Intrafamilial variation in families with a confirmed TCOF1 pathogenic variant.
a. The proband (arrow) has the characteristic facial phenotype with downward-slanting palpebral fissures, hypoplastic zygomatic complex, hypoplasia of mandible, slightly dysplastic ears, and conductive hearing loss. The proband's father was much more mildly affected and his beard and his glasses mask the phenotype: conductive hearing loss was lacking and his ears were surgically corrected. The paternal grandmother has a facial phenotype similar to her son and a positive family history for dysplastic ears. Surprisingly, the paternal grandfather, who has no facial characteristics of TCS, has the pathogenic variant. He could be an example of non-penetrance; he declined personal examination and radiographs.
b. The proband (arrow) is severely affected with hypoplasia of the zygomatic complex, bilateral microtia with atresia of the external auditory canal, cleft palate, and bilateral choanal atresia. The mother has a hypoplasia of the mandible and clinical suspicion of hypoplasia of right zygomatic complex, although she has a normal slant of palpebral fissures. Radiographic examination (Waters' projection) clearly shows the hypoplasia of the zygomatic complex. The authors consider the mother to be mildly affected.
c. The proband (arrow) is severely affected with bilateral microtia, hypoplastic zygomatic complex, and downward slant of palpebral fissures. The authors received some photographs of the father and suggested that he was not affected. After molecular investigation proved him to be heterozygous, the authors were able to personally examine him. The only abnormal facial findings were his slightly downward-slanting palpebral fissures. It is much easier to recognize the mild facial phenotype in childhood. Waters' projection showed bilateral hypoplasia of zygomatic complex with unilateral left-sided aplastic zygomatic arch. The brother and the elder sister of the proband do not have the pathogenic variant.
d. The proband (arrow) is severely affected. Her father only shows mild hypoplasia of the zygomatic complex. He believed that he was unaffected; diagnosis was established after birth of his affected daughter. His sister was severely affected (not molecularly proven) and died at age 20 years of cardiac insufficiency. The paternal grandfather has mild hearing loss and downward-slanting palpebral fissures. He is most likely mildly affected, but DNA was not available for testing.
Reprinted by permission from Nature Publishing Group [Teber et al 2004]
