掌跖角化-牙周破坏综合征临床诊断与治疗

目的：了解掌跖角化一牙周破坏综合征（PLS）临床诊断与治疗。方法：收集并调查一例掌跖角化一牙周破坏综合征病例,进行家谱分析,对其进行全口义齿修复。并对相关文献进行回顾。结果：掌跖角化一牙周破坏综合征是一种罕见的以严重牙周组织破坏及掌跖、膝盖、肘部等部位皮肤过度角化为特征的常染色体隐性遗传病,发病年龄早,最终可导致全口牙列缺失。全口义齿修复可获得较满意的效果。结论：早期发现、早期治疗对改善PLS的预后是非常重要的。     

婴儿及少儿型常染色体隐性多囊性肾病的CT与MRI表现

目的 观察婴儿及少儿型常染色体隐性多囊性肾病（ARPKD）的CT、MRI表现。方法 回顾性分析11例婴儿及少儿型ARPKD患者腹部CT及MRI上肝叶比例、双肾体积改变以及胆管与肾脏囊样病灶的表现。结果 11例婴儿及少儿型ARPKD患者中,5例（5/11,45.45%）肝叶比例失调。5例（5/11,45.45%）中央区域肝内胆管以梭形扩张为主、3例（3/11,27.27%）肝边缘部胆管扩张明显、3例（3/11,27.27%）沿门静脉周围可见多发囊样灶。2例（2/11,18.18%）肾脏体积增大。8例（8/11,72.73%）双肾髓质可见多发小囊样灶、3例（3/11,27.27%）双肾皮髓质多发囊肿。8例（8/11,72.73%）门静脉增粗、脾大。2例（2/11,18.18%）腹部可见多发肿大淋巴结。5例（5/11,45.45%）MR平扫T1WI显示双肾皮髓质分界不清。结论 婴儿或少儿型ARPKD以肝胆改变为主,特征性CT及MRI表现为肝叶比例与肾脏体积的改变合并胆管扩张及双肾囊样灶。     

Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well‐characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family‐based whole‐exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype–phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.     

MCPH1 deletion in a newborn with severe microcephaly and premature chromosome condensation

A newborn with severe microcephaly and a history of parental consanguinity was referred for cytogenetic analysis and subsequently for genetic evaluation. While a 46,XY karyotype was eventually obtained, premature chromosome condensation was observed. A head MRI confirmed primary microcephaly. This combination of features focused clinical interest on the MCPH1 gene and directed genetic testing by sequence analysis and duplication/deletion studies disclosed a homozygous deletion of exons 1–11 of the MCPH1 gene. This case illustrates a strength of standard cytogenetic evaluation in directing molecular testing to a single target gene in this disorder, allowing much more rapid diagnosis at a substantial cost savings for this family.     

Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1

IntroductionNext generation sequencing technologies allow detection of very rare pathogenic gene variants and uncover cerebral palsy. Herein, we describe two siblings with cerebral palsy due to ELOVL1 splice site mutation in autosomal recessive manner. ELOVL1 catalyzes fatty acid elongation to produce very long-chain fatty acids (VLCFAs; ≥C21), most of which are components of sphingolipids such as ceramides and sphingomyelins. Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies (MIM: 618527) stem from ELOVL1 gene deficiency in human.MethodsWe have studied a consanguineous family with whole exome sequencing (WES) and performed in depth analysis of cryptic splicing on the molecular level using RNA. Comprehensive analysis of ceramides in the skin stratum corneum of patients using liquid chromatography-tandem mass spectrometry (LC–MS/MS). ELOVL1 protein structure was computationally modelled.ResultsThe novel c.376-2A > G (ENST00000372458.8) homozygous variant in the affected siblings causes exon skipping. Comprehensive analysis of ceramides in the skin stratum corneum of patients using LC–MS/MS demonstrated significant shortening of fatty acid moieties and severe reduction in the levels of acylceramides.DiscussionIt has recently been shown that disease associated variants of ELOVL1 segregate in an autosomal dominant manner. However, our study for the first time demonstrates an alternative autosomal recessive inheritance model for ELOVL1. In conclusion, we suggest that in ultra-rare diseases, being able to identify the inheritance patterns of the disease-associated gene or genes can be an important guide to identifying the molecular mechanism of genetic cerebral palsy.     

Early replacement therapy in a first Japanese case with autosomal recessive guanosine triphosphate cyclohydrolase I deficiency with a novel point mutation

Autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency is an inborn error of tetrahydrobiopterin (BH4) synthesis from GTP. GTPCH deficiency causes severe reduction of BH4, resulting in hyperphenylalaninemia (HPA) and decreased dopamine and serotonin synthesis. Without treatment, a patient with GTPCH deficiency develops complex neurological dysfunctions, including dystonia and developmental delays. The first Japanese patient with GTPCH deficiency was discovered by HPA during asymptomatic newborn screening. The phenylalanine level at the age of 5 days was 1273 μmol/L (cutoff value, 180.0 μmol/L). The high serum phenylalanine level was decreased to normal after adequate BH4 oral supplementation. Serum and urinary pteridine examination revealed very low levels of neopterin and biopterin. Sequence analysis of GCH1 revealed compound heterozygous point mutations, including a novel point mutation (p.R235W). Replacement therapy with BH4 and L-dopa/carbidopa were started at the age of 1 month, and 5-hydroxytryptophan (5-HTP) was started at the age of 5 months. At 10 months of age, the patient showed slight dystonia but no obvious developmental delay. Cerebrospinal fluid should be examined to determine the appropriate dosage of supplement drugs. In conclusion, it is important to control the serum phenylalanine level and perform early replacement of neurotransmitters to prevent neurological dysfunction.     

Identification of novel variants in Iranian consanguineous pedigrees with nonsyndromic hearing loss by next-generation sequencing

BackgroundThe extremely high genetic heterogeneity of hearing loss due to diverse group of genes encoding proteins required for development, function, and maintenance of the complex auditory system makes the genetic diagnosis of this disease challenging. Up to now, 121 different genes have been identified for nonsyndromic hearing loss (NSHL), of which 76 genes are responsible for the most common forms of NSHL, autosomal recessive nonsyndromic hearing loss (ARNSHL).MethodsAfter excluding mutations in the most common ARNSHL gene, GJB2, by Sanger sequencing, genetic screening for a panel of genes responsible for hereditary hearing impairment performed in 9 individuals with ARNSHL from unrelated Iranian consanguineous pedigrees.ResultsOne compound heterozygote and eight homozygote variants, of which five are novel, were identified: CDH23:p.(Glu1970Lys), and p.(Ala1072Asp), GIPC3:p.(Asn82Ser), and (p.Thr41Lys), MYO7A:p.[Phe456Phe]; p.[Met708Val], and p.(Gly163Arg), TECTA:p.(Leu17Leufs*19), OTOF:c.1392+1G>A, and TRIOBP:p.(Arg1068*). Sanger sequencing confirmed the segregation of the variants with the disease in each family.ConclusionFinding more variants and expanding the spectrum of hearing impairment mutations can increase the diagnostic value of molecular testing in the screening of patients and can improve counseling to minimize the risk of having affected children for at risk couples.