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OBJECTIVE To determine the glycemic impact of dietary fat alone consumed without prandial insulin in individuals with T1D. RESEARCH DESIGN AND METHODS Thirty participants with T1D (aged 8-18 years) consumed a test drink with either 20 g glucose or 1, 13, 26, 39, 51 g of fat with negligible carbohydrate/protein on 6 consecutive evenings, in a randomized order without insulin. Continuous glucose monitoring was used to measure glucose levels for 8 h postprandially. Primary outcome was mean glycemic excursion at each 30 min interval for each test condition. Generalized linear mixed models with a random effect for people with diabetes were used to test for an increase in blood glucose excursion with increasing quantity of fat. RESULTS Glycemic excursions after 20 g glucose were higher than after fat drinks over the first 2 h (p

Advances in genomics and 18F‐DOPA PET‐CT imaging have transformed the management of infants with Congenital Hyperinsulinism. Preoperative diagnosis of focal hyperinsulinism permits limited pancreatectomy with improved clinical outcomes while knowledge of the molecular etiology informs genetic counseling and provides a more accurate recurrence risk to families.

Aim To review the clinical course, outcome and incidence of infantile salt-wasting associated with urinary tract infection (UTI) and/or urinary tract malformation (UTM) over a two-year surveillance period on the island of Ireland. Methods A two-year (2013-14) prospective surveillance undertaken via the Irish and Ulster Paediatric Surveillance Units. Monthly-prepaid postcards were circulated to consultant paediatricians (n = 260) at all paediatric units on the island of Ireland. Infants under one year of age presenting for the first time with hyponatraemia (Na 5.0mmol/L) associated with urosepsis/UTM were reported. Results All 7 reported patients (6 male) had culture-proven UTI and 5 (71%) also had an underlying UTM (one diagnosed antenatally). Four (57%) patients had a documented elevated serum aldosterone supporting secondary pseudohypoaldosteronism (PHA) as the underlying diagnosis. Data on aldosterone was not reported in the other 3 patients but clinical features were suggestive of secondary PHA. The estimated incidence for the Irish population of transient PHA is 1 per 13,200 total live births per year. Conclusions Salt-wasting is a rare complication of UTI, especially if associated with underlying UTM. Boys appear to be at particular risk.

Aims: To investigate the factors impacting on glycaemic control over time including treatment type, educational input and patient demographics within an Irish tertiary paediatric diabetes centre. Methods: Using a prospectively maintained database of clinical encounters, data was analysed in age matched pairs from 2007 to 2019. Pairs were matched by insulin treatment type (pump v multiple daily injection (MDI)). Matching was performed on the basis of gender, current age, age at diagnosis and HbA1c at pump commencement. Panel data regression was performed on the entire sample and analysed for the impact of differing insulin regimens by gender, age and duration of diagnosis. This model was then used to assess the impact of intensive re-education sessions on HbA1c. Results: From 999 patients there were 104 matched pairs. Compared to MDI, matched pump patients had a lower HbA1c 6 months after commencement [Difference in HbA1c = 0.60% p

Aim To review the clinical features, presentation, investigations undertaken, and outcome of infantile salt-wasting presenting in the setting of urinary tract infection (UTI) and/or urinary tract malformation (UTM) over a two-year surveillance period on the island of Ireland. To estimate a population incidence based on the results and to make recommendations on the approach to management of this condition. Methods A two-year (2013–14) prospective surveillance undertaken for the island of Ireland via the Irish and Ulster Paediatric Surveillance Units. Monthly-prepaid postcards were circulated to Consultant Paediatricians (n = 260) at all Paediatric Units on the island of Ireland. Infants under one year of age presenting for the first time with hyponatremia (serum sodium 5.0 mmol/L) associated with urosepsis/UTM were included. Results Seven patients (six male), all aged younger than five months (3 weeks to 20 weeks) were reported during the study period. All had culture-proven UTI and five (71%) also had an underlying UTM (one diagnosed antenatally). Four (57%) patients had a documented elevated serum aldosterone supporting secondary pseudohypoaldosteronism (PHA) as the underlying diagnosis. Data on aldosterone was not reported in the other three patients but clinical features were suggestive of secondary PHA. All had an excellent outcome with full resolution of the electrolyte disturbance. No cases of primary PHA were submitted during the surveillance period. The estimated incidence for the Irish population of transient pseudohypoaldosteronism was 1 per 13,200 live births per year for the study duration. Conclusions Salt-wasting is a rare complication of UTI, especially if associated with underlying UTM. There is a similar annual incidence rate to the previously reported incidence of congenital adrenal hyperplasia in Ireland. Boys appear to be at particular risk. Prognosis is good if the condition is recognised and managed promptly.

Objectives To evaluate and compare the risk for poor glycaemic control at two time points in an Irish cohort of children with T1D. Methods The Risk Index for Poor Glycaemic Control (RI-PCG) is the screening tool to assess psychosocial risk where each score increases the risk of poor control and DKA on 10% (low risk score 0–1, moderate =2, high risk ≥3). The baseline data was collected for 2 years while follow up data collection (T1) began at least 6 months after the start of the study and continued for 2 years. No intervention was involved. Results As a part of 2-year longitudinal study 245 children with T1D (129 males) aged 3–18 years (mean 11.7±3.5) were analysed at baseline. Total of 90 patients out of 245 were assessed for psychosocial risk at baseline and at T1 (Table 1). At baseline: 31.3% of patients had a moderate score and high scores on RIPGC. At T1: 26.2% of patients had a moderate score and high psychosocial risk scores. Paired analysis showed that the difference in RIPGC score between baseline and T1 was not significant (p>0.05). Three patients (3.3%) increased the risk from low to moderate, another 3 patients (3.3%) from low to high risk and 2 patients (2.2%) from moderate to high risk. However, 12 patients (13.3%) reduced the risk with a time: 7 patients (7.7%) moved from category of moderate risk to low risk, 3 (3.3%) – from high to low and 2 (2.2%) - from high to moderate risk category. The distribution of low, moderate and high risk patients did not differ significantly in baseline group and T1 (p>0.05) Conclusions Almost one third of children with T1D in Irish population are at moderate and high psychosocial risk. The routine care provided by health professionals doesn’t reduce this risk significantly with time. Our data indicates the need of intervention by trained clinical psychologist for children with T1D and psychosocial risk.

Introduction Head neck teratomas are rare benign tumors consisting of 3–5% of all teratomas (1,2). Teratomas are embryonal neoplasms that arise when totipotential germ cells escape the developmental control of primary organizers and give rise to more or less organoid masses in which tissues derived from all three blastodermic layers (ectoderm, endoderm, and mesoderm) can be identified. Their histologic features are therefore heterogenous and may include cystic or solid areas with organoid patterns as well as mature or immature components. Case description We report a case of an antenatal diagnosis of a huge neck mass on antenatal ultrasound and fetal in utero MRI at 33 weeks gestation. He was born by ELSCS at 38 weeks gestation and an endocotracheal intubation was performed directly to maintain airway. The MRI neck postnatal confirmed a well circumscribed multicystic and solid anterior neck mass 9.7x5.2x4.9 cm. Surgical resection of the mass and thymectomy were done on day 2 after birth. The thyroid gland was not identified surgically. A single parathyroid gland was identified intraoperatively and preserved. The pathology report of the neck mass confirmed immature teratoma arising within and largely effacing the thyroid gland. No malignant germ cell tumour elements identified. He required levothyroxine treatment to replace the thyroid function. Hypocalcaemia developed postsurgical likely as a result of hypoparathyroidism. He was therefore managed by one alpha and calcium supplements to maintain normocalcaemia. He is feeding orally and continues to show appropriate normal growth and development. Discussion Cervical teratomas in children are almost always benign but locally are aggressive. They can present with respiratory airway compromise and excision is required. A multidisciplinary management is needed with multiple specialties involvement. If complete thyroid tissue is removed replacement therapy is required post operatively. Risk of hypocalcemia secondary to hypoparathyroidism developing post operatively should be monitored and treated accordingly. References Rothschild MA, Catalano P, Urken M, Brandwein M, Som P, Norton K, Biller HF. Evaluation and management of congenital cervical teratoma. Case report and review. Arch Otolaryngol Head Neck Surg. 1994;120(4):444–448. Lack EE. Extragonadal germ cell tumors of the head and neck region: review of 16 cases. Hum Pathol. 1985;16:56–64.

Background Gonadoblastoma (GB) is a rare tumour of the gonads presenting in childhood or adolescence. It is a lesion composed of a mixture of germ cells at different stages of maturation, with low malignant potential. It is associated with disorders of sex development, most commonly Turner mosaic syndrome with Y chromosome material (TMSY), and 46XY gonadal dysgenesis (GD). Little is known about the natural history and incidence, however prophylactic gonadectomy is recommended. Objectives To determine the incidence and clinical features of GB presenting in childhood in the Irish Republic (RoI) from 1999–2018 inclusive. Methods A retrospective review of children and adolescents with a diagnosis of GB was undertaken using the records of the National Cancer Registry Ireland (NCRI) and the Departments of Endocrinology, Pathology and Surgery at the main children’s hospitals. Results Fifteen cases of gonadoblastoma were identified, all except one phenotypically female. Fourteen patients had prophylactic gonadectomy and one presented with an ovarian mass and raised tumour markers. Eight had TMSY (age at gonadectomy 2 weeks – 14 years). Seven were phenotypically female and one was male. Seven cases of 46 XY GD (all female phenotype) were diagnosed with gonadoblastoma with an age range of 4 months – 15 years at time of surgery. Four of these were unilateral. In the remaining three cases, one patient had bilateral gonadoblastoma, one had unilateral dysgerminoma and contralateral gonadoblastoma and the third had bilateral dysgerminoma with features of gonadoblastoma. Conclusions This is the first reported population incidence rate of GB in children with a 20 year incidence of gonadoblastoma in the Republic of Ireland of 1/100,000 live births. The data supports the recommendation for elective gonadectomy in high risk conditions. Due to the wide age range in presentations, however, the timing of gonadectomy should be individualised, based on underlying diagnosis and following multidisciplinary team discussion. The true rate of malignant transformation in early onset GB remains to be studied.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

BACKGROUND AND OBJECTIVES: Congenital hypothyroidism (CHT) is one of the most common preventable causes of learning disability. Newborn screening with whole-blood thyroid-stimulating hormone measurements was introduced in the Republic of Ireland in 1979 and is coordinated from a single center with an unchanged protocol since its inception. Our objective in this study was to describe the incidence of CHT in the Republic of Ireland over the past 37 years in the context of a complete national population and an unchanged screening protocol. METHODS: The newborn screening records of all individuals who were diagnosed with CHT between 1979 and 2016 were reviewed. Infants with positive screening results had a whole-blood thyroid-stimulating hormone value of ≥15 mU/L at 72 to 120 hours of life; values of 8 to 15 mU/L required a repeat whole-blood screening test. RESULTS: Of 2 361 174 infants who were screened between July 1979 and December 2016, 1063 (662 girls) were diagnosed with CHT (incidence: 0.45 cases per 1000 live births). The number of detected cases increased from 0.27 cases per 1000 live births treated between 1979 and 1991 to 0.41 cases per 1000 live births treated between 1992 and 2004 to 0.65 cases per 1000 live births treated between 2005 and 2016. The increase in detected cases of CHT was predominantly in the normal or hyperplastic gland category. CONCLUSIONS: The incidence of CHT has increased significantly in the Republic of Ireland over the past 37 years despite a consistent screening cutoff. The increased rate was not explained by an increased survival rate of preterm infants or a changing population heterogeneity.

Diabetic ketoacidosis (DKA) is one of the most common causes of morbidity and mortality in new onset type 1 diabetes mellitus (T1DM). Children have a higher rate of neurological complications from DKA when compared to adults. The differential for sudden focal neurological deterioration in the setting of DKA is cerebral oedema followed by ischaemic and haemorrhagic stroke. Spontaneous intracranial haemorrhages can present with non-specific features frequently, for example, impaired consciousness, even when biochemical parameters are improving in the setting of DKA. We report the case of a girl with new onset T1D who presented in severe DKA and subsequently developed intracerebral parenchymal and subarachnoid haemorrhages. Our patient is unique in that no focal neurological or neuropsychological deficits have been found at 1-year follow up, compared to the literature which suggests poor outcomes. Our case contrasts with these previous cases as none of the other case reports demonstrated subarachnoid haemorrhages with survival.

Diabetic ketoacidosis (DKA) is one of the most common causes of morbidity and mortality in new-onset type 1 diabetes (T1D). Supraventricular tachycardia (SVT), however, is a very rare complication of DKA. We present the case of a patient with new-onset T1D who presented with DKA. He received intravenous fluid resuscitation, insulin and potassium supplementation and subsequently developed SVT, confirmed on a 12-lead electrocardiograph despite a structurally normal heart. Vagal manoeuvres and adenosine failed to restore sinus rhythm, but flecainide was successful. We conclude that SVT can occur as a complication of DKA, including in new-onset T1D. Our case is the first of this phenomenon occurring in new-onset childhood diabetes, as the few prior documented cases had established diabetes. Furthermore, a combination of potassium derangement, hypophosphataemia and falling magnesium levels may have precipitated the event.

BACKGROUND: Genetic susceptibility to insulin resistance is associated with lower adiposity in adults. Insulin resistance, and therefore adiposity, may alter sensitivity to GH. We aimed to determine the relationship between adiposity, genetic susceptibility to insulin resistance or insulin secretion, and response to GH treatment in short children born small for gestational age (SGA). METHODS: In 89 short prepubertal SGA children (age, 6.2 ± 1.6 y; 55 boys) treated with GH for 1 year in a multicenter study, body fat percentage was estimated at baseline and 1 year using dual-energy x-ray absorptiometry. The main outcome measures were treatment-related changes in height, IGF-1 standard deviation score, insulin sensitivity, insulin secretion, and disposition index. Combined multiallele gene scores based on single nucleotide polymorphisms with known associations with lower insulin sensitivity (gene scores for insulin resistance [GS-InRes]) and insulin secretion (gene scores for insulin secretion [GS-InSec]) were analyzed for their relationships with adiposity. RESULTS: Mean percentage body fat at baseline was low compared to normative data (P = .045) and decreased even further on GH treatment (baseline vs 1-year z-scores, -0.26 ± 1.2 vs -1.23 ± 1.54; P < .0001). Baseline percentage body fat was positively associated with IGF-1 responses (p-trends = .042), first-year height gains (B [95% confidence interval], 0.61 cm/y [0.28,0.95]; P < .0001), insulin secretion at baseline (p-trends = .020) and 1 year (p-trends = .004), and disposition index at 1 year (p-trends = .024). GS-InRes was inversely associated with body mass index (-0.13 SD score per allele [-0.26, -0.01]; P = .040), body fat (-0.49% per allele [-0.97, -0.007]; P = .047), and limb fat (-0.81% per allele [-1.62, 0.00]; P = .049) at baseline. During GH treatment, GS-InRes was related to a lesser decline in trunk fat (0.38% per allele [0.16, 0.59]; P = .001) and a higher trunk-limb fat ratio at 1 year (0.04 per allele [0.01, 0.08]; P = .008). GS-InSec was positively associated with truncal fat (0.36% per allele [0.09, 0.63]; P = .009). CONCLUSIONS: Adiposity in SGA children has favorable effects on GH sensitivity and glucose metabolism. The associations with multiallele scores support a causal role of insulin resistance in linking lesser body fat to reduced sensitivity to exogenous GH.

Key Clinical Message: In infants, especially with novel previously undescribed mutations of the KATP channel causing neonatal diabetes, in vitro studies can be used to both predict the response to sulphonylurea treatment and support a second trial of glibenclamide at higher than standard doses if the expected response is not observed.

Introduction: In Europe a ‘rare disease’ (RD) is defined as a life-threatening or chronically debilitating disease affecting no more than 5/10,000 people. There are an estimated 6-8,000 known RD affecting up to 6% of the total EU population, (at least 30 million Europeans), and perhaps up to 300,000 Irish people during their lives. As chronic conditions, many of which are multisystemic, accurate and timely diagnosis and access to treatment is essential for empowering patients and Health Care Providers to manage care effectively. It is recognised that poorly coordinated care and delays in diagnosis are major issues for patients and families affected by rare diseases which are noted to be more problematic in smaller countries with more limited highly specialised expertise, (Rare Diseases UK, 2015 and Irish HSE 2012 ‘Have your say’ Rare Diseases Public Consultation) and as emphasised in the recent EC Expert Group on Rare Diseases ‘Recommendations to support the incorporation of rare diseases into social services and policies’ (April 2016). Practice change and implementation: In 2014 Ireland published its first National Plan for RD (2014-2018). Establishing a National Rare Diseases Office (NRDO) was a central recommendation of the plan to improve access to reliable information and empower patients and HCPs to make informed decisions about the management of RD. Aims and theory of change: The aim of the NRDO (established in June 2015 by the Irish HSE) is to provide current and reliable information about genetic and RD to patients, families and health professionals. The functions of the office include: Centralisation of Irish RD information through Orphanet Ireland; an international online portal for RD information and resources encompassing > 6,000 RD. (www.orpha.net) Staffing a RD Information Line to provide patients, families and HCPs with information and supports relating to RD. Hosting a website with information and links to relevant RD services and organisations around Ireland and Europe www.rarediseases.ie Engaging with clinicians, expert centres and researchers to map-out Irish RD resources to act as a ‘hub’ for integrating National Centres of Expertise in the emerging European Reference Networks. Initial outcomes: In its first year of functioning, greater than 50% of calls to the information line were from patients and families, most commonly requesting signposting of medical specialists for specific RD. Conclusions and Outlook: Over time, it is proposed that the NRDO will liaise with all national RD Centres of Expertise, with the Irish national integrated care programmes, and Rare Diseases European Reference Networks to progress improved integrated care pathways for RD patients and function as a national ‘hub’ within the Irish and European contexts, in line with the EC Expert Group on Rare Diseases April 2016 Recommendations.

Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by intellectual disability, congenital heart defects, a characteristic facial appearance, gastro-intestinal complications, ectodermal abnormalities and growth failure. The RASopathies result from germline mutations in the Ras/Mitogen-activated-protein-kinase (MAPK) pathway. CFC is associated with mutations in BRAF, KRAS, MEK1 and MEK2. CFC has been considered a "sporadic" disorder, with minimal recurrence risk to siblings. In recent years, vertical transmission of CFC has been seen in mutations involving the MEK2 and KRAS genes, but has not previously been reported with BRAF mutations. Two brothers with clinical features of CFC and mutations in BRAF (c.770A > G, p.Gln257Arg) are described. Neither parent (both phenotypically normal) had the BRAF mutation in their leukocyte DNA. Although this mutation is one of the most common mutations in CFC, to our knowledge, this is the first molecularly confirmed BRAF mutation causing CFC in siblings. This observation also likely represents the first description of germ cell mosaicism in CFC and so it is important to provide optimal genetic counselling to families regarding the risk of reoccurrence.

OBJECTIVE To determine the separate and combined effects of high-protein (HP) and high-fat (HF) meals, with the same carbohydrate content, on postprandial glycemia in children using intensive insulin therapy (IIT). RESEARCH DESIGN AND METHODS Thirty-three subjects aged 8–17 years were given 4 test breakfasts with the same carbohydrate amount but varying protein and fat quantities: low fat (LF)/low protein (LP), LF/HP, HF/LP, and HF/HP. LF and HF meals contained 4 g and 35 g fat. LP and HP meals contained 5 g and 40 g protein. An individually standardized insulin dose was given for each meal. Postprandial glycemia was assessed by 5-h continuous glucose monitoring. RESULTS Compared with the LF/LP meal, mean glucose excursions were greater from 180 min after the LF/HP meal (2.4 mmol/L [95% CI 1.1–3.7] vs. 0.5 mmol/L [−0.8 to 1.8]; P = 0.02) and from 210 min after the HF/LP meal (1.8 mmol/L [0.3–3.2] vs. −0.5 mmol/L [−1.9 to 0.8]; P = 0.01). The HF/HP meal resulted in higher glucose excursions from 180 min to 300 min (P < 0.04) compared with all other meals. There was a reduction in the risk of hypoglycemia after the HP meals (odds ratio 0.16 [95% CI 0.06–0.41]; P < 0.001). CONCLUSIONS Meals high in protein or fat increase glucose excursions in youth using IIT from 3 h to 5 h postmeal. Protein and fat have an additive impact on the delayed postprandial glycemic rise. Protein had a protective effect on the development of hypoglycemia.

Severe hypoglycaemia is a major barrier to optimising glycaemic control. Recent changes in therapy, however, may have altered the epidemiology of severe hypoglycaemia and its associated risk factors. The aim of this study was to examine the incidence rates and risk factors associated with severe hypoglycaemia in a contemporary cohort of children and adolescents with type 1 diabetes.Subjects were identified from a population-based register containing data on99% of patients (16 years of age) who were being treated for type 1 diabetes in Western Australia. Patients attend the clinic approximately every 3 months, where data pertaining to diabetes management, demographics and complications including hypoglycaemia are prospectively recorded. A severe hypoglycaemic event was defined as an episode of coma or convulsion associated with hypoglycaemia. Risk factors assessed included age, duration of diabetes, glycaemic control, sex, insulin therapy, socioeconomic status and calendar year.Clinical visit data from 1,770 patients, providing 8,214 patient-years of data between 2000 and 2011 were analysed. During follow-up, 841 episodes of severe hypoglycaemia were observed. No difference in risk of severe hypoglycaemia was observed between age groups. Good glycaemic control (HbA1c7% [53 mmol/mol]) compared with the cohort average (HbA1c 8-9% [64-75 mmol/mol]) was not associated with an increased risk of severe hypoglycaemia. When compared with patients on injection regimens, subjects aged 12-18 years on pump therapy were at reduced risk of severe hypoglycaemia (incidence risk ratio 0.6; 95% CI 0.4, 0.9).In this population-based sample of children and adolescents with type 1 diabetes, contemporary therapy is associated with a changed pattern and incidence of severe hypoglycaemia.

International audience; This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.

Background Hypoparathyroidism in children is a heterogeneous group with diverse genetic etiologies. To aid clinicians in the investigation and management of children with hypoparathyroidism, we describe the phenotype of a 6-year-old child with hypoparathyroidism and short stature diagnosed with Kenny-Caffey syndrome (KCS) Type 2 and the subsequent response to growth hormone (GH) treatment. Case presentation The proband presented in the neonatal period with hypocalcemic seizures secondary to hypoparathyroidism. Her phenotype included small hands and feet, hypoplastic and dystrophic nails, hypoplastic mid-face and macrocrania. Postnatal growth was delayed but neurodevelopment was normal. A skeletal survey at 2 years of age was suggestive of KCS Type 2 and genetic testing revealed a novel de novo heterozygous mutation c.1622C > A (p.Ser541Tyr) in FAM111A. At 3 years and 2 months, her height was 80cms (SDS −3.86). She had normal overnight GH levels. GH therapy was commenced at a dose of 4.9 mg/m2/week for her short stature and low height velocity of 5cms/year. At the end of the first and second years of GH treatment, height velocity was 6.5cms/year and 7.2cms/year, respectively with maximal dose of 7.24 mg/m2/week. Conclusion This case highlights the phenotype and the limited response to GH in a child with genetically proven KCS type 2. Long-term registries monitoring growth outcomes following GH therapy in patients with rare genetic conditions may help guide clinical decisions regarding the use and doses of GH in these conditions.

Objective: Developmental programming alters growth and metabolic outcome in children born small for gestational age (SGA). We explored insulin and glucose metabolism in SGA children treated with a fixed GH dose over 1 year. Methods: In the North European Small for Gestational Age Study (NESGAS), 110 short SGA children received GH at 67 µg/kg/day for 1 year. Insulin secretion was assessed by acute insulin response (AIR), insulin sensitivity (IS) by HOMA and disposition index (DI) by insulin secretion adjusted for IS. Results: First-year GH therapy led to increases in height and IGF-I standard deviation score (SDS), and reductions in IS (p < 0.0001). Compensatory increases in AIR (p < 0.0001) were insufficient and resulted in reduced DI (p = 0.032). Children in the highest IGF-I SDS tertile at baseline were the least insulin sensitive at baseline (p = 0.024) and 1 year (p = 0.006). IGF-I responses after 1 year were positively related to AIR (r = 0.30, p = 0.007) and DI (r = 0.29, p = 0.005). Conclusion: In SGA children treated with a high GH dose for 1 year, baseline IGF-I levels were related to IS whilst gains in height and IGF-I responses were associated with insulin secretion. Defining heterogeneity in IGF-I in SGA children may be useful in predicting growth and metabolic response.

Johnson and Stricker published an opinion piece in the Journal of Medical Ethics presenting their perspective on the 2008 agreement between the Infectious Diseases Society of America (IDSA) and the Connecticut Attorney General with regard to the 2006 IDSA treatment guideline for Lyme disease. Their writings indicate that these authors hold unconventional views of a relatively common tick-transmitted bacterial infection caused by the spirochete Borrelia burgdorferi. Therefore, it should come as no surprise that their opinions would clash with the IDSA's evidence-based guidelines for the diagnosis and treatment of Lyme disease. Their allegations of conflict of interest against the IDSA resemble those made against the National Institutes of Health, the Food and Drug Administration and the Centers for Disease Control and Prevention in 2000, which were found to be baseless. It is the responsibility of all physicians and medical scientists to stand up to antiscientific, baseless and unethical attacks on those who support an evidence-based approach to caring for patients.

Summary DNA polymerase ε (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polε processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polε complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1. In both Pole4−/− mouse and POLE1 mutant human cells, Polε hypomorphy is associated with replication stress and p53 activation, which we attribute to inefficient replication origin firing. Strikingly, removing p53 is sufficient to rescue embryonic lethality and all developmental abnormalities in Pole4 null mice. However, Pole4−/−p53+/− mice exhibit accelerated tumorigenesis, revealing an important role for controlled CMG and origin activation in normal development and tumor prevention., Graphical Abstract, Highlights • Pole4−/− mice exhibit impaired development and defective lymphocyte maturation • Pole4 is crucial for maintaining the stability of the Polε complex • Polε hypomorphy causes replication stress via inefficient origin activation • p53 inactivation rescues all major developmental defects in Pole4-deficient mice, Bellelli et al. report that Pole4 deficiency in mice or POLE1 mutations in humans result in Pol Epsilon complex instability, replication stress, and inefficient origin activation. As a consequence, Pol Epsilon hypomorphic mice exhibit aberrant growth and development, lymphopenia, and tumor predisposition, which can be rescued by deleting p53.

Mosaic Turner syndrome (TSM) commonly occurs in the form of 45,X/46,XX and 45,X/46,X,i(X)(q10). Mosaicism for a Y chromosome, 45,X/46,XY, has been well documented and is associated with increased risk of gonadoblastoma (GB). To date, there are only six reported cases of TSM with a trisomy 18 karyotype, and only two of these were phenotypically female with 45,X/47,XY,+18 karyotype. We present the case of a phenotypically female infant born with dysmorphic features. G-banded karyotype and interphase FISH of blood showed 45,X in 95% and 47,XY,+18 (trisomy 18) in 5% of cells analysed. However, interphase FISH of buccal cells showed only the presence of the 45,X cell line. Due to the presence of Y chromosome material, elective gonadectomy was performed at 13 months of age. There were bilateral streak ovaries with early evidence of GB bilaterally, a rudimentary uterus and bilateral fallopian tubes with unilateral ectopic adrenal tissue identified histologically. Interphase FISH of the gonadal tissue was similar to the blood findings with 45,X in 86% of cells and 47,XY,+18 in 14% of cells analysed. This case highlights a rare karyotype of TSM and trisomy 18 in the same patient and is the first reporting the associated finding of bilateral GB.

Familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurologic, cutaneous, articular syndrome are related disorders associated with mutations in the CIAS1 gene. They appear to represent a continuum of one disease characterized by IL-1-mediated inflammation. Until recently, these conditions have been difficult to treat; however, with the advent of IL-1-receptor antagonist therapy, many reports of successful treatment of patients with these autoinflammatory diseases have emerged in the past 2 years. We describe an 8-year-old girl, diagnosed with Familial cold auto-inflammatory syndrome, confirmed by presence of a novel CIAS1 mutation, who was refractory to symptomatic treatment. As frequent attacks of urticaria and associated arthralgia had a debilitating effect on the child's lifestyle, a trial of IL-1-receptor antagonist (anakinra) was instituted. Dramatic sustained clinical improvement was evident within days and serum amyloid and C-reactive protein levels normalized within a month. Although several authors have reported successful use of this agent in children with chronic infantile neurologic, cutaneous, articular syndrome, we believe ours is the first report of successful treatment with anakinra in a young child with familial cold auto-inflammatory syndrome.

A primary focus of the management of type 1 diabetes has been on matching prandial insulin therapy with carbohydrate amount consumed. However, even with the introduction of more flexible intensive insulin regimes, people with type 1 diabetes still struggle to achieve optimal glycaemic control. More recently, dietary fat and protein have been recognised as having a significant impact on postprandial blood glucose levels. Fat and protein independently increase the postprandial glucose excursions and together their effect is additive. This article reviews how the fat and protein in a meal impact the postprandial glycaemic response and discusses practical approaches to managing this in clinical practice. These insights have significant implications for patient education, mealtime insulin dose calculations and dosing strategies.

Summary Background It is recognised that individuals with a 45,X/46,XY karyotype, known as Turner mosaic syndrome with Y chromosome material (TMSY), have an increased risk of developing gonadoblastoma (GB), which may then devolve into one of a number of germ cell malignancies. Hence, children with TMSY are usually recommended to undergo prophylactic gonadectomy. Objective We designed this study to describe the phenotypic features of our series of children with TMSY who underwent prophylactic gonadectomy in order to evaluate the prevalence of GB and germ cell malignancies in their resected specimens. Study design This is a retrospective case series wherein we comprehensively reviewed the clinical, histological, and cytogenetic features of all patients who underwent prophylactic gonadectomy at three tertiary paediatric referral centres over 16 years. Cases were identified from surgical logbooks and through the institutional histopathology database. Data were collected with particular reference to clinical phenotype, predominant karyotype cell line, operative management, anatomical findings and the presence of neoplastic changes. Results Fourteen children ranging in age at the time of surgery from 2 weeks to 17 years were included in the series. Eleven children were reared as females. The three children who were reared as males had severe penoscrotal hypospadias. The 46,XY cell line was the predominant cell line in seven (50%) cases in blood lymphocytes. The resected specimens from four patients (28.6%) contained GB, with three patients having bilateral GB. This sub-group of patients with GB were aged 5 months, 48 months, 71 months, and 13 years. GB arose in one patient with and three patients without genital virilisation. There was no focus of invasive germ cell tumour in any specimen. Discussion GB may be present in infants with TMSY as young as 5 months, even with low levels of Y chromosome material. The prevalence of GB in prophylactic gonadectomy specimens is similar to many previously reported series, although the absence of dysgerminoma in our series is reassuring. The exclusive presence of GB in intra-abdominal gonads is in keeping with the findings of several other series. Conclusion Owing to the presence of gonadoblastoma in the gonads of children with TMSY as young as 5 months, we recommend that all patients with intra-abdominal gonads in the context of TMSY should duly undergo prophylactic gonadectomy, although the timing of such surgery can be discussed with parents during counselling regarding the risk of malignancy. Table . Clinical, genetic and histological characteristics of patients with 45,X/46,XY mosaicism who underwent prophylactic gonadectomy. Population characteristics n = 14 Sex of rearing Male 3 (21.4%) Female 11 (78.6%) Median age at surgery 48 months (0.5 – 215 months) Predominant cell line 45,X 4 (28.6%) 46,XY 8 (57.1%) No predominance 2 (14.3%) External genitalia Virilization (cliteromegaly, etc.) 3 (21.4%) Severe hypospadias 3 (21.4%) Normal 8 (57.2%) Gonadal histology (n = 25 gonads) Undifferentiated gonadal tissue (UGT) 1 (4%) Dysgenetic testis 5 (20%) Streak gonad 11 (44%) Vanishing gonad 2 (8%) Dysgenetic gonad/testis with UGT 6 (24%) Gonadoblastoma 7 (28%)

BackgroundShort children born small for gestational age (SGA) are treated with a GH dose based on body size, but treatment may lead to high levels of IGF1. The objective was to evaluate IGF1 titration of GH dose in contrast to current dosing strategies.MethodsIn the North European Small-for-Gestational-Age Study (NESGAS), 92 short pre-pubertal children born SGA were randomised after 1 year of high-dose GH treatment (67 μg/kg per day) to three different regimens: high dose (67 μg/kg per day), low dose (35 μg/kg per day) or IGF1 titration.ResultsThe average dose during the second year of the randomised trial did not differ between the IGF1 titration group (38 μg/kg per day,s.d.0.019) and the low-dose group (35 μg/kg per day,s.d.0.002;P=0.46), but there was a wide variation in the IGF1 titration group (range 10–80 μg/kg per day). The IGF1 titration group had significantly lower height gain (0.17 SDS,s.d.0.18) during the second year of the randomised trial compared with the high-dose group (0.46 SDS,s.d.0.25), but not significantly lower than the low-dose group (0.23 SDS,s.d.0.15;P=0.17). The IGF1 titration group had lower IGF1 levels after 2 years of the trial (mean 1.16,s.d.1.24) compared with both the low-dose (mean 1.76,s.d.1.48) and the high-dose (mean 2.97,s.d.1.63) groups.ConclusionIGF1 titration of GH dose in SGA children proved less effective than current dosing strategies. IGF1 titration resulted in physiological IGF1 levels with a wide range of GH dose and a poorer growth response, which indicates the role of IGF1 resistance and highlights the heterogeneity of short SGA children.

Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance presenting in infancy with renal salt wasting and failure to thrive. Here, we present the case of a 6-week-old baby girl who presented with mild hyponatraemia and dehydration with a background of severe failure to thrive. At presentation, urinary sodium was not measurably increased, but plasma aldosterone and renin were increased, and continued to rise during the subsequent week. Despite high calorie feeds the infant weight gain and hyponatraemia did not improve until salt supplements were commenced. Subsequently, the karyotype was reported as 46,XX,inv (4)(q31.2q35). A search of the OMIM database for related genes at or near the inversion breakpoints, showed that the mineralocorticoid receptor gene (NR3C2) at 4q31.23 was a likely candidate. Further FISH analysis showed findings consistent with disruption of the NR3C2 gene by the proximal breakpoint (4q31.23) of the inversion. There was no evidence of deletion or duplication at or near the breakpoint. This is the first report of a structural chromosome disruption of the NR3C2 gene giving rise to the classical clinical manifestations of pseudohypoaldosteronism type 1 in an infant.

Familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurologic, cutaneous, articular syndrome are related disorders associated with mutations in the CIAS1 gene. They appear to represent a continuum of one disease characterized by IL-1-mediated inflammation. Until recently, these conditions have been difficult to treat; however, with the advent of IL-1-receptor antagonist therapy, many reports of successful treatment of patients with these autoinflammatory diseases have emerged in the past 2 years. We describe an 8-year-old girl, diagnosed with Familial cold auto-inflammatory syndrome, confirmed by presence of a novel CIAS1 mutation, who was refractory to symptomatic treatment. As frequent attacks of urticaria and associated arthralgia had a debilitating effect on the child's lifestyle, a trial of IL-1-receptor antagonist (anakinra) was instituted. Dramatic sustained clinical improvement was evident within days and serum amyloid and C-reactive protein levels normalized within a month. Although several authors have reported successful use of this agent in children with chronic infantile neurologic, cutaneous, articular syndrome, we believe ours is the first report of successful treatment with anakinra in a young child with familial cold auto-inflammatory syndrome.

OBJECTIVE To examine rates of severe hypoglycemia (SH) in a large population-based cohort of children with type 1 diabetes and relationships to HbA1c. RESEARCH DESIGN AND METHODS Data from 1,683 children (mean [SD] age at diagnosis 10.5 [4.2]; range 1–18 years) from 2000 to 2009 were analyzed from the Western Australian Children's Diabetes Database. Rates of SH were related to HbA1c using negative binomial regression. RESULTS A total of 7,378 patient-years of data and 780 SH events were recorded. The rate of SH per 100 patient-years peaked at 17.3 in 2001 and then declined from 2004 to a nadir of 5.8 in 2006. HbA1c CONCLUSIONS In a sample of youth with type 1 diabetes, there has been a decrease in rates of SH and a weaker relationship with glycemic control than previously observed.

Kenny-Caffey syndrome (KCS) is characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of anterior fontanelle, eye abnormalities, and hypoparathyroidism. The autosomal dominant form (KCS Type 2) caused by mutations in FAM111A is distinguished from the autosomal recessive form (KCS Type1), caused by mutations in TBCE gene, by the absence of mental retardation. Our proband presented on day 8 of life with hypocalcaemic seizures secondary to hypoparathyroidism. Normocalcaemia was achieved with IV calcium gluconate and maintained by oral calcium carbonate 100mg BD and calcitriol 0.1mcg BD for the first 2 years of life while serum PTH remained low at A (p.Ser541Tyr) in FAM111A. However, the unusual nails, the reducing calcium requirement and the unexplained microcytic anaemia are unique to our patient. Written informed Consent for this patient has been taken including results of the genetic analyses and images according to the Institutional Ethics Committee procedures of our health service.