Context:
Disorders of sex development (DSD) are clinical conditions where there is a discrepancy between the chromosomal sex and the phenotypic (gonadal or genital) sex of an individual. Such ...conditions can be stressful for patients and their families and have historically been difficult to diagnose, especially at the genetic level. In particular, for cases of 46,XY gonadal dysgenesis, once variants in SRY and NR5A1 have been ruled out, there are few other single gene tests available.
Objective:
We used exome sequencing followed by analysis with a list of all known human DSD-associated genes to investigate the underlying genetic etiology of 46,XY DSD patients who had not previously received a genetic diagnosis.
Design:
Samples were either submitted to the research laboratory or submitted as clinical samples to the UCLA Clinical Genomic Center. Sequencing data were filtered using a list of genes known to be involved in DSD.
Results:
We were able to identify a likely genetic diagnosis in more than a third of cases, including 22.5% with a pathogenic finding, an additional 12.5% with likely pathogenic findings, and 15% with variants of unknown clinical significance.
Conclusions:
Early identification of the genetic cause of a DSD will in many cases streamline and direct the clinical management of the patient, with more focused endocrine and imaging studies and better-informed surgical decisions. Exome sequencing proved an efficient method toward such a goal in 46,XY DSD patients.
First-degree relatives of women with polycystic ovary syndrome (PCOS) present hormonal and metabolic alterations compared to girls unrelated to PCOS. It is unknown whether glucose intolerance in the ...PCOS proband confers a more severe metabolic predisposition on their first-degree relatives.
To determine whether glucose tolerance status in women with PCOS is associated with worsened glucose metabolism and sex hormone levels in their peripubertal daughters or sisters.
Cross-sectional study.
Seven academic centers in North America, South America, and Europe.
Sixty-four pairs of women with PCOS and their daughters or younger sisters aged between 8 and 14 years were recruited. Twenty-five mothers or older sisters with PCOS were glucose intolerant (GI) and 39 were normal glucose tolerant (NGT).
Beta-cell function estimated by the insulin secretion-sensitivity index-2 (ISSI-2) during an oral glucose tolerance test and by the disposition index during a frequently sampled IV glucose tolerance test. Free testosterone and 17-hydroxyprogesterone (17-OHP) levels.
Being related to a GI PCOS proband was associated with a lower ISSI-2 (P-value = 0.032) after adjusting for ethnicity, body mass index z-score, and pubertal stage. They also had higher free testosterone (P-value = 0.011) and 17-OHP levels compared to girls with an NGT proband, the latter becoming significant after adjusting for confounders (P-value = 0.040).
Compared to first-degree female relatives of women with PCOS and NGT, first-degree relatives of women with PCOS and GI display lower beta-cell function and hyperandrogenemia, putting them at higher risk of GI and PCOS development.
Individual inborn errors of metabolism (IEM) are rare disorders, but may not be that uncommon in our patient population. We report the incidence of IEM in a defined cohort of births at the Saudi ...Aramco medical facilities in the Eastern Province of Saudi Arabia over 25 years.
The records of all patients diagnosed with IEM from 1 January 1983 to 31 December 2008 were reviewed and categorized according to accumulated or deficient metabolites into small-molecule disorders (aminoacidemia, organic acidopathies OA, urea cycle defects, fatty acid oxidation, and carbohydrate metabolic disorders) and other disorders, including glycogen and lysosomal storage disorders (LSDs), and organelle disorders.
During the study period, 165,530 Saudi Arabian infants were born at Saudi Aramco and 248 were diagnosed with an IEM, corresponding to a cumulative incidence of 150 cases per 100,000 live births. Small-molecule disorders were diagnosed in 134/248 patients (54%). OA were the most common (48/248 patients; 19%), and methylmalonic aciduria was the most frequently observed OA (13/48 patients; 27%). LSDs were diagnosed in 74/248 patients (30%), and mucopolysaccharidosis was the most frequently observed LSD (28/74; 38%).
We believe that our data underestimate the true incidence of IEM in the region. Regional and national newborn screening programs will provide a better estimation of the incidence of IEM. We recommend a centralized newborn screening program that employs tandem mass spectrometry.
Two children presented with autoimmune alternating hypo- and hyperthyroidism related to the presence of blocking and stimulating thyroid antibodies. It was difficult to control their thyroid function ...adequately with an appropriate single drug regimen, and both children underwent total thyroidectomy with subsequent stable management with levothyroxine replacement therapy postsurgically. Although this phenomenon is well described in adults, this report is the first of such occurrence in children. The possible mechanism for the variation in the type of clinical presentation and options for management are discussed.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Background: Premature adrenarche (PA), the appearance of pubic hair before the age of 8 years in girls and before 9 years in boys, may predict future morbidity, such as metabolic syndrome (MS). ...Objective: The purpose of this study is to assess carotid artery ultrasound changes in children with PA. Design/methods: PA children were matched with a group of prepubertal controls without PA. Subjects and controls underwent clinical and biochemical evaluation and sonograms of the carotid arteries. Results: Twelve children with PA and their matched controls were studied. Carotid artery ultrasonography showed elevation of the inner and outer diameter of the left carotid, and the cross-sectional area of the lumen and outer wall, and the outer diameter of the right carotid artery in PA. However, none of the above results maintained statistical significance when a Hochberg correction was applied. Conclusions: Carotid artery diameter and cross-sectional area may be useful non-invasive markers of vascular pathology and MS in premature pubarche.
A 10.5-year-old Caucasian girl with familial glucocorticoid deficiency (FGD) is presented. She had a homozygous S74I mutation of the ACTH receptor and her parents were heterozygous for the same ...mutation. Around 4 years prior to the diagnosis of FGD, she was diagnosed with antibody positive primary hypothyroidism and was on thyroxin supplementation. FGD patients are considered to be tall. Our patient was only 146.5 cm (4′ 9.25″) tall at age 17 years (–2.21 standard deviations below the mean for her age). The possible mechanism for short stature in FGD is speculated.
Abstract We investigated for evidence of early metabolic syndrome irrespective of body mass index (BMI) in subjects with premature pubarche (PP). Ten children with PP were compared with controls ...matched for age, sex, ethnicity, and BMI. Congenital adrenal hyperplasia and other known causes of PP were excluded by standard methods. Anthropometry, blood pressure (BP), dual-energy x-ray absorptiometry body scan, fasting blood lipid profile, and cytokines were obtained. The children were divided into 2 groups: (1) the total group of children with PP, and their age-, sex-, ethnicity-, and BMI-matched controls and (2) those with PP and normal BMI (<19 kg/m2 ) and their matched controls selected from the original groups. The PP subjects with normal BMI (S1 ) showed significantly higher systolic BP ( P = .028), diastolic BP ( P = .028), and mean arterial pressure ( P = .018) compared with matched controls (C1 ). Nevertheless, for both groups, all the above parameters were statistically not significant when corrected for height. Fat distribution in PP subjects indicated significantly higher android ( P = .047) and android-gynoid ratio ( P = .013). Normal-BMI PP children had significantly higher android-gynoid ratio fat distribution compared with their matched controls ( P = .037). Trunk fat percentage (p: 0.04) and trunk fat (grams) ( P = .007) were significantly elevated in PP children compared with matched controls. Again, for both groups, all the above parameters were not statistically significant when corrected for height. The PP subjects had significantly higher tumor necrosis factor (TNF)– α ( P = .038) and interleukin-8 (picograms per milliliter) ( P = .05) compared with matched controls. Normal-BMI PP children also had higher TNF- α ( P = .028) compared with matched controls. When corrected for height, TNF- α was higher in the total ( P = .037) and normal-BMI ( P = .043) PP children. Premature pubarche can be linked to markers of the metabolic syndrome in lean children.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with ...excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients.
In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817.
90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer for HbA1c, year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol 55·2–77·1) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol 35·5–47·5; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol 41·0–56·3; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years IQR 9·2–10·9). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years IQR 10·5–24·0 vs 4·1 years 1·3–10·2; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients.
High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years.
Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.
Megalencephaly-capillary malformation syndrome (MCAP) is an overgrowth disorder characterized by cerebrocortical malformations, vascular anomalies, and segmental overgrowth secondary to somatic ...activating mutations in the PI3K-AKT-MTOR pathway (
PIK3CA
). Cases of growth failure and hypoglycemia have been reported in patients with MCAP, raising the suspicion for unappreciated growth hormone (GH) deficiency. Here we report an observational multi-center study of children with MCAP and GH deficiency. Eleven participants were confirmed to have GH deficiency, all with very low or undetectable circulating concentrations of insulin-like growth factor-1 and insulin-like growth factor binding protein-3. Seven underwent GH stimulation testing and all had insufficient responses with a median GH peak of 3.7 ng/ml (range 1.1-8.6). Growth patterns revealed a drastic decline in length z-scores within the first year of life but then stabilized afterward. Five were treated with GH; one discontinued due to inconsolability. The other four participants continued on GH with improvement in linear growth velocity. Other endocrinopathies were identified in seven of the 11 participants in this cohort. This study indicates that GH deficiency is associated with MCAP and that children with MCAP and hypoglycemia and/or postnatal growth failure should be evaluated for GH deficiency and other endocrinopathies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective: We hypothesized that there would be evidence of functional ovarian hyperandrogenism in girls with premature pubarche (PP) at diagnosis. Methods: White girls <8 years of age and black girls ...<6 years with PP (n = 15) were studied. Prepubertal girls (n = 13; 5.3-10.9 years) and early pubertal girls (n = 8) served as control subjects. The biochemical marker for functional ovarian hyperandrogenism was the 17-hydroxyprogesterone (17-OHP), androstenedione (AD), and estradiol (E2) response to subcutaneous leuprolide during adrenal suppression with dexamethasone. This was studied in girls with PP and in control subjects. Results: ACTH stimulated 17-hydroxypregnenolone (17-OH Preg), dehydroepiandrosterone (DHEA), and AD levels, and 17-OH Preg:17-OHP and DHEA:AD ratios were significantly higher in girls with PP than in prepubertal control subjects (n = 18) (P ≤.003). The ovarian response to leuprolide stimulation was comparable in girls with PP and prepubertal control subjects, but the response in prepubertal study subjects was significantly lower than in pubertal control subjects (P =.016 for Δ17-OHP, P =.001 for ΔAD, and P =.026 for ΔE2). Conclusions: Contrary to the hypothesis, PP in girls was not associated with prepubertal evidence of ovarian hyperandrogenism but was associated with functional adrenal hyperandrogenism. (J Pediatr 2002;141:91-8)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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