A novel report of a fertile female with partial Y chromosome gain completing a healthy pregnancy.

We present a female patient with a complex sex chromosomal rearrangement [GRCh38] Xp22.33(10701_981101)x1,Yq11.221q11.23(13948013_26483746)x1 who conceived spontaneously and carried a healthy pregnancy to term. The patient presented with extreme short stature (more than 4SD below expected) and a bilateral Madelung deformity suggesting a possible SHOX deletion. The patient was otherwise medically well. This patient's short stature was found to be a result of a complex chromosome rearrangement involving a partial X chromosome deletion, which included the SHOX gene and a gain of Y chromosomal material. The Y chromosome material did not contain the SRY gene locus. This is the first recorded case to date of this rearrangement in a female who spontaneously conceived which resulted in a live birth. This patient had normal external and internal anatomy and normal endocrine evaluation with normal puberty. X-inactivation studies revealed no evidence of skewed inactivation.

Close intervention sessions complement intensive insulin therapy in paediatric diabetes: a longitudinal study.

OBJECTIVE: To examine the impact of multidisciplinary team input and intensive insulin therapy on glycaemic control in children and adolescents with diabetes over a 13-year period. DESIGN: Two statistical approaches were used to interrogate the dataset. First a matched pair analysis to compare insulin treatment-type effect (pump vs multiple daily injections (MDIs)), followed by panel data regression to assess the impact of intensive re-education on glycated haemoglobin (HbA1c), in addition to treatment type. SETTING: A large tertiary paediatric diabetes centre using a prospectively maintained database of clinical encounters from 2007 to 2020. MAIN OUTCOME MEASURES: Difference in HbA1c between treatment types (matching methodology) and expected change in HbA1c with treatment type and re-education (panel data). RESULTS: Compared with MDI, matched pump patients had a lower HbA1c 6 months after pump commencement (ΔHbA1c=-0.53%, CI -0.34% to -0.72%; n=106). This effect was robust in controlling for socioeconomic deprivation (ΔHbA1c=-0.74%, CI -0.40% to -1.08%; n=29). Panel data analysis demonstrated a -0.55% reduction in HbA1c with pump therapy compared with MDI therapy (CI -0.43% to -0.67%). Patients who had intensive re-education had recorded an HbA1c of 0.95% (CI 0.85% to 1.05%) greater than otherwise identical patients prior to re-education. Following these sessions, HbA1c dropped by a mean -0.81% (CI -0.68% to -0.95%) within 6 months. These were also robust in controlling for socioeconomic factors. CONCLUSIONS: Compared with matched peers on MDI regimens, patients on pump therapy have lower expected HbA1c, an effect sustained for up to 8 years. Intensive re-education is associated with a significant drop in previously elevated HbA1c levels.

Does dietary fat cause a dose dependent glycemic response in youth with type 1 diabetes?

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 < 0.05). Glycemic excursion for the fat drinks demonstrated a dose response, statistically significant from 4 h (p = 0.026), such that increasing loads of fat caused a proportionally larger increase in glycemic excursion, remaining statistically significant until 8 h (p < 0.05). Overall, for every 10 g fat added to the drink, glucose concentrations rose by a mean of 0.28 mmol L-1 from 330 min (95% CI 0.15 to 0.39, p < 0.001). CONCLUSIONS: Fat ingested without other macronutrients increases glucose excursions from 4 to 8 h after ingestion, in a dose dependent manner. These observations may impact on insulin dosing for high-fat foods in individuals with T1D.

The incidence of transient infantile pseudohypoaldosteronism in Ireland: A prospective study.

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 < 130 mmol/L) and/or hyperkalaemia (K > 5.0 mmol/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 were 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.

Inheritance of a paternal ABCC8 variant and maternal loss of heterozygosity at 11p15 retrospectively unmasks the etiology in a case of Congenital hyperinsulinism.

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.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

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.

Subarachnoid and parenchymal haemorrhages as a complication of severe diabetic ketoacidosis in a preadolescent with new onset type 1 diabetes.

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.

Incidence of Congenital Hypothyroidism Over 37 Years in Ireland.

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.

Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis.

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.

A sibling pair with cardiofaciocutaneous syndrome (CFC) secondary to BRAF mutation with unaffected parents-the first cases of gonadal mosaicism in CFC?

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.

Supraventricular tachycardia as a complication of severe diabetic ketoacidosis in an adolescent with new-onset type 1 diabetes.

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.

Transient neonatal hypercalcaemia secondary to excess maternal vitamin D intake: too much of a good thing.

We report a case of transient neonatal hypercalcaemia secondary to excess maternal vitamin D intake in pregnancy. Vitamin D insufficiency and deficiency in pregnancy are associated with adverse pregnancy outcomes, but there is no definite benefit to supplementation. The Royal College of Obstetrics and Gynaecology recommends routine supplementation with vitamin D3 400 IU/day, but higher dose preparations usually recommended for the treatment of vitamin D deficiency are readily available over the counter. This case highlights the risks of excess supplementation, especially at higher doses and in women without evidence of vitamin D deficiency. The amount used in this case was at the upper end of the generally accepted safe dose range, but still less than that commonly recognised to cause problems. Neonatal hypercalcaemia is a potentially serious condition. The current local or national recommendations for vitamin D supplementation and the possible adverse effects of excess vitamin D consumption should be clearly communicated to pregnant women.

Short stature and hypoparathyroidism in a child with Kenny-Caffey syndrome type 2 due to a novel mutation in FAM111A gene.

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.

Diagnosis and management of Silver-Russell syndrome: first international consensus statement.

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.

Early Bilateral Gonadoblastoma in a Young Child with Mosaicism for Turner Syndrome and Trisomy 18 with Y Chromosome.

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.

Gonadoblastoma in patients with 45,X/46,XY mosaicism: A 16-year experience.

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.

Adiposity in Children Born Small for Gestational Age Is Associated With ß-Cell Function, Genetic Variants for Insulin Resistance, and Response to Growth Hormone Treatment.

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.

The value of in vitro studies in a case of neonatal diabetes with a novel Kir6.2-W68G mutation.

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.

The Role of Dietary Protein and Fat in Glycaemic Control in Type 1 Diabetes: Implications for Intensive Diabetes Management.

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.