Emily S Doherty

Muenke syndrome (FGFR3-related craniosynostosis): expansion of the phenotype and review of the literature.

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild‐to‐moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling. Published 2007 Wiley‐Liss, Inc.

Novel mitochondrial DNA mutations associated with myopathy, cardiomyopathy, renal failure, and deafness†

Patients with mitochondrial disease usually manifest multisystemic dysfunction with a broad clinical spectrum. When the tests for common mitochondrial DNA (mtDNA) point mutations are negative and the mtDNA defects are still hypothesized, it is necessary to screen the entire mitochondrial genome for unknown mutations in order to confirm the diagnosis. We report an 8‐year‐old girl who had a long history of ragged‐red fiber myopathy, short stature, and deafness, who ultimately developed renal failure and fatal cardiac dysfunction. Respiratory chain enzyme analysis on muscle biopsy revealed deficiency in complexes I, II/III, and IV. Whole mitochondrial genome sequencing analysis was performed. Three novel changes: homoplasmic 15458T > C and 15519T > C in cytochrome b, and a near homoplasmic 5783G > A in tRNAcys, were found in the proband in various tissues. Her mother and asymptomatic sibling also carry the two homoplasmic mutations and the heteroplasmic 5783G > A mutation in blood, hair follicles, and buccal cells, at lower percentage. The 5783G > A mutation occurs at the T arm of tRNAcys, resulting in the disruption of the stem structure, which may reduce the stability of the tRNA. 15458T > C changes an amino acid serine to proline at a conserved α‐helix, which may force the helix to bend. These two mutations may have pathogenic significance. This case emphasizes the importance of pursuing more extensive mutational analysis of mtDNA in the absence of common mtDNA point mutations or large deletions, when there is a high suspicion of a mitochondrial disorder.

Palatal and oral manifestations of Muenke syndrome (FGFR3-related craniosynostosis).

Abstract Although Muenke syndrome is the most common syndromic form of craniosynostosis, the frequency of oral and palatal anomalies including high-arched palate, cleft lip with or without cleft palate has not been documented in a patient series of Muenke syndrome to date. Further, to our knowledge, cleft lip and palate has not been reported yet in a patient with Muenke syndrome (a previous patient with isolated cleft palate has been reported). This study sought to evaluate the frequency of palatal anomalies in patients with Muenke syndrome through both a retrospective investigation and literature review. A total of 21 patients who met criteria for this study were included in the retrospective review. Fifteen patients (71%) had a structural anomaly of the palate. Cleft lip and palate was present in 1 patient (5%). Other palatal findings included high-arched hard palate in 14 patients (67%). Individuals with Muenke syndrome have the lowest incidence of cleft palate among the most common craniosynostosis syndromes. However, high-arched palate in Muenke syndrome is common and may warrant clinical attention, as these individuals are more susceptible to recurrent chronic otitis media with effusion, dental malocclusion, and hearing loss.