Visual function and retinal thickness in children with type 1 diabetes mellitus.

CLINICAL RELEVANCE: The possibility that changes in blue-yellow visual thresholds and some retinal thickness measures in children with diabetes mellitus may be observed before any visible fundus changes points to the possibility of these measures being a useful predictor that the risks of diabetic retinopathy are higher in some children than in others. INTRODUCTION: Previous studies showed mixed results on chromatic and achromatic contrast sensitivity early in the course of diabetes mellitus, and the findings of these studies may have been influenced by a lack of experimental sensitivity to visual deficits, a bias towards tritan-like errors or the cognitive demands of the tests and variations in sample composition. The purpose of this study was to evaluate colour and contrast thresholds and retinal thickness in children with type 1 diabetes mellitus compared with age-matched controls. METHODS: A prospective case-control study was carried out on 9-14-year-old children with type 1 diabetes mellitus (49 cases) and age matched controls (49) in which isoluminant red-green and blue-yellow and achromatic luminance contrast thresholds were measured. Fundus photography was used to grade diabetic retinopathy. Retinal thickness parameters were measured using optical coherence tomography. Data on the duration of diabetes mellitus, glycaemic control (HbA1c), blood glucose level, body mass index, blood pressure and blood oxygenation at the time of testing were obtained. RESULTS: The cases mostly had poorly controlled diabetes, HbA1c 8.6% (6.4-12.8%), for an average (range) duration of 5 (0.4-12) years. The cases had significantly higher blue-yellow thresholds (p = 0.02) and greater total retinal and inner retinal thickness (p < 0.05) than controls. No cases had diabetic retinopathy. Within the cases, poorer visual function and systemic health measures were associated with thinner retinal structures and greater global loss volume percentage in the ganglion cell complex. CONCLUSION: Blue-yellow thresholds of cases were raised compared to normal. Within the cases, higher luminance contrast thresholds were also associated with, mostly, ganglion cell complex reductions.

Sleep-disordered breathing in Australian children with Prader-Willi syndrome following initiation of growth hormone therapy.

AIM: In children with Prader-Willi syndrome (PWS), growth hormone (GH) improves height and body composition; however, may be associated with worsening sleep-disordered breathing (SDB). Some studies have reported less SDB after GH initiation, but follow-up with polysomnography is still advised in most clinical guidelines. METHODS: This retrospective, multicentre study, included children with PWS treated with GH at seven PWS treatment centres in Australia over the last 18 years. A paired analysis comparing polysomnographic measures of central and obstructive SDB in the same child, before and after GH initiation was performed with Wilcoxon signed-rank test. The proportion of children who developed moderate/severe obstructive sleep apnoea (OSA) was calculated with their binomial confidence intervals. RESULTS: We included 112 patients with available paired data. The median age at start of GH was 1.9 years (range 0.1-13.5 years). Median obstructive apnoea hypopnoea index (AHI) at baseline was 0.43/h (range 0-32.9); 35% had an obstructive AHI above 1.0/h. Follow-up polysomnography within 2 years after the start of GH was available in 94 children who did not receive OSA treatment. After GH initiation, there was no change in central AHI. The median obstructive AHI did not increase significantly (P = 0.13), but 12 children (13%, CI95% 7-21%) developed moderate/severe OSA, with clinical management implications. CONCLUSIONS: Our findings of a worsening of OSA severity in 13% of children with PWS support current advice to perform polysomnography after GH initiation. Early identification of worsening OSA may prevent severe sequelae in a subgroup of children.

Proopiomelanocortin deficiency diagnosed in infancy in two boys and a review of the known cases.

Proopiomelanocortin (POMC) deficiency is a rare monogenic disorder characterised by adrenocorticotropic hormone (ACTH) deficiency, red hair and hyperphagic obesity. Two unrelated cases presented with hypoglycaemia due to isolated ACTH deficiency in the neonatal period. POMC deficiency was suspected at age 2 years (c.133-2A>C) and at age 9 months (c.64del) due to infantile hyperphagic obesity. Neither patient had a convincing red hair phenotype at the time of diagnostic suspicion, illustrating the importance of suspecting POMC deficiency in isolated ACTH deficiency. Both patients have normal psychomotor development, whereas the only other reported case of c.64del had significant delay. This suggests, if ACTH deficiency is treated early in the neonatal period, that psychomotor retardation is not a part of the phenotype. We review 24 reported cases of POMC deficiency published to date. Although there is no current specific treatment for obesity in POMC deficiency, we anticipate that setmelanotide may be a useful future treatment option.

Cystic fibrosis-related diabetes and lung disease: an update.

The development of cystic fibrosis-related diabetes (CFRD) often leads to poorer outcomes in patients with cystic fibrosis including increases in pulmonary exacerbations, poorer lung function and early mortality. This review highlights the many factors contributing to the clinical decline seen in patients diagnosed with CFRD, highlighting the important role of nutrition, the direct effect of hyperglycaemia on the lungs, the immunomodulatory effects of high glucose levels and the potential role of genetic modifiers in CFRD.

Pericardial Effusion Associated with Diazoxide Treatment for Congenital Hyperinsulinism.

BACKGROUND: Diazoxide is widely used to manage congenital hyperinsulinism and is generally well tolerated. Pericardial effusion is not a recognized side effect of diazoxide, apart from 2 single case reports. CASE DESCRIPTION: Three patients with congenital hyperinsulinism developed pericardial effusion at the ages of 7 weeks, 8 months, and 17 years. The duration of diazoxide treatment (10-15 mg/kg/day) was 6.5 weeks, 5 months, and 17 years, respectively. There was no evidence of fluid overload or significant other cardiac anomaly. The 7-week-old patient presented with signs of cardiac failure, was treated with diuretics, and the effusion resolved after cessation of diazoxide. The 8-month-old patient required emergency subxiphoid drainage of the effusion due to hemodynamic compromise. The pericardial fluid had high numbers of polymorphonuclear cells, but did not grow any organisms, and histology showed non-specific chronic reactive changes; the effusion did not recur after cessation of diazoxide. The 17-year-old patient presented with atrial fibrillation, was treated with beta blockade and colchicine, and continues on diazoxide with monitoring of the effusion by ultrasound. CONCLUSION: Patients on long-term diazoxide treatment may be at risk of pericardial effusion, the timing and significance of which is unpredictable. The duration of diazoxide treatment before presentation of pericardial effusion varied in our patients from weeks to years. We advise serial echocardiography 1-2 months after commencement of diazoxide and annually thereafter.

Glucose abnormalities detected by continuous glucose monitoring are common in young children with Cystic Fibrosis.

It is not yet known whether continuous glucose monitoring (CGM) abnormalities persist in young children with CF. We evaluated longitudinal CGM results for children with CF < 10 years of age. We performed 3-day CGM at baseline, 12 months, and 24 months on 11 CF children (1 female) initially aged mean (SD) 3.8 (2.5) years. CGM analysis included (i) mean sensor glucose (SG), (ii) standard deviation (SD) for SG, (iii) peak SG and (iv)% time spent above a threshold of 7.8 mmol/L. Only three (3/11, 27%) had normal CGM at all time-points. Nearly three quarters of the participants (8/11, 73%) spent more than 4.5 percent time > 7.8 mmol/L at one time-point, five of whom had an elevated percent time on a subsequent test. Young children with CF have glucose abnormalities detected by CGM that fluctuate over time.

Peak OGTT glucose is associated with lower lung function in young children with cystic fibrosis.

BACKGROUND: Screening for Cystic Fibrosis-related diabetes is recommended in patients with CF <10 years old when there are concerns about growth and lung function. The Oral Glucose Tolerance Test (OGTT) is recommended but has not been validated in this cohort. We sought to determine whether the 2-h OGTT, the gold standard diagnostic test for CFRD, detects clinical decline in children with CF <10 years old. METHODS: We analysed blood glucose(BG) levels collected every 30 min during OGTT in 27 children with CF < 10 years old, comparing the 2-hour BG (BG120min), peak BG (BGmax) and Area Under the Curve(AUC) for glucose and the association with lung function and nutritional status. We also compared the OGTT results with results from Continuous Glucose Monitoring (CGM) performed in 11 participants. RESULTS: The BGmax was higher than the BG120min in 25/27 (93%) participants. There was a significant inverse correlation between BGmax and weight z-score (rs = -0.56, p = .002) and between BGmax and FEV1 (rs = -0.54, p = .014) that was not present for BG120min. A significant inverse correlation was also identified between fasting insulin level and elevated glucose on CGM, defined as AUC >7.8 mmol/L (rs = - 0.69, p = .027) or as % time > 7.8 (rs = - 0.76, p = .011). CONCLUSIONS: Children with CF < 10 years of age with higher BGmax on OGTT have lower lung function and weight z- scores that may not be identified using the 2 h OGTT BG120min. CGM also identifies glucose excursions in young children with CF.

Autoantibodies Directed Toward a Novel IA-2 Variant Protein Enhance Prediction of Type 1 Diabetes.

We identified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys27, Gly608, and Pro671) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (T1D) probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var-specific AAb in relatives was associated with accelerated progression to T1D in those positive for AAb to GAD65 and/or insulin but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1*04-DQB1*03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alters the three amino acids induces changes in the three-dimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb to IA-2var would identify high-risk subjects who would benefit from participation in prevention trials who have one islet antibody by traditional testing and otherwise would be misclassified as "low risk" relatives.

Early glucose abnormalities are associated with pulmonary inflammation in young children with cystic fibrosis.

BACKGROUND: Children with CF are insulin deficient from infancy but very little is known about the impact of glucose abnormalities in early life. We aimed to identify and describe interstitial glucose levels in CF children <6 years and to evaluate the association with pulmonary infection and inflammation. METHODS: We assessed 18 children (5 females) with median age of 3.2 years (range 0·9-5.5) with Continuous Glucose Monitoring for 3 days. Bronchoalveolar lavage (BAL) fluid was cultured for known pathogenic microbial agents and assessed for total white blood cells, percentage of neutrophils and IL-8 level. RESULTS: Peak sensor glucose (SG) was >11.1 mmol/L in 39% of participants. The percentage neutrophil count on BAL was positively correlated with elevated SG (peak SG rs = 0.48, p = .044) and with glucose variability (SG standard deviation r = 0.62, ß = 38.5, p = .006). BAL IL-8 level was significantly correlated with all measures of CGM hyperglycemia including % time > 7.8 mmol/L (p = .008) and standard deviation (p < .001). Participants with a history of Pseudomonas aeruginosa had a higher % time > 7.8 mmol/L glucose (16% versus 3%, p = .015). CONCLUSION: Children with CF frequently demonstrate elevated SG levels before age 6 years, which are associated with increased pulmonary inflammation and Pseudomonas aeruginosa infection. Transient SG elevations into the diabetic range (≥11.1 mmol/L) were identified in children from 1 year of age.

Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome.

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome.  A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown.  Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated.  Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development.

Variants in the NR5A1 gene encoding SF1 have been described in a diverse spectrum of disorders of sex development (DSD). Recently, we reported the use of a targeted gene panel for DSD where we identified 15 individuals with a variant in NR5A1, nine of which are novel. Here, we examine the functional effect of these changes in relation to the patient phenotype. All novel variants tested had reduced trans-activational activity, while several had altered protein level, localization, or conformation. In addition, we found evidence of new roles for SF1 protein domains including a region within the ligand binding domain that appears to contribute to SF1 regulation of Müllerian development. There was little correlation between the severity of the phenotype and the nature of the NR5A1 variant. We report two familial cases of NR5A1 deficiency with evidence of variable expressivity; we also report on individuals with oligogenic inheritance. Finally, we found that the nature of the NR5A1 variant does not inform patient outcomes (including pubertal androgenization and malignancy risk). This study adds nine novel pathogenic NR5A1 variants to the pool of diagnostic variants. It highlights a greater need for understanding the complexity of SF1 function and the additional factors that contribute.

Low dose growth hormone treatment in infants and toddlers with Prader-Willi syndrome is comparable to higher dosage regimens.

OBJECTIVE: Evaluate benefit and risk of low dose growth hormone treatment (GHT, 4.5mg/m2/week) in very young children with Prader-Willi Syndrome (PWS). DESIGN: Prospective longitudinal clinical intervention. METHODS: We evaluated 31 infants (aged 2-12months) and 42 toddlers (13-24months) from the PWS-OZGROW database for height, weight and BMI using the World Health Organization standard deviation scores (SDSWHO) and PWS specific BMI (SDSPWS), bone age, insulin-like growth factor 1 (IGF-I) levels and adverse events over 3years of GHT. RESULTS: At commencement of GHT infants had a lower BMI SDSWHO (-0.88 vs 0.40) than toddlers, while toddlers had a lower height SDSWHO (-1.44 vs -2.09) (both P<0.05). All increased height SDSWHO (2year delta height infants +1.26 SDS, toddlers+1.21 SDS), but infants normalised height sooner, achieving a height SDS of -0.56 within 1year, while toddlers achieved a height SDS of -0.88 in two years. BMI SDSWHO increased, while BMI SDSPWS decreased (both P<0.0001) and remained negative. The GHT response did not differ with gestation (preterm 23%) or genetic subtype (deletion vs maternal uniparental disomy). Bone age advancement paralleled chronological age. All children had low serum IGF-I at baseline which increased, but remained within the age-based reference range during GHT (for 81% in first year). Four children had spinal curvature at baseline; two improved, two progressed to a brace and two developed an abnormal curve over the observation period. Mild to severe central and/or obstructive sleep apnoea were observed in 40% of children prior to GHT initiation; 11% commenced GHT on positive airway pressure (PAP), oxygen or both. Eight children ceased GHT due to onset or worsening of sleep apnoea: 2 infants in the first few months and 6 children after 6-24months. Seven resumed GHT usually after adjusting PAP but five had adenotonsillectomy. One child ceased GHT temporarily due to respiratory illness. No other adverse events were reported. Two children substantially improved their breathing shortly after GHT initiation. CONCLUSION: Initiation of GHT in infants with 4.5mg/m2/week was beneficial and comparable in terms of auxological response to a dose of 7mg/m2/week. Regular monitoring pre and post GH initiation assisted in early detection of adverse events. IGF-I levels increased with the lower dose but not excessively, which may lower potential long-term risks.

Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort.

BACKGROUND: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. RESULTS: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46,XY DSD and 48 with 46,XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46,XY DSD. In patients with 46,XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. CONCLUSIONS: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes.

Diagnosing cystic fibrosis-related diabetes: current methods and challenges.

INTRODUCTION: Cystic fibrosis-related diabetes (CFRD) is the end-point of a spectrum of glucose abnormalities in cystic fibrosis that begins with early insulin deficiency and ultimately results in accelerated nutritional decline and loss of lung function. Current diagnostic and management regimens are unable to entirely reverse this clinical decline. AREAS COVERED: This review summarises the current understanding of the pathophysiology of CFRD, the issues associated with using oral glucose tolerance tests in CF and the challenges faced in making the diagnosis of CFRD. Medline database searches were conducted using search terms "Cystic Fibrosis Related Diabetes", "Cystic Fibrosis" AND "glucose", "Cystic Fibrosis" AND "insulin", "Cystic Fibrosis" AND "Diabetes". Additionally, reference lists were studied. Expert commentary: Increasing evidence points to early glucose abnormalities being clinically relevant in cystic fibrosis and as such novel diagnostic methods such as continuous glucose monitoring or 30 minute sampled oral glucose tolerance test (OGTT) may play a key role in the future in the screening and diagnosis of early glucose abnormalities in CF.

Transient Neonatal Diabetes Mellitus followed by recurrent asymptomatic hypoglycaemia: a case report.

BACKGROUND: Transient Neonatal Diabetes Mellitus is the commonest cause of diabetes presenting in the first week of life. Majority of infants recover by 3 months of age but are predisposed to developing type 2 diabetes later on in life. This condition is usually due to genetic aberrations at the 6q24 gene locus, and can be sporadic or inherited. This disorder has three phases: neonatal diabetes, apparent remission, relapse of diabetes. CASE PRESENTATION: Our case, a neonate presented with low birth weight and growth retardation along with the metabolic profile consistent with transient diabetes mellitus at birth. We report a novel clinical observation of recurrent asymptomatic hypoglycaemia detected on pre-feed blood glucose level monitoring in our case with transient neonatal diabetes mellitus at 6 weeks of age, 4 weeks after the remission of diabetes mellitus. CONCLUSION: This case demonstrates that neonates in remission following transient diabetes mellitus can present with recurrent asymptomatic hypoglycaemia without any other obvious congenital malformations seen. This asymptomatic hypoglycaemia may persist for weeks and may be missed if pre-feed blood glucose level monitoring is not done in these infants. Also, these infants may require an aggressive enteral feeding regimen with high glucose delivery rate to maintain normoglycemia.

Advances in the detection and management of cystic fibrosis related diabetes.

PURPOSE OF REVIEW: This review will outline the screening, diagnosis and management of cystic fibrosis related diabetes (CFRD). It will also discuss advances in the detection of early glucose abnormalities, their clinical significance and the emerging role for early insulin therapy. RECENT FINDINGS: Before the onset of diabetes (as currently defined), patients with cystic fibrosis (CF) display glucose abnormalities, detectable either by 30-minutely sampled oral glucose tolerance testing (OGTT), or by continuous ambulatory interstitial glucose monitoring (CGM). These early glucose abnormalities are associated with the presence of glucose in airway fluid, potentially promoting the growth of airway pathogens and contributing to the progression of respiratory disease. Progressive insulin deficiency underlies these glucose abnormalities, and insulin deficiency also causes catabolism. Pilot studies of once-daily insulin therapy in the early stages of insulin deficiency show improved lung function and weight gain (important predictors of survival in CF). SUMMARY: Early stages of insulin deficiency may be contributing to catabolism and deteriorating lung function in CF. It is plausible that early insulin therapy may prevent this deterioration, a view supported by pilot studies. Randomized controlled trials of early insulin therapy will now determine whether insulin therapy should be commenced earlier than current practice in CF.

A mobile phone and web-based intervention for improving mental well-being in young people with type 1 diabetes: design of a randomized controlled trial.

BACKGROUND: Young people with type 1 diabetes experience elevated levels of emotional distress that impact negatively on their diabetes self-care, quality of life, and disease-related morbidity and mortality. While the need is great and clinically significant, a range of structural (eg, service availability), psychological (eg, perceived stigma), and practical (eg, time and lifestyle) barriers mean that a majority of young people do not access the support they need to manage the emotional and behavioral challenges of type 1 diabetes. OBJECTIVE: The aim of this study is to examine the effectiveness of a fully-automated cognitive behavior therapy-based mobile phone and Web-based psychotherapeutic intervention (myCompass) for reducing mental health symptoms and diabetes-related distress, and improving positive well-being in this vulnerable patient group. METHODS: A two-arm randomized controlled trial will be conducted. Young people with type 1 diabetes and at least mild psychological distress will be recruited via outpatient diabetes centers at three tertiary hospitals in Sydney, Australia, and referred for screening to a study-specific website. Data will be collected entirely online. Participants randomized to the intervention group will use the myCompass intervention for 7 weeks, while at the same time a control group will use an active placebo program matched to the intervention on duration, mode of delivery, and interactivity. RESULTS: The primary outcome will be mental well-being (ie, depression, anxiety, diabetes-related distress, and positive well-being), for which data will be collected at baseline, post-intervention, and after 3 months follow-up. Secondary outcomes will be functional (work and social functioning and diabetes self-care), biochemical measures (HbA1c), and mental health self-efficacy. We aim to recruit 280 people into the study that will be conducted entirely online. Group differences will be analyzed on an intention-to-treat basis using mixed models repeated measures. CONCLUSIONS: We hypothesize that scores on the outcome measures will improve significantly for young people who use the mobile phone and Web-based intervention compared to the control group. myCompass is a public health intervention that is broadly available and free to use. If effective, the program has the capacity to provide convenient and accessible evidenced-based care to the large group of young people with type 1 diabetes who do not currently access the psychosocial support they need. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12614000974606; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366607 (Archived by WebCite at http://www.webcitation.org/6YGdeT0Dk).

Markers of pancreatic function in the breath.

Exhaled breath analysis is able to identify biomarkers of respiratory and systemic diseases. It was hypothesized that markers of pancreatic function would be identified in the breath of those with diabetes mellitus and cystic fibrosis. Children aged 6-18 years old with diabetes mellitus (DM), cystic fibrosis (CF), cystic fibrosis related diabetes (CFRD) and healthy controls (C) contributed exhaled breath condensate (EBC), with concurrent blood glucose measurements taken from a subset. EBC C-peptide, glucose, sodium concentrations and conductivity were subsequently measured.A total of 104 children were recruited (DM = 56, CF = 26, CFRD = 5, C = 17). C-peptide was detected in EBC: CF 19.6 ± 11.7 pmol L(-1); DM: 9.66 ± 8.27 pmol L(-1); CFRD: 11.9 ± 9.23 pmol L(-1) which was significantly higher than in the control group (0.987 ± 2.26 pmol L(-1)) (p < 0.0001). No statistically significant difference was seen between the three groups for glucose, conductivity or sodium concentration.Glucose was not reliably found in EBC, but C-peptide was found to be higher in CF EBC. This may represent inflammation and a change in airway integrity, rather than increased secretion of this peptide.

Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination.

CONTEXT: Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. OBJECTIVE: The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. DESIGN: We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy. METHODS: Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed. RESULTS: The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs. CONCLUSIONS: The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells.