Genotype of congenital adrenal hyperplasia patients with testicular adrenal rest tumor.

Testicular adrenal rest tumor (TART) is one of the important complications that can cause infertility in male patients with congenital adrenal hyperplasia (CAH) and should therefore be diagnosed and treated at an early age. The factors that result in TART in CAH have not been completely understood. The aim of this study is to evaluate the genotype-phenotype correlation in CAH patients with TART. METHOD: Among 230 malepatients with CAH who were followed upwith regular scrotal ultrasonography in 11 different centers in Turkey, 40 patients who developed TARTand whose CAH diagnosis was confirmed by genetic testing were included in this study. Different approaches and methods were used for genotype analysis in this multicenter study. A few centers first screened the patients for the ten most common mutations in CYP21A2 and performed Sanger sequencing for the remaining regions only if these prior results were inconclusive while the majority of the departments adopted Sanger sequencing for the whole coding regions and exon-intron boundaries as the primary molecular diagnostic approach for patients with either CYP21A2 orCYP11B1 deficiency. The age of CAH diagnosis and TART diagnosis, type of CAH, and identified mutations were recorded. RESULTS: TART was detected in 17.4% of the cohort [24 patients with salt-wasting (SW) type, four simple virilizing type, and one with nonclassical type with 21-hydroxylase (CYP21A2) deficiency and 11 patients with 11-beta hydroxylase (CYP11B1) deficiency]. The youngest patients with TART presenting with CYP11B1 and CYP21A2 deficiency were of 2 and 4 years, respectively. Eight different pathogenic variants in CYP21A2were identified. The most common genotypes were c.293-13C>G/c.293-13C>G (31%) followed by c.955C>T/c.955C>T(27.6%) and c.1069C>T/c.1069C>T (17.2%). Seven different pathogenic variants were identified in CYP11B1. The most common mutation in CYP11B1 in our study was c.896T>C (p.Leu299Pro). CONCLUSION: We found that 83% TART patients were affected with SW typeCYP21A2 deficiency,and the frequent mutations detected were c.955C>T (p.Gln319Ter), c.293-13C>G in CYP21A2 and c.896T>C (p.Leu299Pro) inCYP11B1. Patients with CYP11B1 deficiency may develop TART at an earlier age. This study that examined the genotype-phenotype correlation in TART may benefit further investigations in larger series.

Stress Induced Hyperglycemia in Early Childhood as a Clue for the Diagnosis of NEUROD1-MODY

Maturity-onset diabetes of young 'MODY' Type 6 is a rare form of monogenic diabetes caused by mutations in Neuronal differentiation 1 (NEUROD1). Clinical features vary in a large spectrum in terms of age and BMI at diagnosis. Here, we reported the youngest patient with a NEUROD1 variant to the best of our knowledge. A 2.1-year-old girl was referred to pediatric endocrinology clinic for elevated fasting blood glucose (BG) (104 mg/dL) which was detected at another center where she had been evaluated for loss of appetite. Her maternal aunt and uncle had been diagnosed with type 2 diabetes mellitus (DM) at the age of 40 and 45 years; they were obese (BMI: 30.2 and 30.6 kg/m2). At the age of 3.7 years old, she was hospitalized for buccal cellulitis and plasma glucose concentration was 239 mg/dL at admission. Targeted next-generation sequencing (NGS) was performed considering the stress induced hyperglycemia without serious illness, negative islet cell antibodies and insulin autoantibodies, age at the presentation, and family history of DM. NGS analysis revealed a previously reported heterozygous missense variant in NEUROD1. Segregation studies showed that the identified variant was inherited from her 44-year-old mother with a BMI of 27.2 kg/m2 and a normal oral glucose tolerance test (OGTT). Heterozygous NEUROD1 mutations cause low-penetrant diabetes that is heterogeneous in terms of clinical features as some patients fulfill the classic MODY definition and others are mimicking type 2 DM. Clinical manifestations and family history should be carefully evaluated in patients with stress induced hyperglycemia to identify candidate cases for molecular testing, and proper follow-up should be initiated in affected individuals.

Sirolimus treatment of a PTEN hamartoma tumor syndrome presenting with melena.

BACKGROUND: PTEN hamartoma tumor syndrome (PHTS) is an umbrella term including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome. One of the disorders in PHTS spectrum, CS is characterized by macrocephaly, mucocutaneous findings, gastrointestinal system (GIS) polyposis and an increased lifetime risk of GIS, breast, thyroid and other cancers. CASE: In this study, we report an adolescent patient presenting with recurrent life-threatening upper GIS bleeding as a result of hamartomatous polyposis. Genetic studies revealed a known pathogenic nonsense mutation confirming the initial diagnosis of CS. CONCLUSIONS: Additionally, we describe our therapeutic intervention to improve the patient`s clinical symptoms with sirolimus, which its use is infrequently addressed in the literature for pediatric age group harboring PTEN mutations.

De novo interstitial deletion of 11q14.3q22 in a boy with mild intellectual disability and short stature.

BACKGROUND: Interstitial deletions of the 11q region are infrequent. Nonrecurrent chromosomal rearrangements are observed with high variability in size and precise breakpoints of the deleted area. Moreover heterogeneous clinical findings are observed in those harboring 11q interstitial deletions. Main clinical features associated with these deletions include mild dysmorphic findings intellectual disability and moderate developmental or speech delay . METHOD: Conventional high-resolution karyotyping along with microarray studies were performed for the index patient who was found to be a carrier of a de novo interstitial deletion in the long arm of chromosome 11 which is located between the 11q14 and 11q22 band regions. We also investigated the homologous chromosome with next-generation sequencing technology to search for unmasked recessive variants in genes on the nondeleted contralateral allele. RESULTS: Cytogenetic analysis revealed a de novo interstitial deletion on the long arm of chromosome 11 46 XY del(11) (q14q22). Microarray analysis confirmed the deletion of 11.2 Mb in length mapping from 11q14.3 to 11q22.2 [arr (GRCh37) 11q14.3q22.1(90549863_101833022)x1 dn]. Whole-exome sequencing did not detect any other genetic variant (single nucleotide variant ) on the nondeleted allele. CONCLUSION: This study gave us the opportunity for an attempt to define the smallest region of overlap for frequently observed clinical findings by reviewing the literature.

Hypergonadotrophic hypogonadism in a patient with transaldolase deficiency: novel mutation in the pentose phosphate pathway.

BACKGROUND: Transaldolase (TALDO) deficiency (OMIM #606003) is a rare autosomal recessive multi-systemic disorder of carbohydrate metabolism. It has a vast phenotypic spectrum ranging from neonatal liver failure to slowly progressive liver cirrhosis and is characterized by intrauterine growth restriction, hepatosplenomegaly, bicytopenia, nephrolithiasis, and congenital heart disease. METHODS AND RESULTS: We report a patient with a late-onset form of TALDO deficiency characterized by hypergonadotropic hypogonadism and slightly elevated levels of alpha-fetoprotein (AFP). A novel TALDO1 mutation was detected through the application of reverse genetics with the use of clinical exome sequencing (CES). CONCLUSION: This report provides further evidence that reverse genetics is a useful approach in patients who do not manifest the hallmark features of known and recognizable syndromes. TALDO deficiency should be considered in the differential diagnosis of unexplained elevated AFP levels and hypergonadotropic hypogonadism with microlithiasis.

Peters Plus syndrome: a recognizable clinical entity.

Peters plus syndrome is a rare genetic condition wherein multiple systemic involvement with distinctive facial features are manifested, whilst the hallmark is Peters anomaly, occuring from anterior segment dysgenesis. Homozygous variants in the B3GLCT gene were identified to underlie this disorder. We here report on a onemonth- old female patient with typical features characteristic of Peters plus syndrome in whom a homozygous pathogenic mutation in the B3GLCT gene was detected.