ABCD syndrome is caused by a homozygous mutation in the EDNRB gene

ABCD syndrome is an autosomal recessive syndrome characterized by albinism, black lock, cell migration disorder of the neurocytes of the gut (Hirschsprung disease [HSCR]), and deafness. This phenotype clearly overlaps with the features of the Shah-Waardenburg syndrome, comprising sensorineural deafness; hypopigmentation of skin, hair, and irides; and HSCR. Therefore, we screened DNA of the index patient of the ABCD syndrome family for mutations in the endothelin B receptor (EDNRB) gene, a gene known to be involved in Shah-Waardenburg syndrome. A homozygous nonsense mutation in exon 3 (R201X) of the EDNRB gene was found. We therefore suggest that ABCD syndrome is not a separate entity, but an expression of Shah-Waardenburg syndrome.     

Trismus-pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8

Trismus-pseudocamptodactyly syndrome (TPS) is a rare autosomal dominant distal arthrogryposis (DA) characterized by an inability to open the mouth fully (trismus) and an unusual camptodactyly of the fingers that is apparent only upon dorsiflexion of the wrist (i.e., pseudocamptodactyly). TPS is also known as Dutch-Kentucky syndrome because a Dutch founder mutation is presumed to be the origin of TPS cases in the Southeast US, including Kentucky. To date only a single mutation, p.R674Q, in MYH8 has been reported to cause TPS. Several individuals with this mutation also had a so-called "variant" of Carney complex, suggesting that the pathogenesis of TPS and Carney complex might be shared. We screened MYH8 in four TPS pedigrees, including the original Dutch family in which TPS was reported. All four TPS families shared the p.R674Q substitution. However, haplotype analysis revealed that this mutation has arisen independently in North American and European TPS pedigrees. None of the individuals with TPS studied had features of Carney complex, and p.R674Q was not found in 49 independent cases of Carney complex that were screened. Our findings show that distal arthrogryposis syndromes share a similar pathogenesis and are, in general, caused by disruption of the contractile complex of muscle.     

Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase

Gilbert's syndrome, which is characterized by chronic, non-hemolyticunconjugated hyperbilirubinemia, is caused by a reduction inthe activity of hepatic bilirubin UDP-glucuronosyltransferase(UGT). Here, we report that all examined patients with thisdisease carried missense mutations in the gene for UGT and thatthe mutations were heterozygous. An expression study in COScells in vitro, using the expression vector pcDL that carriedthe mutated gene for UGT from a patient, indicated that     

IVIC syndrome is caused by a c.2607delA mutation in the SALL4 locus

The IVIC syndrome described in 1980 in a large Venezuelan family, is an autosomal dominant condition characterized by upper limbs anomalies (radial ray defects, carpal bones fusion), extraocular motor disturbances, congenital bilateral non-progressive mixed hearing loss; other less consistent malformations include heart involvement, mild thrombocytopenia and leukocytosis (before age 50), shoulder girdle hypoplasia, imperforate anus, kidney malrotation or rectovaginal fistula. Since 2002, mutations in the SALL4 locus have been reported producing phenotypic features quite similar to those in IVIC syndrome; this gene was thus proposed as a candidate for the condition. A segregation analysis of four SNPs in exon 2 (c.1520T > G, c.1860A > G, c.2037C > T, and c.2392A > C) was carried out in 14 affected and in 15 normal family members. Haplotype T;A;C;A was found to always segregate with the disease. Sequencing the whole coding regions revealed one heterozygous base deletion in exon 3 (c.2607delA) causing a premature stop signal 44 codons downstream (p.Q869fsX44) which segregates with the phenotype, being absent in controls. The large number of affected individuals presumably carrying the same mutation (n = 26) with quite different degrees of involvement allowed a discussion about possible mechanisms for the SALL4 action. The finding of a SALL4 mutation in a family with such a wide pleiotropic spectrum proves that at least Okihiro, acro-renal-ocular and IVIC syndromes are allelic entities.     

Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a mutation in MYBPC1

Autosomal recessive lethal congenital contractural syndrome (LCCS) is a severe form of neuromuscular arthrogryposis. We previously showed that this phenotype is caused in two unrelated inbred Bedouin tribes by different defects in the phosphatidylinositol pathway. However, the molecular basis of the same phenotype in other tribes remained elusive. Whole exome sequencing identified a novel LCCS founder mutation within a minimal shared homozygosity locus of approximately 1 Mb in two affected individuals of different tribes: a homozygous premature stop producing mutation in MYBPC1, encoding myosin‐binding protein C, slow type. A dominant missense mutation in MYBPC1 was previously shown to cause mild distal arthrogryposis. We now show that a recessive mutation abrogating all functional domains in the same gene leads to LCCS. Hum Mutat 33:1435–1438, 2012. © 2012 Wiley Periodicals, Inc.     

Left-sided CHILD syndrome caused by a nonsense mutation in the NSDHL gene

Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome is a rare X-linked dominant malformation syndrome characterized by unilaterally distributed ichthyosiform nevi, often sharply delimited at the midline, and ipsilateral limb defects. At least two-thirds of cases demonstrate involvement of the right side. Mutations in an essential enzyme of cholesterol biosynthesis, NAD(P)H steroid dehydrogenase-like [NSDHL], have been reported in five unrelated patients with right-sided CHILD syndrome and in a sixth patient with bilaterally, symmetric nevi and mild skeletal anomalies, but not with CHILD syndrome as originally defined. Although all of the molecularly diagnosed cases with the CHILD phenotype to date have had right-sided disease, we report here a novel nonsense mutation (E151X) of NSDHL in an infant with left-sided CHILD syndrome. This result demonstrates that both right- and left-sided CHILD syndrome can be caused by mutations in the same gene.     

Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11

We report a patient with a clinical and molecular diagnosis of LEOPARD syndrome (LS) associated with multiple granular cell tumors (MGCT). Bidirectional sequencing of exons 7, 12, and 13 of the PTPN11 gene revealed the T468M missense mutation in exon 12. This mutation has been previously reported in patients with LS. To our knowledge, this is the first report of MGCT associated with molecularly characterized LS and provides the first molecular evidence linking granular cell tumors (GCT) to the Ras/mitogen-activated protein (MAP) kinase pathway. We propose that MGCT can be associated with LS. Analysis of GCT from this case tested negatively for loss of heterozygosity (LOH) at the PTPN11 and NF1 loci and did not show deletions of the PTEN gene. The absence of LOH of PTPN11 supports published functional data that T468M is a dominant-negative mutation.     

Okamoto syndrome has features overlapping with Au–Kline syndrome and is caused by HNRNPK mutation

Okamoto syndrome is characterized by severe intellectual disability, generalized hypotonia, stenosis of the ureteropelvic junction with hydronephrosis, cardiac anomalies, and characteristic facial gestalt. Several patients have been reported. The basic mechanism of Okamoto syndrome has not been clarified. Au–Kline syndrome is a new syndrome due to loss‐of‐function variants in the HNRNPK (heterogeneous nuclear ribonucleoprotein K) gene. A new patient with Okamoto syndrome visited our hospital. We noticed that the patient had features overlapping with Au–Kline syndrome. We studied the HNRNPK gene by Sanger sequencing, and identified a novel splicing variant. We suggest that Okamoto syndrome is identical to Au–Kline syndrome.     

Recessive congenital myasthenic syndrome caused by a homozygous mutation in SYT2 altering a highly conserved C‐terminal amino acid sequence

Defects in the gene encoding synaptotagmin 2 (SYT2) have been linked to a presynaptic congenital myasthenic syndrome (CMS) and motor neuropathies. However, to date only dominant forms of the disease have been described. We report here a consanguineous patient with a severe recessive form of presynaptic CMS and denervation atrophy caused by the homozygous mutation c.1191delG, p.Arg397Serfs*37 in SYT2. The affected 2‐year‐old girl had profound weakness and areflexia with moderate bulbar deficit. Repetitive nerve stimulation revealed an extreme reduction of compound muscle action potential amplitudes at rest, with a striking facilitation followed by a progressive decline at fast stimulation rates. These findings were reminiscent, but not identical to those seen in the Lambert–Eaton myasthenic syndrome. 3,4 diaminopyridine and pyridostigmine were effective to ameliorate muscle fatigue, but albuterol was ineffective. Modeling of the mutation using the rat Syt1 C2B x‐ray structure revealed that Arg397Serfs*37 disrupts a highly conserved amino acid sequence at the bottom face of the C2B domain not directly involved in calcium binding, but crucial for synaptotagmin‐SNARE interaction and exocytosis. Thus, this report describes a recessive form of synaptotagmin 2‐CMS and highlights the importance of the synaptotagmin C‐terminal on synaptic vesicle fusion and exocytosis.     

先天性梅毒致先天性肾病综合征一例并文献复习

目的探讨先天性梅毒致先天性肾病综合征（CNS）的临床特征及治疗措施。方法先天性梅毒致先天性肾病综合征患儿1例.患儿,女,2月余,因呕吐腹泻5d,腹胀,水肿1d入院。回顾性分析该患儿临床资料,检索国内外文献,进行总结分析。结果患儿急性起病,主要表现为腹胀,水肿,呕吐腹泻,尿隐血3＋,蛋白3＋。生化蛋白降低,血脂升高,梅毒特异性抗体（TPHA）阳性,其母TPHA阳性.经青霉素治疗2周后,尿蛋白,血清蛋白基本恢复正常。检索国内外文献发现,先天性梅毒致先天性肾病综合征患儿均有梅毒接触史,临床以腹胀、水肿为主要表现,符合先天性肾病综合症的主要诊断标准。青霉素足量治疗,疗效较佳,不需激素治疗,预后良好。结论对于CNS伴腹胀,肝脾大患儿应考虑到先天性梅毒致肾病可能,应对患儿父母进行梅毒血清学检查,以期早期确诊.及时足量青霉素治疗是关键。     

Marfan syndrome caused by a novel FBN1 mutation with associated pigmentary glaucoma

Mutations in fibrillin‐1 (FBN1) cause a wide spectrum of disorders, including Marfan syndrome, which have in common defects in fibrillin‐1 microfibrils. Ectopia lentis and myopia are frequently observed ocular manifestations of Marfan syndrome. Glaucoma is also associated with Marfan syndrome, though the form of glaucoma has not been well‐characterized. In this report, ocular examination of a patient diagnosed with Marfan syndrome based on family history and aortic dilatation was performed, including measurement of facility of aqueous humor outflow by tonography. The patient did not have ectopia lentis at the age of 42 years. Based on optic nerve appearance, reduced outflow facility, elevated IOP with open angles and clear signs of pigment dispersion, the patient was diagnosed with pigmentary glaucoma. The patient was heterozygous for a novel truncating mutation in FBN1, p.Leu72Ter. Histology of normal human eyes revealed abundant expression of elastic fibers and fibrillin‐1 in aqueous humor outflow structures. This is the first report of a patient with Marfan syndrome that is caused by a confirmed FBN1 mutation with associated pigmentary glaucoma. In addition to identifying a novel mutation of FBN1 and broadening the spectrum of associated ocular phenotypes in Marfan syndrome, our findings suggest that pigmentary glaucoma may involve defects in fibrillin‐1 microfibrils. © 2013 Wiley Periodicals, Inc.     

晶体蛋白βA1 基因缺失突变导致常染色体显性遗传核性先天性白内障

目的 对一个中国人的常染色体显性遗传核性先天性白内障家系的致病基因进行定位克隆研究。方法 选取候选基因附近的短串联重复序列多态性标记进行连锁分析，对提示连锁的染色体区域内的候选基因测序，寻找突变。结果 该家系致病基因定位在17q11．1-12约11．78cM的范围内，并在候选基因晶体蛋白βA1基因(CRYBA1)的外显子4发现一个密码子缺失(△G91)与家系患者共分离，在正常人群中没有检测到。结论 该家系的核性先天性白内障系由CRYBA基因外显子4的缺失突变△G91引起．这是首次报道由CRYBA1基因突变导致先天性核性自内障表型的发生。     

An epidermal nevus syndrome with cerebral involvement caused by a mosaic FGFR3 mutation

A 5-year-old Mexican girl had a bilateral, systematized epidermal nevus of a non-epidermolytic, non-organoid type covering large parts of her body with the exception of the scalp. Clinically, this nevus was of a soft, velvety type showing affinity to the large body folds. Histopathological examination revealed orthohyperkeratosis and papillomatosis without granular degeneration and without any abnormality of adnexal structures. During infancy she developed seizures, and subsequently a delayed mental development was noted. Computer tomography of the brain revealed cortical and subcortical atrophy, a subdural hygroma in the left frontoparietotemporal region, and hypoplasia of corpus callosum. Molecular analysis of a biopsy specimen obtained from the epidermal nevus revealed a heterozygous R248C hotspot mutation in FGFR3, whereas in normal skin the FGFR3 wild-type allele was exclusively found. The R248C mutation was also present in DNA extracted from blood leukocytes. Because FGFR3 is involved in the development of the central nervous system, the clinical and genetic findings of this case indicate a widespread mosaicism of the FGFR3 mutation. This unusual mosaic phenotype may represent a distinct entity within the group of epidermal nevus syndromes.