Muenke Syndrome

A number sign (#) is used with this entry because Muenke craniosynostosis syndrome is caused by a specific heterozygous mutation of the fibroblast growth factor receptor-3 gene (FGFR3; 134934), pro250 to arg (P250R; 134934.0014), on chromosome 4p16.

Description

Muenke syndrome is an autosomal dominant disorder characterized by uni- or bicoronal synostosis, macrocephaly, midfacial hypoplasia, and developmental delay. Other more variable features include thimble-shaped middle phalanges, brachydactyly, carpal/tarsal fusion, and deafness. The phenotype is variable and can range from no detectable clinical manifestations to complex findings (summary by Abdel-Salam et al., 2011).

Clinical Features

On the basis of 61 individuals from 20 unrelated families where coronal synostosis was caused by the P250R mutation in the FGFR3 gene, Muenke et al. (1997) defined a new clinical syndrome distinct from previously defined craniosynostosis syndromes, including the Pfeiffer (101600), Crouzon (123500), Jackson-Weiss (123150), and Apert (101200) syndromes. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe to suggest Apert syndrome or Pfeiffer syndrome, respectively. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiologic findings of hands and feet can be helpful in the recognition of this syndrome, it was not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, Muenke et al. (1997) suggested that all patients with coronal synostosis, a particularly frequent and distinctive feature of the disorder, should be tested for this specific mutation.

In a report of 9 individuals with the P250R mutation of the FGFR3 gene, Reardon et al. (1997) noted unisutural craniosynostosis in 3. They documented a variable clinical presentation. In 4 of the 9 cases, they noted mental retardation, which was unrelated to the management of the craniosynostosis. In a large German family, Golla et al. (1997) noted considerable phenotypic variability among individuals with the identical mutation. Gripp et al. (1998) found the P250R mutation in 4 of 37 patients with synostotic anterior plagiocephaly (literally 'oblique head'). In 3 mutation-positive patients with full parental studies, a parent with an extremely mild phenotype was found to carry the same mutation. None of the 6 patients with nonsynostotic plagiocephaly and none of the 4 patients with additional suture synostosis had the FGFR3 mutation.

Hollway et al. (1998) reported a family in which the P250R mutation was associated with autosomal dominant congenital bilateral sensorineural deafness of moderate degree. Some of the family members also had craniosynostosis, which is a known manifestation of the P250R mutation. The low penetrance of symptomatic craniosynostosis in this 5-generation family raised the possibility that some families with the P250R mutation may present with deafness alone.

Lajeunie et al. (1999) studied 62 patients with sporadic or familial forms of coronal craniosynostosis. The P250R mutation was identified in 20 probands from 27 unrelated families (74%), while only 6 of 35 sporadic cases (17%) were found to have this mutation. In both familial and sporadic cases, females were more severely affected, with 68% of females but only 35% of males having brachycephaly. In the most severely affected individuals, bicoronal craniosynostosis was associated with hypertelorism and marked bulging of the temporal fossae, features that Lajeunie et al. (1999) concluded might be helpful for clinical diagnosis. Lajeunie et al. (1999) concluded that the P250R mutation is most often familial and is associated with a more severe phenotype in females than in males.

Lowry et al. (2001) reported a family in which members with coronal craniosynostosis, skeletal abnormalities of the hands, and sensorineural hearing loss had the P250R mutation. One female family member also had a Sprengel shoulder anomaly (184400) and multiple cervical spine anomalies consistent with Klippel-Feil anomaly (118100). The authors reported an additional case with an identical phenotype without the mutation.

Like Muenke syndrome, hypochondroplasia (HCH; 146000) is caused by mutations in the FGFR3 gene. FGFR3 is known to play a role in controlling nervous system development. Grosso et al. (2003) described the clinical and neuroradiologic findings of a patient with Muenke syndrome and a patient with hypochondroplasia, each of whom had bilateral dysgenesis of the medial temporal lobe structures. Both were mentally normal and showed similarities in early-onset temporal lobe-related seizures. In both patients, EEG recorded bilateral temporal region discharges. MRI detected temporal lobe anomalies with inadequate differentiation between white and gray matter, defective gyri, and abnormally shaped hippocampus. The patient with hypochondroplasia carried the asn540-to-lys missense mutation (134934.0010); the patient with Muenke syndrome carried the P250R mutation.

Kress et al. (2006) provided a phenotypic comparison between 42 patients from 24 kindreds with Muenke syndrome caused by the FGFR3 P250R mutation and 71 patients from 39 families with Saethre-Chotzen syndrome (SCS; 101400) caused by mutations in the TWIST1 gene (601622). Patients with classic SCS could be distinguished from the Muenke phenotype by presence of low-set frontal hairline, gross ptosis of the eyelids, subnormal ear length, dilated parietal foramina, interdigital webbing, and broad great toe with bifid distal phalanx. Patients with SCS also tended to have intracranial hypertension as a consequence of early progressive multisutural fusion and normal mental development; those with Muenke syndrome tended to have mental delay and sensorineural hearing loss. Kress et al. (2006) concluded that SCS and Muenke should be considered separate syndromes.

Shah et al. (2006) reported a family in which a female infant with Muenke syndrome due to the P250R mutation died suddenly on day 3 of life, most likely due to respiratory insufficiency resulting from upper airway obstruction associated with craniosynostosis. Her affected mother, who also had the mutation, had been diagnosed in infancy with Treacher Collins syndrome (154500). A second-born female child also had the P250R mutation but did not display respiratory compromise.

In a male infant with trigonocephaly, van der Meulen et al. (2006) identified the P250R mutation, which was also present in the mother, who had barely detectable sequelae of a bicoronal synostosis. The authors suggested that mutation analysis of the FGFR1, FGFR2, and FGFR3 genes should be routinely performed in children with nonsyndromic trigonocephaly.

Doherty et al. (2007) evaluated 9 patients, 5 children and 4 adults, with Muenke syndrome due to the P250R mutation. Six patients had bicoronal synostosis, and 3 had unicoronal synostosis. Feeding and/or swallowing difficulties were found in all of the children. The most common ocular complication was strabismus, which was found in 4 of the 9 patients. Oral findings consisted primarily of dental malocclusion and highly arched palate. A review of audiograms from these patients and an additional 13 patients with Muenke syndrome showed that 95% had mild to moderate, low frequency sensorineural hearing loss. Doherty et al. (2007) suggested that the hearing loss is a direct result of the FGFR3 mutation, not a secondary effect of craniosynostosis. Data from their patients and 312 previously reported cases of Muenke syndrome showed that females with the P250R mutation were significantly more likely to be reported with craniosynostosis than males (p less than 0.01).

Mansour et al. (2009) evaluated hearing in 37 patients with Muenke syndrome due to the P250R mutation. The Muenke syndrome patients showed significant, but incompletely penetrant, predominantly low-frequency sensorineural hearing loss. The finding was confirmed in a mouse model of Muenke syndrome.

Escobar et al. (2009) reported a pair of identical female twins with variable manifestations of Muenke syndrome despite having the same de novo P250R mutation. They were born at 35 weeks' gestation and were noted to have abnormal head shape at birth. The less severely affected twin, who showed no abnormalities on prenatal ultrasound, had acrocephaly with a prominent forehead, wide-open anterior fontanel, coronal craniosynostosis, significant midface hypoplasia with malar hypoplasia, a short upturned nose, low-set ears, and a high-arched palate. She also had brachydactyly with shortening of the fifth finger and mild clinodactyly. Behavioral abnormalities included developmental delay, generalized anxiety disorder, and ADHD. The more severely affected twin was noted to have hydrocephaly due to aqueductal stenosis at 25 weeks' gestation. She had neonatal apnea and bradycardia requiring bag mask ventilation. Brain MRI showed a large poroencephalic cyst of the occipital horn of the left ventricle, hydrocephaly, and absence of the corpus callosum. She had atrial and ventricular septal defects and esophageal atresia with a tracheoesophageal fistula requiring surgery. Skull and facial features were similar to the other twin. Cognitive defects included pervasive developmental disorder, developmental delay, and ADHD. Both patients developed developed bilateral sensorineural hearing loss. Although the pregnancy was complicated by prenatal exposure to nortriptyline, the Escobar et al. (2009) did not believe that this affected the phenotype.

Abdel-Salam et al. (2011) reported a boy, born of consanguineous parents, with craniosynostosis due to a heterozygous P250R mutation in the FGFR3 gene. In addition to right coronal, sagittal, and lambdoid suture synostosis, he had left hemimegalencephaly with poor differentiation of white and gray matter, an underdeveloped corpus callosum, and an abnormal hippocampus. Despite these cranial findings, he had mild developmental delay and symmetric strength, tone, and reflexes, with hyperreflexia. Dysmorphic features included craniofacial asymmetry with left frontal bossing, midface hypoplasia, proptosis, low-set ears, and brachydactyly. At age 18 months, he developed asymmetric hydrocephalus requiring third ventriculostomy. Postoperative cranial MRI showed a Chiari I-like malformation, but less dysplastic cerebral cortex. In addition, he had curly, light hair, and oval hypomelanotic patches on the abdomen, lower limbs, and back, with 1 hyperpigmented patch in the groin. Some of these features had not previously been reported in Muenke syndrome, but Abdel-Salam et al. (2011) noted that additional genetic effects could not be ruled out because of the consanguinity in this family.

Inheritance

Muenke syndrome is an autosomal dominant disorder (Muenke et al., 1997).

Rannan-Eliya et al. (2004) studied 19 cases of Muenke syndrome due to heterozygous de novo P250R mutations in FGFR3. All 10 informative cases were of paternal origin; the average paternal age at birth for all 19 cases was 34.7 years.

Population Genetics

The birth rate for the Muenke FGFR3 P250R mutation is estimated to be 7.6 per 1,000,000 (Wilkie, 1997).

Animal Model

Mansour et al. (2009) generated mice homozygous and heterozygous for a P244R mutation in the Fgfr3 gene, which is the equivalent of the human P250R mutation, as a mouse model of Muenke syndrome. Fgfr3 P244R/+ and P244R/P244R mice showed dominant, fully penetrant low-frequency hearing loss that was similar but more severe than in Muenke syndrome patients. Mouse hearing loss correlated with an alteration in the fate of supporting cells (Deiters-to-pillar cells) along the entire length of the cochlear duct, especially at the apical or low-frequency end. There was excess outer hair cell development in the apical region. Hearing loss was dosage sensitive as homozygotes were more severely affected than heterozygotes.