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Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.

ABSTRACT: Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine; clinically, it manifests as a short neck with reduced mobility and a low posterior hairline. Several genes have been proposed as candidates for KFS when it is present with other associated anomalies, but the genetics of isolated KFS have been difficult to study because of the syndrome's mostly sporadic occurrence. We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.31 locus that harbors a homozygous frameshift deletion in MEOX1; this deletion results in complete instability of the transcript. Direct sequencing of this gene in two siblings from another consanguineous family affected by isolated KFS uncovered another homozygous truncating (nonsense) MEOX1 mutation that also leads to complete degradation of the transcript. This gene encodes a transcription factor with a well-established and nonredundant role in somite development, and homozygous null alleles of Meox1 in mice have a cervical skeletal defect that is remarkably similar to the one we observe in human individuals with MEOX1 mutations. Our data strongly suggest that KFS is the human phenotypic equivalent of the sclerotome polarity defect that results from Meox1 deficiency in mice.

SUBMITTER: Mohamed JY

PROVIDER: S-EPMC3542464 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.

Mohamed Jawahir Y JY Faqeih Eissa E Alsiddiky Abdulmonem A Alshammari Muneera J MJ Ibrahim Niema A NA Alkuraya Fowzan S FS

American journal of human genetics 20130103 1

Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine; clinically, it manifests as a short neck with reduced mobility and a low posterior hairline. Several genes have been proposed as candidates for KFS when it is present with other associated anomalies, but the genetics of isolated KFS have been difficult to study because of the syndrome's mostly sporadic occurrence. We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.31 locus th ...[more]

PMID: 23290072

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Project description:Importance:Children with Klippel-Feil syndrome (KFS), characterized principally by abnormal fusion of 2 or more cervical vertebrae, may have many additional congenital anomalies. The overall prevalence of otolaryngologic manifestations among patients with KFS has not been previously characterized. Objective:To define the otolaryngologic diagnoses made and procedures performed in 95 patients with KFS, which, to our knowledge, is the largest series of this challenging patient population published to date. Design, Setting, and Participants:For this retrospective review, all patients with KFS who underwent otolaryngology consultation at our institution over a 26-year period (January 1989 to December 2015) were included. Patients were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes and were confirmed through individual medical record review. Relevant otolaryngologic diagnoses and procedures were extracted using ICD-9 and Current Procedural Terminology codes, respectively. Selected demographics included age, sex, number of clinic visits, and number of procedures. Main Outcomes and Measures:The primary outcomes were the otolaryngologic diagnoses and procedures associated with the KFS patient population; the secondary outcome was Cormack-Lehane classification documented during airway procedures. Results:Overall, 95 patients with KFS were included in this study (55 males [58%] and 40 females [42%]); mean (range) age at time of presentation to the otorhinolaryngology clinic was 5.8 (birth-23.0) years. Each patient with KFS averaged 8 visits to the otorhinolaryngology office and 5 otolaryngologic diagnoses. The most common diagnosis was conductive hearing loss (n?=?49 [52%]), followed by sensorineural hearing loss (n?=?38 [40%]), and dysphagia (n?=?37 [39%]). Sixty-two (65%) patients underwent otolaryngologic procedures, with 44 (46%) undergoing multiple procedures. The most common procedure was tympanostomy tube placement (n?=?36 [38%]), followed by office flexible endoscopy (n?=?23 [24%]). Twelve of the 20 patients who underwent direct laryngoscopy had documented Cormack-Lehane classification; 5 of 12 patients (42%) had a compromised view (grade 2, 3, or 4) of the larynx. Three patients required tracheotomies at this institution for airway stabilization purposes; each had severe upper airway obstruction leading to respiratory failure. Conclusions and Relevance:Patients with KFS require consultation for a variety of otolaryngologic conditions. Among these, hearing loss is the most common, but airway issues related to cervical spine fusion are the most challenging. Formulating an appropriate care plan in advance is paramount, even for routine otolaryngology procedures.

Dataset Information

Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.

Publications

Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly.

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