Pendred syndrome among patients with congenital hypothyroidism detected by neonatalscreening: identification of two novel <Emphasis Type="Italic">PDS/SLC26A4</Emphasis> mutations

Pendred syndrome is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by mutations in the PDS/SLC26A4 gene (OMIM 605646) encoding for pendrin. Hypothyroidism in Pendred syndrome can be—although rarely—present from birth and therefore diagnosed by neonatal screening. The aim of our study was to identify patients with Pendred syndrome among a historical cohort of patients with congenital hypothyroidism (CH) identified by neonatal screening, and to find their mutations in the PDS/SLC26A4 gene. We investigated 197 Czech Caucasian children with CH detected by the neonatal screening between the years 1985 and 2005. The clinical diagnosis of Pendred syndrome was based on the laboratory and sonographic signs of thyroid dyshormonogenesis in association with sensorineural hearing loss. In subjects clinically diagnosed with Pendred syndrome, we sequenced all exons and exon-intron boundaries of the PDS/SLC26A4 gene. Hearing loss was present in 10/197 children with screening-detected CH. Of these, three fulfilled the diagnostic criteria of Pendred syndrome. Two patients were compound heterozygotes for PDS/SLC26A4 mutations: patient 1 carried c.2089+1G>A / c.3G>C and patient 2 carried p.Tyr530His / p.Val422Asp. Two of the four identified mutations were novel (c.3G>C in patient 1 and p.Val422Asp in patient 2). The third patient was free of mutations in the PDS/SLC26A4 gene, representing a phenocopy. In conclusion, our results indicate the rarity of Pendred syndrome as a cause of CH. The identification of two novel mutations expands the spectrum of mutations in the PDS/SLC26A4 gene and emphasizes their marked allelic heterogeneity. The study was supported by grants of the Czech Ministry of Education (MSM 0021620814) and Charles University in Prague (GAUK 2008/2007).     

Pendred syndrome

Pendred Syndrome, first described in 1896, is phenotypically characterized as the coexistence of sensorineural deafness and enlarged goiter with elevated iodine discharge after perchlorate administration. In 1996 the syndrome was mapped to chromosome 7 and the following year, the responsible gene was cloned and mutations were identified. The gene, pds, codes for a 780 amino acid protein, pendrin, which functions as an ion transporter. Located on the apical membrane of thyrocytes, it appears to be responsible for the transport of iodide out of the cell into the colloid where iodination of thyroglobulin occurs, catalyzed by the enzyme thyroid peroxidase. In the absence of the transporter, apical iodide transport is defective and thus organification of iodide is defective, the hallmark of Pendred Syndrome. However, organification is only partially deficient, even in the complete absence of pendrin, suggesting that other, as yet undefined, mechanisms exist that can partially compensate for lack of the protein. The pathophysiology of the hearing loss associated with Pendred syndrome is less well understood. Animal studies suggest that abnormal transporter function may cause abnormal endolymphatic pressure or composition and this results in secondary degeneration of sensory cells and in structural changes of the inner ear. This mechanism, although yet to be proven, suggests the intriguing possibility that early diagnosis and intervention could perhaps prevent at least some of the hearing loss.     

Solitary thyroid nodule as presenting symptom of Pendred syndrome caused by a novel splice-site mutation in intron 8 of the <Emphasis Type="Italic"> SLC26A4</Emphasis> gene

Thyroid nodules are a rare occurrence in children but represent an important clinical problem because of the possibility of malignancy. We report the case of a 4-year-old boy with sensorineural deafness, who presented with a painless mass in the right anterior cervical region. Cervical ultrasound demonstrated a solid nodule (1.4×2.5×1.7 cm) in the right thyroid lobe. Thyroid function tests revealed compensated hypothyroidism (free T4 1.0 ng/dl; TSH 57 mIU/l) with no detectable thyroid antibodies. A ^99m Tc thyroid scan showed a generalised slightly increased tracer retention (4.6%) with an enlarged right lobe, without distinct nodules. A fine-needle aspiration biopsy revealed normal follicular cells. The boy was treated with l-thyroxine which resulted in a complete clinical and sonographical disappearance of the nodule. A CT scan of temporal bones revealed a bilaterally enlarged vestibular aqueduct with Mondini malformation of the cochlea. The combination of all these symptoms suggested the diagnosis of Pendred syndrome (PDS), a disorder characterised by congenital sensorineural hearing loss and a variable degree of thyromegaly due to mutations in the SLC26A4/PDS gene. DNA analysis disclosed a so far unreported homozygous splice site mutation (1002–4 C>G) in intron 8 of the SLC26A4 gene confirming this diagnosis. Conclusion: a solitary thyroid nodule may therefore be another presenting symptom of thyroid involvement in Pendred syndromeAbbreviation PDS Pendred syndrome     

Identification of SLC26A4 gene mutations in Iranian families with hereditary hearing impairment

Mutations in the SLC26A4 gene at the DFNB4 locus are responsible for Pendred syndrome and non-syndromic hereditary hearing loss (DFNB4). This study included 80 nuclear families with two or more siblings segregating presumed autosomal recessive hearing loss. All deaf persons tested negative for mutations in GJB2 at the DFNB1 locus and were, therefore, screened for autozygosity by descent (ABD) using short tandem repeat polymorphisms (STRPs) that flanked SLC26A4. In 12 families, homozygosity for STRPs suggested possible ABD in this genomic region. Affected individuals in five families had a positive perchlorate discharge test. Sequence analysis of SLC26A4 identified ten mutations in eight families (T420I, 1197delT, G334V, R409H, T721M, R79X, S448L, L597S, 965insA and L445W), of which, four are novel (T420I, G334V, 965insA and R79X). These results imply that Pendred syndrome is the most prevalent form of syndromic hereditary hearing loss in Iran.     

The association of thyroid dyshormonogenesis and deafness (Pendred syndrome): Experience of the Victorian Neonatal Thyroid Screening Programme

Between 1977 and 1989, the Victorian Neonatal Thyroid Screening Programme detected five subjects with thyroid dyshormonogenesis and sensorineural deafness. These patients have been diagnosed as having Pendred syndrome. In two of the children, thyroid function tests which were initially abnormal at birth returned to normal spontaneously without treatment. However, hypothyroidism subsequently recurred and the children required thyroxine therapy. These two children could have been mistakenly diagnosed as having transient hypothyroidism. The detection of five patients with Pendred syndrome illustrates the importance of audiological assessment in all babies with thyroid dyshormonogenesis in whom there is increased uptake of isotope on thyroid scanning. In our experience, hearing loss in patients with Pendred syndrome may be progressive over time, so that repeated audiological assessments are necessary.     

Two novel mutations in the human thyroid peroxidase (TPO) gene: genetics and clinical findings in four children

We report four children originating from two unrelated German families with congenital hypothyroidism (CH) due to mutations in the thyroid peroxidase (TPO) gene. Three female siblings (family 1) were found to be compound heterozygous for two mutations, a known mutation in exon 9 (W527C), and a mutation in exon 8 (Q446H), which has not been described before. In the second family we identified a boy with goitrous CH, who had a novel homozygous mutation in the TPO gene in exon 16 (W873X). All children of family 1 were diagnosed postnatally by newborn screening. The case of the boy of family 2 has already been reported for the in utero treatment of a goiter with hypothyroidism.
Conclusion: Our results confirm existing data on the phenotypic variability of patients with TPO gene mutations.     

A novel SGCE gene mutation causing myoclonus dystonia in a family with an unusual phenotype

Background: Myoclonus dystonia is an autosomal dominant dystonia‐plus syndrome, characterized by symptom variability within families. Most often is the myoclonus the most debilitating symptom, and many patients report myoclonus reduction after alcohol intake. In several families, mutations in the SGCE gene have been identified. Method: We report of a three‐generation family with myoclonus dystonia displaying a varied phenotype and maternal imprinting. Additionally, this family displays some unusual clinical presentations including alcohol‐induced dystonia in an adult man, which will be discussed. Results: A novel mutation c.386T>C [p.I129T] was found within exon 3 of the SGCE gene in all three affected family members. In addition, two additional mutations [c.305G>A and IVS3+15G>A], judged to be polymorphisms in the SGCE gene, were found in two affected and one healthy family member. Conclusions: This report presents a novel mutation in the SGCE gene causing myoclonus dystonia and extends the phenotype of myoclonus dystonia to also include alcohol‐induced dystonia.     

儿童Alport综合征COL4A5基因4种新突变分析

目的 分析4例儿童Alport综合征的基因型和临床表型特点。方法 总结4例患儿的临床特点,采用外显子捕获-第二代测序技术对4例诊断为Alport综合征患儿的COL4A5、COL4A4和COL4A3基因进行突变检测。结果 4例均为男性,年龄6～8岁,首发症状均为血尿,均伴有不同程度的蛋白尿。1例表现为高频听力区受损,1例右侧视网膜脱色素改变。4例肾功能均正常。肾穿刺活检电镜检查均显示典型Alport综合征基底膜病变。在4个家系中发现4种COL4A5基因突变,分别为Gly132Glu、Gly1238Arg、Gly267Arg和Gly1033Ser, 均为未报道的新突变。经家系验证Gly132Glu和Gly1033Ser为新生突变。用 SIFT 和PolyPhen 软件进行蛋白功能预测均显示4种突变为有害突变。结论 本研究采用外显子捕获-第二代测序技术共检测到4种COL4A5基因新突变,其中2种为新生突变。为人类Alport综合征基因突变数据库增添了4个新成员,对进一步研究中国人群Alport综合征的发病机制以及遗传咨询和产前诊断有重大意义。     

Genetic deafness:the primary cause of sensorineural hearing loss in children]

Genetically-transferred hearing impairments account for more than 50% of cases of pediatric sensorineural hearing defects. Multiple clinical aspects are involved in genetic hearing impairment, including the involvement of other organs, genetic inheritance, and the degree and age at onset of hearing loss. Diagnosis relies on family history, on the systematic investigation of the symptomatology including an associated syndrome, and audiometry testing in parents and siblings. Analysis of the connexin 26 gene is also indicated, as it is frequently involved in this disorder. Further genetic analysis in affected families will aid in detecting other as yet unidentified genes responsible for hearing impairment.     

A family with a novel TSH receptor activating germline mutation (p.Ala485Val)

Autosomal dominant nonautoimmune hyperthyroidism (ADNAH) is caused by gain of function mutations in the TSH receptor (TSHr) gene and characterized by toxic thyroid hyperplasia with a variable age of onset in the absence of thyroid antibodies and clinical symptoms of autoimmune thyroid disease in at least two generations. We report here a Turkish family with a novel TSHr gene mutation with distinct features all consistent with ADNAH. Thyroid function tests of the proband were as follows: free T3: 13.1 pg/ml (N: 1.8–4.6); free T4: 5.1 ng/dl (N: 0.9–1.7); TSH: 0.01 μIU/ml (N: 0.2–4.2); and TSH receptor antibody: 2 IU/ml (N: 0–10). A heterozygous missense mutation in exon 10 of the TSHr gene (c.1454C>T) resulting in the substitution of valine for alanine at codon 485 (p.Ala485Val) was found in the father and his son and daughter. This mutation had arisen de novo in the father. Functional studies of the novel TSHr germline mutation demonstrated a higher constitutive activation of adenyl cyclase than wild type without any effect on phospholipase C activity. In conclusion, our data indicate that gain of function germline mutations in the TSHr gene should be investigated in families with members suffering from thyrotoxicosis and progressive growth of goiter, but without clinical and biochemical evidence of autoimmune thyroid disease. In addition, patients harboring the same mutation of the TSHr gene may show wide phenotypic variability with respect to the age at onset, and severity of hyperthyroidism and thyroid growth.     

Nonsyndromic sensorineural deafness--analysis of etiology in relatives

We present the results of complex clinical examination of children affected with sensorineural hearing loss. The siblings (minimum two) were born from unaffected parents and came from twelve families. Molecular studies confirmed genetic background of hearing loss in 6 families and enabled identification of GJB2 mutations in investigated probants.     

Phenotypic spectrum of CHARGE syndrome with CHD7 mutations

CHD7 gene mutations were identified in 17 (71%) of 24 children clinically diagnosed to have CHARGE syndrome (C, coloboma of the iris or retina; H, heart defects; A, atresia of the choanae; R, retardation of growth and/or development; G, genital anomalies; and E, ear abnormalities). Colobomata, hearing loss, laryngomalacia, and vestibulo-cochlear defect were prevalent. Molecular testing for CHD7 enables an accurate diagnosis and provides health anticipatory guidance and genetic counseling to families with CHARGE syndrome.     

Resistance to thyroid hormone and its molecular basis

Generalized resistance to thyroid hormone (GRTH) is an inherited syndrome characterized by hyposensitivity of target tissues to thyroid hormone. The clinical presentation is variable. The syndrome is usually suspected when elevated serum thyroid hormone levels are associated with a non-suppressed thyroid-stimulating hormone (TSH). While goiter and thyroid test abnormalities have more often led to the suspicion of thyroid gland dysfunction, short stature, hyperactivity, learning disability and goiter in children or adolescents and recalcitrant goiter in adults, should raise the suspicion of GRTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom and thyrotoxicosis when confronted with attention deficit, hyperactivity or tachycardia. Failure to recognize the inappropriate persistence of TSH secretion in spite of elevated thyroid hormone levels has commonly resulted in erroneous diagnosis leading to antithyroid treatment. More than 300 subjects with this syndrome have been identified. The mode of inheritance in the majority of families is autosomal dominant. Recessive transmission has been found in only one family. It has long been speculated that this defect is likely to be caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TRα and TRβ. Mutations in the TRβ gene have been identified in 42 families with GRTH. All are located in the T₃-binding domain straddling the putative dimerization region and exhibit various degrees of hormone-binding impairment. This finding, and the fact that heterozygous subjects with complete TR deletion are not affected while those with point mutations are, indicates that interactions of a mutant TR with normal TR and with other factors are responsible for the dominant inheritance of GRTH and its heterogeneity. Elucidation of the etiology of GRTH has not only added a new means for the early diagnosis of the syndrome but provided new insights in the understanding of the mechanism of hormone action.     

GJB2 and GJB6 mutations in children with congenital cytomegalovirus infection

Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL) in children. Whether connexin mutations are factors in the development of CMV-related hearing loss has not been explored. We examined gap junction protein beta-2 (GJB2) and gap junction protein beta-6 (GJB6) mutations in 149 children with congenital CMV infection and 380 uninfected neonates. Mutations in GJB2 and GJB6 were assessed by nucleotide sequencing and polymerase chain reaction (PCR) methods, respectively. The study population was predominantly African American, and 4.3% of the subjects were carriers of a connexin 26 mutation. The overall frequency of GJB2 mutations was significantly higher in the group of children with CMV infection and hearing loss (21%) compared with those with CMV infection and normal hearing (3%, p = 0.017) and the group of uninfected newborns (3.9%, p = 0.016). Eight previously reported mutations (M34T, V27I, R127H, F83L, R143W, V37I, V84L, G160S), and four novel mutations (V167M, G4D, A40T, and R160Q) were detected. None of the study children had the 342-kb deletion (delGJB6-D13S1830) in GJB6, which suggests that this mutation does not play a role in hereditary deafness in the African American population. Although GJB2 mutations were detected in children with and without CMV-related hearing loss, those with hearing loss had a higher frequency of GJB2 mutations.     

Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature

Background: Wolcott-Rallison syndrome is a rare autosomal recessive condition characterized by early infancy onset diabetes mellitus and multiple epiphyseal dysplasia. So far, 17 children have been described in the world literature. Recently, mutations in the gene encoding EIF2AK3 have been shown to segregate with the syndrome in three affected families. Aims: We aimed to describe the clinical characterization and mutation analysis of a further child, and full clinical and follow-up details on our first family including the longest surviving child. Methods: Retrospective case notes review of three children presenting to the diabetic unit at our institution; mutation analysis of the EIF2AK3 gene in our most recent patient; and review of the literature on Wolcott-Rallison syndrome. Results: Previously unreported phenotypic features in our patients included developmental regression after episodes of hepatic failure, and pachygyria on brain imaging. We have identified a novel 4-base pair deletion (nt 3021-3024 del GAGA) in exon 13, which results in a frameshift and premature stop codon (R908 F/S +22X), causing premature truncation of the protein and abolition of the carboxy- segment of the catalytic domain.

Conclusions: Wolcott-Rallison syndrome causes early-onset diabetes and acute hepatic failure, before epiphyseal dysplasia is manifest. We have identified a novel mutation in EIF2AK3, and prenatal diagnosis may now be offered to affected families.     

Microangiopathy of brain, retina, and inner ear (Susac's syndrome) in an adolescent female presenting as acute disseminated encephalomyelitis

Susac's syndrome is a rare disorder that consists of microangiopathy of the brain, retina, and inner ear and usually affects young women in young adulthood. The triad of clinical manifestations consists of acute encephalopathy with neurologic signs, branch retinal artery occlusion (BRAO), and sensorineural hearing loss. We present a case of an adolescent female who presented at age 16 years with clinical and neuroimaging features of acute disseminated encephalomyelitis (ADEM). The full triad did not develop until 2.5 years after the initial neurologic presentation.     

X连锁Alport综合征女性患者临床表型差异的可能机制

Alport综合征(Alport syndrome,AS)是以血尿、感音神经性耳聋和进行性肾功能减退为临床特点的遗传性肾脏疾病,X连锁显性遗传(X-linked Alport syndrome,XLAS)为其主要遗传方式,因COL4A5和(或)COL4A6基因突变所致。X连锁Alport综合征女性患者临床表型差异很大,轻者无症状或仅表现为镜下血尿,重者有慢性肾功能衰竭,尤其是来自同一家系的女性患者临床表型可以明显不同,这种现象不能完全用COL4A5基因突变类型来解释。近年来,研究显示XLAS女性患者临床表型的差异与COL4A5突变mRNA及基底膜a5(Ⅳ)链的表达量相关,而COL4A5突变mRNA及基底膜a5(Ⅳ)链的表达量不同的机制可能与X染色体失活有关,其他表观遗传学调控方式也可能参与其中。该文就X连锁Alport综合征女性患者临床表型差异的可能机制进行了文献综述。     

Familial arthrogrypotic-like hand abnormality and sensorineural deafness.

We describe a family with arthrogrypotic-like hand abnormalities. There were ten affected members in two generations. Three of ten affected persons showed an associated sensorineural hearing loss. The degree of the hand deformities and hearing loss varied in affected individuals. The pattern of inheritance seems to be autosomal dominant with variable expressivity. The findings in this syndrome resemble those reported previously.     

Novel mutation of Endothelin-B receptor gene in Waardenburg–Hirschsprung disease

Homozygous mutations of EDNRB in human have been reported to result in Waardenburg–Hirschsprung disease (WS4), while mutated heterozygotes manifested isolated Hirschsprung disease in lower penetrance. We investigated a case of WS4 together with all members of her nuclear family for the alteration of the EDNRB gene by using PCR–SSCP and direct sequencing technique. The index patient, who was born to a family with no history of Hirschsprung disease, presented total colonic aganglionosis with small bowel extension, sensorineural hearing loss and generalized cutaneous pigmentary defects. Interestingly, both irides were normally black. The study detected a homozygous missense mutation at codon 196 in exon 2 (Ser196Asn), which has not been reported. Both parents and four in six siblings harbored heterozygous mutation without any clinical manifestation. Our findings were consistent with previous observations that full spectrum of WS4 occurred to the mutate homozygotes. Moreover, the non-penetrance of heterozygotes in our pedigree, which differs from other reports, demonstrates the high pleiotropic effect of EDNRB mutations in human.