Proximal Symphalangism, Hyperopia, Conductive Hearing Impairment, and the NOG Gene

Thomeer, Hans G. X. M.; Admiraal, R.J.C.; Hoefsloot, Lies H.; Kunst, Henricus P. M.; Cremers, C.W.R.J.

doi:10.1097/mao.0b013e318211fada

Cited by 17 publications

(17 citation statements)

References 35 publications

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“…[25][26][27][28][29] Two previously reported 17q22 microdeletion, patients were intellectually disabled. 7,8 All patients in our study, including patient 6, have intellectual disability and deletions of NOG and C17ORF67.…”

Section: Discussionmentioning

confidence: 99%

Molecular and clinical delineation of the 17q22 microdeletion phenotype

et al. 2013

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Deletions involving 17q21-q24 have been identified previously to result in two clinically recognizable contiguous gene deletion syndromes: 17q21.31 and 17q23.1-q23.2 microdeletion syndromes. Although deletions involving 17q22 have been reported in the literature, only four of the eight patients reported were identified by array-comparative genomic hybridization (array-CGH) or flourescent in situ hybridization. Here, we describe five new patients with 1.8-2.5-Mb microdeletions involving 17q22 identified by array-CGH. We also present one patient with a large karyotypically visible deletion involving 17q22, fine-mapped to B8.2 Mb using array-CGH. We show that the commonly deleted region in our patients spans 0.24 Mb and two genes; NOG and C17ORF67. The function of C17ORF67 is not known, whereas Noggin, the product of NOG, is essential for correct joint development. In common with the 17q22 patients reported previously, the disease phenotype of our patients includes intellectual disability, attention deficit hyperactivity disorder, conductive hearing loss, visual impairment, low set ears, facial dysmorphology and limb anomalies. All patients displayed NOG-related bone and joint features, including symphalangism and facial dysmorphology. We conclude that these common clinical features indicate a novel clinically recognizable, 17q22 contiguous microdeletion syndrome.

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Section: Discussionmentioning

confidence: 99%

Molecular and clinical delineation of the 17q22 microdeletion phenotype

et al. 2013

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“…8,[27][28][29][30] In patient with incus fixation, incudal mobilization was required at the time of stapes surgery. 8,[27][28][29][30] In the present study, fixation of the incus was identified in patient 2, but because the …”

Section: Surgerymentioning

confidence: 99%

Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism

et al. 2014

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In this study, we describe three unrelated Japanese patients with hearing loss and symphalangism who were diagnosed with proximal symphalangism (SYM1), atypical multiple synostosis syndrome (atypical SYNS1) and stapes ankylosis with broad thumb and toes (SABTT), respectively, based on the clinical features. Surgical findings in the middle ear were similar among the patients. By next-generation and Sanger sequencing analyses, we identified two novel mutations, c.559C>G (p.P178A) and c.682T>A (p.C228S), in the SYM1 and atypical SYNS1 families, respectively. No pathogenic changes were found in the protein-coding regions, exon-intron boundaries or promoter regions of the NOG, GDF5 or FGF9 genes in the SABTT family. Such negative molecular data suggest there may be further genetic heterogeneity underlying SYNS1, with the involvement of at least one additional gene. Stapedotomy resulted in good hearing in all patients over the long term, indicating no correlation between genotype and surgical outcome. Given the overlap of the clinical features of these syndromes in our patients and the molecular findings, the diagnostic term 'NOG-related-symphalangism spectrum disorder (NOG-SSD)' is advocated and an unidentified gene may be responsible for this disorder.

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“…These two families had similar phenotypes, with the exception of tall stature (>90% percentile) and lack of childbearing by affected females in one family. Several additional NOG mutations associated with SABTT were subsequently reported [Hirshoren et al, 2008; Thomeer et al, 2011; Weekamp et al, 2005] (Table 1). Notably, in contrast to the missense mutations in NOG typically associated with SYM1, SYNS1, and TCC, six of the eight known mutations to cause SABTT are inactivating mutations, suggesting that haploinsufficiency of NOG may specifically lead to the SABTT phenotype.…”

Section: Phenotypesmentioning

confidence: 99%

“…Surgical exploration of the middle ear is necessary to evaluate the mobility of the ossicular chain by palpation. Fixation of the short process of the incus, elongation of the long process of the incus, and fixation of the malleoincudal joint or other ossicular articulations may also be observed [Ensink et al, 1999; Stephan, 2006; Thomeer et al, 2011; Weekamp et al, 2005]. Previous histological reports on resected stapes have noted an abnormal bony bridge between the crura and footplate, local bony fusion of the stapes footplate with thickened bone in the oval window niche, and abnormal ossification in the vestibular area of the footplate with calcification of the annular ligament [Declau et al, 2001].…”

Section: Clinical Relevancementioning

confidence: 99%

“…Temporal bone CT may reveal narrowing of the oval window and deformities of the stapes [Brown et al, 2003]. However, high‐resolution CT and MRI scans of the temporal bone are often normal in patients with NOG ‐SSD [Declau et al, 2001; Thomeer et al, 2011]. As stapes ankylosis is a clinical diagnosis, imaging may be most useful to exclude other causes of conductive hearing loss.…”

Section: Clinical Relevancementioning

confidence: 99%

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A comprehensive review of reported heritable noggin‐associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term:NOG‐related‐symphalangism spectrum disorder (NOG‐SSD)

2011

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ABSTRACT:The NOG gene encodes noggin, a secreted polypeptide that is important for regulating multiple signaling pathways during human development, particularly in cartilage and bone. The hallmark of NOG-related syndromes is proximal symphalangism, defined by abnormal fusion of the proximal interphalangeal joints of the hands and feet. Many additional features secondary to NOG mutations are commonly but inconsistently observed, including a characteristic facies with a hemicylindrical nose, congenital conductive hearing loss due to stapes fixation, and hyperopia. The variable clinical presentations led to the designation of five different autosomal dominant syndromes, all subsequently found to have resulted from NOG mutations. These include (1) proximal symphalangism; (2) multiple synostoses syndrome 1; (3) stapes ankylosis with broad thumbs and toes; (4) tarsal-carpal coalition syndrome; and (5) brachydactyly type B2. Herein, we review the phenotypic features associated with mutations in the NOG gene, demonstrating the overlapping characteristics of these syndromes. Due to the variable phenotypic spectrum within families and among families with the same mutation, we propose a unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD), to aid in the clinical recognition and evaluation of all affected individuals with these phenotypes. These NOG gene variants are available in a new locus-specific database (https://NOG.lovd.nl).

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Proximal Symphalangism, Hyperopia, Conductive Hearing Impairment, and the NOG Gene

Cited by 17 publications

References 35 publications

Molecular and clinical delineation of the 17q22 microdeletion phenotype

Molecular and clinical delineation of the 17q22 microdeletion phenotype

Identification of two novel mutations in the NOG gene associated with congenital stapes ankylosis and symphalangism

A comprehensive review of reported heritable noggin‐associated syndromes and proposed clinical utility of one broadly inclusive diagnostic term:NOG‐related‐symphalangism spectrum disorder (NOG‐SSD)

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