Mandibulofacial Dysostosis With Alopecia

A number sign (#) is used with this entry because of evidence that mandibulofacial dysostosis with alopecia (MFDA) is caused by heterozygous mutation in the EDNRA gene (131243) on chromosome 4q31.

Clinical Features

Cushman et al. (2005) described a 4-year-old Caucasian girl who presented at 27 months of age for evaluation of significant scalp alopecia and malformed ears. Examination at age 3 showed mild facial asymmetry and horizontal palpebral fissures with broad dimples at the lateral aspect of the eyes, small thin lashes, laterally displaced lacrimal punctae, and mild left eyelid coloboma. Her ears were low set and significantly malformed with crumpled helices and bilateral preauricular tags, with a pit anterior to the tag on the right; the ear canals appeared normal. Her mouth was slightly asymmetric, with normal teeth and intact palate. She also had significant alopecia, especially on the top of the head, with normal-appearing hair around the sides. External genitalia were normal, as were fingernails and toenails. Cushman et al. (2005) noted that this patient exhibited many of the features of Johnson-McMillin syndrome (147770) as well as features not previously reported in that phenotype, including preauricular pits and tags, broad depression at the lateral aspects of the eyes, and abnormal left lower eyelid.

Zechi-Ceide et al. (2010) reported a 2-year-old boy who was noted at birth to have cleft palate and abnormal lower eyelids. Examination at 4 months of age showed sparse eyebrows and eyelashes, wide coloboma of the lower eyelid bilaterally, zygomatic hypoplasia, and bilateral mark on the cheek just below the lower lid coloboma. His lacrimal punctae were normal. He had a broad nasal bridge and tip, micrognathia, and cleft palate. Ears were small and prominent, showing lumps of extra tissue on the superior region of the helices as well as uptilted lobules; the external auditory canals were normal. Reevaluation at 2 years of age showed alopecia, slightly asymmetric mouth, delayed primary dentition, and hearing loss. External genitalia, skin pigmentation, and nails were normal. Zechi-Ceide et al. (2010) concluded that the facial phenotype of this patient was consistent with mandibulofacial dysostosis, and suggested that it could represent a severe form of Johnson-McMillin syndrome.

Gordon et al. (2015) studied 3 patients with highly similar facial dysmorphism, including the boy previously reported by Zechi-Ceide et al. (2010), as well as a more mildly affected girl originally described by Cushman et al. (2005). Features included scalp alopecia, scant eyebrows and eyelashes, severe hypoplasia or aplasia of eyelids, lateral depression below eyes, small cupped dysplastic ears with ectopic tissue at the attachment of the helix to the scalp, conductive hearing loss, short nose with squared tip, cleft palate, dental anomalies, micrognathia, and limited jaw mobility. Craniofacial 3-dimensional CT scan in 3 patients revealed maxillary dysmorphism with dysplastic zygomatic arch and hypoplastic mandible in all. Gordon et al. (2015) designated the phenotype of the 4 patients mandibulofacial dysostosis with alopecia (MFDA).

Molecular Genetics

By whole-exome sequencing, Gordon et al. (2015) identified a de novo heterozygous missense mutation in the EDNRA gene (Y129F; 131243.0002) in a patient with mandibulofacial dysostosis and alopecia. Sanger sequencing confirmed that the mutation was present in the patient and absent in his parents. Sequencing of EDNRA in 2 more MFDA patients, including a boy previously reported by Zechi-Ceide et al. (2010), revealed de novo heterozygosity for the same missense mutation, for which 1 of the patients was somatic mosaic. Whole-exome sequencing of a more mildly affected girl who was originally described by Cushman et al. (2005) revealed somatic mosaicism for a different de novo missense mutation in the EDNRA gene (E303K; 131243.0003).