Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental ...biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes.
Aim
Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia, and alacrimia. This disorder is caused by mutations in the
AAAS
gene. The aim of ...this study is to discuss the clinical, laboratory and molecular genetic analysis results of 12 patients with TAS.
Method
We evaluated 12 patients from 8 families. Clinical and laboratory data were retrospectively collected from the medical records of the patients in the database for the period 2015–2020. All exons and exon-intron junctions of the
AAAS
gene were evaluated by next-generation sequencing method. Detected variants were classified according to American Collage of Medical Genetics criteria.
Results
Alacrimia was found in all patients (100%); achalasia was found in 10 patients (83.3%) and adrenal insufficiency was found in 10 patients (83.3%). In addition, hyperreflexia(6/12), learning disability(5/12), hypernasal speech(5/12), muscle weakness(8/12), delayed walking(7/12), delayed speech(6/12), excessive sweating(7/12), optic atrophy(1/12), epilepsy(1/12), palmoplantar hyperkeratosis(5/12), multiple dental caries(9/12), atrophy of the thenar/hypothenar muscles(4/12) and short stature(4/12) were detected. The DHEA-S levels were measured in 10 patients and were found to be low in 8 of them. In all patients, the sodium and potassium levels were found to be normal. AAAS gene sequencing revealed four previously reported c.1066_1067del (p.Leu356fs*8), c.1432 C > T (p.Arg478*), c.688 C > T (p.Arg230*), and c.1368_1372del (p.Gln456fs*38) variants and two novel homozygous c.1250-1 G > A and c.398_399 + 2del variants in the
AAAS
gene.
Conclusion
We detected two novel variants in the
AAAS
gene. While the classic triad is present in 66.7% of the cases, neurological dysfunction, skin and dental pathologies also occur quite frequently. The earliest and most common finding of TAS is alacrimia. Therefore, adrenal insufficiency should be investigated in all patients with alacrimia and if necessary, genetic analysis should be performed for TAS. In addition, TAS should be followed up with a multidisciplinary approach since it involves many systems.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Subclinical hypothyroidism (SH) may influence both ventricular functions. The aim of this study was to evaluation the findings of Tissue Doppler Imaging (TDI) and other echocardiography modalities in ...children with SH. We compared left ventricular mass index (LVMI) and TDI parameters of patients with SH and children with euthyroidism. Subclinical hypothyroidism was diagnosed when thyroid stimulating hormone level was higher than the reference value of the laboratory (> 4.2 mIU/L) and free thyroxine level was in normal range. The study included a group of 35 patients with SH and a control group of 38 children with euthyroidism (mean age was 7.6 ± 3.5 years and 9.0 ± 2.4 years, respectively). LVMI was significantly higher in the patient group (p = 0.005). TDI parameters including mitral septal ejection time was lower (p = 0.003) and mitral septal myocardial performance index was higher (p = 0.009) in the patient group. Right ventricular TDI revealed that tricuspid lateral E/Ea and tricuspid septal E/Ea were higher (p = 0.015 and p = 0.024, respectively) and tricuspid septal Ea/Aa and ejection time were lower (p = 0.018 and p = 0.017, respectively) in the patient group. SH may lead to increase LVMI. Left ventricular systolic and diastolic TDI parameters (lower mitral septal ejection time, higher mitral septal myocardial performance index) as well as right ventricular systolic (lower tricuspid septal ejection time) and diastolic (higher tricuspid septal and lateral E/Ea, lower tricuspid septal Ea/Ea) functions may be also impaired in children with subclinical hypothyroidism. TDI is a useful method used for the assessment of the effect of SH on cardiac functions.
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The prevalence of celiac disease (CD) varies between 1% and 10% in patients with type 1 diabetes mellitus (T1DM). This study aimed to determine the frequency of spontaneous recovery of celiac ...serology and the biopsy-proven CD (BPCD) frequency in patients with T1DM.
The data of 668 patients with available celiac serology tests from a total of 779 patients who were followed for the last 10 years with the diagnosis of T1DM were retrospectively evaluated.
Positive serology was detected in 103 out of 668 (15.4%) patients. There was spontaneous normalization in 24 (23.3%), fluctuation in 11 (10.7%) and permanently positive serology in 68 (66%). In 46 out of 53 (86.8%) patients with positive serology and biopsy, CD diagnosis was confirmed by biopsy (BPCD). The frequency of BPCD was 6.9%, and the serology in 76.1% was positive at the time of diagnosis of T1DM. The weight, height and body mass index-standard deviation score at diagnosis were lower in patients with BPCD compared to the group without CD. An anti-tissue transglutaminase-IgA (anti-TTG-IgA) level of 11.8 times the upper limit of normal was the most sensitive (93%) and specific (90%) cut-off for BPCD (area under the curve: 0.95; 95% confidence interval: 0.912-1; p<0.001).
In our cohort, the frequency of positive serology for CD was 15.4%, while the rate of BPCD was 6.9%. The majority (97.8%) of cases were diagnosed within the first five years of T1DM. In 23.3% of cases, positive anti-TTG-IgA spontaneously resolved without a gluten-free diet (GFD). Therefore, serological follow-up instead of immediate duodenal biopsy or GFD therapy, particularly for patients with asymptomatic and mild anti-TTG IgA level, is warranted.
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Aim
17α-hydroxylase enzyme deficiency is a rare form of congenital adrenal hyperplasia (CAH) and is caused by mutations in the
CYP17A1
gene. The main clinical findings are delayed puberty and primary ...amenorrhea in girls, and disorders of sex development in boys. It can also cause hypertension and hypokalemia in both genders. In this study, we aimed to present the clinical, laboratory and genetic results of 13 patients from eight different families who were diagnosed with complete 17α-hydroxylase enzyme deficiency.
Methods
The age, symptoms, anthropometric measurements, blood pressure, Tanner stages, and hormonal and chromosome analysis results at the time of admission were recorded from the medical records of the patients. Whole gene next-generation sequencing of
CYP17A1
gene was performed to detect mutations. Multiplex ligation dependent probe amplification (MLPA) method were used to detect deletions in the seven patients who had no point mutation were detected in the CYP17A1 gene.
Results
The average age of the patients at the time of admission was 14.8 (range: 12.9–16.6) years. Also at this time, all patients were in adolescence and were raised as females. The karyotypes of eight patients were 46,XY, and of five patients were 46,XX. Ten patients presented with delayed puberty and primary amenorrhea, one patient with delayed puberty and hypertension, and two patients with hypertension and/or hypokalemia. Hypertension and hypokalemia were detected in nine and seven patients, respectively.
Conclusions
P450c17 enzyme deficiency should be considered in patients presenting with delayed puberty or primary amenorrhea in the adolescence period and diagnosed with hypergonadotropic hypogonadism, if hypertension and hypokalemia accompany. Early diagnosis prevents the occurrence of important health problems such as hypertension, psychological problems, and gender identity disorders, which affect the majority of these patients.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
What is already known on this topic? Setting a lower thyroid stimulating hormone (TSH) referral cut-off value in neonatal screening programs is increasingly common. However, this had resulted in ...referral of neonates with lower TSH concentrations and an increase in transient mild TSH elevation. Identifying infants who are likely to have transient TSH elevation and therefore withdrawing replacement therapy earlier would be of clinical benefit. What this study adds? L-thyroxine replacement dose requirement at the sixth month of therapy may be a good marker for predicting those with transient elevated TSH in patients with an eutopic thyroid gland. Objective: The tendency to reduce thyroid stimulating hormone (TSH) referral cut-off values in congenital hypothyroidism (CH) neonatal screening programs has resulted in an increase in the incidence of CH, but also the referral of infants with mild transient elevation of TSH. Therefore, there is a need to develop markers for differentiation of transient elevated TSH and permanent CH as early as safely possible to avoid unnecessary treatment. The aim was to evaluate sixth-month L-thyroxine (LT4) dose as a predictive marker for differentiation of transient elevated TSH and permanent CH. Methods: Data of patients who had been followed after referral from the neonatal screening programme between the year 2010 and 2019 in a tertiary pediatric endocrine centre were examined retrospectively. Results: There were 226 cases referred, of whom 186 (82.3%) had eutopic thyroid gland, and 40 (17.7%) had dysgenetic gland. In patients with a dysgentic gland there was a non-significant tendency to have lower diagnostic free thyroxine concentration but significantly higher TSH compared with those with eutopic gland (p=0.44 and p=0.023, respectively). Patients with thyroid dysgenesis required higher initial and six month LT4 doses compared with those with eutopic glands (p=0.001). Receiver operator curve analysis showed the optimum cut-off value for LT4 at six months for transient vs. permanent CH was 2 microg/kg/day (sensitivity 77% and specificity 55%), regardless of etiology. Similarly, in patients with eutopic glands the optimum cut-off value for LT4 dose at six months for permanent vs. transient patients was 2 microg/kg/day (sensitivity 72% and specificity 54%). Conclusion: Results suggest that LT4 requirement at six months of therapy may be a good marker for predicting transient TSH elevation in patients with eutopic thyroid gland, thus facilitating the decision to halt LT4 therapy. Keywords: Congenital hypothyroidism, transient, permanent, six month L-thyroxine dose
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Aromatase deficiency is a rare autosomal recessive genetic disorder with an unknown incidence. Aromatase converts androgens into estrogen in the gonadal and extra-gonadal tissues. Aromatase ...deficiency causes ambiguous genitalia in the female fetus and maternal virilization (hirsutism, acne, cliteromegaly, deep voice) during pregnancy due to increased concentration of androgens. A 19 months old girl patient was assessed due to presence of ambiguous genitalia. There were findings of maternal virilization during pregnancy. The karyotype was 46,XX. Congenital adrenal hyperplasia was not considered since adrenocorticotropic hormone, cortisol, and 17-hydroxyprogesterone levels were within normal ranges. At age two months, follicle-stimulating hormone and total testosterone levels were elevated and estradiol level was low. Based on these findings, aromatase deficiency was suspected. A novel homozygous mutation IVS7-2A>G (c.744-2A>G) was identified in the
gene. Pelvic ultrasound showed hypoplasic ovaries rather than large and cystic ovaries. We identified a novel mutation in the
gene in a patient who presented with ambiguous genitalia and maternal virilization during pregnancy. Presence of large and cystic ovaries is not essential in aromatase deficiency.
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A novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in the GLI2 gene is reported. There was an extremely distinct phenotypical
expression in two siblings and their father. The index case was a boy ...who developed cholestasis and hypoglycaemia in the neonatal period.
He had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, and bilateral cryptorchidism. Laboratory
examination revealed a diagnosis of multiple pituitary hormone deficiency. There was severe anterior pituitary hypoplasia, absent
pituitary stalk and ectopic posterior pituitary on magnetic resonance imaging which suggested pituitary stalk interruption syndrome
with no other midline structural abnormality. Molecular genetic analysis revealed a novel heterozygous splicing IVS11-2A>C(c.1957-
2A>C) mutation detected in the GLI2 gene. His father and a six-year-old brother with the identical mutation also had unilateral postaxial
polydactyly and mid-facial hypoplasia although there was no pituitary hormone deficiency. This novel heterozygous GLI2 mutation
detected appears to present with an extremely variable clinical phenotype, even in related individuals with an identical mutation,
suggesting incomplete penetrance of this GLI2 mutation.
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Abstract
Context
Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with ...loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized.
Objective
To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations.
Setting
Twelve tertiary pediatric endocrine referral centers.
Patients
Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years.
Main Outcome Measures
Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis.
Results
Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = –3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: –2.35, median BMI SDS: –0.52 SDS) with 20/29 (69%) cases having growth retardation.
Conclusion
We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.
Aim of this study is to determine the final adult height(FAH) achieved by recombinant growth hormone (rhGH) treatment, the factors affecting FAH and the success of capturing the genetic potential.
...Data of 133 patients treated with rhGH therapy were reviewed retrospectively. Patients were grouped according to diagnosis isolated growth hormone deficiency(IGHD) and multiple pituitary hormone deficiency(MPHD), sex, and pubertal status at the beginning of treatment.
The mean age of initiation of treatment was 12.3±2.18 years, and the mean duration of GH treatment was 3.65 ± 1.5 years. The mean height SDS at diagnosis was -3.11±0.75 SD. All patients received a standardized GH dose of 0.033 mg/kg/day. Mean FAH-SDS was -1.8±0.77 and Delta Height-SDS (the height SDS difference at the beginning and end of treatment) was 1.28±0.94 SD. FAH SDS was -1.79± 0.86 SD in males; -1.82±0.64 in females (p:0.857); -1.94 ±0.71 at the beginning of treatment in pubertal patients; -1.68±0.81 (p:0.056) in prepubertal patients; -1.84±0.89 in patients with IGHD; -0.47±0.2 in patients with MPHD (p:˃0.05). In multiple regression analysis, First Year Delta Height-SDS was the most predictive factor for both FAH-SDS and Delta Height-SDS.
GH treatment provided the majority of our patients to achieve a final height compatible with their genetic potential as well as population standards. First Year Delta Height-SDS was found a predictive factor for FAH. Commencement of GH therapy at the prepubertal period was not found associated with a better height outcome.
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