Sarah Ehtisham

Persistent Müllerian duct syndrome: lessons learned from managing a series of eight patients over a 10‐year period and review of literature regarding malignant risk from the Müllerian remnants

Study Type – Therapy (case series)

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

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 (Ca2+o) homeostasis. To elucidate the role of AP2σ2 in Ca2+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.

Childhood idiopathic chondrolysis of the hip: MRI features

BackgroundChildhood idiopathic chondrolysis of the hip (ICH) causes progressive destruction of the articular cartilage of the hip joint with associated bone remodelling. The MRI features of this disease have not previously been described.ObjectiveTo document the MRI features of childhood ICH and determine which features may help distinguish ICH from other causes of hip joint destruction in the paediatric population.Materials and methodsA retrospective review of the MRI examinations of children with clinically diagnosed ICH. All children had undergone synovial biopsy and/or joint aspiration with plain hip radiography to exclude causes of secondary chondrolysis.ResultsTen MRI examinations were performed on six children. Cartilage loss, small hip joint effusions, bone remodelling and significant regional muscle wasting were seen in all children. Cartilage loss was most severe in the central part of the joint. Synovial enhancement was not a constant feature of ICH. Serial imaging in three children showed disease progression.ConclusionsMRI in ICH clearly demonstrates cartilage loss and enables delineation of bone and muscle abnormalities. It is helpful in the differential diagnosis of hip joint disease in children and may provide further information on the progression and aetiology of ICH.

Abnormal Neurodevelopmental Outcomes are Common in Children with Transient Congenital Hyperinsulinism

Introduction: Neuroglycopenia is recognized to be associated with abnormal neurodevelopmental outcomes in 26–44% of children with persistent congenital hyperinsulinism (P-CHI). The prevalence of abnormal neurodevelopment in transient CHI (T-CHI) is not known. We have aimed to investigate abnormal neurodevelopment and associated factors in T-CHI and P-CHI. Materials and Methods: A cohort of children with CHI (n = 67, age 2.5–5 years) was assessed at follow-up review and noted to have normal or abnormal (mild or severe) neurodevelopmental outcomes for the domains of speech and language, motor, and vision. Children were classified as P-CHI (n = 33), if they had undergone surgery or remained on medical therapy, or T-CHI (n = 34), if medical treatment for hypoglycemia was stopped. Results: Overall, abnormal neurodevelopment was present in 26 (39%) children with CHI, of whom 18 (69%) were severe. Importantly, the incidence of abnormal neurodevelopment in T-CHI was similar to that in P-CHI (30 vs. 47% respectively, p = 0.16). The prevalence of severe abnormal neurodevelopment in speech, motor, and vision domains was similar in both T-CHI and P-CHI children. For this cohort, we found that the severity of disease [based upon maximal diazoxide dose (odds ratio 95% confidence intervals) 1.3 (1.1; 1.5), p = 0.03], and early presentation of CHI <7 days following birth [5.9 (1.3; 27.8), p = 0.02] were significantly associated with abnormal neurodevelopment. There was no significant association with gender, genotype, or the histopathological basis of CHI. Conclusion: Abnormal neurodevelopment was evident in one third of children with both T-CHI and P-CHI, early presentation and severe CHI being risk factors. Early recognition and rapid correction of hypoglycemia are advocated to avoid abnormal neurodevelopment in children with CHI.

The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres

OBJECTIVES The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.

The association of cardiac ventricular hypertrophy with congenital hyperinsulinism.

OBJECTIVE Ventricular hypertrophy (VH) has been observed in children with congenital hyperinsulinism (CHI), a condition of hypoglycaemia characterised by dysregulated insulin secretion, but the prevalence is not known. PATIENTS AND METHODS Cardiac assessment was performed in children (n=49) with CHI at diagnosis and follow-up. Two dimensional and Doppler echocardiography studies were used to assess cardiac structures, while M-mode study was used to measure left ventricular (LV) dimensions, subsequently converted to Z scores. Where possible, LV hypertrophy was confirmed by LV mass index (g/m(2.7)) >95th centile. RESULTS Cardiac structural lesions were found in 14 (28%) children. At initial echocardiography, VH was present in 31 (65%) children with median (range) LV posterior wall dimension in diastole Z scores of +1.6 (-2.4 to +5.8) and interventricular septal wall dimension in end diastole Z scores of +1.9 (-1.7 to +17.2). At follow-up echocardiography, performed after an interval of 178 (45-390) days, VH persisted in 16 (33%) children. In regression analysis, the presence of VH (odds ratio (95% confidence intervals) 1.1 (1.0-1.2), P=0.04) at initial echocardiography was correlated with maximum glucose requirement at diagnosis, indicating that severity of CHI at presentation may play a role in the pathogenesis of VH. CONCLUSIONS A significant proportion of children with CHI have cardiac structural lesions. A majority also have VH, which may be associated with the severity of CHI at diagnosis. VH may persist in some children, which requires careful long-term cardiac review.

Feeding Problems Are Persistent in Children with Severe Congenital Hyperinsulinism

Background Congenital hyperinsulinism (CHI) is a rare but severe disorder of hypoglycemia in children, often complicated by brain injury. In CHI, the long-term prevention of hypoglycemia is dependent on reliable enteral intake of glucose. However, feeding problems (FPs) often impede oral glucose delivery, thereby complicating the management of hypoglycemia. FPs have not been systematically characterized in follow-up in a cohort with CHI. Aims We aimed to determine the prevalence, types, and persistence of FPs in a cohort of children with CHI and investigate potential causal factors. Methods FPs were defined as difficulty with sucking, swallowing, vomiting, and food refusal (or a combination) in an observational study in 83 children in a specialized CHI treatment center. The prevalence of FPs at diagnosis, 6, and 12 months after diagnosis were noted. Genetic mutation status and markers of severity of CHI were tested for association with FPs. Results A third of children with CHI had FPs (n = 28), of whom 93% required antireflux medication and 75% required nasogastric and gastrostomy tube feeding. Sucking and swallowing problems were present at diagnosis but absent later. Vomiting was present in 54% at 6 months, while food refusal was present in 68% at 6 months and 52% at 12 months. The age at commencing and stopping nasogastric tube feeding did not correlate with FPs frequency at 6 and 12 months. Children with FPs had severe hypoglycemia at diagnosis and required glucagon infusion more often [odds ratio (OR) (95% confidence intervals) (95% CI) 28.13 (2.6–300.1), p = 0.006] to normalize glucose levels. FPs were more frequent in those with diffuse CHI undergoing subtotal pancreatectomy [n (%) = 10 (35%) vs. 0 (0%), p < 0.001], in contrast to those with spontaneous resolution [6 (22%) vs. 32 (58%), p = 0.002]. Those undergoing focal lesionectomy also had reduced FPs at 6 months after diagnosis [OR (95% CI) 0.01 (0.0–0.2), R2 = 0.42, p = 0.004]. These observations suggest that persistence of hyperinsulinism was associated with FPs. Conclusion FPs occur in a significant proportion of children with CHI. Severe hyperinsulinism, rather than nasogastric tube feeding or medications, is the main factor associated with FPs.

Reduced Glycemic Variability in Diazoxide-Responsive Children with Congenital Hyperinsulinism Using Supplemental Omega-3-Polyunsaturated Fatty Acids; A Pilot Trial with MaxEPAR

Objective: Congenital hyperinsulinism (CHI) is a rare condition of hypoglycemia where therapeutic options are limited and often complicated by side-effects. Omega-3-polyunsaturated fatty acids (PUFA), which can suppress cardiac myocyte electrical activity, may also reduce ion channel activity in insulin-secreting cells. PUFA supplements in combination with standard medical treatment may improve glucose profile and may reduce glycemic variability in diazoxide-responsive CHI. Design: Open label pilot trial with MaxEPAR liquid (eicosapentaenoic and docosahexaenoic acid) PUFA (3 ml/day for 21 days) in diazoxide-responsive CHI patients (https://eudract.ema.europa.eu/, EudraCT number 201100363333). Methods: Glucose levels were monitored pre-treatment, end of treatment, and at follow-up by subcutaneous continuous glucose monitoring systems (CGMS) in 13 patients (7 girls) who received PUFA. Outcome measures were an improved glucose profile, reduced glycemic variability quantified by a reduction in the frequency of glucose levels <4 and >10 mmol/l, and safety of PUFA. All children were analyzed either as intention to treat (n = 13) or as per protocol (n = 7). Results: Mean (%) CGMS glucose levels increased by 0.1 mmol/l (2%) in intention to treat and by 0.4 mmol/l (8%) in per protocol analysis (n = 7). The frequency of CGMS <4 mmol/l was significantly less at the end of treatment than in the pre-treatment period [556 (7%) vs. 749 (10%)]. Similarly, the frequency of CGMS >10 mmol/l, was also less at the end of treatment [27 (0.3%) vs. 49 (0.7%)]. Except for one child with increased LDL cholesterol, all safety parameters were normal. Conclusion: MaxEPAR was safe and reduced glycemic variability, but did not increase glucose profiles significantly in diazoxide-responsive CHI. The supplemental value of PUFA should be evaluated in a comprehensive clinical trial.

A Pilot Interventional Study to Evaluate the Impact of Cholecalciferol Treatment on HbA1c in Type 1 Diabetes (T1D)

Background Higher 25(OH)D3 levels are associated with lower HbA1c, but there are limited UK interventional trials assessing the effect of cholecalciferol on HbA1c. Aims (1) To assess the baseline 25(OH)D3 status in a Manchester cohort of children with type 1 diabetes (T1D). (2) To determine the effect of cholecalciferol administration on HbA1c. Methods Children with T1D attending routine clinic appointments over three months in late winter/early spring had blood samples taken with consent. Participants with a 25(OH)D3 level <50 nmol/L were treated with a one-off cholecalciferol dose of 100,000 (2–10 years) or 160,000 (>10 years) units. HbA1c levels before and after treatment were recorded. Results Vitamin D levels were obtained from 51 children. 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 were vitamin D deficient, but 2 were excluded from the analysis. All South Asian children were vitamin D deficient, with mean 25(OH)D3 of 28 nmol/L. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1c (r = −0.484, P < 0.01). In treated participants, there was no significant difference in mean HbA1c at 3 months (t = 1.010, P = 0.328) or at 1 year (t = −1.173, P = 0.248) before and after treatment. One-way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in Δ HbA1c level. Conclusion We report important findings at baseline, but in children treated with a stat dose of cholecalciferol, there was no effect on HbA1c. Further studies with larger sample sizes and using maintenance therapy are required.

G460(P) Treatment with a single bolus dose of cholecalciferol does not improve HBA1C levels in a cohort of paediatric patients with type one diabetes

Background Intensive glycaemic control in type one diabetes (T1D) reduces progression of complications (DCCT and EDIC). In clinical practice, glycosylated haemoglobin (Hba1c) levels reflect control. Previous studies show that higher 25(OH)D3 levels are associated with lower Hba1c (US SEARCH study). However, there are limited interventional trials assessing the effect of cholecalciferol on Hba1c. Aims. 1. To assess the baseline 25(OH)D3 status in a paediatric cohort of patients with T1D. 2. To determine the effect of cholecalciferol administration on Hba1c. Methods Children with T1D attending routine clinic appointments from February to April 2011 had blood samples taken with consent, and patients with a 25(OH)D3 level <20ng/ml were treated with a one-off stat cholecalciferol dose of 100 000 (2–10 years) or 160 000 (>10 years) units. Hba1c levels from the year preceding treatment and the year after treatment were recorded. Results Vitamin D levels were obtained from 51 patients (30 male, 21 female). 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 subjects were vitamin D deficient, but 2 were excluded from the analysis (one moved away, one was non-compliant). All South Asian patients were vitamin D deficient, with mean 25(OH)D3 of 11.2 ng/ml. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1C (r= –0.484, p < 0.01), but not in South Asians. In treated patients, paired t tests showed no significant difference in mean Hba1c at 3 months (t=1.010, p 0.328) or at 1 year (t=-1.173, p = 0.248) before and after treatment. One way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in change in Hba1c level between those treated and not treated, at 3m and at 1 year before and after treatment. Conclusion We confirmed a high prevalence of vitamin D deficiency in this clinic cohort of children with T1D, and found a negative relationship between baseline 25(OH)D3 level and HbA1C in Caucasians. However, in patients treated with a stat dose of cholecalciferol there was no effect on Hba1c. Further studies with larger sample sizes, and using maintenance 25(OH)D3 therapy rather than stat therapy are required.