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Background The NADH:ubiquinone oxidoreductase complex assembly factor gene (NDUFAF5) has been linked to the occurrence of Leigh syndrome, but few causative mutations have been identified. Here we report a rare case of Leigh syndrome in an infant who died in the early postnatal period. Methods We performed whole‐exome sequencing (WES) and mutation analysis of NDUFAF5 to obtain genetic data on the patient and describe the clinical and genetic characteristics. Results The proband was a 2‐month‐old male infant who suffered from recurrent vomiting and persistent seizure and died at 2 months of age after early medical support and treatment. His parents reported the unexplained death of the infant's older brother at 1 year of age. WES of the patient's DNA revealed c.357C>G and c.611C>T compound heterozygous mutations in NDUFAF5; analysis with the MutationTaster application indicated that both were pathogenic (p = 0.99). Significant structural changes in the transport domain of the protein were predicted using SWISS‐MODEL. We estimated the stability of the mutant protein using a mutation cutoff scanning matrix and found reductions in Gibbs free energy (−0.623 kcal/mol for p.D119E and −0.813 kcal/mol for p.A204V), indicating that the mutations led to an unstable protein structure. We speculated that the patient died as a result of impaired mitochondrial function caused by the NDUFAF5 mutations, and made a diagnosis of Leigh syndrome. Conclusion Our results demonstrate that molecular genetic screening is useful for the diagnosis of mitochondrial diseases, especially in children with a positive family history. Leigh syndrome should be considered in the diagnosis of patients presenting with severe recurrent vomiting and feeding difficulties with persistent seizure. Our findings expand the mutation spectrum of the NDUFAF5 gene and contribute to the genotype–phenotype map of mitochondrial respiratory chain complex I deficiency., Our results demonstrate that molecular genetic screening is useful for the diagnosis of mitochondrial diseases, especially in children with a positive family history. Leigh syndrome should be considered in the diagnosis of patients presenting with severe recurrent vomiting and feeding difficulties with persistent seizure. Our findings expand the mutation spectrum of the NDUFAF5 gene and contribute to the genotype‐phenotype map of mitochondrial respiratory chain complex I deficiency.

Background Unbalanced translocations between the q arm of chromosomes 5 and 13 are exceedingly rare and there is only one reported case with distal trisomy 5q/monosomy 13q. In this report, we describe a second patient with a similar rearrangement arising from a paternal balanced translocation. Methods Karyotype analysis was performed on the proband and their parents. Microarray was also conducted on the proband. Results Our patient was found to have global developmental delay, distinct facial features, short stature, growth hormone deficiency, delayed puberty, and brain anomalies including a small pituitary. Karyotype and microarray analysis revealed a terminal duplication of chromosome regions 5q33.3 to 5qter and a terminal deletion of chromosome regions 13q34 to 13qter that resulted from a balanced translocation in her father. The endocrine abnormalities and neuroimaging findings have not been previously described in patients with either copy number change. Conclusions This case helps expand on the phenotype of patients with distal trisomy 5q/monosomy 13q as well as possibly providing useful information on the more common individual copy number changes., In this report, we describe a patient with a terminal duplication of chromosome regions 5q33.3 to 5qter and a terminal deletion of chromosome regions 13q34 to 13qter. Only one patient has been so far reported with a similar genetic complement, and in our patient, we report unique features including growth hormone deficiency and brain anomalies. We review the clinical features previously described in patients with distal trisomy 5q and monosomy 13q and find that neither of these has been reported in patients with either copy number variation.

Background Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS). Methods and Results We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non‐conserved position of the 5’ donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in‐frame loss of 71 amino acids and a dominant‐negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. Conclusion This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype–phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies., We report on a family with heritable thoracic aortic aneurysm and/or dissection with patent ductus arteriosus (FTAAD/PDA) caused by a variant leading to a skipping of the exon 32 in the MYH11 gene. This transcripts defect previously shown to lead to a strong dominant negative effect in the smooth muscle myosin rod is recurrent. It highlights some unclear genotype‐phenotype correlations suggested by literature with some alleles associated with autosomal dominant FTAAD/PDA while others result in recessive visceral myopathies.

Background Stickler syndrome is a group of connective tissue disorders that can affect eye (myopia, cataract, and retinal detachment), skeleton (spondyloepiphyseal dysplasia and precocious arthritis), craniofacies (midfacial under development and cleft palate), and inner ear (conductive and sensorineural); with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, and COL9A3 procollagen genes cause Stickler syndrome. Case presentation A 16‐year‐old Mongolian girl approached our clinics with retinal detachment. The proband had vitreous degeneration in both eyes, rhegmatogenous retinal detachment in her right eye, a large area of retina degeneration in her left eye, and coupled with severe myopia. No obvious hearing disorder was found, no abnormalities in bones and joints, and her communication and learning capability were also normal. Further clinical examination showed that the patient's other five family members across three generations had vitreous and retina degenerations. Exome sequencing showed a heterozygous splicing variant in COL2A1 in all patients. Conclusions In this case report, a pathogenic splicing variant in the COL2A1 gene was identified in a Mongolian family affected with Stickler syndrome type I by exome sequencing. This heterozygous splicing variant in COL2A1 (NM_001844.4:C.2518‐1G>A) that may impair splicing, which was suggested by in silico prediction. Next‐generation sequencing is helpful for the differential diagnosis of this clinically variable and genetically heterogeneous disorder., For the first time, our study reports a Mongolian family case of STL1 in Chinese population, which expand the spectrum of COL2A1 mutations.

Background Recessive loss‐of‐function mutations in HINT1 are associated with predominantly motor axonal peripheral neuropathy with neuromyotonia. Twenty‐four distinct pathogenic variants are reported all over the world, including four confirmed founder variations in Europe and Asia. The majority of patients carry the ancient Slavic founder variant c.110G>C (p.Arg37Pro) that shows a distribution gradient from east to west throughout Europe. Methods We report a case of HINT1 neuropathy in South America, identified by massive parallel sequencing of a neuropathy gene panel. To investigate the origin of the variant, we performed haplotyping analysis. Results A Brazilian adolescent presented with recessive axonal motor neuropathy with asymmetric onset and fasciculations. Neuromyotonia was found on needle electromyography. His parents were not consanguineous and had no European ancestry. The patient carried biallelic pathogenic p.Arg37Pro alterations in the first exon of HINT1. Both alleles were identical by descent and originated from the same ancestral founder allele as reported in Europe. Conclusion Our findings expand the geographic distribution of HINT1 neuropathy to South America, where we describe a recognized founder variant in a Brazilian adolescent with no apparent European ancestry. We confirm the association of the hallmark sign of neuromyotonia with the disease., Our findings expand the geographic distribution of HINT1 neuropathy to South America, where we describe a recognized founder variant in a Brazilian adolescent with no apparent European ancestry. We confirm the association of the hallmark sign of neuromyotonia with the disease.

Background Combined methylmalonic acidemia and homocystinuria is a rare inherited disorder of intracellular cobalamin metabolism caused by biallelic variants in one of the following genes: MMACHC (cblC), MMADHC (cblD), LMBRD1 (cblF), ABCD4 (cblJ), THAP11 (cblX‐like), and ZNF143 (cblX‐like), or a hemizygous variant in HCFC1 (cblX). Prenatal diagnosis of combined methylmalonic acidemia with homocystinuria is crucial for high‐risk couples since the disorder can be life‐threatening for offspring. We would like to describe two infant deaths both of which are likely attributable to cblC despite not having a genetic confirmation, and subsequent pregnancy and prenatal genetic testing. Methods Parental clinical exome sequencing and targeted Sanger sequencing of MMACHC gene in amniotic fluid was performed to check the carrier status of the fetus. Results Parental clinical exome sequencing revealed a heterozygous pathogenic variant [NM_015506.2:c.217C>T (p.Arg73*)] in the MMACHC gene of the mother and [NM_015506.2:c.609G>A (p.Trp203*)] in the MMACHC gene of the father. Targeted Sanger sequencing of MMACHC gene in amniotic fluid revealed that the fetus carried only one nonsense variant [NM_015506.2:c.609G>A (p.Trp203*)], which was inherited from the father. The mother delivered a healthy baby and the neonate did not show any symptoms or signs of combined methylmalonic acidemia and homocystinuria after birth. Conclusion We present a case of prenatal diagnosis with parental exome sequencing, which successfully diagnosed the carrier status of the fetus and parents in a combined methylmalonic acidemia and homocystinuria family., Figure shows the Sanger sequencing analysis of the family with methylmalonic acidemia and homocystinuria cobalamin C type. We did successfuly prenatal diagnosis of combined methylmalonic acidemia and homocystinuria cobalamin C type using clinical exome sequencing and targeted gene analysis.

Background Terminal deletions of the long arm of chromosome 7 are well known and frequently associated with syndromic holoprosencephaly due to the involvement of the SHH (aliases HHG1, SMMCI, TPT, TPTPS, and MCOPCB5) gene region. However, interstitial deletions including CNTNAP2 (aliases Caspr2, KIAA0868, and NRXN4) and excluding the SHH region are less common. Methods We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients as detected by oligonucleotide‐based array‐CGH analysis. Results The common clinical features were abnormal maternal serum screening during first‐trimester pregnancy, low occipitofrontal circumference at birth, hypotonia, abnormal feet, developmental delay, impaired language development, generalized seizures, hyperactive behavior, friendly personality, and cranio‐facial dysmorphism. Both deletions occurred de novo and sequencing of CNTNAP2, a candidate gene for epilepsy and autism showed absence of mutation on the contralateral allele. Conclusion Combined haploinsufficiency of GALNTL5 (alias GalNAc‐T5L), CUL1, SSPO (aliases SCO‐spondin, KIAA0543, and FLJ36112), AOC1 (alias DAO), RHEB, and especially KMT2C (alias KIAA1506 and HALR) with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia, and exostoses. Haploinsufficiency of PRKAG2 (aliases AAKG, AAKG2, H91620p, WPWS, and CMH6) and KCNH2 (aliases Kv11.1, HERG, and erg1) genes may be responsible of long QT syndrome observed for one patient., Interstitial deletions of the long arm of chromosome 7 including CNTNAP2 and excluding the SHH region are not common. We report the clinical and molecular characterization associated with pure 7q35 and 7q35q36.1 deletion in two unrelated patients. Combined haploinsufficiency of GALNTL5, CUL1, SSPO, AOC1, RHEB and KMT2C with monoallelic disruption of CNTNAP2 may explain neurologic abnormalities, hypotonia and exostoses; haploinsufficiency of PRKAG2 and KCNH2 may be responsible of long QT syndrome observed for one patient.

Background Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1‐related myopathies (RYR1‐RM); the most common subgroup of congenital myopathies. Methods Congenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole‐exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole‐genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis. Results WGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1‐RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries. Conclusion While there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1‐RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.

Background Biallelic pathogenic variants in HTRA1 cause CARASIL. More recently, monoallelic variants have been associated with the autosomal dominant disorder CADASIL2 but not all carriers develop disease manifestations. We describe the clinicoradiologic and mutation spectrum of four new CADASIL2 individuals. Methods Medical records at Mayo Clinic between 2013 and 2020 were retrospectively reviewed to identify patients with cerebral small vessel disease related to monoallelic HTRA1 variants. Results Four patients met the study inclusion criteria for cerebral small vessel disease related to HTRA1 monoallelic variants. The mean age at onset of first clinical stroke was 51.25 years (range 41–64 years). The mean disease duration was 6.5 years (range 4–12). All individuals had recurrent strokes within the duration of follow‐up with a mean number of strokes per patient being 5.5 (range 2–12). Three individuals had leukoencephalopathy with brain stem involvement. Microhemorrhages were seen on brain MRI in three patients. HTRA1 monoallelic variants identified in our cohort were missense variants in three patients and a novel frameshift variation in one patient. Interestingly, two of these missense variants were previously reported in an autosomal recessive pattern of inheritance and here are associated with a dominant effect. Conclusions Clinicoradiologic characteristics of heterozygous HTRA1‐related CSVD may overlap with sporadic CSVD. Heterozygous HTRA1 variants can contribute to dominant or recessive disease mechanisms., Clinicoradiologic features of heterozygous HTRA1‐related CSVD may overlap with sporadic CVSD. The presence of vascular risk factors and a noncontributory family history should not exclude late‐onset CSVD of inherited etiology. HTRA1 variants can be disease‐causing in both heterozygous and biallelic states, but so far, there are no defining variant characteristics to determine the pattern of inheritance.

Background Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare autosomal recessive disorder characterized by severe pre‐ and postnatal growth restrictions, microcephaly, skeletal dysplasia, severe teeth deformities, and typical facial features. Previous studies have shown that MOPD II is associated with mutations in the pericentrin (PCNT) gene. Methods We evaluated the clinical features of a 10‐year and 7‐month‐old Chinese girl with MOPD II. Subsequently, next‐generation sequencing and flow cytometry were performed to investigate genetic characteristics and the expression of PCNT protein respectively. Results The patient presented with short stature, microcephaly, typical craniofacial features, teeth deformity, thrombocytosis, and a delayed bone age (approximately 7 years). No abnormality in growth hormone or insulin‐like growth factor 1 was detected. Notably, the patient was found to carry a novel homozygous PCNT mutation (c.6157G>T, p.Glu2053Ter), which was inherited from her healthy heterozygous parents. Meanwhile, significant deficiency of PCNT expression was identified in the patient. Conclusion Our study identified a novel PCNT mutation associated with MOPD II, expanded the mutation spectrum of the PCNT gene and improved our understanding of the molecular basis of MOPD II., We describe a rare case of MOPD II in a 10‐year and 7‐month old Chinese female. A novel homozygous mutation was identified in exon 30 of the PCNT gene (c.6157G>T, p.Glu2053Ter) by next‐generation sequencing. Meanwhile, flow cytometry revealed a deficiency in the PCNT protein expression of the patient. This is the first report of a Chinese MOPD II patient with a homozygous PCNT gene mutation.

Background Nicolaides–Baraitser syndrome (NCBRS) is a severe neurodevelopmental disorder with multiple abnormalities. To date, all pathogenic variants in SMARCA2 causing NCBRS are de novo and most are missense variants located in the ATPase domain of SMARCA2 protein. Methods In this study, a familial trio whole‐exome sequencing was performed on the proband presenting with intellectual disability, early‐onset epilepsy, and autistic features. A novel missense variant c.553C>G (p.Gln185Glu) in SMARCA2 was identified, which is located in the QLQ domain. The same variant was subsequently also found in the mother's ongoing pregnancy. Samples from accessible tissues such as saliva and sperm other than blood were collected from the parents, and the detection of the target variant was performed by amplicon‐based deep sequencing. Results Low‐level mosaicism of the target variant c.553C>G (p.Gln185Glu) was detected in the father's sperm with allele fraction of 2.8% by amplicon‐based deep sequencing, which was not detected in either parents’ blood or saliva specimens. Heterozygosity of this variant was confirmed in the proband. Conclusion This is the first report of paternal germline mosaicism for a SMARCA2 disease‐causing variant. In addition, the missense variant c.553C>G (p.Gln185Glu) in the QLQ domain causes mainly neurological and developmental phenotypes with unremarkable characteristic facial features and limb abnormalities. Our findings expand the phenotypic spectrum and mode of genetic transmission associated with the SMARCA2 variants., A novel SMARCA2 missense variant in the proband was found due to low‐level paternal germline mosaicism as the first disease‐causing variant in the QLQ domain associated with solely neurological and developmental phenotypes of NCBRS, which provides new insights into the structure–function relationship of this subunit in the SWI/SNF complexes.

Reversible data hiding (RDH) is a recently emerged research domain in the field of information security domain with broad applications in medical images and meta-data handling in the cloud. The amount of data required to handle the healthcare sector has exponentially increased due to the increase in the population. Medical images and various reports such as discharge summaries and diagnosis reports are the most common data in the healthcare sector. The RDH schemes are widely explored to embed the medical reports in the medical image instead of sending them as separate files. The receiver can extract the clinical reports and recover the original medical image for further diagnosis. This manuscript proposes an approach that uses a new lossless compression-based RDH scheme that creates vacant room for data hiding. The proposed scheme uses run-length encoding and a modified Elias gamma encoding scheme on higher-order bit planes for lossless compression. The conventional Elias gamma encoding process is modified in the proposed method to embed some additional data bits during the encoding process itself. The revised approach ensures a high embedding rate and lossless recovery of medical images at the receiver side. The experimental study is conducted on both natural images and medical images. The average embedding rate from the proposed scheme for the medical images is 0.75 bits per pixel. The scheme achieved a 0 bit error rate during image recovery and data extraction. The experimental study shows that the newly introduced scheme performs better when compared with the existing RDH schemes.

Background Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues leading to cumulative disability. The genetic cause of FOP are mutations in the ACVR1 gene that encodes a type I receptor of Bone Morphogenetic Proteins. The most recurrent mutation in FOP patients is R206H affecting the Glycine‐Serine rich domain and causing the hyper‐activation of the receptor and the responsivity to the non‐canonical ligand, Activin A. In the present study, we described a 3‐years old child with early and highly suggestive clinical features of FOP who was found negative for the recurrent p.R206H substitution. Methods Molecular screening of the whole ACVR1 coding sequence and functional characterization in transfection‐based assays. Results and Conclusions We identified a novel, de novo variant in the fifth ACVR1 coding exon (NM_001111067.4:c.772A>T; NP_001104537.1:p.(R258W)). This substitution, never reported in association with FOP, affects a conserved arginine residue in the kinase domain of the protein. In silico analysis predicted the pathogenicity of this substitution, demonstrated by in vitro assays showing that the p.R258W ACVR1 mutated receptor acquires the ability to transduce the aberrant Activin A‐mediated signaling, as observed for the gene variants associated with FOP., FOP is a rare genetic disease representing the most severe and disabling condition due to heterotopic ossification associated with gain‐of‐function mutations of the ACVR1 gene. We describe here a little patient with an early clinical presentation of the disease carrying a novel substituton of the ACVR1 causative gene.

Supplemental Digital Content is available in the text., Autophagy-related long-chain noncoding ribonucleic acids play a vital role in the development of esophageal adenocarcinoma. This study aimed to construct a prognostic model of autophagy-related long-chain noncoding ribonucleic acids and identify potential therapeutical targets for esophageal adenocarcinoma. We downloaded 261 long-chain noncoding RNA transcript samples and clinical data of 87 esophageal adenocarcinoma patients from the Cancer Genome Atlas and 307 autophagy-related genes from www.autophagy.com. We performed Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses and Gene Set Enrichment Analysis to determine risk characteristics and bioinformatics functions of signal transduction pathways. Univariate and multivariate Cox regression analyses were used to determine the correlation between autophagy-related long-chain noncoding ribonucleic acids and independent risk factors. The receiver operating characteristic analysis was used to evaluate the feasibility of the prognostic model. Finally, we performed survival analysis, risk analysis and independent prognostic analysis to verify the prognostic model of esophageal adenocarcinoma. We identified 22 autophagic long-chain noncoding ribonucleic acids that were highly correlated with the overall survival of esophageal adenocarcinoma patients. The areas under the receiver operating characteristic curve (0.941) and the calibration curve were significantly similar. Moreover, univariate and multivariate Cox regression analyses indicated that autophagy-related long-chain noncoding ribonucleic acids were independent predictors of esophageal adenocarcinoma. We found that autophagy-related long-chain noncoding ribonucleic acids might affect tumor development and prognosis in esophageal adenocarcinoma patients. The findings indicate that the prognostic model of esophageal adenocarcinoma has potential therapeutic applications in patients with esophageal adenocarcinoma.

Background Variants in ATP1A3 cause well‐known phenotypes—alternating hemiplegia of childhood (AHC), rapid‐onset dystonia‐parkinsonism (RDP), cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS), and severe early infantile epileptic encephalopathy. Recently, there has been growing evidence for genotype–phenotype correlations in the ATP1A3 variants, and a separate phenotype associated with variants in residue 756—two acronyms are proposed for the moment—FIPWE (fever‐induced paroxysmal weakness and encephalopathy) and RECA (relapsing encephalopathy with cerebellar ataxia). Materials and Methods Herein, we are describing two new pediatric cases with a p.Arg756His change in the ATP1A3 gene. Both patients have had more than one episode of a neurological decompensation triggered by fever with severe hypotonia and followed by ataxia. Thirty‐three cases from literature were analyzed to define and strengthen the genotype‐phenotype correlation of variants located in residue 756 (p.Arg756His, p.Arg756Cys, p.Arg756Leu). Conclusions Patients with a ATP1A3 variant in residue 756 are characterized by recurrent paroxysmal episodes of neurological decompensations triggered by fever, with severe hypotonia, ataxia, dysarthria, symptoms from the orofacial area (dysphagia, drooling) as well as with altered consciousness. Recovery is slow and usually not full with the persistent symptoms of cerebellar ataxia, dysarthria, dystonic and choreiform movements., In this article we analysed and summarized the genotype‐phenotype correlation in patients with a ATP1A3 variant in residue 756 from literature and also we described two new patients with a p.Arg756His variant.

Background The condition of uniparental disomy (UPD) occurs when an individual inherits two copies of a chromosome, or part of a chromosome, from one parent. Most cases of uniparental heterodisomy (UPhD) do not cause diseases, whereas cases of uniparental isodisomy (UPiD), while rare, may be pathogenic. Theoretically, UPiD may cause rare genetic diseases in a homozygous recessive manner. Methods A 4‐year‐old girl presented with congenital hearing loss, developmental delay, hepatomegaly, and other clinical features. She and her parents were genetically tested using trio whole exome sequencing (Trio‐WES) and copy number variation sequencing (CNV‐seq). In addition, we built a structural model to further examine the pathogenicity of the UPiD variants. Results Trio‐WES identified a paternal UPiD in chromosome 1, and two homozygous pathogenic variants AGL c.4284T>G/p.Tyr1428* and USH2A c.6528T>A/p.Tyr2176* in the UPiD region. We further analyzed the pathogenicity of these two variations. The patient was diagnosed with Usher syndrome type 2A (USH2A) and glycogen storage disease type III (GSD3). Conclusions Our study reports a rare case of a patient carrying two pathogenic variants of different genes caused by paternal UPiD, supporting the potential application of Trio‐WES in detecting and facilitating the diagnosis of UPD., Our study reports a rare case of a patient carrying two pathogenic variants of different genes caused by paternal UPiD, supporting the potential application of Trio‐WES in detecting and facilitating the diagnosis of UPD.

Background Rhizomelic chondrodysplasia punctata (RCDP) is a clinical entity resulting from defects of peroxisomal metabolism whose clinical phenotype is characterized by rhizomelia, calcified foci in periarticular cartilage, coronal lesions of vertebral bodies, cataracts and severe cognitive delay. Usually, survival does not exceed the first decade of life. Transmission is autosomal recessive and is related to mutations in the PEX7, GNPAT or AGPS. Methods A detailed description of the prenatal ultrasound signs of RCDP found in two successive pregnancies in a consanguineous couple is reported. Molecular genetic investigations included the study of the coding regions and the exon–intron junctions of the GNPAT (high‐throughput amplification and sequencing performed with Roche NimbleGen SeqCap Target kit on Illumina platform); the confirmation test was carried out by amplification and Sanger sequencing with automatic capillary sequencer. Results In addition to the typical prenatal ultrasound signs described in the literature in association with RCDP, the presence of prefrontal oedema, never previously described, has been detected in both pregnancies. Moreover, genetic investigations have found a new splicing variant c.924+1G>A of the homozygous GNPAT. Conclusion The role of mutation in the GNPAT suggests a likely association with the clinical phenotype., Rhizomelic chondrodysplasia punctata (RCDP) is a rare developmental disorder, characterized by rhizomelic bone shortening and epiphyseal stippling, microcephaly, characteristic facial features and severe psychomotor retardation. Transmission is autosomal recessive and is related to mutations in the PEX7, GNPAT or AGPS genes. A fetal diagnosis of RCDP with a new mutation of the GNPAT gene is reported.

Background Isolated myelosarcoma of infancy is a rare presentation of acute myelogenous leukaemia (AML). Because of its rarity and early onset in infancy underlying genetic predisposition is potentially relevant in disease initiation. Methods and Results We report an oncologic emergency in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma causing acute myelon compression and lower leg palsy. Whole‐exome sequencing of the patient's germline DNA identified a rare PALB2 (OMIM 610355) variant (p.A1079S), which is located in a domain critical for the gene's proper function within the homology‐directed repair pathway. In line with potential DNA damage repair defects mediated by the PALB2 deregulation, the patient's fibroblasts showed increased sensitivity towards radiation and DNA intercalating agents. Conclusion Therefore, we suggest PALB2 p.A1079S as a pathogenic variant potentially contributing to the here observed patient phenotype., We present the finding of an infant with thoracic and intraspinal aleukemic myeloid sarcoma with a rare germline PALB2 variant (p.A1079S). The identified variant is located in a domain critical for the gene's proper function within the homology‐directed repair pathway. A functional role of the variant is further supported by increased sensitivity towards irradiation and DNA intercalating agents observed in primary cells from the patient carrying PALB2 p.A1079S.

Background Understanding the basis of the phenotypic variation in Gaucher's disease (GD) has proven to be challenging for efficient treatment. The current study examined cardiopulmonary characteristics of patients with GD type 1. Methods Twenty Caucasian subjects (8/20 female) with diagnosed GD type I (GD‐S) and 20 age‐ and sex‐matched healthy controls (C), were assessed (mean age GD‐S: 32.6 ± 13.1 vs. C: 36.2 ± 10.6, p > .05) before the initiation of treatment. Standard echocardiography at rest was used to assess left ventricular ejection fraction (LVEF) and pulmonary artery systolic pressure (PASP). Cardiopulmonary exercise testing (CPET) was performed on a recumbent ergometer using a ramp protocol. Results LVEF was similar in both groups (GD‐S: 65.1 ± 5.2% vs. C: 65.2 ± 5.2%, p > .05), as well as PAPS (24.1 ± 4.2 mmHg vs. C: 25.5 ± 1.3 mmHg, p > .05). GD‐S had lower weight (p, Our study demonstrate that patients with Gaucher's disease (GD) type I have an abnormal Cardiopulmonary exercise testing response compared to healthy controls. These findings are likely due to the complex pathophysiologic process in GD that impacts multiple systems integral to the physiologic response to exercise.

Introduction Although over 1000 hemoglobin (Hb) variants were identified so far, Hb Port Phillip compound with α‐thalassemia deletion had no reported before. Methods Two patients and the associated families from Guangdong province in China were recruited. Hematological parameters were determined by blood routine examination and hemoglobin electrophoresis. Genotyping was performed by Gap‐PCR and Sanger sequencing. Results One patient was diagnosed as Hb Port Phillip, while her daughter was compounded with ‐α4.2 deletion, with normal Hb level (150 g/L), mean corpuscular volume (MCV) 108.4 fl and mean corpuscular hemoglobin (MCH) (30.5 pg). Another patient was diagnosed as compound Hb Port Phillip and ‐‐SEA deletion. This proband presented with more severe α‐thalassemia trait than the patient compounded with ‐α4.2 deletion, with hemoglobin 80 g/L, MCV 61.7 fl, and MCH 18.7 pg. Conclusion Here we first time identified two patients compound with Hb Port Phillip and ‐α4.2 and ‐‐SEA deletions, respectively, which had never been reported. Our study widens the genotypes of hemoglobinopathy and provides reference for genetic counselling and prenatal diagnosis in this population., Hemoglobin variants are a group of hereditary hemoglobin diseases and the phenotype ranges from asymptomatic to severe clinical manifestations. Hb Port Phillip was reported with decreased hemoglobin stability and presented as hypochromic polyglobulia microcytic red blood cells. In this study, we first time identified two probands compound with Hb Port Phillip and ‐α4.2 and ‐‐SEA deletions, respectively, and provided reference for genetic counselling and prenatal diagnosis in Chinese population.

Adenoid cystic carcinoma (ACC) is a rare salivary glands tumor and often displays aggressive behavior with frequent relapse and metastasis. The terminal ACC lacks standard treatment guidelines and is always accompanied by poor prognosis. Here, we report a case of rare perianal ACC who received resection and palliative adjuvant radiation. Five years later, PET-computed tomography (CT) showed perianal recurrence and multiple pulmonary metastases. Combined chemotherapy with doxorubicin, carboplatin and cyclophosphamide was applied for two cycles but ineffective. Further next-generation sequencing analysis of perianal tissue demonstrated the v-myb avian myelobastosis viral oncogene homolog and nuclear factor I/B fusion gene and two novel BCL-6 corepressor (BCOR) mutations (p.F1106Tfs*5 and p.L1524Hfs*8). The therapy was switched to eribulin and anlotinib and has been performed for eight cycles. At recent follow-ups, MRI and CT examinations revealed the diminishing perianal and pulmonary lesions. This study presented the first case of perianal ACC with multiple pulmonary metastases and particular BCOR mutations, who presented a durable response to eribulin and anlotinib, providing a potential therapeutic option for advanced refractory ACC.

Background Vascular Ehlers–Danlos syndrome (vEDS) is a heritable connective tissue disorder caused by defects in the type III collagen protein. It is generally considered the most severe form of Ehlers–Danlos syndrome (EDS) due to an increased risk of spontaneous artery or organ rupture. vEDS has an extremely heterogeneous presentation and muscle rupture is considered a minor diagnostic criterium. Methods A patient with a long history of inconclusive examinations and investigations was referred to our unit. The clinical picture was mainly characterized by muscle ruptures, whereas the cardiovascular involvement was limited to mitral regurgitation. We performed a panel analysis of genes associated with inheritable heart diseases using the TruSight Cardio kit (Illumina). A skin biopsy was then performed for functional studies to analyze the different forms of collagen molecules produced in vitro by cutaneous fibroblasts. Results The patient presented the novel variant c.3478A>G (p.Ile1160Val) in COL3A1 (NM_000090.3), whose pathogenicity was supported by biochemical analysis of type III collagen. Conclusion In this report, we describe a case of vEDS with predominant and severe musculoskeletal involvement. Our findings provide insight into genetic variants and clinical expression of vEDS, broadening the clinical scenario of the syndrome., In this report, we describe a case of vEDS with predominant and severe musculoskeletal involvement. Our findings provide insight into genetic variants and clinical expression of vEDS, enlarging the clinical scenario of the syndrome.

Health-related quality of life (HRQoL) is an important consideration in managing patients. Spleen aminopeptide oral lyophilized powder (SAOLP) has been used to enhance cellular immunity in a patient. This multicenter, randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the safety and efficacy of SAOLP for improving HRQoL in patients with breast cancer. Patients diagnosed with advanced breast cancer were included, and were administered SAOLP or placebo 4 mg qd for two cycles. The primary endpoint was improvement in HRQoL on day 42 measured by the EORTC QLQ-C30 and EORTC QLQ-BR23. Secondary endpoints included immunologic function, improvement in HRQoL on day 21 and 84, objective response rate, disease control rate, BMI and adverse events. On day 42, on the EORTC QLQ-C30 or EORTC QLQ-BR23, scores on the functional scales and QoL scale were significantly higher and scores on symptom scales were significantly lower in patients who received SAOLP compared to placebo (P < 0.05). On day 84, the number of CD3, CD4 and CD8 cells were significantly higher in patients who received SAOLP. There were no significant differences in objective response rate, disease control rate or BMI. SAOLP may improve HRQoL and the immune response in patients with advanced breast cancer, represents a convenient and safe adjuvant therapy.

Background Diarrhea is a common occurrence in children below the age of 5 years. In chronic cases, it induces malnutrition that severely stunts growth. Bile acid diarrhea (BAD), caused by malabsorption of bile acid (BA), is a rare form of chronic diarrhea seldom observed in pediatric patients. Here, we present a clinical report on a novel case of chronic BAD, with severe stunting in an infant, induced by a homozygous mutation of SLC10A2. Methods We performed DNA extraction, whole‐exome sequencing analysis, and mutation analysis of SLC10A2 to obtain genetic data on the patient. We subsequently analyzed the patient's clinical and genetic data. Results The patient's clinical manifestations were chronic diarrhea with increased BAs in the feces and extreme stunting, which was diagnosed as BAD. A homozygous mutation of SLC10A2 at the c.313T>C (rs201206937) site was detected. Conclusion Our report reveals the youngest case illustrating the characteristics of BAD induced by genetic variant at 313T>C, and the second case entailing a clear association between a SLC10A2 genetic mutation and the onset of BAD. Our findings expand the mutant spectrum of the SLC10A2 gene and contribute to the refinement of the genotype–phenotype mapping of severe stunting induced by pediatric BAD. Moreover, they highlight the value of molecular genetic screening for diagnosing BAD in young patients., The SLC10A2 313T>C mutation leads to molecular dysfunction, which results in bile acid diarrhea. And the predicted protein stability revealed a decline in Gibbs free energy, indicating an unstable protein structure associated with this mutation.

Background Pyruvate dehydrogenase complex (PDHC) deficiency is a common neurodegenerative disease associated with abnormal mitochondrial energy metabolism. The diagnosis of PDHC is difficult because of the lack of a rapid, accurate, and cost‐effective clinical diagnostic method. Methods A 4‐year‐old boy was preliminarily diagnosed with putative Leigh syndrome based on the clinical presentation. PDHC activity in peripheral blood leukocytes and a corresponding gene analysis were subsequently undertaken. Sodium pyruvate 1‐13C was used for the analysis of PDHC activity in peripheral leukocytes. The genes encoding PDHC were then scanned for mutations. Results The results showed that the corresponding PDHC activity was dramatically decreased to 10.5 nmol/h/mg protein as compared with that of healthy controls (124.6 ± 7.1 nmol/h/mg). The ratio of PDHC to citrate synthase was 2.1% (control: 425.3 ± 27.1). The mutation analysis led to the identification of a missense mutation, NM_000284.4:g214C>T, in exon 3 of PDHC. Conclusion The peripheral blood leukocyte PDHC activity assay may provide a practical enzymatic diagnostic method for PDHC‐related mitochondrial diseases., The peripheral blood leukocyte PDHC activity assay may provide a practical enzymatic diagnostic method for PDHC‐related mitochondrial diseases.

This study describes the feasibility of using the Canadian Occupational Performance Measure (COPM) as a multidisciplinaryoutcome measure for pediatric telerehabilitation (TR). The COPM was administered at monthly time points over four months. A follow-up survey was conducted with the therapists to assess clinical utility of the COPM. Seventy-three percent of the children seen in TR > one month had at least two administrations of the COPM. Eighty percent of therapists agreed or strongly agreed that the COPM was easy to use in a reasonable amount of time, helped identify functional goals, could be used with various children with varied diagnoses, and measured functional change. In 37 children, the median clinical change in performance and satisfaction was two points or greater on the COPM over the episode of TR. The COPM is a feasible measure perceived positively by pediatric therapists for TR use.

The COVID-19 pandemic necessitated a general reorganization of rehabilitation services in Italy. The lockdown in Italy led to the use of telepractice for the delivery of speech therapy, including stuttering. The aim of the present work was to evaluate the effectiveness of the Multidimensional, Integrated, Differentiated, Art-Mediated Stuttering Program (MIDA-SP; Tomaiuoli et al., 2012), delivered online for school-age children who stutter. A non-randomized controlled pre- and post-treatment study included an experimental group (11 children) receiving a telepractice adaptation of MIDA-SP and a historical control group (11 children) receiving in-person MIDA-SP. Both groups had been assessed with the Stuttering Severity Instrument - Fourth Edition (SSI-4) and Overall Assessment of the Speaker's Experience of Stuttering (OASES-S) pre- and post-treatment. No statistically significant differences were found between the two modes of delivery. These findings suggest that MIDA-SP treatment delivered via telepractice is effective for school-age children who stutter.

Funder: Wellcome, Aim: Coats plus syndrome (CP) is a rare autosomal recessive disorder, characterised by retinal telangiectasia exudates (Coats disease), leukodystrophy, distinctive intracranial calcification and cysts, as well as extra‐neurological features including abnormal vasculature of the gastrointestinal tract, portal hypertension and osteopenia with a tendency to fractures. CP most frequently occurs due to loss‐of‐function mutations in CTC1. The encoded protein CTC1 constitutes part of the CST (CTC1‐STN1‐TEN1) complex, and three patients have been described with CP due to biallelic mutations in STN1. Together with the identification of homozygosity for a specific loss‐of‐function mutation in POT1 in a sibling pair, these observations highlight a defect in the maintenance of telomere integrity as the cause of CP, although the precise mechanism leading to the micro‐vasculopathy seen at a pathological level remains unclear. Here, we present the investigation of a fourth child who presented to us with retinal exudates, intracranial calcifications and developmental delay, in keeping with a diagnosis of CP, and later went on to develop pancytopenia and gastrointestinal bleeding. Genome sequencing revealed compound heterozygous variants in STN1 as the likely genetic cause of CP in this present case. Methods: We assessed the phenotype to be CP and undertook targeted sequencing. Results: Whilst sequencing of CTC1 and POT1 was normal, we identified novel compound heterozygous variants in STN1 (previous gene symbol OBFC1): one loss‐of‐function––c.894dup (p.(Asp299Argfs*58)); and one missense––c.707T>C (p.(Leu236Pro)). Conclusion: Given the clinical phenotype and identified variants we suggest that this is only the fourth patient reported to date with CP due to mutations in STN1.

Background X‐linked hyper‐IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects. Methods We identified three patients with XHIGM in Ho Chi Minh City, Vietnam. Whole‐exome sequencing, immunological analyses and western blot were performed to investigate phenotypic and genotypic features. Results Despite showing symptoms typical of XHIGM, including recurrent sinopulmonary infections, oral ulcers and otitis media, the diagnosis was significantly delayed. One patient developed anti‐phospholipid syndrome, which has been documented for the first time in XHIGM syndrome. Two patients had elevated IgM levels and all of them had low IgG levels. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non‐frameshift deletion c.436_438delTAC, stop‐gain c.654C>A). Due to these mutations, the CD40 ligand was not expressed in any of the three patients, as demonstrated by western blot analysis. Conclusion This is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy., X‐linked hyper‐IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non‐frameshift deletion c.436_438delTAC, stop‐gain c.C654A). This first is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy.

Background Costello syndrome (CS, OMIM 218040) is a rare congenital disorder caused by mutations in HRAS. Previous studies reported that approximately 80% of patients with CS share the same pathogenic variant in HRAS gene in c.34G> A (p.G12S). Here, we report a CS patient with c.34G> A (p.G12D) variant in HRAS gene and she presented with special manifestation. Methods and Results We describe a 31‐year‐old female patient who presented with distinctive facial appearance, intellectual disability, dental abnormalities, hyperkeratosis of palmer and planter, loose skin at birth, papillomata on the face and nipples. The whole‐exome sequencing (WES) technology provided by Haotian Biotechnology (China) confirmed p.G12D variant in HRAS gene. To elucidate the typical features of CS with p.G12D variant, we further reviewed these previously reported cases and found that patients with G12D variant died within three months after birth due to multiple organ failure. They had the typical facial characteristics, failure to thrive, skin and cardiac abnormalities, and gene testing confirmed the diagnosis of CS. Conclusion To the best of our knowledge, this is the first article to report a patient with a p.G12D variant that had special but mild manifestation. Moreover, this report and literature review casts new light on the clinical features of p.G12D variant., BLURB FOR ETOC: Costello syndrome with p.G12D mutation in HRAS gene. Costello syndrome with irregular hypo‐and hyperpigmentation.

Background Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma‐pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh‐like syndromes. Methods and Results Here, we describe a case of a 9‐year‐old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder. Conclusion We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant., Progressive cerebellar atrophy in a patient with complexes II and III deficiency and SDHA compound heterozygous variants. These variants were considered pathogenic, given respiratory chain findings, and the family was counseled based on the presence of pathogenic variants.

Background Osteogenesis imperfecta (OI) is a rare heritable bone disorder that is characterised by increased bone fragility and recurrent fractures. To date, only 19 OI patients have been reported, as caused by BMP1 gene mutations, worldwide. Here, we report a patient with a BMP1 gene mutation to explore the relationship between genotype and phenotype, and the patient was followed up for 4 years. Methods Detailed clinical features were collected, and BMP1 mutational analysis was performed by next‐generation sequencing and Sanger sequencing. Results The patient had recurrent fractures, low bone mass, bone deformities and growth retardation but did not have hearing loss or dentinogenesis imperfecta. Next‐generation sequencing and Sanger sequencing revealed a heterozygous novel missense variant (c.362C>T in exon 3, p.Ala121Val) and a heterozygous novel deletion mutation (c.1252delA in exon 10, p.Ser418AlafsX22). The parents of the proband were heterozygous carriers of these mutations. The patient received regular weekly treatment of 70 mg oral alendronate for 3 years, and her BMD Z‐score for the femur significantly increased from −1.3 to 0.9 at L1‐4 and from −1.7 to −0.1. She had no fracture during 4 years of follow‐up. Conclusion We discovered two heterozygous novel mutations in an OI patient with BMP1 gene mutations, expanding the spectrum of gene mutations in OI., Osteogenesis imperfecta (OI) is a rare heritable bone disorder that is characterized by increased bone fragility and recurrent fractures. Up to now, only 19 OI patients have been reported, caused by BMP1 gene mutation around the world. Here, we reported a patient with BMP1 gene mutation, trying to explore the relationship between genotype and phenotype, and the patient was followed up for 4 years.

Background and objectives Treatment of photoaging and intrinsic aging of the chest, with the associated concerns of skin roughness, uneven pigmentation, laxity, atrophy, and telangiectasias, can be problematic because of the potential for worsened esthetic outcomes with existing treatments. This study assessed the efficacy and safety of using nonablative fractional laser therapy (FLT) pretreatment with photodynamic therapy (PDT) versus PDT alone for chest rejuvenation. Study design/materials and methods In a randomized, evaluator-blinded, split-sided study, adult female patients with photodamage to the chest received three treatment courses over an 8-week period with follow-up visits at Weeks 12 and 20. FLT was applied to one side of the chest, randomly assigned at baseline, followed by aminolevulinic acid-based PDT, delivered using a thermal, short incubation, broad area technique, to both sides of the chest. In-person and photographic assessments were conducted using five-point scales to evaluate outcomes including rhytides, pigmentation, skin texture, and telangiectasias. Results Eleven adults completed the study, of whom 11 had improved scores for rhytides and 10 had improved scores for skin texture at Week 20. There was no significant difference in any efficacy outcome between FLT and PDT and standard PDT alone. The severity of adverse events was rated significantly greater with the combined FLT-PDT treatment vs PDT alone. Conclusions Significant improvements were observed vs baseline for both sides of the chest treated with FLT-PDT or standard PDT following three treatment sessions. No significant difference in efficacy was observed between treatment approaches, although adverse events were more severe on the FLT-pretreated side. This study was not registered as it qualified as a nonsignificant risk study. Lasers Surg. Med. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Pegylated liposomal doxorubicin (Peg-Dox) treatment resulted in a good outcome for patients with lymphoma and multiple myeloma, with reduced cardiotoxicity and an improved pharmacokinetic profile when compared to those of conventional doxorubicin. However, the use of Peg-Dox in myeloid neoplasms remains poorly studied. In this study, we first tested the role of Peg-Dox in the killing of myeloid cell lines and of primary myeloid leukemia cells. Then, a Peg-Dox-based protocol was used to treat patients with myeloid neoplasms. The results showed that the Peg-Dox and Peg-Dox-based protocols had a similar killing ability in myeloid cell lines and in primary myeloid leukemia cells compared to that of conventional doxorubicin. The complete remission rate was 87.5% and 100% for patients with refractory/relapsed acute myeloid leukemia and myelodysplastic syndrome with excess blasts, respectively, after treatment with Peg-Dox. All patients developed grade 3 or 4 hematological toxicity and recovered approximately 2 weeks after completing chemotherapy. No deaths or other severe complications were reported. Our results showed that Peg-Dox can be used in the treatment of myeloid neoplasms with high rates of complete remission and with mild complications.

In the past decade, tumour flare reaction (TFR) was considered as a new side effect associated with immunomodulatory agents (IMiDs) and as a condition of chronic lymphocytic leukaemia (CLL). However, this phenomenon is also observed with immune checkpoint inhibitors in solid tumours. It is still poorly understood and its incidence is underestimated. TFR has been associated with morbidity, therefore, early recognition and management of patients with TFR is critical. An exhaustive literature research between 1985 and 2016 was performed using PubMed; American Society of Clinical Oncology and American Society of Hematology abstracts reporting TFR or pseudoprogression were identified. The incidence of TFR in CLL ranged from 28 to 58%. Tumour response in patients treated beyond progression was reported in 9.7% with ipilimumab, 10% with nivolumab, 6.7 and 12% with pembrolizumab, and in renal cell carcinoma 69% with nivolumab. Rare life-threatening or fatal cases were reported; symptoms were usually mild. Studies showed that treating patients beyond progression yielded tumour responses, considering TFR as predictive of response. Treatment with immunomodulatory agents is associated with TFR, often misinterpreted as progression. Therefore, the identification of appropriate clinical benefit criteria and the use of immune-related response criteria in prospective trials for a better understanding are compulsory.

Background and Objectives The ability to provide improved tattoo fading using multiple laser passes in a single office laser tattoo removal session is limited. In part, this is due to the loss of laser effectiveness caused by epidermal and dermal vacuole “whitening” generated during the initial laser pass at the tattoo site. The Rapid Acoustic Pulse (RAP) device generates acoustic shock wave pulses that clear epidermal and dermal vacuoles to enable multiple laser passes in a single office laser tattoo removal session. The objectives of this study were to determine if the RAP device, when used as an accessory to the 1064 nm Nd:YAG Q‐switched (QS) laser can enable delivery of multiple laser passes in a single office laser tattoo removal session, and therefore result in increased tattoo fading compared to the clinical standard single‐pass QS laser tattoo removal session. Study Design/Materials and Methods The RAP device was evaluated in a single‐center (SkinCare Physicians), prospective, IRB approved study. A total of 32 black ink tattoos, from 21 participants, were divided into three zones and treated with either multiple QS laser passes, each followed by 1 minute of RAP device application (Laser + RAP) in zone one and single‐pass QS laser treatment (Laser‐Only) in zone two, separated by an untreated control zone. The treatment sites were assessed for the number of laser passes and adverse events immediately, 6 weeks, and 12 weeks following the treatment session. Photographs of the treatment sites were assessed for percent fading at 12 weeks post‐treatment by three blinded reviewers. Results When the RAP device was applied as an accessory to the QS laser in a multi‐pass laser tattoo removal treatment, an average of 4.2 laser passes were delivered in a single session, with no unexpected or serious RAP device‐related adverse events. At the 12‐week follow‐up, tattoos treated with Laser + RAP showed a statistically significant increase in average fading (44.2%) compared with tattoos treated with Laser‐Only (24.8%) (P 50% fading compared with tattoos treated with QS Laser‐Only (9.4%) (P 75% fading from Laser + RAP treatment (21.9%) compared with Laser‐Only treatment (3.1%) (P

Background and objectives To evaluate the feasibility and efficacy of single-fiber laser ablation (LA) under ultrasound guidance and appropriate ablation modes in the treatment of selected metastatic lymph nodes of papillary thyroid carcinoma (PTC) and benign cold thyroid nodules STUDY DESIGN/MATERIALS AND METHODS: A total of 18 patients (consisting of 8 patients with 18 metastatic lymph nodes of PTC and 10 patients with 10 benign cold thyroid nodules) each underwent one session of single-fiber LA under ultrasound guidance. On the basis of the sizes of the nodules, the ablation modes were chosen accordingly. The single-dot ablation mode was used in the nodules with three orthogonal diameters measuring no greater than 10 mm in diameter, with a dot, a level and an insertion. The double-dots overlapping ablation mode was used in the nodules with the largest diameters measuring greater than 10 mm (in which the nodules measured no more than 15 mm in diameter and with the other two perpendicular diameters measuring no greater than 10 mm in diameter) with two dots, a level and two insertions. The multiple levels and dots overlapping ablation mode was used in the nodules with the three orthogonal diameters all measuring larger than 10 mm, with multiple dots, levels and insertions. Results After 12 months of follow-up in the treated nodules of the metastatic lymph nodes of PTC and benign cold thyroid nodules, the mean baseline volumes decreased from 0.29 ± 0.12 to 0.03 ± 0.03 ml and 3.85 ± 0.64 to 1.1 ± 0.37 ml, respectively, and the mean volume reduction ratios (VRRs), which was calculated as {[(initial volume-final volume) × 100%]/initial volume}, were 90.3 ± 7.6% and 72 ± 5.8%, respectively. There were six ablative zones that completely disappeared, whereas the ablative zones that still existed presented as scar-like areas or small hyperechoic areas that were compatible with scar tissue among the 18 malignant nodules at the last follow-up. Conclusions Single-fiber LA under ultrasound guidance, with the appropriate ablation modes, is feasible and effective for the treatment of selected metastatic lymph nodes of PTC and benign cold thyroid nodules. This study suggests that single-fiber LA may be applied to selected cases with appropriate ablation modes. Lasers Surg. Med. 2019 © 2019 Wiley Periodicals, Inc.

Cantú syndrome (CS), characterized by hypertrichosis, distinctive facial features, and complex cardiovascular abnormalities, is caused by pathogenic variants in ABCC9 and KCNJ8 genes. These genes encode gain‐of‐function mutations in the regulatory (SUR2) and pore‐forming (Kir6.1) subunits of KATP channels, respectively, suggesting that channel‐blocking sulfonylureas could be a viable therapy. Here we report a neonate with CS, carrying a heterozygous ABCC9 variant (c.3347G>A, p.Arg1116His), born prematurely at 32 weeks gestation. Initial echocardiogram revealed a large patent ductus arteriosus (PDA), and high pulmonary pressures with enlarged right ventricle. He initially received surfactant and continuous positive airway pressure ventilation and was invasively ventilated for 4 weeks, until PDA ligation. After surgery, he still had ongoing bilevel positive airway pressure (BiPAP) requirement, but was subsequently weaned to nocturnal BiPAP. He was treated for pulmonary hypertension with Sildenafil, but failed to make further clinical improvement. A therapeutic glibenclamide trial was commenced in week 11 (initial dose of 0.05 mg–1 kg–1 day–1 in two divided doses). After 1 week of treatment, he began to tolerate time off BiPAP when awake, and edema improved. Glibenclamide was well tolerated, and the dose was slowly increased to 0.15 mg−1 kg−1day−1 over the next 12 weeks. Mild transient hypoglycemia was observed, but there was no cardiovascular dysfunction. Confirmation of therapeutic benefit will require studies of more CS patients but, based on this limited experience, consideration should be given to glibenclamide as CS therapy, although problems associated with prematurity, and complications of hypoglycemia, might limit outcome in critically ill neonates with CS.

Background and Objectives Urinary incontinence is a common and distressing condition which interferes with everyday life. Patients frequently experience discomfort related to urine leakage and the subsequent need to use absorbent pads. Since the continence mechanism is primarily maintained by a proper function of pelvic floor muscles (PFM), many treatment methods focused on strengthening of the PFM have been introduced in the past. The aim of this study was to evaluate the safety and efficacy of a high‐intensity focused electromagnetic technology (HIFEM) for treatment of urinary incontinence with emphasis on effects on prospective patients’ quality of life. Study Design/Materials and Methods The study followed an institutional review board approved protocol. A total of 75 women (55.45 ± 12.80 years, 1.85 ± 1.28 deliveries) who showed symptoms of stress, urge, or mixed urinary incontinence were enrolled. They received six HIFEM treatments (2 per week) in duration of 28 minutes. Outcomes were evaluated after the sixth treatment and at the 3‐month follow‐up. The primary outcome was to assess changes in urinary incontinence by the International Consultation on Incontinence Questionnaire‐Short Form (ICIQ‐SF) and changes in the number of absorbent pads used per day. The secondary outcome was subjective evaluation of the therapy and self‐reported changes in quality of life. The statistical analysis was conducted by paired T‐test and Pearson correlation coefficient ( α = 0.05). Results After the sixth session, 61 out of 75 patients (81.33%) reported significant reduction of their symptoms. The average improvement of 49.93% in ICIQ‐SF score was observed after the sixth treatment, which further increased to 64.42% at the follow‐up (both P

Supplemental Digital Content is available in the text., The aims of this study were (i) to evaluate the effect of talazoparib (1 mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6 h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15 min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia’s (QTcF) and Bazett’s (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from −3.5 to 6.9 ms, with the greatest change 1 h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1 mg once daily) had no clinically relevant effects on cardiac repolarization.

BACKGROUND AND OBJECTIVES Cafe-au-lait spots, also known as cafe-au-lait macules (CALMs), are a common pigmentary disorder. Although various laser modalities have been used to treat CALMs, the efficacy of laser treatment in children differs from that in adults. We investigated the efficacy, safety, and clinical factors of the treatment of CALMs using Q-switched alexandrite laser (755 nm) therapy in children. METHODS In total, 471 children with CALMs underwent Q-switched alexandrite laser therapy at a treatment interval of 3-12 months. The safety and efficacy of the laser treatment were evaluated by reviewing clinical records and photographs before and after treatments. RESULTS Of the 471 patients, 140 (29.72%) were cured completely, 124 (26.33%) showed substantial improvement, 110 (23.35%) showed improvement, and 97 (20.60%) showed no improvement after one to nine treatments. The overall treatment success rate was 79.41%, and the treatment efficacy was positively correlated with the number of laser treatments (rs = 0.26, P

The US Food and Drug Association has approved interferon-α (IFN-α) and interleukin-2 (IL-2) as adjuvant therapy in malignant melanoma. The objective of the study was to compare efficacy and safety of subcutaneous interferon-α with continuous intravenous IL-2 in Chinese patients with malignant melanoma. A total of 250 patients with unresectable malignant melanoma were subjected to randomized in 1 : 1 ratio. Patients received subcutaneous 9×106 IU/m2 IFN-α (IFN-α group, n=125) or continuous intravenous 9×106 IU/m2 IL-2 (IL-2 group, n=125) at every 21 days for 4 months. The response, progression-free survival, overall survival, adverse effects, and cost were evaluated by experts in the field. IL-2 and IFN-α were effective in improvement of malignant melanoma after 4 months of intervention. IL-2 was effective in improving brain metastasis. Patients of the IL-2 group had a higher overall survival (P

Supplemental Digital Content is available in the text., This study aimed to explore the correlation between survival and tumor calcification in patients with metastatic colorectal cancer who received cetuximab combined with chemotherapy. The study was a single-center retrospective analysis that enrolled 111 patients who had received therapy between April 2011 and October 2016. Tumor calcification and treatment efficacy were evaluated independently by radiologists on the basis of computed tomography scans. Clinical characteristics and follow-up data were collected from electronic medical records. Correlations between tumor calcification and clinical characteristics, tumor response rate, and patient survival were analyzed. Among the 111 enrolled patients, 27 had tumor calcification [27/111 (24.3%)]. The median progression-free survival was significantly longer for patients with tumor calcification than for those without calcification (9.3 vs. 6.2 months, P=0.022). Patients with tumor calcification also had a higher objective response rate (55.6 vs. 31%, P=0.021) and better overall survival (21.9 vs. 16.5 months, P=0.084). The correlation between calcification features and prognosis showed that patients with an increasing number of calcifications after treatment had a significantly longer median overall survival (22.9 vs. 9.1 months, P=0.033). Simultaneously, new liver metastases and multiple calcifications also showed a trend toward better overall survival. There were also no significant correlations between clinical characteristics (sex, age, gene mutation, primary tumor location, pathological type, blood test result) and survival (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/ACD/A280). Tumor calcification is associated with a better treatment outcome and is a potential prognostic marker.

Author(s): Hosking, Anna-Marie; Coakley, Brandon J; Chang, Dorothy; Talebi-Liasi, Faezeh; Lish, Samantha; Lee, Sung Won; Zong, Amanda M; Moore, Ian; Browning, James; Jacques, Steven L; Krueger, James G; Kelly, Kristen M; Linden, Kenneth G; Gareau, Daniel S | Abstract: ObjectivesEarly melanoma detection decreases morbidity and mortality. Early detection classically involves dermoscopy to identify suspicious lesions for which biopsy is indicated. Biopsy and histological examination then diagnose benign nevi, atypical nevi, or cancerous growths. With current methods, a considerable number of unnecessary biopsies are performed as only 11% of all biopsied, suspicious lesions are actually melanomas. Thus, there is a need for more advanced noninvasive diagnostics to guide the decision of whether or not to biopsy. Artificial intelligence can generate screening algorithms that transform a set of imaging biomarkers into a risk score that can be used to classify a lesion as a melanoma or a nevus by comparing the score to a classification threshold. Melanoma imaging biomarkers have been shown to be spectrally dependent in Red, Green, Blue (RGB) color channels, and hyperspectral imaging may further enhance diagnostic power. The purpose of this study was to use the same melanoma imaging biomarkers previously described, but over a wider range of wavelengths to determine if, in combination with machine learning algorithms, this could result in enhanced melanoma detection.MethodsWe used the melanoma advanced imaging dermatoscope (mAID) to image pigmented lesions assessed by dermatologists as requiring a biopsy. The mAID is a 21-wavelength imaging device in the 350-950 nm range. We then generated imaging biomarkers from these hyperspectral dermoscopy images, and, with the help of artificial intelligence algorithms, generated a melanoma Q-score for each lesion (0 = nevus, 1 = melanoma). The Q-score was then compared to the histopathologic diagnosis.ResultsThe overall sensitivity and specificity of hyperspectral dermoscopy in detecting melanoma when evaluated in a set of lesions selected by dermatologists as requiring biopsy was 100% and 36%, respectively.ConclusionWith widespread application, and if validated in larger clinical trials, this non-invasive methodology could decrease unnecessary biopsies and potentially increase life-saving early detection events. Lasers Surg. Med. 51:214-222, 2019. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Grange syndrome is an autosomal recessive condition characterized by arterial occlusions and hypertension. Syndactyly, brachydactyly, bone fragility, heart defects, and learning disabilities have also been reported. Loss-of-function variants in YY1AP1 have only recently been associated with Grange syndrome. YY1AP1 encodes for the transcription coactivator yin yang 1-associated protein 1 which regulates smooth muscle cell proliferation and differentiation. We here report on three siblings with steno-occlusive arterial disorder and syndactyly in two of them. Whole exome sequencing including near-splice regions led to the identification of two intronic YY1AP1 variants which were predicted to interfere with normal splicing. Sanger sequencing demonstrated compound-heterozygosity in all affected siblings. RT-PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other. This is the first report of biallelic YY1AP1 variants in noncoding regions and just the second family with multiple affected siblings. Therefore, our report further delineates the phenotypic spectrum of Grange syndrome.

Background There is a small, but growing number of reports of pediatric patients with terminal deletions at 3p26.3 involving only the cell adhesion molecule L1‐like (CHL1) gene that has been found to have language delays and intellectual disability. Here we report a one month of age patient who developed seizures and tone abnormalities, with persistent and prominent gross and fine motor delays. The patient has microcephaly and deficits in language and cognitive delays, similar to what has been seen in previous case reports. Methods Chromosome and microarray comparative genomic hybridization (aCGH) analysis was performed to identify clinically significant copy number variants (CNVs). In addition, Fluorescent in‐situ hybridization (FISH) was performed to confirm the aCGH findings. Results Chromosome analysis revealed an apparently normal (46,XX) female karyotype. Microarray CGH analysis revealed a 639 kb loss at 3p26.3 from 62199 to 701052 base pairs encompassing the whole CHL1 gene that was confirmed by FISH. Parental follow‐up revealed the deletion as maternal in origin. Conclusion This case report adds to the limited body of literature that exists on this terminal deletion at 3p26.3 that involves CHL1 gene, and supports prior proposals of an emerging CHL1 microdeletion syndrome that results in language and cognitive delays. Further studies are needed to understand the degree of phenotypic heterogeneity associated with CHL1 gene deletion and whether the size of the deletion or presence of additional copy number variants (CNVs) which were seen in other case reports help predict the expected phenotype for a patient., This case report adds to the limited body of literature that exists on this terminal deletion at 3p26.3 that involves CHL1 gene, and supports prior proposals of an emerging CHL1 microdeletion syndrome that results in language and cognitive delays.

Background Mitochondrial membrane protein‐associated neurodegeneration (MPAN) is a genetic neurodegenerative condition previously thought to be inherited only in an autosomal recessive pattern through biallelic pathogenic variants in C19orf12. Recent evidence has proposed that MPAN can also follow autosomal dominant forms of inheritance. We present a case of a de novo pathogenic variant in C19orf12 identified in a female with clinical features consistent with a diagnosis of MPAN, adding further evidence that the disease can be inherited in an autosomal dominant fashion. Methods A 17‐year‐old Hispanic female was born to non‐consanguineous healthy parents. She developed progressive muscle weakness and dystonia beginning when she was 12 years old. Trio, whole‐exome sequencing with mitochondrial genome sequencing, and deletion/duplication analysis of both nuclear and mitochondrial genomes was performed in December 2019. Results Whole‐exome sequencing analysis revealed a single de novo variant in C19orf12. The specific variant is c.256C>T (p.Q86X) located in exon 3. Conclusion Our clinical report provides further clinical evidence that MPAN can be inherited in an autosomal dominant or recessive fashion. The patient's age of onset and clinical symptoms are very similar to the previous patient published with this specific variant as well as others with heterozygous pathogenic variants in C19orf12 in Gregory et al. 2019. Our case report highlights the importance of considering both autosomal dominant and autosomal recessive version of MPAN with all patients demonstrating clinical features suggestive of MPAN., This article presents a case of a patient with a heterozygous mutation in C19orf12. This gene causes Mitochondrial Membrane Protein Associated Neurodegeneration (MPAN), and has previously been thought to be caused only by autosomal recessive modes of inheritance. We reference two similar publications identifying heterozygous cases of MPAN, and emphasize that our clinical report provides further evidence that MPAN can be caused by homozygous or heterozygous genetic changes in C19orf12.

Background Bardet–Biedl syndrome (BBS) is a rare and genetically heterogeneous disease with a broad spectrum of clinical features, including but not limited to rod‐cone dystrophy, postaxial polydactyly, central obesity, intellectual disability, hypogonadism, and renal dysfunction. Twenty‐one BBS (Bardet–Biedl syndrome) genes have been identified to date. There is minimal mutation information on BBS in Chinese populations and the exact pathogenic mechanism of the null mutation of BBS9 remains unknown. Methods A patient from a Chinese consanguineous family presented with polydactyly, truncal obesity, intellectual disability, genital anomaly, and retinitis pigmentosa was analyzed in this study. Blood DNA and RNA were extracted from the blood of the proband and the parents. The proband was screened for mutations by whole‐exome sequencing. The likely pathogenic mutation detected in the proband was further confirmed by the Sanger sequence in the family. Real‐time RT‐PCR was used to measure the expression of BBS9 in the proband and the control. Results Targeted exome sequencing identified a novel homozygous null mutation (NM_198428.3: c.445C>T) in the 6th exon of the BBS9 gene in the proband and Sanger sequencing was used to validate the heterozygosity in the parents. The mutation was validated to induce the nonsense‐mediated decay of BBS9 messenger RNAs by real‐time RT‐PCR. Conclusions The molecular findings helped to explain the clinical manifestations. The novel homozygous pathogenic variation expanded the mutational spectrum of the BBS9 gene in the Chinese population and will help to understand the pathogenic mechanism of BBS9 null mutation., The study identifies a novel null variation in PTHB1 and validates there is NMD in the nonsense of PTHB1, which will help to interpret the null variation of PTHB1 in BBS patients.

Introduction Patients with a homozygous β0‐thalassemia mutation usually have a transfusion‐dependent β‐thalassemia major phenotype. However, some β‐thalassemia patients present with a relatively mild and even normal phenotype and always have a high level of Hb F induced by genetic modifiers. Methods In this study, we identified a homozygous β0‐thalassemia mutation (HBB: c.126_129delCTTT) in a 36‐year‐old pregnant woman. She had not presented any clinical symptoms of β‐thalassemia since birth. To investigate her unexpected mild phenotype, known genetic modifiers that ameliorate the severity of β‐thalassemia were analysed. Besides, we described the haematological changes during pregnancy. Results Two genetic modifiers (a heterozygous KLF1: c.519_525dup mutation; and two homozygous HBS1L‐MYB locus SNP variants: rs7776054 and rs9399137) were identified. However, she showed a gradually decreased level of Hb during pregnancy, and serious transfusion complication of hyperhaemolysis was induced and complicated the pregnancy. Conclusion This report is in accordance with previous findings that genetic modifiers can ameliorate the clinical severity of β‐thalassemia, even without obvious clinical symptoms in a prolonged steady state. However, the steady state can be disrupted during pregnancy. In addition, raising awareness of hyperhaemolysis among clinicians treating patients with thalassemia is necessary., We identified a homozygous β0‐thalassemia mutation (HBB: c.126_129delCTTT) and two genetic modifiers in a 36‐year‐old pregnant woman, who had not presented any clinical symptoms of β‐thalassemia since birth. However, she showed a gradually decreased level of Hb during pregnancy, and serious transfusion complication of hyperhaemolysis was induced and complicated the pregnancy. ​