required to allow prompt detection even in the presence of confounding factors such as prematurity

Congenital hypothyroidism: Space-time clustering of thyroid dysgenesis indicates a role for environmental factors in disease etiology

Background: The etiology of most cases of congenital hypothyroidism (CHT) due to thyroid dysgenesis (DG) is unknown. If transient environmental factors can impact on thyroid gland development, then clustering of cases in time and/or space may occur, and this would be more likely in thyroid DG than dyshormonogenesis (DHG). Methods: The newborn screening program for CHT in Scotland is linked to a central database that includes case details such as postcode. The etiology of CHT is investigated in many cases of CHT using scintigraphy and/or ultrasonography. We looked for evidence of a change in CHT incidence with year of birth and according to season of the year. We then undertook space–time clustering analysis (using a method based on K-functions, with nearest neighbor thresholds) of CHT in Scotland between 1979 and 2015. We also looked for evidence of overall changes associated with sex and area-based birth density. Results: Of 531 cases with CHT during the study period, 290 cases had been categorized as DG (n = 229) or DHG (n = 61) following more detailed investigation. The incidence of CHT increased with year of birth and was in part linked to changing methodology, but there was no seasonality. There was no evidence of overall space–time clustering (p = 0.06), but there was evidence of clustering in babies with DG (p = 0.007). This picture appeared to be most closely linked to underlying thyroid gland hypoplasia rather than thyroid gland agenesis or ectopia. There was significant space–time clustering for both males and females, but clustering was restricted to lesser birth density areas. There was also evidence of clustering for unknown cases (p < 0.001). Clustering of these cases was restricted to females but was present for cases from both greater and lesser birth density areas. There was no evidence of clustering in cases of DHG. Conclusions: These data suggest that an unidentified environmental factor or factors may be involved in the etiology of thyroid DG in Scotland. The variation in CHT incidence observed internationally may reflect environmental as well as genetic factors

Parent-reported outcomes in young children with disorders/differences of sex development

Background: There is a paucity of tools that can be used in routine clinical practice to assess the psychosocial impact of Disorders/Differences of Sex Development (DSD) on parents and children. Objective: To evaluate the use of short Parent Self-Report and Parent Proxy-Report questionnaires that can be used in the outpatient setting. Methods: Previously validated DSD-specific and generic items were combined to develop a Parent Self-Report questionnaire and a Parent Proxy-Report questionnaire for children under 7 years. Of 111 children approached at one tertiary paediatric hospital, the parents of 95 children (86%) with DSD or other Endocrine conditions completed these questionnaires. Results: Questionnaires took under 10 min to complete and were found to be easy to understand. Compared to reference, fathers of children with DSD reported less stress associated with Clinic Visits (p = 0.02) and managing their child’s Medication (p = 0.04). However, parents of children with either DSD or other Endocrine conditions reported more symptoms of Depression (p = 0.03). Mothers of children with DSD reported greater Future Concerns in relation to their child’s condition (median SDS − 0.28; range − 2.14, 1.73) than mothers of children with other Endocrine conditions (SDS 1.17; − 2.00, 1.73) (p = 0.02). Similarly, fathers of children with DSD expressed greater Future Concerns (median SDS -1.60; − 4.21, 1.00) than fathers of children with other Endocrine conditions (SDS 0.48; − 2.13, 1.52) (p = 0.04). Conclusion: DSD was associated with greater parental concerns over the child’s future than other Endocrine conditions. Brief parent-report tools in DSD can be routinely used in the outpatient setting to assess and monitor parent and patient needs

Increases in bioactive IGF do not parallel increases in total IGF-I during growth hormone treatment of children born SGA.

BACKGROUND: Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. AIM: To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). RESULTS: Bioactive IGF increased with age in healthy pre-pubertal children (n=94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, p2SD (mean IGF-I 2.8 SDS), whereas only 15% (n=15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r=0.29, p=0.005), in contrast to IGF-I (SDS) (r=0.17, p=0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r=-0.22, p=0.02). CONCLUSION: In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment

The effect of COVID-19 on the presentation of thyroid disease in children

Introduction: Although studies suggest a potential link between COVID-19 and thyroid dysfunction in adults, there are insufficient data to confirm that association in children, and whether there is any effect on presentation to healthcare services. Aims: To identify whether presentations of thyroid dysfunction in children to a tertiary paediatric hospital changed as a result of the COVID-19 pandemic. Methods: A retrospective case note review was conducted of all children with abnormal thyroid function tests between 1st January 2016 and 31st December 2021 at a tertiary paediatric endocrine centre in the United Kingdom. Results: Overall, 244 children whose first presentation was within the timeframe of interest were included in this study, with a median age (range) of 11.5 (6.1, 16.8) years. Of these, 43 (18%) were hyperthyroid and 201 (82%) were hypothyroid. The greatest number of thyroid presentations occurred in 2021 (n=60, 25% of total over time period) and the fewest in 2020 (n=10, 4% of total over time period). Prior to this, the median (range) number of presentations per year was 34 (28, 39). There were no statistically significant differences in biochemistry, antibody status or other clinical characteristics between those who presented with hyperthyroidism prior to the pandemic or after. In those with hypothyroidism, baseline biochemistry was similar between the 2 groups, but the presence of other autoimmune conditions was greater pre-pandemic (17.2% vs 15.0%, p=0.03). In addition, patients were more likely to have transient thyroid dysfunction, which did not require treatment post-pandemic (70.0% vs 49.6%, p=0.0086). Conclusions: Although overall rates of presentation with thyroid dysfunction have not altered since the first wave of the COVID-19 pandemic, presentations with transient thyroid dysfunction, not requiring ongoing treatment have increased. Further research regarding the relationship between COVID-19 and thyroid function in children and young people, is needed