Publications by authors named "Tony Hulse"

7 Publications

  • Page 1 of 1

Prolactinoma in childhood and adolescence-Tumour size at presentation predicts management strategy: Single centre series and a systematic review and meta-analysis.

Clin Endocrinol (Oxf) 2021 Mar 26;94(3):413-423. Epub 2020 Dec 26.

Paediatric Endocrinology, Variety Club Children's Hospital, King's College Hospital NHS Foundation Trust, London, UK.

Objective: To report the clinical presentation, management and outcomes of young patients with prolactinomas (<20 years) and conduct a systematic review and meta-analysis.

Patients And Design: Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age <20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p < .02) and higher serum prolactin concentration (p < .005). All patients with macroprolactinoma >20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p < .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%).

Conclusions: Macroprolactinoma, particularly if >20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in <20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males.
View Article and Find Full Text PDF

Download full-text PDF

Source Listing
March 2021

Xq27.1 Duplication Encompassing SOX3: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date - A Large Case Series of Unrelated Patients and a Literature Review.

Horm Res Paediatr 2019 1;92(6):382-389. Epub 2019 Nov 1.

Department of Paediatric Endocrinology, King's College Hospital NHS Foundation Trust, London, United Kingdom.

Background: Xq27.1 duplication encompassing SOX3 has been implicated in the aetiology of X-linked hypopituitarism associated with intellectual disability and neural tube defects. We describe the largest case series to date of 5 unrelated patients with SOX3 duplication with a variable clinical phenotype, including the smallest reported SOX3 duplication.

Case Reports: Five male patients who presented with congenital hypopituitarism (CH) were identified to have Xq27.1 duplication encompassing SOX3. The size of the duplication ranged from 323.8 kb to 11 Mb. The duplication was maternally inherited or de novo in 2 patients each (and of unknown inheritance in 1 patient). The age at presentation was variable. Three patients had multiple pituitary hormone deficiencies, whereas 2 patients had isolated growth hormone deficiency. All patients had micropenis and/or small undescended testes. Structural pituitary and/or other midline cranial abnormalities (callosal hypogenesis/absence of the septum pellucidum) were present in all patients. Two patients had a neural tube defect in addition to CH.

Conclusions: This is the largest series reported to date of unrelated patients with CH in association with Xq27.1 duplication encompassing SOX3. The clinical phenotype is variable, which may be due to genetic redundancy or other unknown aetiological factors. We have expanded the phenotypic spectrum through description of the smallest Xq27.1 duplication (323.8 kb) with CH reported to date, as well as a second family with CH and a neural tube defect.
View Article and Find Full Text PDF

Download full-text PDF

Source Listing
July 2020

High-dose biotin in infants mimics biochemical hyperthyroidism with some commercial assays.

Clin Endocrinol (Oxf) 2018 03 26;88(3):507-510. Epub 2018 Jan 26.

Department of Paediatric Endocrinology and Diabetes, Evelina London Children Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source Listing
March 2018

Interstage somatic growth in children with hypoplastic left heart syndrome after initial palliation with the hybrid procedure.

Cardiol Young 2017 Jan 8;27(1):131-138. Epub 2016 Apr 8.

Department of Congenital Heart Disease,Evelina London Children's Hospital,London,United Kingdom.

Introduction The hybrid procedure is one mode of initial palliation for hypoplastic left heart syndrome. Subsequently, patients proceed with either the "three-stage" pathway - comprehensive second stage followed by Fontan completion - or the "four-stage" pathway - Norwood procedure, hemi-Fontan, or Fontan completion. In this study, we describe somatic growth patterns observed in the hybrid groups and a comparison primary Norwood group.

Methods: A retrospective analysis of patients who have undergone hybrid procedure and Fontan completion was performed. Weight-for-age and height-for-age z-scores were recorded at each operation.

Results: We identified 13 hybrid patients - eight in the three-stage pathway and five in the four-stage pathway - and 49 Norwood patients. Weight: three stage: weight decreased from hybrid procedure to comprehensive second stage (-0.4±1.3 versus -2.3±1.4, p<0.01) and then increased to Fontan completion (-0.4±1.5 versus -0.6±1.4, p<0.01); four stage: weight decreased from hybrid procedure to Norwood (-2.0±1.4 versus -3.3±0.9, p=0.06), then stabilised to hemi-Fontan. Weight increased from hemi-Fontan to Fontan completion (-2.7±0.6 versus -1.0±0.7, p=0.01); primary Norwood group: weight decreased from Norwood to hemi-Fontan (p<0.001) and then increased to Fontan completion (p<0.001). Height: height declined from hybrid procedure to Fontan completion in the three-stage group. In the four-stage group, height decreased from hybrid to hemi-Fontan, and then increased to Fontan completion. The Norwood group decreased in height from Norwood to hemi-Fontan, followed by an increase to Fontan completion.

Conclusion: In this study, we show that patients undergoing the hybrid procedure have poor weight gain before superior cavopulmonary connection, before returning to baseline by Fontan completion. This study identifies key periods to target poor somatic growth, a risk factor of morbidity and worse neurodevelopmental outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source Listing
January 2017

Conservative or radical surgery for pediatric papillary thyroid carcinoma: A systematic review of the literature.

Int J Pediatr Otorhinolaryngol 2015 Oct 10;79(10):1620-4. Epub 2015 Aug 10.

Department of Otolaryngology, Head and Neck Surgery, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

Background: Pediatric papillary thyroid carcinoma (PTC) is characterized by an aggressive clinical course. Early diagnosis is a challenge and treatment consists principally of partial or total thyroidectomy±neck dissection and radioactive iodine therapy. Due to the rarity of PTC in children, there is no consensus on optimal surgical treatment.

Methods And Results: A literature search was carried out using PubMed, Embase, Medline, Cochrane and Web of Science. Seven studies (489 patients) investigating the outcome of surgically managed pediatric PTC were identified. No clear advantage in survival or recurrence rate was found for total thyroidectomy compared to other surgical approaches.

Conclusion: Despite the aggressive behavior of PTC, prognosis is good, with low mortality. After removal of disease and prevention of recurrence, reduction of iatrogenic complications are a priority in this age group. Due to the paucity of available evidence, this review cannot recommend conservative or radical surgery for pediatric papillary thyroid carcinoma. To answer this question, we recommend the establishment of a randomized controlled trial with adequately matched baseline variables.
View Article and Find Full Text PDF

Download full-text PDF

Source Listing
October 2015

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

Hum Mol Genet 2015 Sep 16;24(18):5079-92. Epub 2015 Jun 16.

Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK,

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.
View Article and Find Full Text PDF

Download full-text PDF

Source Listing
September 2015

Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia.

J Clin Endocrinol Metab 2013 Mar 5;98(3):E547-57. Epub 2013 Feb 5.

Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, University College London (UCL)-Institute of Child Health, London WC1N 1EH, United Kingdom.

Context: Loss-of-function mutations in PROK2 and PROKR2 have been implicated in Kallmann syndrome (KS), characterized by hypogonadotropic hypogonadism and anosmia. Recent data suggest overlapping phenotypes/genotypes between KS and congenital hypopituitarism (CH), including septo-optic dysplasia (SOD).

Objective: We screened a cohort of patients with complex forms of CH (n = 422) for mutations in PROK2 and PROKR2.

Results: We detected 5 PROKR2 variants in 11 patients with SOD/CH: novel p.G371R and previously reported p.A51T, p.R85L, p.L173R, and p.R268C-the latter 3 being known functionally deleterious variants. Surprisingly, 1 patient with SOD was heterozygous for the p.L173R variant, whereas his phenotypically unaffected mother was homozygous for the variant. We sought to clarify the role of PROKR2 in hypothalamopituitary development through analysis of Prokr2(-/-) mice. Interestingly, these revealed predominantly normal hypothalamopituitary development and terminal cell differentiation, with the exception of reduced LH; this was inconsistent with patient phenotypes and more analogous to the healthy mother, although she did not have KS, unlike the Prokr2(-/-) mice.

Conclusions: The role of PROKR2 in the etiology of CH, SOD, and KS is uncertain, as demonstrated by no clear phenotype-genotype correlation; loss-of-function variants in heterozygosity or homozygosity can be associated with these disorders. However, we report a phenotypically normal parent, homozygous for p.L173R. Our data suggest that the variants identified herein are unlikely to be implicated in isolation in these disorders; other genetic or environmental modifiers may also impact on the etiology. Given the phenotypic variability, genetic counseling may presently be inappropriate.
View Article and Find Full Text PDF

Download full-text PDF

Source Listing
March 2013