This randomized, crossover trial compared an artificial-pancreas system with a sensor-augmented pump for nocturnal glucose control in young persons with type 1 diabetes at a diabetes camp. The ...artificial pancreas resulted in less hypoglycemia and tighter glucose control.
Intensive insulin therapy is considered to be the standard treatment for tight blood glucose control in patients with type 1 diabetes, since it prevents long-term complications. Several studies have promoted the use of insulin pumps, glucose sensors, or a combination of the two devices (sensor-augmented pump)
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to improve glucose control. However, the risk of hypoglycemia is still present with the use of all currently available therapies.
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Maintenance of nocturnal euglycemia is extremely important and is challenging, since most cases of severe hypoglycemia occur at night.
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Such episodes account for 75% of total hypoglycemic seizures in children
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To investigate the effect of acute hyperglycemia on brain function in adolescents with type 1 diabetes (T1D).
Twenty participants with T1D (aged 14.64 ± 1.78 years) and 20 age-matched healthy control ...subjects (aged 14.40 ± 2.82 years) performed two functional MRI sessions. Participants with T1D performed the first scanning session under euglycemic and the second under hyperglycemic clamp (20 mmol/L 360 mg/dL).
Lower spatial working memory (sWM) capacity during acute hyperglycemia and significant differences in activation of regions of interest during different stages of the sWM task (
= 0.014) were observed.
Acute hyperglycemia negatively affected sWM capacity in adolescents with T1D, which is relevant for daily functioning and academic performance.
The occurrence of prolactinomas in sex hormone treated patients with central hypogonadism is extremely rare.
We present a Caucasian male patient who was diagnosed with Kallmann syndrome (KS) at age ...15 years. Testosterone treatment was started. At age 26 the patient presented with mild headache. MRI revealed two separate pituitary adenomas along with the absence of the olfactory bulbs. Given the presence of marked hyperprolactinemia (17x upper limit of the reference range) the diagnosis prolactinoma was made and treatment with cabergoline was started which resulted in a complete biochemical response and in marked reduction of both adenomas in size. Hypogonadism persisted and testosterone replacement therapy was continued. Genetic testing of genes associated with pituitary tumors, Kallmann syndrome and idiopathic hypogonadotropic hypogonadism was negative. Mild concomitant hypercalcemia in accordance with familial hypocalciuric hypercalcemia (FHH) prompted mutation analysis of the calcium receptor (
gene which yielded a pathogenic inactivating variant.
The presence of two separate prolactinomas in a patient with KS has not yet been reported in the literature. The effect of sex hormone treatment of KS patients on the possible development of prolactinoma is unknown at present. The occurance of multiple prolactinomas in our patient suggests increased susceptibility. Although CaSR is expressed in GnRH neurons in mouse brain and CaSR deficient mice have a reduced hypothalamic GnRH neuronal population, the relevance of the
gene variant in our patient for the KS phenotype is unclear at present.
Lipopolysaccharide-responsive, beige-like anchor protein (LRBA) deficiency is characterized by primary immunodeficiency and autoimmunity. Cancer may present another feature of LRBA deficiency. We ...describe a case history of a young adult with LRBA deficiency and two independent malignancies.
Family-trio whole exome sequencing with unbiased phenotype ontology approach was used for identification of causative mutations of a primary immune deficiency disorder. Additionally, we sought to identify germline mutations in genes known to be associated with two independent malignancies using a targeted approach. A cytotoxic T-lymphocyte associated protein 4 (CTLA4) expression in T lymphocytes was determined by flow cytometry.
In the patient with clinical signs of LRBA deficiency multifocal gastric carcinoma and malignant melanoma were diagnosed and surgically treated at 19 and 27 years of age, respectively. Despite refusal of any adjuvant chemotherapy or radiotherapy, the patient demonstrated disease free survival for at least 13 years after the first cancer diagnosis. A homozygous frameshift deletion in LRBA gene (p.Glu946Ter) and two common variants in TYR gene were identified. Reduced CTLA4 expression in a subset of regulatory T lymphocytes was identified in the patient and his unaffected mother carrying a heterozygous LRBA mutation as compared to control in a dose-dependent manner.
This is the first description of gastric cancer and malignant melanoma in a young adult with LRBA deficiency. The role of LRBA gene knockout in cancer development and its prognosis remains to be elucidated.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aims
To evaluate the safety, efficacy and need for remote monitoring of the MD‐Logic closed‐loop system during short‐term overnight use at home.
Methods
Seventy‐five patients (38 male; aged 10‐54 ...years; average A1c, 7.8% ± 0.7%, 61.8 ± 7.2 mmol/mol) were enrolled from 3 clinical sites. Patients were randomly assigned to participate in 2 overnight crossover periods, each including 4 consecutive nights, 1 under closed‐loop control and 1 under sensor‐augmented pump (SAP) therapy in the patient's home. Both study arms were supervised using a remote‐monitoring system in a blinded manner. Primary endpoints were time spent with glucose levels below 70 mg/dL and percentage of nights in which mean overnight glucose levels were within 90 to 140 mg/dL.
Results
The median interquartile range percentage of time spent in hypoglycaemia was significantly lower on nights when MD‐Logic was used, compared to SAP therapy (2.07 0, 4.78 and 2.6 0, 10.34, respectively; P = .004) and the percentage of individual nights with a mean overnight glucose level in target was significantly greater (75 42, 75 and 50 25,75, respectively; P = .008). The time spent in target range was increased by a median of 28% (P = .001), with the same amount of insulin (10.69 7.28, 13.94 and 10.416.9, 14.07, respectively; P = .087). The remote monitoring triggered calls for hypoglycaemia at twice the rate during SAP therapy compared to closed‐loop control (62 and 29, respectively; P = .002).
Conclusions
The MD‐Logic system demonstrated a safe and efficient profile during overnight use by children, adolescents and adults with type 1 diabetes and, therefore, provides an effective means of mitigating the risk of nocturnal hypoglycaemia.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
To analyze the mutational spectrum, clinical characteristics, genotype-phenotype correlations, testicular adrenal rests tumor prevalence, and role of neonatal screening in congenital adrenal ...hyperplasia (CAH) patients from Slovakia and Slovenia.
Data were obtained from 104 patients with CAH registered in Slovak and Slovenian databases. Low-resolution genotyping was performed to detect the most common point mutations. To detect deletions, conversions, point mutations, or other sequence changes in the
gene, high-resolution genotyping was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C).
64% of the individuals had the salt-wasting form (SW-CAH), 15% the simple virilizing form (SV-CAH), and 21% the non-classic (NC-CAH).
gene deletion/conversion and c.293-13A/C>G pathogenic variant accounted together for 55.5% of the affected alleles. In SV-CAH p.Ile172Asn was the most common pathogenic variant (28.13%), while in NC-CAH p.Val282Leu (33.33%),
gene deletion/conversion (21.43%), c.293-13A/C>G (14.29%), Pro30Leu (11.90%). The frequency of alleles with multiple pathogenic variants was higher in Slovenian patients (15.83% of all alleles). Severe genotypes (0 and A) correlated well with the expected phenotype (SW in 94.74% and 97.3%), while less severe genotypes (B and C) correlated weaklier (SV in 50% and NC in 70.8%). The median age of SW-CAH patients at the time of diagnosis was 6 days in Slovakia vs. 28.5 days in Slovenia (p=0.01). Most of the Slovak patients in the cohort were detected by NBS. (24 out of 29). TARTs were identified in 7 out of 24 male patients, of whom all (100%) had SW-CAH and all had poor hormonal control. The median age at the diagnosis of TARTs was 13 years.
The study confirmed the importance of neonatal screening, especially in the speed of diagnosis of severe forms of CAH. The prediction of the 21-OH deficiency phenotype was reasonably good in the case of severe pathogenic variants, but less reliable in the case of milder pathogenic variants, which is consistent compared to data from other populations. Screening for TARTs should be realized in all male patients with CAH, since there is possible remission when identified early.
Abstract
Background
Congenital hypogonadotropic hypogonadism (CHH) is a clinically and genetically heterogeneous disease characterized by absent or incomplete puberty and infertility. Clinical ...characteristics are secondary to insufficient gonadotropin secretion, caused by deficient gonadotropin-releasing hormone (GnRH) production, secretion, or action. Loss-of-function variants of the gonadotropin-releasing hormone receptor (GNRHR) are associated with CHH without anosmia. CHH was previously considered a permanent condition, but in the past two decades, cases of spontaneous recovery of CHH have been reported. The reversal of hypogonadism in CHH is currently unpredictable, and can happen unnoticed.
Case presentation
The male proband was diagnosed with CHH due to compound heterozygosity for two previously reported pathogenic missense variants in the
GNRHR
gene, NM_000406.2:c.416G > A (NP_000397.1:p.Arg139His) and c.785G > A (p.Arg262Gln) at 16 years of age. In addition to arrested partial puberty, he had a low testosterone level, gonadotropins in the range of early puberty, and a normal inhibin B level. A therapy with increasing doses of intramuscular testosterone undecanoate was received for 2.5 years, while there was no change in testicular volume. At the age of 19 years, testosterone supplementation was interrupted. During the next two years, he had spontaneous pubertal development to achieve a testicular volume of 20 mL, with normal adult levels of gonadotropins and testosterone.
Conclusions
Genetic diagnostics can help discriminate congenital hypogonadotropic hypogonadism, deserving therapeutic intervention, from the self-limited constitutional delay of growth and puberty (CDGP). Patients with
GNRHR
associated hypogonadism can experience spontaneous recovery of the hypothalamic-pituitary–gonadal axis. Spontaneous testis enlargement in patients with central hypogonadism not taking gonadotropins or pulsatile GnRH therapy can indicate recovery of hypogonadism.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Klinefelter syndrome is the most commonly reported sex chromosome abnormality. It is heavily underdiagnosed due to the substantial variability of clinical presentations but is generally characterized ...by small, firm testes, hypergonadotropic hypogonadism, and the absence of spermatogenesis. Most patients with Klinefelter syndrome have a 47,XXY genotype. If they present with mosaicism, two different cell lines are usually identified, an aneuploid 47,XXY cell line and a normal male 46,XY cell line. There are very few cases of 47,XXY mosaicism with the additional female cell line 46,XX described in the literature. We report a case of an adolescent with the male phenotype and a rare variant mosaic 47,XXY/46,XX karyotype who presented with painless bilateral gynaecomastia. 47,XXY and 46,XX mosaic cell lines were identified with GTG-banding and further characterized using fluorescent in situ hybridization. We summarized the available clinical presentations of reported male patients with 47,XXY/46,XX mosaicism. To improve the clinical management and quality of life in individuals with rare and cryptic genomic imbalances, the genetic diagnosis would need to be extended to atypical cases.
Pathogenic variants within the gene encoding the pituitary-specific transcription factor, POU class 1 homeobox 1 (
), are associated with combined pituitary hormone deficiency (CPHD), including ...growth hormone, prolactin, and thyrotropin stimulating hormone deficiencies. The aim of the study was to identify genetic aetiology in 10 subjects with CPHD from four consanguineous Sudanese families. Medical history, as well as hormonal and radiological information, was obtained from participants' medical records. Targeted genetic analysis of the
gene was performed in two pedigrees with a typical combination of pituitary deficiencies, using Sanger sequencing, and whole-exome sequencing was performed in the other two pedigrees, where hypocortisolism and additional neurologic phenotypes were also initially diagnosed. In
gene (NM_001122757.2) a novel homozygous splice-site deletion-namely, c.744-5_749del-was identified in all 10 tested affected family members as a cause of CPHD. Apart from typical pituitary hormonal deficiencies, most patients had delayed but spontaneous puberty; however, one female had precocious puberty. Severe post-meningitis neurologic impairment was observed in three patients, of whom two siblings had Dyke-Davidoff-Masson syndrome, and an additional distantly related patient suffered from cerebral infarction. Our report adds to the previously reported
gene variants causing CPHD and emphasises the importance of genetic testing in countries with high rates of consanguineous marriage such as Sudan. Genetic diagnostics elucidated that the aetiologies of hypopituitarism and brain abnormalities, identified in a subset of affected members, were separate. Additionally, as central hypocortisolism is not characteristic of POU1F1 deficiency, hydrocortisone replacement therapy could be discontinued. Elucidation of a genetic cause, therefore, contributed to the more rational clinical management of hypopituitarism in affected family members.
Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously ...described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the
gene. The patients were followed until the ages of 21.6, 20.2, and 4.2 years. PAI was diagnosed in the eldest two brothers after an Addisonian crisis and the third was diagnosed at the age of 4.5 months in the asymptomatic stage due to the genetic screening of family members. Whole exome sequencing with a targeted interpretation of variants in genes related to PAI was performed in all the patients. The urinary steroid metabolome was determined by gas chromatography-mass spectrometry in the asymptomatic patient. The three patients, who were homozygous for c.1575dup in the
gene, developed isolated glucocorticoid deficiency. The urinary steroid metabolome showed normal excretion of cortisol metabolites. The adolescent patients had slow pubertal progression with low-normal testicular volume, while testicular endocrine function was normal. Bone mineral density was in the range for osteopenia in both grown-up siblings. Echocardiography revealed no structural or functional heart abnormalities. This article is among the first with a comprehensive and chronologically-detailed description of patients with NNT deficiency.
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