Autosomal dominant stapes fixation, syndactyly, and symphalangism in a family with NOG mutation: Long term follow-up on surgical treatment

https://doi.org/10.1016/j.ijporl.2018.03.008Get rights and content

Abstract

Objective

Evaluation of clinical findings and audiological outcome after surgery in a Danish family with autosomal dominant facio-audio-symphalangism syndrome with stapes fixation, syndactyly and symphalangism.

Methods

Retrospective report on eight affected family members in a Danish family. Clinical investigation included X-ray, audiology and in one case video-recorded surgery. Main outcome measure was audiologic results after stapedectomy. Sanger DNA sequencing of NOG was performed on peripheral blood.

Results

Audiologic analysis showed that seven of eight affected family members had bilateral conductive hearing loss. Three patients were treated with stapedectomy, on one or both ears, due to fixation of stapes. All the affected members had syndactyly and symphalangism. A not previously reported mutation in the NOG gene (c.688_699del, p.Cys230_Cys232delins11) was found to segregate with the stapes fixation, syndactyly, and symphalangism. p.Cys230_Cysdelins11 was classified as likely pathogenic according to guidelines from the American College of Medical Genetics and Genomics.

Conclusion

The clinical presentation of the reported mutation corresponds with previous case reports of families with NOG mutation. In this family, surgery with stapedectomy had lasting effect without renewed fixation of the stapes in a follow up period of 18 months–38 years.

Introduction

Syndromic congenital stapes fixation is rare, but can cause conductive hearing loss with early onset. In 1990, Teunissen and Cremers reported data on a family with conductive hearing loss caused by stapes ankyloses [1]. The affected family members had severe hyperopia, broad thumbs and first toes, brachytelephalangia and, in one case, symphalangism. The syndrome was reported within several other families and named Teunissen-Cremers syndrome [2,3]. Nine years later, genetic analysis found a mutation in the NOG gene to be responsible for the syndrome [4].

Since the first presentation of a mutation in the NOG gene, more than 35 mutations have been identified causing overlapping variations of the syndrome: Teunissen-Cremers syndrome [[1], [2], [3]], Proximal symphalangism [[5], [6], [7], [8]], Multiple synostoses syndrome/facioaudiosymphalangism syndrome [[6], [7], [8], [9], [10], [11], [12]], Tarsal-carpal coalition syndrome [8] and Bradydactyly type B [13]. In addition to heterogeneity among the syndromes, there are inter- and intrafamilial variations in phenotypes [8,10,14,15]. Consequently, it can be difficult to distinguish between the syndromes and clinical diagnoses and an unifying term, NOG-related symphalangism spectrum disorder (NOG-SSD), has been introduced [16].

The NOG gene encodes the protein Noggin which inactivates bone morphogenetic proteins (BMPs). Absence of Noggin increase BMP-activity, resulting in recruitment of the cartilage cells, hyperplasia and bone growth [17]. Patients with stapes ankyloses caused by NOG mutation and morphological changes in Noggin may have an increased risk of refixation of stapes after surgery [18].

The aim of this study is to present long term audiological results after stapedectomy in a Danish family with a NOG mutation not earlier described.

Section snippets

Ethics

The study was conducted in accordance with the Danish law for scientific ethics committee and approved by the Danish Data Protection Agency. Informed consent was obtained from all included patients or from parents of the children.

Subjects

The family was presented by P. Vase et al., in 1975, where five family members had a syndrome with conductive hearing loss, syndactyly and symphalangism [19]. At this follow up study, there were eight affected family members in four generations. The pattern of

Otologic and audiologic findings

None of the individuals had a history of trauma or noise damage. Two of the affected patients (II:2 and IV:2) had an anamnesis with middle ear infections. Patient IV:2 had tubulation of both tympanic membranes at the age of 2 years. The tympanic membrane was healed at the time of examination and there was no suspicion of glue or infection in the middle ear. Three patients (III:1, IV:1 and III:2) had gone through stapedectomy on one or both ears at the time of examination. The ears (n = 5) who

Discussion

Congenital or early onset of conductive hearing loss is rare. However, mutations in NOG can result in stapes ankyloses and conductive hearing loss. A wide range of mutations in NOG have been described, all resulting in autosomal dominant syndromes with various affection of joints and hearing loss [2,3,6,14,15,26,27]. The variety of phenotypes combined with relatively few patients in all ages complicates studies on epidemiology, treatment and prognosis.

In this study, we presented a family with

Conclusion

Though conductive hearing loss in children is most likely due to otitis media serosa or other affections in the middle ear, NOG mutations can cause early onset of conductive hearing loss. Family history and genetic testing may be useful in discriminating in these cases. Clinical findings and a family history of conductive hearing loss should lead to further evaluations. The literature is not consistent on the longterm effect of surgery, but results of this study indicates that stapedectomy may

Conflict of interest statement

None of the authors have any conflicts of interest and no funds have been granted.

Acknowledgement

We are grateful to the family members for their participation. We thank Poul Vase for early attention on the family and the syndrome, and Claus Barfoed for video and surgical reports.

References (31)

  • Y. Gong

    Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis

    Nat. Genet.

    (1999)
  • R.J. Ensink et al.

    Proximal symphalangism and congenital conductive hearing loss: otologic aspects

    Am. J. Otol.

    (1999)
  • T. Takahashi

    Mutations of the NOG gene in individuals with proximal symphalangism and multiple synostosis syndrome

    Clin. Genet.

    (2001)
  • M. Mangino

    Identification of a novel NOG gene mutation (P35S) in an Italian family with symphalangism

    Hum. Mutat.

    (2002)
  • Y. Hilhorst-Hofstee

    The autosomal dominant syndrome with congenital stapes ankylosis, broad thumbs and hyperopia

    Clin. Dysmorphol.

    (1997)
  • Cited by (5)

    • HIF-1α drives the transcription of NOG to inhibit osteogenic differentiation of periodontal ligament stem cells in response to hypoxia

      2022, Experimental Cell Research
      Citation Excerpt :

      NOG (±) mice exhibited hearing loss owing to additional bone tissue on the stapes because of myelodysplastic chondrocytes [37]. Pathological mutation NOG was verified to be an autosomal dominant genetic disease, which led to segregate with the stapes fixation, syndactyly, and symphalangism [38]. Noggin inhibits osteogenesis because it can bind strongly to BMP family proteins (BMP2, BMP4, BMP7, etc.) to form a finger loop [36].

    • Multiple synostoses syndrome: Clinical report and retrospective analysis

      2020, American Journal of Medical Genetics, Part A
    View full text