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The compression of the proximal part of the celiac trunk by median arcuate ligament of the diaphragm during expiration is defined as median arcuate ligament syndrome. It is a rare cause of chronic mesenteric ischemia. We report two cases with this syndrome, primarily diagnosed by Doppler ultrasound. The diagnosis was confirmed with digital substraction and computed tomography angiography in both cases. The role of ultrasound in the diagnostic work up of this syndrome is discussed with regard to the recent literature. [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta, a common genetic connective tissue disorder affecting bone with multisystemic implications, is caused by genomic alterations at various levels that disrupt the biosynthesis stages of collagen Type I. This study evaluated the intraoral and clinical findings of 43 OI cases in relation to genetic variants, aiming to contribute new insights into the roles of collagen and non-collagen genes in the oral-dental pathology of OI. Significant associations were found between OI variants and dental anomalies such as dentinogenesis imperfecta, enamel hypoplasia, taurodontism, and hypodontia. COL1A1/2-truncated variants were linked to atypical intercanine width, and midface hypoplasia correlated with reduced overjet and overbite. Bisphosphonate treatment, especially when initiated before age two, was associated with enamel hypoplasia. Oral hygiene habits, including brushing frequency and use of additional products, were linked to lower DMFT. In the OI group, significant associations were noted between Angle Class III malocclusion and reduced brushing frequency, as well as between deep palatal vault and increased DMFT. A correlation was also observed between maximum mouth opening and joint hypermobility. These findings, along with new dental observations related to non-collagen variants, shed light on the oral health challenges in OI patients. Our study underscores the importance of multidisciplinary collaboration between dentistry and medical genetics in understanding complex conditions like OI. The comprehensive analysis of oral and dental findings in OI cases is expected to inform future research and enhance clinical approaches to managing the dental challenges associated with this disorder., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest. Patient consent: The data that support the findings of this study are presented within the manuscript and the supplementary materials. Additional data related to this study, within limits of study participant privacy and ethi- cal restrictions, are available on request from the corresponding author., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

SOFT syndrome (SOFTS) is an autosomal recessive disorder caused by biallelic POC1A variants, characterized by short stature, distinctive facial features, onychodysplasia, and hypotrichosis. To date, 21 pathogenic POC1A variants have been reported in 26 families. This study aims to broaden the phenotypic and genotypic spectrum of SOFTS with emphasis on the long-term effects of growth hormone (GH) therapy. We report four unrelated patients with three homozygous POC1A variants and demonstrate the transcriptional effects of two canonical splicing variants. All four patients had severe growth retardation, sparse hair/eyebrows, high/prominent forehead, long/triangular face, prominent nose, short middle/distal phalanges, puffy/tapering fingers, and prominent heels. Endocrine abnormalities included insulin resistance and impaired glucose tolerance, dyslipidemia, GH deficiency, central hypothyroidism, and precocious puberty. Two patients treated long-term with recombinant human GH showed insufficient responses. We also provide an extensive review of 43 cases including those we report, contributing to a better understanding of the full clinical and endocrinological spectrum of SOFTS., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Multiple congenital contractures (MCC) due to fetal akinesia manifest across a broad spectrum of diseases, ranging from mild distal arthrogryposis to lethal fetal akinesia deformation sequence. We hereby present a series of 26 fetuses displaying severe MCC phenotypes from 18 families and describe detailed prenatal ultrasound findings, postmortem clinical evaluations, and genetic investigations. Most common prenatal findings were abnormal facial profile (65%), central nervous system abnormalities (62%), polyhydramnios (50%), increased nuchal translucency (50%), and fetal hydrops (35%). Postmortem examinations unveiled additional anomalies including facial dysmorphisms, dysplastic skeletal changes, ichthyosis, multiple pterygia, and myopathy, allowing preliminary diagnosis of particular Mendelian disorders in multiple patients. Evaluation of the parents revealed maternal grip myotonia in one family. By exome sequencing and targeted testing, we identified causative variants in ACTC1, CHST14, COG6, DMPK, DOK7, HSPG2, KLHL7, KLHL40, KIAA1109, NEB, PSAT1, RAPSN, USP14, and WASHC5 in 15 families, and one patient with a plausible diagnosis associated with biallelic NEB variants. Three patients received a dual diagnosis. Pathogenic alterations in newly discovered genes or in previously known genes recently linked to new MCC phenotypes were observed in 44% of the cohort. Our results provide new insights into the clinical and molecular landscape of lethal MCC phenotypes., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: Multisystemic findings of inherited bone marrow failure syndromes may cause difficulty in diagnosis. Exome sequencing (ES) helps to define the etiology of rare diseases and reanalysis offers a valuable new diagnostic approach. Herein, we present the clinical and molecular characteristics of a girl who was referred for cytopenia and frequent infections., Case Report: A 5-year-old girl with cytopenia, dysmorphism, short stature, developmental delay, and myopia was referred for genetic counseling. Reanalysis of the ES data revealed a homozygous splice-site variant in the DNAJC21 (NM_001012339.3:c.983+1G>A), causing Shwachman-Diamond Syndrome (SDS). It was shown by the RNA sequencing that exon 7 was skipped, causing an 88-nucleotide deletion., Conclusions: Precise genetic diagnosis enables genetic counseling and improves patient management by avoiding inappropriate treatment and unnecessary testing. This report would contribute to the clinical and molecular understanding of this rare type of SDS caused by DNAJC21 variants and expand the phenotypic features of this condition., Competing Interests: The authors have no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Pathogenic biallelic RNPC3 variants cause congenital hypopituitarism (CH) with congenital cataracts, neuropathy, developmental delay/intellectual disability, primary ovarian insufficiency, and pituitary hypoplasia. Here, we aimed to evaluate the clinical and molecular characteristics of 2 patients with CH and neuropathy., Materials and Methods: Proband was evaluated by clinical, laboratory, and radiological exams, followed by exome sequencing (ES). Clinical investigation of an affected sibling and variant segregation in the family was performed by Sanger sequencing. A three-dimensional protein model study was conducted to predict the effect of the variant on the function of the RNPC3 peptide., Results: Proband was a 16-month-old girl who was referred for the evaluation of failure to thrive. Her height, weight, and head circumference were 55.8 cm (-7.6 SDS), 6.5 kg (-3.6 SDS), and 41.8 cm (-3.82), respectively. She had a developmental delay and intellectual disability. Central hypothyroidism, growth hormone, and prolactin deficiencies were identified, and MRI revealed pituitary hypoplasia. Electroneuromyography performed for the gait abnormality revealed peripheral neuropathy. A homozygous novel variant c.484C>T/p.(Pro162Ser) in the RNPC3 was detected in the ES. Her brother had the same genotype, and he similarly had pituitary hormone deficiencies with polyneuropathy., Conclusion: Expanding our knowledge of the spectrum of RNPC3 variants, and apprehending clinical and molecular data of additional cases, is decisive for accurate diagnosis and genetic counseling., (© 2023 S. Karger AG, Basel.)

Introduction: Genetic forms of growth hormone deficiency (GHD) may occur as isolated GHD (IGHD) or as a component of multiple pituitary hormone deficiency (MPHD). This study aimed to present the clinical and molecular characteristics of patients with IGHD/MPHD due to the GH1 gene variants., Methods: A gene panel accommodating 25 genes associated with MPHD and short stature was used to search for small sequence variants. Multiplex ligation-dependent probe amplification was performed in patients with normal panel results to investigate gross deletion/duplications. Segregation in the family was performed by Sanger sequencing., Results: The GH1 gene variants were detected in 5 patients from four unrelated families. One patient had IGHD IA due to homozygous whole GH1 gene deletion and one had IGHD IB due to novel homozygous c.162C>G/p.(Tyr54*) variant. Two patients from a family had previously reported heterozygous c.291+1G>A/p.(?) variant in which clinical and genetic characteristics were compatible with IGHD II accompanying MPHD. One patient had clinical and laboratory characteristics of IGHD II with MPHD but the heterozygous c.468 C>T/p.(R160W) variant had conflicting results about the relationship with the phenotype., Conclusion: Expanding our knowledge of the spectrum of GH1 gene variants by apprehending clinical and molecular data of more cases, helps to identify the genotype-phenotype correlation of IGHD/MPHD and the GH1 gene variants. These patients must be regularly followed up for the occurrence of additional pituitary hormone deficiencies., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Counseling osteogenesis imperfecta (OI) pregnancies is challenging due to the wide range of onsets and clinical severities, from perinatal lethality to milder forms detected later in life., Methods: Thirty-eight individuals from 36 families were diagnosed with OI through prenatal ultrasonography and/or postmortem clinical and radiographic findings. Genetic analysis was conducted on 26 genes associated with OI in these subjects that emerged over the past 20 years; while some genes were examined progressively, all 26 genes were examined in the group where no pathogenic variations were detected., Results: Prenatal and postnatal observations both consistently showed short limbs in 97%, followed by bowing of the long bones in 89%. Among 32 evaluated cases, all exhibited cranial hypomineralization. Fractures were found in 29 (76%) cases, with multiple bones involved in 18 of them. Genetic associations were disclosed in 27 families with 22 (81%) autosomal dominant and five (19%) autosomal recessive forms, revealing 25 variants in six genes (COL1A1, COL1A2, CREB3L1, P3H1, FKBP10, and IFITM5), including nine novels. Postmortem radiological examination showed variability in intrafamily expression of CREBL3- and P3H1-related OI., Conclusion: Prenatal diagnosis for distinguishing OI and its subtypes relies on factors such as family history, timing, ultrasound, genetics, and postmortem evaluation., (© 2024 S. Karger AG, Basel.)

Objective: Recent reports have indicated the role of the prokineticin receptor 2 gene ( PROKR2 ) in the etiology of pituitary hormone deficiencies, suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in gonadotropin releasing hormone-expressing neuron development. Here, we present the clinical and molecular findings of four patients with PROKR2 mutations., Methods: Next-generation targeted sequencing was used to screen 25 genes in 59 unrelated patients with multiple pituitary hormone deficiency (MPHD), isolated growth hormone (GH) deficiency, or idiopathic short stature., Results: Two different, very rare PROKR2 missense alterations classified as pathogenic (NM_144773.4:c.518T>G; NP_658986.1:p. (Leu173Arg)) and likely pathogenic (NM_144773.4:c.254G>A; NP_658986.1:p.(Arg85His)) were identified in four patients in heterozygous form. Patient 1 and Patient 2 presented with short stature and were diagnosed as GH deficiency. Patient 3 and Patient 4 presented with central hypothyroidism and cryptorchidism and were diagnosed as MPHD. No other pathogenic alterations were detected in the remaining 24 genes related to short stature, MPHD, and hypogonadotropic hypogonadism. Segregation analysis revealed asymptomatic or mildly affected carriers in the families., Conclusion: PROKR2 dominance should be kept in mind as a very rare cause of GH deficiency and MPHD. Expressional variation or lack of penetrance may imply oligogenic inheritance or other environmental modifiers in individuals who are heterozygous carriers., Competing Interests: Conflict of interest: None declared, (©Copyright 2023 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)

Classic galactosemia (OMIM#230400) is an autosomal recessive inborn error of carbohydrate metabolism caused by a deficiency of the galactose-1-phosphate-uridyl-transferase enzyme encoded by the GALT gene. Even though a galactose-restricted diet efficiently resolves the acute complications, it is insufficient to prevent long-term complications regarding speech defects, intellectual functioning, premature ovarian failure, cataract, hepatomegaly, dysarthria, ataxia, and tremor. Seventy-seven patients who were genetically diagnosed with classic galactosemia were included in this cohort. Identified novel variants were classified based on their predicted effect on the GALT function. Further, potential genotype-phenotype correlations were investigated via statistical analysis. In total, 18 different sequence variants were identified, including four novels (c.200delG/p.(Arg67Profs * 19), c.533T>G/ p.(Met178Arg), c.708_709delGT/p.(Ser236Argfs * 30), c.467C>A/p.(Ser156 * )). Jaundice was the most common short-term finding with 80% (61/77). Even with early diagnosis, intellectual disability is encountered with 36% (27/74) of the long-term complications. Patients with biallelic missense variants have a significantly higher prevalence of cataracts (OR: 17.9). Longitudinal observations showed attenuation of cataracts and hepatomegaly. This study has shown the GALT variation spectrum of the Turkish population with a 30-year retrospective cohort, submitting a significant contribution to the genotype/phenotype correlation in galactosemia. This study also highlights the cost-effective importance of Sanger sequencing in the diagnosis of single-gene metabolic diseases., (© 2023 University College London (UCL) and John Wiley & Sons Ltd.)

Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed. Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alterations in five other affected family members and healthy parents. Results: Exome sequencing revealed 14 different pathogenic variants in nine genes encoding mitochondrial function peptides ( AARS2, EARS2, ECHS1, FBXL4, MICOS13, NDUFAF6, OXCT1, POLG , and TK2 ) in 12 patients from nine families and four variants in genes encoding important for muscle structure ( CAPN3, DYSF, and TCAP ) in six patients from four families. Three probands carried pathogenic mtDNA variations in two genes ( MT-ATP6 and MT-TL1 ). Nine variants in five genes are reported for the first time with disease association: ( AARS2 : c.277C>T/p.(R93*), c.845C>G/p.(S282C); EARS2 : c.319C>T/p.(R107C), c.1283delC/p.(P428Lfs*); ECHS1 : c.161G>A/p.(R54His); c.202G>A/p.(E68Lys); NDUFAF6 : c.479delA/p.(N162Ifs*27); and OXCT1 : c.1370C>T/p.(T457I), c.1173-139G>T/p.(?). Conclusion: Bi-genomic DNA sequencing clarified genetic etiology in 67% (16/24) of the families. Diagnostic utility by mtDNA sequencing in 13% (3/24) and exome sequencing in 54% (13/24) of the families prioritized searching for nuclear genome pathologies for the first-tier test. Weakness and muscle wasting observed in 17% (4/24) of the families underlined that limb-girdle muscular dystrophy, similar to mitochondrial myopathy, is an essential point for differential diagnosis. The correct diagnosis is crucial for comprehensive genetic counseling of families. Also, it contributes to making treatment-helpful referrals, such as ensuring early access to medication for patients with mutations in the TK2 gene., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gedikbasi, Toksoy, Karaca, Gulec, Balci, Gunes, Gunes, Aslanger, Unverengil, Karaman, Basaran, Demirkol, Gokcay and Uyguner.)

Transaldolase deficiency is a rare inborn autosomal recessive disorder caused by biallelic mutations in the TALDO1 gene. It is characterized by intrauterine growth restriction, dysmorphism, abnormal skin, cytopenia, hepatosplenomegaly, liver cirrhosis, endocrine problems, renal and cardiac abnormalities. We present two siblings of Turkish origin with early-onset form of transaldolase deficiency and hypergonadotropic hypogonadism in both sexes. The girl (index) was followed-up with cryptogenic cirrhosis, leukopenia and thrombocytopenia, skin abnormalities, congenital heart defects, hypercalciuria, nephrolithiasis, proteinuria, chronic kidney disease throughout childhood. She developed hypergonadotropic hypogonadism in adolescence period. Whole exome sequencing due to the multisystemic involvement revealed a previously described homozygous inframe deletion in TALDO1 gene. Her brother was born as a small for gestational age baby and was also followed-up with cryptogenic cirrhosis since his infancy, together with cytopenia, congenital heart defects, bilateral cryptorchidism, short stature, hypercalciuria, proteinuria and chronic kidney disease in childhood. He presented with testicular microlithiasis and hypergonadotropic hypogonadism in adolescence. Sanger sequencing of TALDO1 gene confirmed the presence of the same homozygous deletion with his sister. The mother was found to be a heterozygous carrier for this deletion. We describe two patients with multisystemic involvement since neonatal period who presented with an additional hypergonadotropic hypogonadism in adolescence. The diagnosis of transaldolase deficiency should be kept in mind for these patients, and they must be evaluated for gonadal functions especially during puberty.

Objective: Androgen insensivity syndrome (AIS) and 5α-reductase deficiency (5α-RD) present with indistinguishable phenotypes among the 46,XY disorders of sexual development (DSD) that usually necessitate molecular analyses for the definitive diagnosis in the prepubertal period. The aim was to evaluate the clinical, hormonal and genetic findings of 46,XY DSD patients who were diagnosed as AIS or 5α-RD., Methods: Patients diagnosed as AIS or 5α-RD according to clinical and hormonal evaluations were investigated. Sequence variants of steroid 5-α-reductase type 2 were analyzed in cases with testosterone/dihydrotestosterone (T/DHT) ratio of ≥20, whereas the androgen receptor ( AR ) gene was screened when the ratio was <20. Stepwise analysis of other associated genes were screened in cases with no causative variant found in initial analysis. For statistical comparisons, the group was divided into three main groups and subgroups according to their genetic diagnosis and T/DHT ratios., Results: A total of 128 DSD patients from 125 non-related families were enrolled. Birth weight SDS and gestational weeks were significantly higher in 5α-RD group than in AIS and undiagnosed groups. Completely female phenotype was higher in all subgroups of both AIS and 5α-RD patients than in the undiagnosed subgroups. In those patients with stimulated T/DHT <20 in the prepubertal period, stimulated T/DHT ratio was significantly lower in AIS than in the undiagnosed group, and higher in 5α-RD. Phenotype associated variants were detected in 24% (n=18 AIS, n=14 5α-RD) of the patients, revealing four novel AR variants (c.94G>T, p.Glu32*, c.330G>C, p.Leu110=; c.2084C>T, p.Pro695Leu, c.2585&#95;2592delAGCTCCTG, p.(Lys862Argfs*16), of these c.330G>C with silent status remained undefined in terms of its causative effects., Conclusion: T/DHT ratio is an important hormonal criterion, but in some cases, T/DHT ratio may lead to diagnostic confusion. Molecular diagnosis is important for the robust diagnosis of 46,XY DSD patients. Four novel AR variants were identified in our study.

Objective: The aim of this study was to assess the prevalence of ovarian and paraovarian adrenal rest tumors (ARTs) in gonadectomy materials of a subgroup of congenital adrenal hyperplasia (CAH) patients., Methods: A total of 20 historical cases with clinical/molecular diagnosis of classical CAH were included in the study. All patients had 46,XX karyotype and underwent gonadectomy because of being raised as male., Results: Median age at diagnosis of CAH was 5.7 years and was markedly delayed. All patients revealed severe virilization. Bone age was significantly advanced, and bone age/chronological age ratio was increased with a median ratio of 1.8. Median age at the time of gonadectomy was 9.2 years. Ovarian and paraovarian ARTs were detected during the pathological evaluation of gonadectomy materials in four patients (20%) (two with simple virilizing 21-hydroxylase and two with 11-beta-hydroxylase deficiency) with previously normal pelvic imaging. In three cases with ARTs, paraovarian area was composed of medium-sized polygonal cells, with round or oval monomorphic nuclei and abundant granular eosinophilic cytoplasm which is characteristic of adrenocortical tissue. The fourth case had bilateral ovarian 'steroid cell tumors, not otherwise specified', and the tumor was accepted as benign. Except for the ARTs, heterotopic prostate and bilateral paratubal epididymis tissue were detected in a patient., Conclusions: Ovarian and paraovarian ARTs might be more common than previously described, especially among patients with excessive and prolonged adrenocorticotropic hormone exposure. These tumors could be detected histopathologically even if not detected by classical imaging methods.

Multiple congenital contractures (MCC) comprise a number of rare, non-progressive conditions displaying marked phenotypic and etiologic heterogeneity. A genetic cause can be established in approximately half of the affected individuals, attributed to genetic defects in the formation and functioning of the central and peripheral nervous system, neuromuscular junctions, skeletal muscles, and connective tissue. Ubiquitin-specific protease 14 (USP14) encodes a major proteasome-associated deubiquitinating enzyme with an established dual role as an inhibitor and an activator of proteolysis, maintaining protein homeostasis. Usp14-deficient mice show a phenotype similar to lethal human MCC phenotypes, with callosal anomalies, muscle wasting, and early lethality, attributed to neuromuscular junction defects due to decreased monomeric ubiquitin pool. We describe a new, autosomal recessive MCC phenotype in three fetuses from two different branches of a consanguineous family, presenting with distal arthrogryposis, underdevelopment of the corpus callosum, and dysmorphic facial features. Exome sequencing identified a biallelic 4-bp deletion (c.233&#95;236delTTCC; p.Leu78Glnfs*11, SCV002028347) in USP14, and sequencing of family members showed segregation with the phenotype. RT-qPCR experiment in an unaffected heterozygote revealed that mutant USP14 was expressed, indicating that abnormal transcript escapes nonsense-mediated mRNA decay. We propose that herein described fetuses represent the first human phenotype of USP14 loss, with callosal anomalies and/or cortical malformations, multiple contractures, and recognizable dysmorphic facial features., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by increased bone fragility and deformities. Although most patients with OI have heterozygous mutations in COL1A1 or COL1A2, 17 genes have been reported to cause OI, most of which are autosomal recessive (AR) inherited, during the last years. The aim of this study is to determine the mutation spectrum in Turkish OI cohort and to investigate the genotype-phenotype correlation., Methods: 150 patients from 140 Turkish families with OI phenotype were included in this study. Mutations in OI-related genes were identified using targeted gene panel, MLPA analysis for COL1A1 and whole exome sequencing. 113 patients who had OI disease-causing variants were followed for 1-20 years., Results: OI disease-causing variants were detected in 117 families, of which 62.4% in COL1A1/A2, 35.9% in AR-related genes. A heterozygous variant in IFITM5 and a hemizygous in MBTPS2 were also described, one in each patient. Eighteen biallelic variants (13 novel) were identified in nine genes (FKBP10, P3H1, SERPINF1, TMEM38B, WNT1, BMP1, CRTAP, FAM46A, MESD) among which FKBP10, P3H1 and SERPINF1 were most common. The most severe phenotypes were in patients with FKBP10, SERPINF1, CRTAP, FAM46A and MESD variants. P3H1 patients had moderate, while BMP1 had the mild phenotype. Clinical phenotypes were variable in patients with WNT1 and TMEM38B mutations. We also found mutations in ten genes (PLS3, LRP5, ANO5, SLC34A1, EFEMP2, PRDM5, GORAB, OCRL1, TNFRSF11B, DPH1) associated with diseases presenting clinical features which overlap OI, in eleven families., Conclusion: We identified disease-causing mutations in 83.6% in a large Turkish pediatric OI cohort. 40 novel variants were described. Clinical features and long-term follow-up findings of AR inherited OI types and especially very rare biallelic variants were presented for the first time. Unlike previously reported studies, the mutations that we found in P3H1 were all missense, causing a moderate phenotype., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Three siblings born to Turkish parents from the same village had normal brain development until acute neurological deterioration between 12 months and 8 years of age. Consequent loss of all acquired motor, social, and language functions following infections was associated with a pontine cyst, calcification, and cerebellar atrophy. Exome sequencing revealed a homozygous c.1297G>A (p.Gly433Ser) alteration in BEND4 , which was predicted to be deleterious in in silico analysis tools and segregated in multiple affected individuals in the family. BEND4 has not been associated with any existing disease. Immunofluorescence microscopy analysis of wild-type and mutant BEND4 expressing Vero cells showed nuclear and cytoplasmic localization. Wild-type BEND4 displayed a network-like distribution, whereas mutant BEND4 showed a juxtanuclear distribution pattern. Differential proteome analysis of Vero cells expressing BEND4 revealed that mutant BEND4 expression caused selective increase in reticulocalbin-1 and endoplasmic reticulum resident protein-29. Both proteins are associated with the endoplasmic reticulum and are primarily involved in protein processing and folding pathways. Any defect or stress in protein folding creates stress on cells and may cause chronic damage. This is the first study showing that pathogenic BEND4 variants may lead to an infection-induced acute necrotizing encephalopathy as demonstrated in characteristic neuroimaging findings., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Introduction: The majority of Parkinson's disease (PD) ensue late-onset with a complex spectrum of environmental and genetic risk factors. Awareness of genetic causes in patients with PD is essential for genetic counseling and future genotype-oriented therapeutic developments., Methods: Large pathogenic changes in eight PD-related genes and small pathogenic sequence variants in 22 PD-related genes were investigated simultaneously in 82 PD patients from 79 families where clinical evaluations were performed. The phenotypic characteristics of the patients with molecular changes were examined for genotype-phenotype relations., Results: Pathogenic variants in SNCA, PRKN, DJ-1, FBXO7, and GBA genes were determined in 25 patients from 24 families (24/79, 30%). Associated variants were found in PRKN in 14, SNCA in three, FBXO7 in two, and DJ-1 in one patient. A novel homozygous deletion (c.491delT, p.(V164Dfs*13) (SCV001733595)) leading to protein truncation in the PRKN gene was identified in two patients from the same family. Furthermore, heterozygous GBA gene variants were detected in five patients from different families., Conclusion: It has been shown that the most common cause of genetically transmitted PD is the PRKN gene, while LRRK2 does not play an essential role in this selected population. It has been suggested that even if the autosomal recessive inheritance is expected, genes with autosomal dominant effects such as SNCA should not be overlooked and suggested for investigation. Our study is also the first for evaluating the pathogenic GBA variants' frequency in PD patients from Turkey., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Loss or decrease of function in runt-related transcription factor 2 encoded by RUNX2 is known to cause a rare autosomal-dominant skeletal disorder, cleidocranial dysplasia (CCD). Clinical spectrum and genetic findings in 51 CCD patients from 30 unrelated families are herein presented. In a majority of the patients, facial abnormalities, such as delayed fontanel closure (89%), parietal and frontal bossing (80%), metopic groove (77%), midface hypoplasia (94%), and abnormal mobility of shoulders (90%), were recorded following clinical examination. In approximately one-half of the subjects, wormian bone (51%), short stature (43%), bell-shaped thorax (42%), wide pubic symphysis (50%), hypoplastic iliac wing (59%), and chef's hat sign (44%) presented in available radiological examinations. Scoliosis was identified in 28% of the patients. Investigation of RUNX2 revealed small sequence alterations in 90% and gross deletions in 10% of the patients; collectively, 23 variants including 11 novel changes (c.29&#95;30insT, c.203delAinsCG, c.423 + 2delT, c.443&#95;454delTACCAGATGGGAinsG, c.505C > T, c.594&#95;595delCTinsG, c.636&#95;637insC, c.685 + 5G > A, c.1088G > T, c.1281delC, Exon 6-9 deletion) presented high allelic heterogeneity. Novel c.29&#95;30insT is unique in affecting the P1-driven long isoform of RUNX2, which is expected to disrupt the N-terminal region of RUNX2; this was shown in two unrelated phenotypically discordant patients. The clinical findings highlighted mild intra-familial genotype-phenotype correlation in our CCD cohort., (© 2021 Wiley Periodicals LLC.)

Background: There is evidence that alterations in functional connectivity (FC) of the striatocortical circuits may appear before the onset of clinical symptoms of Parkinson's disease (PD)., Objective: The aim of this study was to investigate FC of the striatocortical circuitry in asymptomatic carriers of heterozygous glucocerebrosidase (GBA) mutations, which pose a significant risk for developing PD., Methods: Twenty-one parents of confirmed Gaucher disease patients who were carrying heterozygous GBA mutations and 18 healthy individuals matched for age and gender were included. GBA mutation analysis was performed in all participants. Clinical evaluation included neurological examination, Mini Mental State Examination, and UPDRS Part III. Structural and functional MRI data of 18 asymptomatic GBA mutation carriers (asGBAmc) and 17 healthy controls (HC) were available. FC was analyzed with seed-based approach., Results: Eleven asymptomatic mutation carriers had heterozygous p.L483P mutation, 6 subjects heterozygous p.N409S mutation and 1 subject heterozygous p.R392G mutation in GBA gene. Mini-Mental State Examination mean score was 28.77 (±1.16) and 29.64 (±0.70) in asGBAmc and HC groups, respectively (p = 0.012). Significant increased connectivityConclusion:Our results suggest that alterations in striatocortical FC can be detected in asymptomatic heterozygous GBA mutation carriers who are at risk of developing PD. These findings may provide insight into network changes during the asymptomatic phase of PD.

Duchenne muscular dystrophy (DMD) has been found to be associated with cognitive impairment. However, few studies have addressed cognitive impairment among mothers of children with DMD. In the present study, the neuropsychological profiles of both carrier mothers (C-Ms) and noncarrier mothers (NC-Ms) were examined, and the findings were compared with healthy control mothers (HC-Ms). There were 90 participants, consisting of 31 C-Ms, 24 NC-Ms, and 35 HC-Ms, each of whom completed a neuropsychological test battery. C-Ms had poorer cognition performance in attention, working memory, immediate verbal memory, visuospatial skills, and executive functions than NC-Ms, and HC-Ms. This study provides evidence that there may be cognitive impairment in mothers of patients with DMD. The cognitive impairment of C-Ms has similarities to that seen in children with DMD., (© 2020 Wiley Periodicals LLC.)

Fanconi anemia (FA) is a rare multigenic chromosomal instability syndrome that predisposes patients to life-threatening bone marrow failure, congenital malformations, and cancer. Functional loss of interstrand cross-link (ICL) DNA repair system is held responsible, though the mechanism is not yet fully understood. The clinical and molecular findings of 20 distinct FA cases, ages ranging from perinatal stage to 32 years, are presented here. Pathogenic variants in FANCA were found responsible in 75%, FANCC, FANCE, FANCJ / BRIP1, FANCL in 5%, and FANCD1 / BRCA2 and FANCN / PALB2 in 2.5% of the subjects. Altogether, 25 different variants in 7 different FA genes, including 10 novel mutations in FANCA, FANCN / PALB2, FANCE, and FANCJ / BRIP1, were disclosed. Two compound heterozygous germline cases were mosaic for one allele, revealing that the incidence of reverse mutations may not be uncommon in FA. Another case with de novo FANCD1/BRCA2 and paternally inherited FANCN/PALB2 pathogenic alleles at first glance suggested a digenic inheritance, because the presence of a second pathogenic variant in the unexamined regions of FANCD1/BRCA2 and FANCN/PALB2 were exluded by sequencing and deletion/duplication analysis. A better understanding of the complexity of the FA genotype may provide further access to undiscovered ICL components and apparently dispensable cellular pathways where FA proteins may play important roles., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Objective: Premature ovarian insufficiency is a lack of ovarian functions in patients younger than 40 years old. Genetic causes leading to accelerated follicle depletion may result in premature ovarian insufficiency. We aimed to determine genetic etiology of nonsyndromic premature ovarian insufficiency cases from Turkey., Materials and Methods: We analyzed 86 nonsyndromic premature ovarian insufficiency cases and 26 matched control female participants. Participants have been investigated in cytogenetic analysis followed by FMR1 repeat size expansions and search of variants for nine premature ovarian insufficiency-associated genes., Results: Four cases had a structural cytogenetic abnormality. Two cases revealed with premutation size FMR1 triplet repeat expansion. Four cases carried variants in which two were very rare in FSHR and PDPK1, and three were novel in NR5A1, PDPK1, and POF1B genes. Six novel variants have been identified in NOBOX, NR5A1, POF1B, and PDPK1 in control population assigned to be benign alterations., Conclusion: Mosaicism of sex chromosomes was responsible in 4.6% and FMR1 premutation in 2.4% of premature ovarian insufficiency cases, while the association of premature ovarian insufficiency-related genes was found very subtle. Novel variants in NR5A1, PDPK1, and POF1B may necessitate further evaluation for their association with premature ovarian insufficiency via functional studies., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Aim: We evaluated the ability of fetal neurosonography and magnetic resonance imaging (MRI) to asses callosal anomalies (CA) and associated cranial malformations. We also aimed to determine the long-term prognosis of the cases., Methods: Thirty-six cases of CA diagnosed combined with neurosonography and MRI between January 2012 and October 2017 were retrospectively reviewed., Results: Seventeen of 36 fetuses were diagnosed complete agenesis of corpus callosum (CACC) (47.2%), 9 had partial agenesis of corpus callosum (PACC) (25%) and 10 was dysgenesis of the corpus callosum (DCC) (27.2%) at ultrasonography (US) examination. Fetal MRI reported 16 of cases as CACC (44.4%), 11 PACC (30.5%) and nine (25%) DCC. The overall consistency between neurosonography and MRI in the definition of CA were 91% of cases. Sulcation anomalies were present in 9 cases in the US (25%) and 11 cases in MRI (30.4%). Seven of cases showed posterior fossa abnormalities in the US (19.4%) and eight cases in MRI (22.1%). Neonatal MRI added new findings to fetal MRI and neurosonography including grade-1 intraventricular hemorrhage and periventricular leukomalacia in two cases (12.5%). Eighteen cases were terminated (50%), 17 cases were followed up and mean follow up interval was 39 ± 5.1 months. The neurologic outcome was abnormal in seven (41.7%) patients. Presence of associated brain anomalies worsened the prognosis., Conclusion: Fetal neurosonography has a comparable performance with MRI in the diagnosis of CA and associated anomalies. It should be used in collaboration with MRI to achieve accurate diagnosis which is crucial for counseling., (© 2019 Japan Society of Obstetrics and Gynecology.)

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by biallelic mutations in GALNS gene and characterized by progressive skeletal deformities with short stature. The aim of this study was to evaluate the genotype, longitudinal height measurement and clinical features of MPS IVA patients. Thirty-two patients from 22 families were enrolled. The ages of patients at diagnosis ranged from two months to 18 years of age, and followed up for three to twenty years. They were classified as severe and attenuated form (intermediate and mild) according to their height measurements. The mean height standard deviation scores (SDS) for Turkish standards at 0-3, 5 and 10 years of ages were found to be -1.1, -4.2 and -7.3 respectively in patients with severe phenotype, while they were +0.4, -1.5 and -3 for intermediate phenotype. Patients with severe form reached a mean final height of -8.5 SDS, and mild phenotype -3.6 SDS. The most common initial and current symptoms in the patients with the severe phenotype were pectus carinatus and/or kyphosis deformities which occurred between 5 months and 3 years of age, and genu valgum deformity which developed after 3 years of age. However, kyphoscoliosis was the most common initial and current findings in the attenuated phenotype. Although, initial symptoms appeared in early childhood in the intermediate phenotype, similar to the severe phenotype, the clinical findings progressed slowly and genu valgum deformity did not develop. In patients with mild phenotype, the onset of symptoms was after 5 years of age. In conclusion, this study provides significant insights into the initial and follow-up clinical features and height values that contribute to the differential diagnosis of the severe and intermediate phenotypes in early childhood. Eleven mutations in GALNS gene in which one of them is novel (c.416G>A) were associated with the severe phenotype and three mutations (c.1038C>A, c.850T>G, c.752G>A) lead to the attenuated phenotype., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Central precocious puberty (CPP) or early puberty (EP) is a rare entity in combined pituitary hormone deficiency (CPHD), the latter caused by mutations in pituitary transcription factor genes. The early onset of puberty in two patients with CPHD with POU1F1 gene mutation was evaluated. A 3-month-old boy was diagnosed with central hypothyroidism, and L-thyroxine was commenced. He was referred for the evaluation of short stature at 20 months of age. Anthropometric evaluation revealed severe short stature (- 6.1 SDS), and growth hormone (GH) and prolactin deficiencies were diagnosed. Homozygous POU1F1 gene mutation (c.731T>G, p. I244S) was also detected. Testicular enlargement and high luteinizing hormone (LH) levels were observed at 7 years and 9 months of age while he was on GH and L-thyroxine treatment. Due to rapid progression of puberty, gonadotropin-releasing hormone analogue (GnRHa) was initiated at 11.3 years of age. This patient recently turned 19.2 years old, and his final height was - 2.3 SDS. The second patient, a 6-month-old boy, was also referred for growth retardation. His height was - 2.7 SDS, and GH and thyroid-stimulating hormone (TSH) deficiencies were diagnosed. He also had homozygous (c.10C>T, p.Q4*) POU1F1 gene mutation. Onset of puberty was relatively early, at 10 years, with advanced bone age. He was on GnRHa treatment between 11.5 and 12.5 years of age. Recent evaluation of the patient was at 13.6 years of age, and he is still on levothyroxine and GH treatment. The relationship between the POU1F1 genotype and CPP or EP has not as yet been firmly established in humans. Animal studies have revealed that the Pou1f1 gene has a major effect on regulation of GnRH receptor function and the Gata2 gene. It has also been demonstrated that this gene controls gonadotrope evolution and prevents excess gonadotropin levels. Further studies are, however, needed to elucidate the relation between POU1F1 function and CPP.

Introduction: Fibrodysplasia ossificans progressiva previously known as myositis ossificans progressiva is a rare connective tissue disorder with autosomal dominant genetic inheritance. Patients develop heterotrophic ossification starting with the first decade of life. Diagnosis is extremely difficult until ossifications are visible., Case Report: We report a case of fibrodysplasia ossificans progressiva in a 5-year-old boy who has characteristic extracapsular joint movement limitation with bilateral great toe malformation. Before clinical suspicion and genetic confirmation, the patient had undergone various medical tests including biopsy. The patient was diagnosed by the help of characteristic great toe malformations with the help of X-ray taken after ossification signs revealed., Conclusion: Fibrodysplasia ossificans progressiva is an unforgiving disease. Late diagnosis can lead the physicians to perform additional invasive test and restrains patients to avoid the exposure of more daily trauma. Although there is no treatment for the disease in current literature, we believe with the characteristic features, it could be diagnosed in short notice and managed properly., Competing Interests: Conflict of Interest: Nil

Background: Pallister Killian syndrome (PKS, OMIM 601803) is a rare genetic disorder with a distinct phenotype caused by tissue- limited mosaicism tetrasomy of the short arm of chromosome 12, which usually cytogenetically presents as an extra isochromosome 12p.Wide phenotypic variability in PKS has been reported, ranging from pre-to perinatal death due to multiple congenital anomalies, especially diaphragmatic hernia, and classic phenotypes including seizures, severe developmental delay, macrosomia at birth, deafness, and distinct dysmorphic features, such as coarse face, temporal alopecia, a small nose with anteverted nostrils, long philtrum, and hypo-/hyper- pigmented streaks on the skin., Results: Karyotypes obtained from cultured peripheral lymphocytes of 13 cases, who were diagnosed as PKS, were normal, while karyotypes obtained from cultured skin samples and buccal mucosa revealed the supernumerary mosaic i(12p). Mosaic karyotype was found in both fibroblast and buccal mucosa in 14 of 15 patients in our series, whereas in one stillbirth, following the clinical diagnosis of PKS, skin and buccal smear samples were taken, and all karyotypes from cultured fibroblasts revealed a supernumerary i(12p), while I-FISH study showed 60% mosaicism in mucosal cells., Conclusions: We here share the clinical, cytogenetic and molecular cytogenetic findings of 15 cases with PKS phenotype and the parental origin of seven i(12p) identified by molecular analyses. To our knowledge, this is the largest series of PKS patients with parental origin study from a single center. We believe that our study makes a significant contribution to the literature because we specifically found no differences in the phenotypes of cases with either a maternal or paternal origin of the extra element and differential imprinting appeared not to be a factor., Competing Interests: These work were a part of routine clinical genetic evaluation. Written informed consent was obtained from the parents for all genetic tests.The parents of patients gave written informed consent allowing the publication of this manuscript and any accompanying images. A copy of the written consent is available and can be sent if desired.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: 17α-hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH), characterized by hypertension and varying degrees of ambiguous genitalia and delayed puberty. The disease is associated with bi-allelic mutations in the CYP17A1 gene located on chromosome 10q24.3. We aimed to present clinical and genetic findings and follow-up and treatment outcomes of 17OHD patients., Methods: We evaluated six patients with 17OHD from five families at presentation and at follow up. Standard deviation score of all auxological measurements was calculated according to national data and karyotype status. CYP17A1 gene sequence alterations were investigated in all patients., Results: The mean (±standard deviation) age of patients at presentation and follow-up time was 14.6±4.2 and 5.0±2.7 years respectively. Five patients were referred to us because of delayed puberty and primary amenorrhea and four for hypertension. One novel single nucleotide insertion leading to frame shift and another novel variant occurring at an ultra rare position, leading to a missense change, are reported, both of which caused 17OHD deficiency. Steroid replacement was started. The three patients with 46,XY karyotype who were raised as females underwent gonadectomy. Osteoporosis was detected in five patients. Four patients needed antihypertensive treatment. Improvement in osteoporosis was noted with gonadal steroid replacement and supportive therapy., Conclusion: 17OHD, a rare cause of CAH, should be kept in mind in patients with pubertal delay and/or hypertension. Patients with 46,XY who are raised as females require gonadectomy. Due to late diagnosis, psychological problems, gender selection, hypertension and osteoporosis are important health problems affecting a high proportion of these patients.

Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11BOHD) is a rare autosomal recessive disorder and the second most common form of CAH., Aim: To investigate genotype-phenotype correlation and to evaluate clinical characteristics and long-term outcomes of patients with 11BOHD., Methods: A total of 28 patients (n = 14, 46,XX; n = 14, 46,XY) with classical 11BOHD from 25 unrelated families were included in this study. Screening of CYP11B1 is performed by Sanger sequencing. Pathogenic features of novel variants are investigated by the use of multiple in silico prediction tools and with family based co-segregation studies. Protein simulations were investigated for two novel coding region alterations., Results: The age at diagnosis ranged from 6 days to 12.5 years. Male patients received diagnose at older ages than female patients. The rate of consanguinity was high (71.4%). Five out of nine 46,XX patients were diagnosed late (age 2-8.7 years) and were assigned as male due to severe masculinization. Twenty one patients have reached adult height and sixteen were ultimately short due to delayed diagnosis. Two male patients had testicular microlithiasis and 5 (35.7%) patients had testicular adrenal rest tumor during follow up. Four patients (28.6%) had gynecomastia. Mutation analyses in 25 index patients revealed thirteen different mutations in CYP11B1 gene, 4 of which were novel (c.393 + 3A > G, c.428G > C, c.1398 + 2T > A, c.1449&#95;1451delGGT). The most frequent mutations were c.896T > C with 32%, c.954G > A with 16% and c.1179&#95;1180dupGA with 12% in frequency. There was not a good correlation between genotype and phenotype; phenotypic variability was observed among the patients with same mutation., Conclusion: This study presents the high allelic heterogeneity of CYP11B1 mutations in CAH patients from Turkey. Three dimensional protein simulations may provide additional support for the pathogenicity of the genetic alterations. Our results provide reliable information for genetic counseling, preventive and therapeutic strategies for the families., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by skeletal anomalies such as delayed closure of the cranial sutures, underdeveloped or absent clavicles, multiple dental abnormalities, short stature and osteoporosis. RUNX2, encoding Runt DNA-binding domain protein important in osteoblast differentiation, is the only known gene related to the disease and identified as responsible in 70% of the cases. Our clinical evaluations revealed that short stature present at a rate of 28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%. In this study, RUNX2 sequencing revealed nine different variations in 11 families, eight being pathogenic of which one was novel gross insertion (c.1271&#95;1272ins20) and one other being predicted benign in frame gross deletion (c.241&#95;258del)., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)