Homozygous Mutation in the Insulin Receptor Gene Associated with Mild Type A Insulin Resistance Syndrome: A Case Report

Insulin receptor (INSR) mutations lead to heterogeneous disorders that may be as severe as Donohue syndrome or as mild as "type A insulin resistance syndrome". Patients with severe disorders usually harbor homozygous or compound heterozygous mutations. In contrast, type A insulin resistance syndrome has been associated with heterozygous mutations; homozygous mutations are rarely responsible for this condition. We report a novel, homozygous mutation, p.Leu260Arg in exon 3, of the INSR gene in a female adolescent patient with type A insulin resistance syndrome together with clinical details of her medical follow-up. Different mutations in the INSR gene cause different phenotype and vary depending on the inheritance pattern. This report adds to the literature, increases understanding of the disease mechanism and aids in genetic counseling.

Exome Sequencing of a Primary Ovarian Insufficiency Cohort Reveals Common Molecular Etiologies for a Spectrum of Disease.

CONTEXT: Primary ovarian insufficiency (POI) encompasses a spectrum of premature menopause, including both primary and secondary amenorrhea. For 75% to 90% of individuals with hypergonadotropic hypogonadism presenting as POI, the molecular etiology is unknown. Common etiologies include chromosomal abnormalities, environmental factors, and congenital disorders affecting ovarian development and function, as well as syndromic and nonsyndromic single gene disorders suggesting POI represents a complex trait. OBJECTIVE: To characterize the contribution of known disease genes to POI and identify molecular etiologies and biological underpinnings of POI. DESIGN, SETTING, AND PARTICIPANTS: We applied exome sequencing (ES) and family-based genomics to 42 affected female individuals from 36 unrelated Turkish families, including 31 with reported parental consanguinity. RESULTS: This analysis identified likely damaging, potentially contributing variants and molecular diagnoses in 16 families (44%), including 11 families with likely damaging variants in known genes and five families with predicted deleterious variants in disease genes (IGSF10, MND1, MRPS22, and SOHLH1) not previously associated with POI. Of the 16 families, 2 (13%) had evidence for potentially pathogenic variants at more than one locus. Absence of heterozygosity consistent with identity-by-descent mediated recessive disease burden contributes to molecular diagnosis in 15 of 16 (94%) families. GeneMatcher allowed identification of additional families from diverse genetic backgrounds. CONCLUSIONS: ES analysis of a POI cohort further characterized locus heterogeneity, reaffirmed the association of genes integral to meiotic recombination, demonstrated the likely contribution of genes involved in hypothalamic development, and documented multilocus pathogenic variation suggesting the potential for oligogenic inheritance contributing to the development of POI.

A Case of the Perinatal Form Hypophosphatasia Caused by a Novel Large Duplication of the ALPL Gene and Report of One Year Follow-up with Enzyme Replacement Therapy

Hypophosphatasia (HPP) is a rare disease caused by mutations in the ALPL gene encoding tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Duplications of the ALPL gene account for fewer than 1% of the mutations causing HPP. It has been shown that asfotase alfa enzyme replacement treatment (ERT) mineralizes the skeleton and improves respiratory function and survival in severe forms of HPP. Our patient was a newborn infant evaluated for respiratory failure and generalized hypotonia after birth. Diagnosis of HPP was based on low-serum ALP activity, high concentrations of substrates of the TNSALP and radiologic findings. On day 21 after birth, ERT using asfotase alfa (2 mg/kg three times per week, subcutaneous injection) was started. His respiratory support was gradually reduced and skeletal mineralization improved during treatment. We were able to discharge the patient when he was seven months old. No mutation was detected in the ALPL gene by all exon sequencing, and additional analysis was done by quantitative polymerase chain reaction (qPCR). As a result, a novel homozygote duplication encompassing exons 2 to 6 was detected. Early diagnosis and rapid intervention with ERT is life-saving in the severe form of HPP. qPCR can detect duplications if a mutation cannot be detected by sequence analysis in these patients.

Genetic and Clinical Characteristics of Patients with Vitamin D Dependent Rickets Type 1A

Objective: Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder caused by mutations in the 1α-hydroxylase gene (CYB27B1). As it may be confused with nutritional rickets and hypophosphatemic rickets, genetic analysis is important for making a correct diagnosis. Methods: We analysed genomic DNA from 11 patients from eight different Turkish families. The patients were recruited for our studies if they presented with a diagnosis of VDDR. Results: The mean ± standard deviation age at diagnosis was 13.1±7.4 months. Seven patients had mild hypocalcemia at presentation while four patients had normal calcium concentrations. All patients underwent CYP27B1 gene analysis. The most prevalent mutation was the c.195 + 2T>G splice donor site mutation, affecting five out of 11 patients with VDDR1A. Two patients from the fourth family were compound heterozygous for c.195 + 2T>G and c.195 + 2 T>A in intron-1. Two patients, from different families, were homozygous for a previously reported duplication mutation in exon 8 (1319_1325dupCCCACCC, Phe443Profs*24). One patient had a homozygous splice site mutation in intron 7 (c.1215 + 2 T>A) and one patient had a homozygous mutation in exon 9 (c.1474 C>T). Conclusion: Intron-1 mutation was the most common mutation, as previously reported. All patients carrying that mutation were from same city of origin suggesting a "founder" or a "common ancestor" effect. VDDR1A should definitely be considered when a patient with signs of rickets has a normal 25-OHD level or when there is unresponsiveness to vitamin D treatment.

Glycogen storage disease type 0 due to a novel frameshift mutation in glycogen synthase 2 (GYS2) gene in a child presenting with fasting hypoglycemia and postprandial hyperglycemia.

Hacihamdioglu B, Özgürhan G, Çaran B, Meydan-Aksanli E, Keskin E. Glycogen storage disease type 0 due to a novel frameshift mutation in glycogen synthase 2 (GYS2) gene in a child presenting with fasting hypoglycemia and postprandial hyperglycemia. Turk J Pediatr 2018; 60: 581-583. Glycogen storage disease type 0 (GSD0) has been considered a rare disorder, it is characterized with ketotic hypoglycemia after prolonged fasting and postprandial hyperglycemia. Herein, we report a novel mutation in the glycogen synthase 2 gene in a Turkish child, as well as her clinical characteristics and 12-month follow-up. We evaluated a 5-year-old girl for asymptomatic fasting ketotic hypoglycemia with postprandial hyperglycemia diagnosed with glycogen storage disease type 0. We identified a novel frameshift mutation, c.1081delA (p.Thr361Glnfs*2) in exon 8 on glycogen synthase 2 gene. Children with GSD0 may have a mild phenotype and GSD0 may be underdiagnosed due to subclinical or asymptomatic hypoglycemia. The diagnosis of GSD0 should be considered in a child with ketotic fasting hypoglycemia with postprandial hyperglycemia but without hepatomegaly.

Worldwide view of nephropathic cystinosis: results from a survey from 30 countries.

BACKGROUND: Nephropathic cystinosis is a rare inherited metabolic disorder leading to progressive renal failure and extra-renal comorbidity. The prognosis relies on early adherence to cysteamine treatment and symptomatic therapies. Developing nations [DiN] experience many challenges for management of cystinosis. The aim of this study was to assess the management characteristics in DiN compared with developed nations [DeN]. METHODS: A questionnaire was sent between April 2010 and May 2011 to 87 members of the International Pediatric Nephrology Association, in 50 countries. RESULTS: A total of 213 patients were included from 41 centres in 30 nations (109 from 17 DiN and 104 from 13 DeN). 7% of DiN patients died at a median age of 5 years whereas no death was observed in DeN. DiN patients were older at the time of diagnosis. In DiN, leukocyte cystine measurement was only available in selected cases for diagnosis but never for continuous monitoring. More patients had reached end-stage renal disease in DiN (53.2 vs. 37.9%, p = 0.03), within a shorter time of evolution (8 vs. 10 yrs., p = 0.0008). The earlier the cysteamine treatment, the better the renal outcome, since the median renal survival increased up to 16.1 [12.5-/] yrs. in patients from DeN treated before the age of 2.5 years of age (p = 0.0001). However, the renal survival was not statistically different between DeN and DiN when patients initiated cysteamine after 2.5 years of age. The number of transplantations and the time from onset of ESRD to transplantation were not different in DeN and DiN. More patients were kept under maintenance dialysis in DiN (26% vs.19%, p = 0.02); 79% of patients from DiN vs. 45% in DeN underwent peritoneal dialysis. CONCLUSIONS: Major discrepancies between DiN and DeN in the management of nephropathic cystinosis remain a current concern for many patients living in countries with limited financial resources.

Association of neck circumference and pulmonary function in children.

BACKGROUND: Childhood obesity leads to many complications including impaired respiratory function. There are various anthropometric parameters related to obesity. OBJECTIVE: To investigate the correlation between anthropometric indices and pulmonary function test results in children without asthma. METHODS: Children without any respiratory disorders were enrolled in this study. Anthropometric measurements, such as height, weight, neck circumference (NC), and waist circumference, were obtained from the enrollees and body mass index was calculated. Afterward, pulmonary function tests were performed using spirometry. RESULTS: A total of 178 children (106 boys, 59.5%) with a mean age of 9.7 years were included the study. NC was above the 90th percentile in 65 children. Importantly, pulmonary parameters, such as forced expiratory volume during the first second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC), were lower in subjects with a large NC. Similarly, waist circumference was above the 90th percentile in 67 children, and FEV1/FVC was significantly lower in children with a large waist circumference. Moreover, there was a statistically significant negative correlation among FEV1, FEV1/FVC, and body mass index SD score. Also, multivariable linear regression analysis showed that an NC above the 90th percentile was associated with lower FEV1 and FEV1/FVC values. CONCLUSION: We identified NC as a novel anthropometric index that is strongly correlated with respiratory functions in children. Therefore, close monitoring of respiratory symptoms, particularly in children with obesity and a large NC, could help with early and prompt determination of respiratory complications of obesity.

CCDC141 Mutations in Idiopathic Hypogonadotropic Hypogonadism.

Context: Gonadotropin-releasing hormone neurons originate outside the central nervous system in the olfactory placode and migrate into the central nervous system, becoming integral components of the hypothalamic-pituitary-gonadal axis. Failure of this migration can lead to idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS). We have previously shown that CCDC141 knockdown leads to impaired migration of GnRH neurons but not of olfactory receptor neurons. Objective: The aim of this study was to further describe the phenotype and prevalence of CCDC141 mutations in IHH/KS. Design: Using autozygosity mapping, candidate gene screening, whole-exome sequencing, and Sanger sequencing, those individuals carrying deleterious CDCD141 variants and their phenotypes were determined in a cohort of 120 IHH/KS families. Patients and Interventions: No interventions were made. Results: Our studies revealed nine affected individuals from four independent families in which IHH/KS is associated with inactivating CCDC141 variants, revealing a prevalence of 3.3%. Affected individuals (with the exception of those from family 1 who concomitantly have FEZF1 mutations) have normal olfactory function and anatomically normal olfactory bulbs. Four affected individuals show evidence of clinical reversibility. In three of the families, there was at least one more potentially deleterious variant in other known puberty genes with evidence of allelic heterogeneity within respective pedigrees. Conclusions: These studies confirm that inactivating CCDC141 variants cause normosmic IHH but not KS. This is consistent with our previous in vitro experiments showing exclusively impaired embryonic migration of GnRH neurons upon CCDC141 knockdown. These studies expand the clinical and genetic spectrum of IHH and also attest to the complexity of phenotype and genotype in IHH.

Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.

Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1-/- mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1-/- mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.

Escherichia coli Meningitis after Rotavirus Gastroenteritis in an Infant.

Although rotavirus gastroenteritis is quite common in the pediatric population, secondary bacterial sepsis following rotavirus infection is a rare clinical entity. Gram-negative bacilli are the fifth most common cause of meningitis in infants but this infection rarely occurs after gastroenteritis. Here, we report a 2.5-month-old infant who developed Escherichia coli (E. coli) meningitis after acute rotavirus gastroenteritis. The 2.5-month-old male infant with fever, vomiting, and watery diarrhea that started 1 day earlier was admitted to the hospital. Rotavirus antigen in stool sample was positive. He was hospitalized, and fever was measured at 39.5°C on the second day. Lumbar puncture was done for suspicion of meningitis, and cerebrospinal fluid (CSF) findings suggested meningitis. Intravenous vancomycin and cefotaxime were started empirically. Since E. coli reproduction was seen in blood culture and CSF culture, treatment was continued with cefotaxime. The patient was discharged with minimal midlevel hydrocephalus findings in cranial ultrasonography and magnetic resonance imaging following 21 days of antibiotics treatment. Septicemia development following rotavirus gastroenteritis is an extremely rare clinical condition. It is vital to start prompt antibiotic treatment as soon as the diagnosis of secondary bacterial infection is made because of high mortality and morbidity rates.

Risk assessment of obstructive sleep apnea syndrome in pediatric patients with vitamin D deficiency: A questionnaire-based study.

The aim of the following study is to evaluate the risk of obstructive sleep apnea syndrome (OSAS) in subjects with vitamin D deficiency.Prospective and comparative study.We enrolled 240 subjects into the study. The participants were divided into 2 groups based on 25-hydroxyvitamin D (25[OH]D) levels: low level of 25(OH)D (<20 ng/mL) group (n = 120) and control (>20 ng/mL) group (n = 120). Subjects were classified as being at a high or low risk of developing OSAS by using the Berlin Questionnaire. Risk of developing OSAS, gender, age, and body mass index (BMI) z-score were assessed by comparing the low level of 25(OH)D group and control group.No statistically significant difference was observed between the low level of 25(OH)D group and control group in terms of gender, age, and BMI z-score distributions; P = 0.323, P = 0.387, and P = 0.093, respectively. There were 24 subjects with high risk of developing OSAS in 2 groups (17 subjects in the low level of 25[OH]D group and 7 subjects in the control group). In the low level of 25(OH)D group, the risk of developing OSAS was found to be significantly higher than the control group (P = 0.030). BMI z-score was found significantly higher in high-risk groups than low-risk groups (P = 0.034 for low-level 25[OH]D group and P = 0.023 for control group).The findings revealed that low level of 25(OH)D increases the risk of developing OSAS.

Association of wider neck circumference and asthma in obese children.

BACKGROUND: Obesity is a well-established risk factor for asthma. Previous studies have reported that central obesity is associated with asthma. OBJECTIVE: To investigate the association between fat distribution, which is determined by anthropometric measures, including neck circumference (NC), and asthma in school-aged children. METHODS: Children diagnosed as having asthma were enrolled along with controls who were admitted to our outpatient department with allergic symptoms, such as rhinitis, urticaria and atopic dermatitis. Anthropometric measures, including height, weight, NC, waist circumference, and hip circumference, were obtained. Skin prick tests, blood eosinophil counts, and serum total IgE level measurements were performed. RESULTS: A total of 196 children (92 male [46.9%]) were included. Asthma was present in 102 patients (52.1%). Ninety-one of the patients (46.4%) were overweight, and 45 patients (22.9%) were obese. The NC of children with asthma was significantly higher than that of children in the control group. Grades defined according to NC percentiles were also significantly different between groups. In children with asthma, the prevalence of children with an NC higher than the 90th percentile (grade 6) was more frequent when compared with controls. The median NC of obese-overweight children with asthma was significantly higher compared with obese-overweight controls without asthma. Results of multivariable logistic regression analysis revealed that the presence of an NC in the greater than 90th percentile was associated with asthma in obese-overweight children. CONCLUSION: This study found that NC, which is a simple anthropometric measure, is associated with asthma in obese children.

The Association between Serum 25-Hydroxy Vitamin D Level and Urine Cathelicidin in Children with a Urinary Tract Infection.

OBJECTIVE: Cathelicidin is an important antimicrobial peptide in the urinary tract. Cathelicidin expression is strongly stimulated by 1,25-dihydroxy vitamin D in epithelial cells, macrophages/monocytes, and neutrophils. Vitamin D and cathelicidin status in children with urinary tract infection (UTI) caused by Escherichia coli is unknown. To establish the relationship between serum vitamin D and urine cathelicidin levels in children with a UTI caused by Escherichia coli. METHODS: Serum 25-hydroxy vitamin D and urine cathelicidin levels were measured in 36 patients with UTI (mean age 6.8±3.6 years, range: 0.25-12.6 years) and 38 controls (mean age 6.3±2.8 years, range: 0.42-13 years). RESULTS: There were no significant differences in urine cathelicidin levels between the study and control groups (p>0.05). Eight (22.2%) patients in the study group and 21 (58.3%) children in the control group were found to have sufficient vitamin D (≥20 ng/mL). Patients with sufficient vitamin D had higher urine cathelicidin levels than the controls with sufficient vitamin D (respectively 262.5±41.1 vs. 168±31.6 ng/mL, p=0.001). There were no significant differences between the patients and controls with insufficient vitamin D (p>0.05). CONCLUSION: The children with vitamin D insufficiency may not be able to increase their urine cathelicidin level during UTI caused by Escherichia coli. There is a need of prospective studies in order to prove a beneficial effect of vitamin D supplementation for the restoration of cathelicidin stimulation and consequently for prevention of UTI recurrence.

Urinary Netrin-1: A New Biomarker for the Early Diagnosis of Renal Damage in Obese Children.

OBJECTIVE: Urinary netrin-1 is a new marker to demonstrate early tubular damage. The aim of this study was to determine whether urinary netrin-1 is increased in obese children. METHODS: A total of 68 normoalbuminuric and normotensive obese patients and 65 controls were included in the study. Urine samples were collected for assessment of urinary phosphorus, sodium, potassium, creatinine, albumin, and netrin-1. Blood samples were collected for measurements of fasting glucose, insulin, lipid, phosphorus, sodium, potassium, and creatinine levels. Homeostatic model assessment insulin resistance index was calculated. RESULTS: Gender and age were similar between obese and control groups (12.01±3.03 vs. 11.7±3.2 years, p=0.568 and 33 vs. 35 girls, p=0.543, respectively). Obese patients had significantly higher netrin-1 excretion than the controls (841.68±673.17 vs. 228.94±137.25 pg/mg creatinine, p=0.000). Urinary netrin-1 level was significantly higher in obese subjects with insulin resistance compared to those without insulin resistance (1142±1181 vs. 604.9±589.91 pg/mg creatinine, p=0.001). CONCLUSION: In normotensive and normoalbuminuric obese children, urinary netrin-1 level can increase before onset of albuminuria. Urinary netrin-1 excretion appears to be affected predominantly by insulin resistance and hyperinsulinemia. Urinary netrin-1 may be a new biomarker for determining early tubular injury in obese children.

Regulatory T Cells and Vitamin D Status in Children with Chronic Autoimmune Thyroiditis.

OBJECTIVE: It is suggested that vitamin D is one of the factors that can regulate the function of Treg cells. In this study, the relationships between Treg cells and vitamin D levels was investigated in pediatric chronic autoimmune thyroiditis (CAT) patients. METHODS: Thirty-two children with CAT and 24 healthy subjects were studied. FOXP3 expressing CD4+CD25+high Foxp3+T cells were identified as Treg cells. At diagnosis, 25-hydroxycholecalciferol (25OHD3) levels were determined in all patients. FOXP3 expression was measured before and after vitamin D replacement therapy in patients having low levels of 25OHD3. RESULTS: In the CAT patients, Treg cell levels did not differ from the control group, while the frequency of vitamin D deficiency was higher and FOXP3 molecule expression was lower. FOXP3 molecule expression significantly increased in CAT patients having vitamin D deficiency who were given vitamin D replacement. CONCLUSION: FOXP3 expression is decreased in pediatric CAT patients. This reduction seems to be associated with vitamin D levels. Vitamin D can play a role in enhancing natural Treg cell functions.

Gonadotropin-Releasing Hormone Analogue Treatment in Females with Moderately Early Puberty: No Effect on Final Height.

OBJECTIVE: To investigate the effects of treatment with gonadotropin-releasing hormone analog (GnRHa) on final height in girls who experienced moderately early puberty with symptoms beginning at 7-8.5 years of age. METHODS: Female cases diagnosed with moderately early puberty which had started between ages 7 to 8.5 years were included in the study. In the treatment groups, all cases with a bone age ≤10.5 years constituted group 1 (n=18) and those with a bone age >10.5 years constituted group 2 (n=23). The 8 patients for which treatment approval could not be obtained constituted group 3. The 49 cases in all three groups were observed until they reached their final height. RESULTS: Target height, target height standard deviation score (SDS), final height, and final height SDS values were similar in all 3 groups. Final height showed a significant positive correlation with target height (p=0.000, r=0.54) and height at diagnosis (p=0.003, r=0.467) in all groups. Linear regression analysis revealed that a 1 cm longer height at diagnosis increased the final height 0.213 fold, and a 1 cm longer target height at diagnosis increased the final height 0.459 fold. CONCLUSION: We found that GnRHa did not make a positive contribution to final height in cases of moderately early puberty.

Investigation of SHOX Gene Mutations in Turkish Patients with Idiopathic Short Stature.

OBJECTIVE: The frequency of mutations in the short stature homeobox (SHOX) gene in patients with idiopathic short stature (ISS) ranges widely, depending mostly on the mutation detection technique and inclusion criteria. We present phenotypic and genotypic data on 38 Turkish patients with ISS and the distinctive features of 1 patient with a SHOX deletion. METHODS: Microsatellite markers (MSMs) DXYS10092 (GA repeats) and DXYS10093 (CT repeats) were used to select patients for fluorescent in situ hybridisation (FISH) analysis and to screen for deletions in the SHOX gene. The FISH analysis was applied to patients homozygous for at least one MSM. A Sanger sequencing analysis was performed on patients with no deletions according to FISH to investigate point mutations in the SHOX gene. RESULTS: One patient (2.6%) had a SHOX mutation. CONCLUSION: Although the number of cases was limited and the mutation analysis techniques we used cannot detect all mutations, our findings emphasize the importance of the difference in arm span and height when selecting patients for SHOX gene testing.

Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development.

AIM: Androgen receptor (AR) gene mutations are the leading cause of 46,XY disorders of sex development (DSD) and are associated with varying degrees of androgen insensitivity. The aim of this study is to investigate AR gene mutations in 46,XY DSD patients with normal testosterone secretion, either normal or high testosterone/dihydrotestosterone (T/DHT) ratio and normal SRD5A2 gene analysis, collectively, suggestive of androgen insensitivity syndrome (AIS). METHODS: We direct sequenced all eight exons of the AR gene in 21 index patients with varying degrees of undervirilization. RESULTS: We detected AR gene alterations in five patients. In patients with complete AIS we found p.Val30Met in exon 1 and p.Gly689* in exon 4. One patient with partial AIS had p.Gln712Glu in exon 4. In two patients with partial phenotype, we found common p.Glu213Glu (c.639G>A) SNP, and an additional p.Ile817Ile (c.2451T>C) mutation was found in one of these two patients. DISCUSSION: Despite the fact that T/DHT ratio is frequently used in diagnosis of AIS, lack of precisely determined cutoffs compromises correct diagnosis. Hence, depending on clinical and biochemical findings solely may delay correct diagnosis. Direct sequence analysis of the AR is essential for precise diagnosis of AIS.

Anaphylaxis to gonadorelin acetate in a girl with central precocious puberty.

Gonadotropin-releasing hormone analogues are generally regarded as safe drugs. Gonadorelin acetate has been widely used for the diagnosis of central precocious puberty, and life-threatening reactions to gonadorelin acetate are extremely rare. Herein, we described - to the best of our knowledge - the first pediatric case in which severe anaphylaxis was encountered after intravenous gonadorelin acetate administration. An 8-year-old girl who was diagnosed with central precocious puberty was receiving triptorelin acetate treatment uneventfully for 6 months. In order to evaluate the efficacy of the treatment, an LH-RH stimulation test with gonadorelin acetate was planned. Within 3 min after intravenous administration of gonadorelin acetate, she lost consciousness and tonic seizures began in her hands and feet. She was immediately treated with epinephrine, diphenhydramine, and fluids. Her vital signs recovered within 30 min. Based on the results, anaphylaxis should be anticipated and the administration of these drugs should be performed in a setting that is equipped to deal with systemic reactions.

22q11 deletion syndrome: current perspective.

Chromosome 22q11 is characterized by the presence of chromosome-specific low-copy repeats or segmental duplications. This region of the chromosome is very unstable and susceptible to mutations. The misalignment of low-copy repeats during nonallelic homologous recombination leads to the deletion of the 22q11.2 region, which results in 22q11 deletion syndrome (22q11DS). The 22q11.2 deletion is associated with a wide variety of phenotypes. The term 22q11DS is an umbrella term that is used to encompass all 22q11.2 deletion-associated phenotypes. The haploinsufficiency of genes located at 22q11.2 affects the early morphogenesis of the pharyngeal arches, heart, skeleton, and brain. TBX1 is the most important gene for 22q11DS. This syndrome can ultimately affect many organs or systems; therefore, it has a very wide phenotypic spectrum. An increasing amount of information is available related to the pathogenesis, clinical phenotypes, and management of this syndrome in recent years. This review summarizes the current clinical and genetic status related to 22q11DS.