# A Novel Clinical Feature in NOG Gene Mutation-Associated Syndrome

## TL;DR

This paper reports a family with a NOG gene mutation showing mixed hearing loss, a new clinical feature not previously documented in this genetic disorder.

## Contribution

The first report of preoperatively confirmed mixed hearing loss associated with a NOG gene mutation.

## Key findings

- A mother and daughter with NOG gene mutations exhibited bilateral mixed hearing loss.
- Sensorineural hearing loss may be a new manifestation of NOG-related symphalangism spectrum disorder.
- Bilateral stapedotomy improved hearing, but complete recovery required hearing aids due to sensorineural loss.

## Abstract

Introduction: Noggin encoding (NOG) gene plays a critical role in early embryogenesis and development of bones, joints, cartilage, eyes, and neural tissue. The NOG gene encodes the noggin protein. Noggin is the only secreted inhibitor of bone morphogenetic protein (BMP) that is associated with abnormal phenotypes in humans. The most commonly observed manifestations of NOG gene mutations include bilateral conductive hearing loss, proximal symphalangism, broad thumbs, hyperopia, and a distinct facial appearance. This genetic disorder was first reported in 1990 by Teunissen and Cremers. Since then, various phenotypic presentations of NOG mutation have been reported, leading to the introduction of the term NOG-related symphalangism spectrum disorder (NOG-SSD). Case report: In this report, we describe a family (mother and daughter) with bilateral mixed hearing loss. Both patients had hyperopia, distinct facial appearance with hemicylindrical nose, broad thumbs, and syndactyly of the second and third toes. Genetic testing confirmed a NOG gene mutation. Bilateral stapedotomy was successfully performed, resulting in significant hearing improvement. However, due to sensorineural component of hearing loss, complete hearing recovery was only achieved with the use of hearing aids. Discussion: The etiology of the sensorineural component of hearing loss in NOG-SSD remains unclear. In animal models, the NOG gene is essential for inner ear development, while in humans, only middle ear malformations have been reported. The phenotypic variability observed in individuals with NOG mutations is very wide, suggesting that the sensorineural component of hearing loss could represent one of the possible manifestations. Conclusions: Conductive hearing loss is the primary manifestation of the NOG-SSD, and all previously reported cases of NOG gene mutations have presented exclusively with conductive hearing loss. It is possible that additional genetic factors, not necessarily directly related to the NOG gene but present in this family, contribute to the development of the sensorineural component of hearing loss, although thorough genetic testing did not reveal any additional mutation. This is, to our knowledge, the first report of mixed hearing loss associated with a NOG mutation confirmed preoperatively. Further studies are needed to determine whether the sensorineural component represents a primary manifestation or arises from secondary mechanisms.