An inherited malformative syndrome characterized by low birth weight, distinctive craniofacial malformations, and atrophic skin lesion.
BOF Syndrome; BOFS; Hemangiomatous Branchial Cleft-Lip Pseudocleft Syndrome; Imperforate Nasolacrimal Duct and Premature Aging Syndrome; Lip Pseudocleft-Hemangiomatous Branchial Cyst Syndrome; Branchial Clefts, Characteristic Facies, Growth Retardation, Imperforate Nasolacrimal Duct, Premature Aging Syndrome; Lee-Root-Fenske Syndrome.
Approximately hundred cases have been confirmed with molecular genetic analysis to date. Both genders are equally affected.
Autosomal dominant. However, in up to 60% of affected individuals the mutations are considered to be de novo. The defect is caused by mutations in the TFAP2A (Transcription Factor AP2-Alpha) gene, which has been mapped to chromosome 6p24.3. The protein encoded by this gene is a DNA-binding transcription factor expressed in ectodermal and neural crest cells and as such is involved in the regulation of embryonic gene expression in the neural tube, eye, ear, face, body wall, and limbs. In animal studies, loss of TFAP2A-function leads to facial clefting, anomalies of the eyes, ears, neural tube, heart, body wall, and limbs.
Based on the classical clinical findings of branchial defects, ocular anomalies, and typical facial findings. For the diagnosis, one classical feature can be replaced by the existence of an affected first-degree relative or the presence of ectopic dermal thymus. Intra- and interfamilial clinical variability can be marked. Molecular genetic testing (sequence analysis) can be used to confirm TFAP2A mutations.
Features of this disorder involve several systems. Branchial (cutaneous) defects affect the lateral cervical region in over 90% of patients (eg, sinus tracts, skin aplasia) and approximately 60% have infra- or supraauricular sinuses. Their appearance varies from almost imperceptible defects with thinning of the skin to large, erythematous (hemangiomatous) or weeping, nonhealing lesions (in about one-third of patients). Further significant features involve the head (dolichocephaly, high forehead, malar hypoplasia, depressed nasal bridge, short nasal septum, broad or divided nasal tip, micrognathia, cleft lip and palate or high arched palate, prominent philtral pillars (“pseudocleft lip”), lip pits, clefts of the lower lip and chin, hypoplastic teeth, hypoplasia of the lower facial nerve and/or muscles with asymmetric crying face), the ears (inner ear and petrous bone anomalies, cochlear dysplasia with sensorineural hearing loss, conductive hearing loss secondary to fusion of the middle ear ossicles, microtia, low-set and/or posteriorly rotated, overfolded with hypoplastic superior helix, posterior and preauricular pits, upturned pinnae) the eyes (hypertelorism, telecanthus, ptosis, upslanting palpebral fissures, strabismus, micro- or anophthalmia, iris and retinal coloboma, cataract, heterochromia irides, myopia, recurrent or persistent dacryocystitis, nasolacrimal duct stenosis or atresia; depending on the extent of the eye anomalies, these patients can be blind), the kidneys (eg, renal agenesis, aplasia, dysplasia, multicystic kidney disease, hydronephrosis, vesicoureteral reflux), the skeleton (kyphosis, hyperlordosis, hypoplastic thumbs, brachy-, clino- ...