Facial Clefting, Oblique, 1

A number sign (#) is used with this entry because of evidence that oblique facial clefting-1 (OBLFC1) is caused by heterozygous mutation in the SPECC1L gene (614140) on chromosome 22q11. One such patient has been reported.

Heterozygous mutation in the SPECC1L gene can also cause Opitz GBBB syndrome type II (GBBB2; 145410), which includes facial clefting as a feature.

Description

Oblique facial clefts are a rare form of orofacial clefting, comprising about 0.25% of all facial clefts. Two major types have been described classically: nasoocular and oroocular, the latter of which can be subdivided into oromedial-canthal and orolateral-canthal (summary by Dasouki et al., 1988).

Clinical Features

Dasouki et al. (1988) reported an 8-month-old girl with congenital bilateral oblique facial clefts. On each side of the face, a complete cleft extended from the lateral nostril to the medial canthus, consistent with an oromedial-canthal type of cleft. The cleft involved the lip, gingiva, and palate to the vomer bone. The corneae and sclerae were covered by cutaneous ectoderm and granulation tissue, and there were synechiae between this tissue and the eyelids. There was severe ocular hypoplasia and coloboma of the right eye. Brain imaging showed normal brain parenchyma. The rest of the physical examination was notable for 4 symmetric circumferential cutaneous folds on the arms and legs, deep palmar creases, and unilateral calcaneovarus foot deformity. However, the symmetric distribution of the facial clefts suggested that amniotic bands were unlikely to be causal. The patient had a type 4 Tessier cleft (Tessier, 1976; Saadi et al., 2011).

Saadi et al. (2011) reported a Brazilian infant with severe Tessier 4 clefting on the right and mild Tessier 7 clefting on the left. He had normal eyes and no other birth defects.

Clinical Variability

Richieri-Costa and Gorlin (1994) described 4 patients with oblique facial clefts. Complex clefts of the face of this type had usually been considered a disruptive event resulting from amniotic bands. Three of them had clefts of Tessier type 5; the fourth had Tessier type 4 on the right and Tessier type 6 on the left. Limb abnormalities were present in 2 of the 4. The authors suggested that these cases represented a distinct autosomal recessive oculomaxillofacial dysplasia in light of the parental consanguinity, absence of chromosomal abnormalities, and normal relatives.

Inheritance

Although most reported cases of oblique facial clefting are sporadic (Saadi et al., 2011), 3 of 4 patients reported by Richieri-Costa and Gorlin (1994) were the products of first-cousin marriages, suggesting autosomal recessive inheritance.

Cytogenetics

In an 8-month-old girl with congenital bilateral oblique facial clefts, Dasouki et al. (1988) identified a balanced de novo reciprocal translocation t(1;22)(q21;q12) by karyotype analysis. Saadi et al. (2011) provided follow-up of the patient reported by Dasouki et al. (1988), and revised the translocation breakpoints to t(1;22)(q21.3;q11.23). Saadi et al. (2011) determined that the 22q11.23 breakpoint occurred within a 5-kb region in intron 14 of the SPECC1L gene, whereas there were no known genes within the 1q21 breakpoint region. Patient-derived lymphoblastoid cells showed SPECC1L haploinsufficiency at the RNA level. Cultured cells failed to form large clumps due to a defect in integrin-based cell adhesion and showed reduced numbers of F-actin microspikes and filopodia.

Molecular Genetics

In 1 of 23 patients with Tessier 4 oblique facial clefting, Saadi et al. (2011) identified a heterozygous de novo pathogenic missense mutation in the SPECC1L gene (Q415P; 614140.0001). The patient was of Brazilian origin. In vitro functional expression studies in human osteosarcoma cells showed that the mutant protein impaired the formation of stabilized acetylated alpha-tubulin-containing microtubules. Saadi et al. (2011) concluded that the orofacial clefting resulted from defects in the cells involved in the developing facial prominences; namely, impaired cell migration and adhesion due to an inability to reorganize actin properly.