M Guftar Shaikh

Role of Gut Microbiota in the Aetiology of Obesity: Proposed Mechanisms and Review of the Literature

The aetiology of obesity has been attributed to several factors (environmental, dietary, lifestyle, host, and genetic factors); however none of these fully explain the increase in the prevalence of obesity worldwide. Gut microbiota located at the interface of host and environment in the gut are a new area of research being explored to explain the excess accumulation of energy in obese individuals and may be a potential target for therapeutic manipulation to reduce host energy storage. Several mechanisms have been suggested to explain the role of gut microbiota in the aetiology of obesity such as short chain fatty acid production, stimulation of hormones, chronic low-grade inflammation, lipoprotein and bile acid metabolism, and increased endocannabinoid receptor system tone. However, evidence from animal and human studies clearly indicates controversies in determining the cause or effect relationship between the gut microbiota and obesity. Metagenomics based studies indicate that functionality rather than the composition of gut microbiota may be important. Further mechanistic studies controlling for environmental and epigenetic factors are therefore required to help unravel obesity pathogenesis.

Longitudinal Changes in Body Mass Index in Children with Craniopharyngioma

Objective: We investigated the relationship of body mass index at presentation and pituitary status with long-term changes in BMI over a period of 5 years. Study Design: Craniopharyngioma patients (n = 25) attending a tertiary pediatric endocrine center were divided into three groups based on their BMI at presentation [BMI ≥2 standard deviation scores (SDS), 0-1.99 SDS, and <0 SDS) and then analyzed for trends of BMI over a period of up to 5 years. Results: Median (interquartile range) BMI SDS and hypopituitarism at presentation versus at the 5-year follow-up were as follows: BMI SDS ≥2 group (n = 10): 3.55 (0.68), 6/10 versus 3.76 (1.13), 8/10; BMI SDS 0-1.99 group (n = 11): 1.68 (1.05), 3/11 versus 1.64 (2.04), 7/11, and BMI SDS <0 group (n = 4): -0.23 (0.93), 2/4 versus 0.61, 4/4. At the 5-year follow-up, 10/10, 7/11, and 1/4 subjects when divided in groups according to BMI at presentation were obese. Conclusions: Our data indicate that obesity at presentation, rather than panhypopituitarism either at or after presentation, predicts obesity 5 years after diagnosis. However, obesity at presentation is not always associated with the subsequent development of panhypopituitarism. Pediatric craniopharyngioma subjects who have BMI SDS ≥2 at presentation require early and aggressive intervention to help prevent the complications of obesity.

The relationship between bone mass and body composition in children with hypothalamic and simple obesity

Obesity has been associated with a positive influence on bone mass. This is thought to be due to a mechanical load exerted on the skeleton, together with various hormones and adipocytokines that control appetite and weight, such as leptin, some of which directly affect bone mass. However, there are conflicting reports of the association between fat mass and bone mass in children. Animal studies demonstrate increased bone mass where there is impaired central leptin signalling. Hypothalamic damage can cause abnormal central leptin action, which contributes to the development of obesity.

Permanent congenital hypothyroidism with blood spot thyroid stimulating hormone <10 mU/L

Background The UK recommended lower threshold for neonatal blood spot thyroid stimulating hormone (TSH) screening for congenital hypothyroidism (CHT) is 10.0 mU/L. Some laboratories use lower thresholds. This will lead to referral of mildly or unaffected infants but some will require thyroxine therapy. Methods Laboratory referrals with a first or repeat capillary TSH between 8.0 and <10.0 mU/L were identified (January 2004 to March 2014). The outcome of these cases was examined. Results 26 infants had one or more blood spot TSH values between 8.0 and 9.99 mU/L; 65% had transient elevated neonatal TSH while one is awaiting diagnostic challenge. The remaining eight (31%) have permanent CHT; three with dyshormonogenesis, two with thyroid ectopia and the others met the criteria for definite CHT. Two out of three with dyshormonogenesis presented with decompensated hypothyroidism. Conclusions Infants with permanent and occasionally severe CHT may have a screening TSH below the UK recommended lower cut-off.

How well does the capillary thyroid-stimulating hormone test for newborn thyroid screening predict the venous free thyroxine level?

Objectives To determine, in newborn infants referred with elevated capillary thyroid-stimulating hormone (TSH), a threshold below which a frankly subnormal venous free thyroxine (fT4) level of <10 pmol/L is unlikely, so that treatment with levo-thyroxine (L-T4) might be deferred until venous thyroid function tests (TFTs) become available. Subjects and methods All infants referred in Scotland since 1979 with capillary TSH elevation were studied, with particular focus on infants screened using the AutoDELFIA assay between 2002 and 2013. Results Of the 321 infants referred with capillary TSH elevation using AutoDELFIA, 35 were excluded (fT4/TSH unavailable (12), venous sample either preceding or >10 days after capillary sampling (13, 10)), leaving 286 eligible for analysis (208 definite/probable hypothyroidism, 61 transient TSH elevation, 17 of uncertain thyroid status). Capillary TSH and venous T4 were strongly correlated (Spearmans rank correlation coefficient −0.707355). The optimal capillary TSH threshold for predicting a venous fT4 of <10 pmol/L was found to be >40 mU/L (90.3% sensitivity and 65.9% specificity compared with 90.25% and 59.1% for >35 mU/L and 88.3% and 68.2% for >45 mU/L). 93 infants (32.5%) had capillary TSH ≤40 mU/L at referral of whom 15 (9.7%) had venous fT4 <10 pmol/L, comprising seven with true congenital hypothyroidism, five with transient TSH elevation and three with uncertain status, two of whom died. Conclusion For infants in whom capillary TSH is ≤40 mU/L, it is reasonable to defer L-T4 treatment until venous TFT results are known provided that the latter become available quickly.

Early identification of pituitary dysfunction in congenital nasal pyriform aperture stenosis: recommendations based on experience in a single centre.

Background: Congenital nasal pyriform aperture stenosis (CNPAS) is an increasingly recognised cause of upper airway obstruction associated with midline abnormalities. Studies have described pituitary dysfunction in 40% of patients. We aimed to develop guidelines for: (a) the early identification of pituitary insufficiency to minimise surgical risk and (b) to stratify patients for follow-up. Methods: Retrospective case note review of patients with CNPAS between 2000 and 2014 in a tertiary paediatric unit. Results: 20 patients (12 female:8 male) were analysed; 16 were diagnosed during the neonatal period while 4 were diagnosed later. There was no consistent approach in the evaluation of the pituitary axis at diagnosis. Pituitary dysfunction was identified in 3 (15%) patients, 2 of whom were found during evaluation of short stature in mid-late childhood. Hypoglycaemia and conjugated hyperbilirubinaemia, but not the degree of stenosis, were highly predictive of pituitary dysfunction (p < 0.05). Available height standard deviation score (SDS) data at 1 year of 70% of our patients identified both of the late-diagnosed growth hormone-deficient patients, with SDS of -2.6 and -3.6, respectively. Conclusion: All CNPAS patients should have MRI of the brain and baseline endocrine investigations at diagnosis. Growth monitoring for at least 1 year is recommended as low, or falling, height SDS at 1 year is a good predictor of pituitary dysfunction.

Screening for Hypothyroidism in Down Syndrome Using the Capillary Thyroid Stimulating Hormone Method

OBJECTIVES To analyze data from the Scottish capillary thyroid stimulating hormone (TSH) screening program for hypothyroidism in Down syndrome to identify a threshold for capillary TSH elevation below which low venous free thyroxine (fT4) (<9 pmol/L) and/or frank venous TSH elevation (>10 mU/L) range is unlikely. STUDY DESIGN Review of proformas prospectively submitted on all children with Down syndrome referred via the screening program between 2003 and 2013. RESULTS Ninety-nine patients with Down syndrome (50 females, 49 males) were identified, 76 school-age (≥ 5 years) and 23 preschool (<5 years), mean (range) age at referral 9.4 (0.9-18.1) years. Pearson correlation between capillary TSH and venous TSH was 0.814; between capillary TSH and venous fT4 -0.522 (P = .01). Receiver operator curve analysis showed that capillary TSH values of 4 and 6 mU/L were 95.9% and 73.5% sensitive, 5.8% and 80.8% specific, respectively, in predicting venous TSH >10 mU/L. Fifty-three children had capillary TSH values of 4-5.9 mU/L of whom only one, a boy of 15.8 years, had subnormal venous fT4 (<9 pmol/L), and venous TSH >10 mU/L was found in 13 (4 preschool). CONCLUSIONS Venous fT4 is normal in almost all patients with Down syndrome with capillary TSH 4-6 mU/L. We propose an algorithm incorporating rescreening by finger prick after 6 months, rather than venepuncture, in school-aged children with borderline capillary TSH elevation. Further data are needed before this approach can be recommended for preschool children.

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

Objective: Early diagnosis is of proven benefit in Prader-Willi syndrome (PWS). We therefore examined key perinatal features to aid early recognition. Methods: Data were collected from case records of subjects attending a multi-disciplinary clinic and from a retrospective birth questionnaire. Results: 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 <2500 g (24%), polyhydramnios (23%), breech presentation (23%) and need for nasogastric feeding (83%). Reduced fetal movements (FM) were reported 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 seven; and 3.75-10.5 years in five. 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. Conclusion: 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.

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.

Urinary gonadotrophins: role in assessment and management of disorders of puberty

AND MANAGEMENT OF DISORDERS OF PUBERTY Laura Lucaccioni1,2, Jane McNeilly3, Avril Mason1, Claudio Giacomozzi1,4, M Guftar Shaikh1, Lorenzo Iughetti2, S Faisal Ahmed1 1 Developmental Endocrinology Research Group, Royal Hospital for Sick Children, University of Glasgow, G3 8SJ, UK 2 Paediatric Unit, Department of Medical and Surgical Sciences of the Mother, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy 3 Dept. Biochemistry, Royal Hospital for Sick Children, Glasgow G3 8SJ,UK 4 U.O.C. Broncopneumologia, Department of Paediatric Medicine, Bambino Gesù Childrens Hospital, Rome, Italy