A novel homozygous nonsense NDNF variant in Kallmann syndrome.

Kallmann syndrome (KS) is a rare genetic disease characterized by pubertal failure and olfactory defects. Although many genes associated with KS have been reported, most are rare. Recently, heterozygous inactivating mutations in the neuron-derived neurotrophic factor gene (NDNF) were reported to cause KS. Here, we present a 14-year-old Kurdish boy with KS who has a novel homozygous nonsense c.1251C>A (p.Tyr417Ter) variant in NDNF. The variant was not observed in reference population databases and was predicted to be deleterious. Segregation analysis performed with Sanger sequencing indicated the autosomal recessive inheritance of the clinical phenotype. His heterozygous parents have experienced timely pubertal development and normal reproductive features. This study reported the first homozygous truncating NDNF variant, enabling the direct observation of the clinical consequences of predictively absent NDNF function. These results support the contention that the inactivating mutations in NDNF cause KS, and provide additional evidence for the complex inheritance of KS.

Molecular genetic studies in a case series of isolated hypoaldosteronism due to biosynthesis defects or aldosterone resistance.

BACKGROUND AND AIM: Hypoaldosteronism is associated with either insufficient aldosterone production or aldosterone resistance (pseudohypoaldosteronism). Patients with aldosterone defects typically present with similar symptoms and findings, which include failure to thrive, vomiting, hyponatremia, hyperkalemia and metabolic acidosis. Accurate diagnosis of these clinical conditions therefore can be challenging. Molecular genetic analyses can help to greatly clarify this complexity. The aim of this study was to obtain an overview of the clinical and genetic characteristics of patients with aldosterone defects due to biosynthesis defects or aldosterone resistance. DESIGN AND PATIENTS: We investigated the clinical and molecular genetic features of 8 consecutive patients with a clinical picture of aldosterone defects seen in our clinics during the period of May 2015 through October 2017. We screened CYP11B2 for aldosterone synthesis defects and NR3C2 and the three EnaC subunits (SCNN1A, SCNN1B and SCNN1G) for aldosterone resistance. RESULTS: We found 4 novel and 2 previously reported mutations in the genes CYP11B2, NR3C2, SCNN1A and SCNN1G in 9 affected individuals from 7 unrelated families. CONCLUSION: Molecular genetic investigations can help confidently diagnose these conditions and clarify the pathogenicity of aldosterone defects. This study may expand the clinical and genetic correlations of defects in aldosterone synthesis or resistance.

Anthropometric findings from birth to adulthood and their relation with karyotpye distribution in Turkish girls with Turner syndrome.

To evaluate the anthropometric features of girls with Turner syndrome (TS) at birth and presentation and the effect of karyotype on these parameters. Data were collected from 842 patients with TS from 35 different centers, who were followed-up between 1984 and 2014 and whose diagnosis age ranged from birth to 18 years. Of the 842 patients, 122 girls who received growth hormone, estrogen or oxandrolone were excluded, and 720 girls were included in the study. In this cohort, the frequency of small for gestational age (SGA) birth was 33%. The frequency of SGA birth was 4.2% (2/48) in preterm and 36% (174/483) in term neonates (P < 0.001). The mean birth length was 1.3 cm shorter and mean birth weight was 0.36 kg lower than that of the normal population. The mean age at diagnosis was 10.1 ± 4.4 years. Mean height, weight and body mass index standard deviation scores at presentation were -3.1 ± 1.7, -1.4 ± 1.5, and 0.4 ± 1.7, respectively. Patients with isochromosome Xq were significantly heavier than those with other karyotype groups (P = 0.007). Age at presentation was negatively correlated and mid-parental height was positively correlated with height at presentation. Mid-parental height and age at presentation were the only parameters that were associated with height of children with TS. The frequency of SGA birth was found higher in preterm than term neonates but the mechanism could not be clarified. We found no effect of karyotype on height of girls with TS, whereas weight was greater in 46,X,i(Xq) and 45,X/46,X,i(Xq) karyotype groups.

New onset diabetes in children during the COVID-19 Pandemic: an assessment of biomarkers and psychosocial risk factors at play in Mississippi.

Purpose: The COVID-19 pandemic has shown a rise in pediatric diabetes. Studies have indicated an increased likelihood of children with COVID-19 infection developing diabetes. Our objective was to assess not only for an increase in pediatric diabetes at our hospital and identify possible risk factors but also to correlate psychosocial changes resulting from the pandemic with new-onset diabetes during this time. Methods: We analyzed data from 58 children aged 1-18 years admitted to our hospital with new-onset diabetes between March 2020 and December 2021, including inflammatory biomarkers and SARS-CoV-2 antibodies (Ab), as well as results of a lifestyle questionnaire. Results: Average monthly hospital admissions for new-onset diabetes rose from 10 to 18 with the start of the pandemic. Of the 58 children in our analysis, 33% had positive SARS-CoV-2 IgG Ab, 31% had type 1 diabetes mellitus (T1DM), and 62% had type 2 diabetes mellitus (T2DM). More than half (54%) were in DKA. Those with T2DM were older, majority African American, had higher median BMI percentiles, and lower Vitamin D levels. There were no significant correlations between any psychosocial risk factors and either diabetes type or SARS-CoV2 Ab status. Conclusions: Despite the increased incidence of new-onset diabetes among children in Mississippi during the pandemic, this study was unable to demonstrate significant correlations between COVID-19 infection and new-onset diabetes. This study highlighted the correlation between increased BMI and type 2 diabetes, which speaks to the significant problem of obesity and diabetes in Mississippi and the need for further research.

Textile dye removal in wastewater by peroxymonosulfate (PMS) activation on a zero-valent iron nanoparticle-modified ultrafiltration catalytic membrane (nZVI@PES).

The use of the nano zero-valent iron (nZVI) nanoparticle-based advanced oxidation systems in conjunction with an activator such as peroxymonosulfate (PMS) to generate hydroxyl and sulfate radicals for the degradation of organic pollutants has been extensively used in recent studies. In this study, a nZVI-modified polyethersulfone (PES) membrane (nZVI@PES) was produced successfully by attaching the nZVI catalytic nanoparticles on the surface of a commercial microporous polymeric membrane material using a simple and easy filter press coating method. The presence of nZVI nanoparticles on the nZVI@PES membrane was confirmed by XRD, SEM, and EDS analyses. The nZVI@PES membrane was applied in the dead-end filtration system in the presence of the PMS activator to treat the reactive black 5 (RB5) dye solution. The effect of catalyst loading, RB5 dye concentration, PMS dosage, and pH level on the nZVI@PES membrane/PMS system was investigated. Quenching experiments were carried out to identify the reactive species responsible, and reusability tests were conducted on the membrane. The highest decolorization efficiency (96.8%) was obtained at 20 mg/L RB5 dye solution, initial pH of 3, the nZVI loading of 5 mg/cm2, and the PMS dosage of 300 mg/L at the end of a reaction time of 30 min. The formation of HO•, [Formula: see text], [Formula: see text] and, 1O2 was confirmed by quenching experiments. The results indicate that the nZVI@PES membrane/PMS system could successfully treat wastewater contaminated with an organic dye.

Chromium levels in healthy and newly diagnosed type 1 diabetic children.

BACKGROUND: The aim of this study was to compare the chromium levels of plasma (PCL), erythrocyte (ECL) and urine (UCL) in type 1 diabetics and healthy subjects and to review the relation between metabolic parameters. METHODS: We evaluated 165 subjects who were: newly diagnosed type 1 diabetics (group 1 [n= 29]); previously diagnosed type 1 diabetics (group 2 [n= 18]); non-diabetic control subjects who were admitted and treated for any reason in hospital (group 3 [n= 21]); and two other groups of control subjects from two schools that have different socioeconomic levels (group 4 [n= 48] and group 5 [n= 49]). RESULTS: PCL in group 1 and group 2 subjects (7.21 ± 4.78 and 10.94 ± 3.04 mcg/L, respectively) was significantly lower than in all control groups (21.84 ± 7.87, 16.11 ± 7.44, 17.25 ± 8.58 mcg/L, respectively) (P < 0.05). A significant difference in PCL between the group 1 and group 2 subjects was present (7.21 ± 4.78 and 10.94 ± 3.04, respectively) (P= 0.021). ECL (as tissue chromium) in group 1 and group 2 subjects (13.99 ± 11.37 and 19.64 ± 12.58, respectively) was significantly lower than in all control groups (28.20 ± 7.34.25, 49 ± 12.47, 26.37 ± 9.77 mcg/L, respectively) (P= 0.05). UCL in group 1 and group 2 subjects (11.44 ± 6.88 and 15.68 ± 6.75 mcg/L, respectively) was significantly lower than in group 3 subjects (28.83 ± 9.37 mcg/L) (P < 0.05). There were significant correlations between length, bodyweight and PCL in the group 1 subjects (r = 0.42, P= 0.22 and r = 0.53, P= 0.03, respectively). There was a negative correlation between plasma glucose and UCL, which was not statistically significant in group 2 subjects (r =-0.4, P= 0.061). CONCLUSION: There was a negative chromium balance in type 1 diabetics. This negative balance may affect the insulin function badly. If this negative balance should be confirmed by recent studies we suggest that chromium supplementation with insulin is necessary for type 1 diabetes.

Relationship between metabolic control and neurocognitive functions in children diagnosed with type I diabetes mellitus before and after 5 years of age.

We aimed to investigate the effects of age onset of diabetes, glycemic control and frequency of hypoglycemia on neurocognitive functions in type I diabetic children. Sixty type I diabetic children with diagnosis before (Group 1) or after (Group 2) five years of age and 40 healthy children were tested. Wechsler Intelligence Scale for Children Revised (WISC-R), Stroop Test, and Visual Auditory Digit Span Test Form B were applied to all children in the two groups. Neurocognitive functions such as visual perception, short-term memory and selective attention were seen to be negatively affected at a significant level. Group 1 patients with poor glycemic control were found to have significant dysfunction in verbal, performance and general intelligence. Neurocognitive functions were negatively affected by early onset of diagnosis, poor glycemic control and frequent hypoglycemia in children with type I diabetes mellitus. We suggest that negative effects on neurocognitive functions in type I diabetes should be considered in the follow-up of these patients.

Pathogenic Variants in ZSWIM7 Cause Primary Ovarian Insufficiency.

CONTEXT: Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers. OBJECTIVE: We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis. SETTING: Study subjects were recruited at academic centers. PATIENTS OR OTHER PARTICIPANTS: Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected. RESEARCH DESIGN: Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene. MAIN OUTCOME MEASURE(S): Rare deleterious variants in known and candidate genes associated with POI. RESULTS: Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function. CONCLUSIONS: Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.

A homozygous recurring mutation in WISP3 causing progressive pseudorheumatoid arthropathy.

WISP3 is a member of the CCN (for CTGF, CYR61, and NOV) gene family, which encodes cysteine-rich secreted proteins with roles in cell growth and differentiation. Mutations in the WISP3 gene are associated with the autosomal recessive skeletal disorder, also known as progressive pseudorheumatoid arthropathy of childhood (PPAC). We diagnosed three siblings from a non-consanguineous family with PPAC. The patients were asymptomatic in early childhood. Signs and symptoms of disease that include progressive joint stiffness, swelling of the finger joints, and osteopenia, and slow linear growth developed between 2 and 8 years of age. PCR amplification and direct sequencing of the WISP3 gene revealed a homozygous mutation at nucleotide 156 of the WISP3 gene, resulting in a Cys52-to-ter substitution. This mutation has previously been reported in French, Italian, and Arab families. Interestingly, the C52X mutation was found to be associated with a c.248G-->A (G83E) variation, suggesting the existence of a founder effect. By contrast, the presence of the same aberration in three different ethnic groups could imply that this particular site is prone to mutation. Basal fasting concentrations of growth hormone, insulin-like growth factor-1, and insulin-like growth factor binding protein-3, as well as glucose and insulin levels revealed no aberrations. In conclusion, consideration of this rare disease that causes significant morbidity with short stature, osteopenia and arthritic complaints would prevent unnecessary examinations and treatment attempts. Testing for this specific mutation in suspected cases could provide a rapid and definitive diagnosis.

DLG2 Mutations in the Etiology of Pubertal Delay and Idiopathic Hypogonadotropic Hypogonadism.

INTRODUCTION: Idiopathic hypogonadotropic hypogonadism (IHH) is caused by dysfunction of the hypothalamic-pituitary-gonadal axis. DLG2 was recently implicated as a gene associated with delayed puberty and which may also contribute to IHH. The confirmation of the candidate puberty genes in independent IHH cohorts has become crucial due to the lack of proper genotype-phenotype segregations in reported pedigrees. Therefore, we aimed to screen DLG2 in patient variants in a large cohort of IHH patients. METHODS: The present study included a total of 336 IHH patients from 290 independent families. The coding and flanking regions of DLG2 were screened for potentially important variants in the WES data. Candidate variants were evaluated in the -gnomAD and GME databases according to their allele frequencies, and only those with a frequency <0.0001 were considered rare. Detected variants were classified according to the ACMG/AMP criteria. RESULTS: We found 1 homozygous and 2 heterozygous missense variants in 3 independent pedigrees. Identified variants were found extremely rare or not reported in gnomAD. Two variants were categorized as "uncertain significance," and the other one was "likely pathogenic" according to the ACMG criteria. All patients were normosmic, and in 2 of the 3 families, there were no causal variants in other IHH-related genes. CONCLUSION: We detected 3 rare sequencing variants in DLG2 in 5 patients with IHH or delayed puberty in a large IHH cohort. Our results support the contention that the DLG2 mutations are associated with IHH in human puberty.

Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets.

OBJECTIVES: Hereditary Hypophosphatemic Rickets (HHR) is a heterogeneous group of disorders characterized by hypophosphatemia. Although the X-linked dominant HHR is the most common form, the genetic etiology of HHR is variable. Recently, developed next-generation sequencing techniques may provide opportunities for making HHR diagnosis in a timely and efficient way. METHODS: We investigated clinical and genetic features for 18 consecutive probands and their 17 affected family members with HHR. All patient's clinical and biochemical data were collected. We first analyzed a single gene with Next-generation sequencing if the patients have a strong clue for an individual gene. For the remaining cases, a Hypophosphatemic Rickets gene panel, including all known HHR genes by Next-generation sequencing, was employed. RESULTS: We were able to diagnosis all of the consecutive 35 patients in our tertiary care center. We detected nine novel and 10 previously described variants in PHEX (9; 50%), SLC34A3 (3; 17%), ENPP1 (3; 17%), SLC34A1 (1; 5%), CLCN5 (1; 5%), and DMP1 (1; 5%). CONCLUSIONS: To delineate the etiology of HHR cases in a cost and time-efficient manner, we propose single gene analysis by next-generation sequencing if findings of patients indicate a strong clue for an individual gene. If that analysis is negative or for all other cases, a Next-generation Sequence gene panel, which includes all known HHR genes, should be employed.

Molecular causes of hypogonadotropic hypogonadism.

PURPOSE OF REVIEW: What controls puberty remains largely unknown and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately important developments have occurred in this field. RECENT FINDINGS: Substantial variation in clinical expression, from complete anosmia and hypogonadotropic hypogonadism to delayed puberty and normosmia, of the same Kallmann syndrome gene defects including in newer ones (FGF8 and CHD7) continues to be repeatedly observed. Digenic or oligogenic inheritance becomes another feature of Kallmann syndrome. Recent reports of mutations in TAC3 or TACR3 [encoding neurokinin B (NKB) and its receptor, NK3R, respectively] provided compelling evidence for the involvement of NKB signaling in puberty. This energized the field to understand the exact mechanism through which NKB signaling exerts its effects. With the important findings from these recent studies in association with the substantial data from kisspeptin studies in the last 6 years a sketch of GnRH pulse generator has emerged in which NKB signaling appears to play a key role. SUMMARY: Autozygosity mapping may continue helping identify the other genes including those upstream to the GnRH pulse generator in this complex and elusive developmental process.

Novel growth hormone receptor gene mutation in a patient with Laron syndrome.

Growth Hormone (GH) is a 22 kDa protein that has effects on growth and glucose and fat metabolisms. These effects are initiated by binding of growth hormone (GH) to growth hormone receptors (GHR) expressed in target cells. Mutations or deletions in the growth hormone receptor cause an autosomal disorder called Laron-type dwarfism (LS) characterized by high circulating levels of serum GH and low levels of insulin like growth factor-1 (IGF-1). We analyzed the GHR gene for genetic defect in seven patients identified as Laron type dwarfism. We identified two missense mutations (S40L and W104R), and four polymorphisms (S473S, L526I, G168G and exon 3 deletion). We are reporting a mutation (W104R) at exon 5 of GHR gene that is not previously reported, and it is a novel mutation.

Gender Identity and Assignment Recommendations in Disorders of Sex Development Patients: 20 Years' Experience and Challenges

Objective: Gender assignment in infants and children with disorders of sex development (DSD) is a stressful situation for both patient/families and medical professionals. Methods: The purpose of this study was to investigate the results of gender assignment recommendations in children with DSD in our clinic from 1999 through 2019. Results: The mean age of the 226 patients with DSD at the time of first admission were 3.05±4.70 years. 50.9% of patients were 46,XY DSD, 42.9% were 46,XX DSD and 6.2% were sex chromosome DSD. Congenital adrenal hyperplasia (majority of patients had 21-hydroxylase deficiency) was the most common etiological cause of 46,XX DSD. In 46,XX patients, 87 of 99 (89.7%) were recommended to be supported as a female, 6 as a male, and 4 were followed up. In 46,XY patients, 40 of 115 (34.8%) were recommended to be supported as a female, and 70 as male (60.9%), and 5 were followed up. In sex chromosome DSD patients, 3 of 14 were recommended to be supported as a female, 9 as a male. The greatest difficulty in making gender assignment recommendations were in the 46,XY DSD group. Conclusion: In DSD gender assignment recommendations, the etiologic diagnosis, psychiatric gender orientation, expectation of the family, phallus length and Prader stage were effective in the gender assignment in DSD cases, especially the first two criteria. It is important to share these experiences among the medical professionals who are routinely charged with this difficult task in multidisciplinary councils.

Thyroid peroxidase gene mutations causing congenital hypothyroidism in three Turkish families.

In Turkey congenital hypothyroidism (CH) occurs with a prevalence of one in 2,736 newborns while the worldwide incidence is one in 3,000-4,000 newborns. 85-90% of these cases are due to dysgenesis of the thyroid gland, whereas defects in thyroid hormone synthesis account for 10-15%. The majority of patients with dyshormonogenesis have a defect in thyroid peroxidase (TPO). To date, more than 60 different mutations have been described in the TPO gene, mostly single nucleotide substitutions. Five children from three consanguineous families were diagnosed with CH on the basis of clinical symptoms and signs--goiter, macroglossia and prolonged jaundice at newborn age. Two different mutations in the TPO gene were identified. Affected children in families I and II had a nonsense mutation in exon 10 (R540X). Genotyping of polymorphic markers within the TPO gene revealed that these families shared a common haplotype, suggesting a founder effect. In the third family, a novel mutation (G319R) in exon 8 was identified.

A Novel Frameshift Mutation in ESCO2 Gene in Roberts Syndrome.

Roberts syndrome is a very rare autosomal recessive inheritance pattern genetic disorder characterised by symmetric bilateral extremity deformities, midfacial defect, and severe intellectual deficit. These patients also grow slowly prenatal and postnatal. RBS is caused by mutation in the ESCO2 gene. With these clinical and radiological findings, the case was diagnosed as Roberts syndrome. Full gene sequencing of the ESCO2 gene for the patient was done. In this patient, a novel frameshift mutation was identified in the ESCO2 gene.

Impaired glucose tolerance in Fanconi-Bickel syndrome: Eight patients with two novel mutations.

Seker-Yilmaz B, Kör D, Bulut FD, Yüksel B, Karabay-Bayazit A, Topaloglu AK, Ceylaner G, Önenli-Mungan N. Impaired glucose tolerance in Fanconi-Bickel syndrome: Eight patients with two novel mutations. Turk J Pediatr 2017; 59: 434-441. Fanconi-Bickel syndrome (FBS) is a rare, autosomal recessive disorder of carbohydrate metabolism caused by defects in the facilitative glucose transporter 2 (GLUT2 or SLC2A2) gene. Prominent findings are failure to thrive, renal tubular acidosis, hypoglycemia and postprandial hyperglycemia even mimicking diabetes mellitus. Eight patients from 6 families with FBS were included in this study. c.482_483insC homozygous mutation was detected in six patients from four different families. Mutation analysis of SLC2A2 gene revealed two novel homozygous mutations; c.1069delGinsAATAA and c.575A > G. Standard oral glucose tolerance test with 1.75 g/kg oral glucose was performed in six of the patients who were older than 3-years of age. Impaired glucose tolerance was found in all patients as expected and two of them had overt diabetes. None of the antidiabetic medications were given to them in order to avoid significant hypoglycemia. Beside the conservative treatment, follow up with frequent oral glucose tolerance tests are planned. We report these cases of FBS, as GSD XI is rare, two novel mutations were detected and also to highlight the risk of diabetes mellitus; although there is not a consensus about the treatment.

Sertoli cell only syndrome with ambiguous genitalia.

The Sertoli cell only syndrome (SCOS) is a rare genetic disorder with a variable phenotype ranging from a severe ambiguous genitalia to a normal male phenotype with infertility. SCOS is diagnosed on testicular histopathology as germ cells are absent without histological impairment of Sertoli or Leydig cells. The SRY positive XX male syndrome is usually diagnosed in adulthood during infertility investigations. Here, we report a rare case of 46,XX maleness with ambiguous genitalia due to Sertoli cell only syndrome (SCOS).

Withdrawal syndrome and hypomagnesaemia and in a newborn exposed to valproic acid and carbamazepine during pregnancy.

The usage of drugs during pregnancy affect the fetus and the newborn. In this report, we present findings from a newborn baby, whose mother was epileptic, and was under the treatment of valproic acid and carbamazepine during pregnancy. We have found symptoms of withdrawal syndrome, hyponatremia and feeding problem, which was most probably related to exposure to the mentioned drugs. We have also diagnosed hypomagnesaemia and atrial septal defect 4 milimeters in diameter. There are already many reports about the side effects of valproic acid and carbamazepine usage during pregnancy. To the best of our knowledge, hypomagnesaemia has not yet been reported as a side effect. We think that hypomagnesaemia is also related to the usage of antiepileptics.