Orofacial Cleft 11

Watchlist

(log in to enable)

Retrieved

2019-09-22

Source

Omim

Trials

—

Genes

IRF6, MSX1, TP63, NECTIN1, CDH1, BMP4, DLX4, ARHGAP29, DLG1, CALML3, COTL1, TERT, TGFA, CLPTM1L, CSRP3, MTHFR, PHF8, RPE65, CKAP4, UVRAG, TGFB3, SUMO1, PART1, CHD7, PTCH1, TIMP2, FGFR1, MTR, MAFB, MMP3, NAT2, WNT9B, NAT1, TBX22, BHMT, CBS, HFM, BMP2, SYNJ2, IFT88, KISS1R, WNT3A, KLF17, PGAP2, ARTN, WNT5A, WNT3, B3GLCT, PRSS35, MIR494, TPM1, CPO, KLF4, RAB34, TINAGL1, ACSS2, GTPBP4, RIC1, SHTN1, GRHL3, VAX1, CAMKMT, SNAP91, POMT1, ADAMTS20, SAE1, WNT10A, DNAJC5, NECTIN4, BHMT2, RARA, TGFB1, SPP1, FGF10, FGF9, FGF8, FGF3, FGF2, STOM, DMD, DLX1, DEFB1, DCN, CLPTM1, CDH2, KRIT1, CALM3, CALM2, CALM1, BCL3, ARSD, AGRP, AFP, ABCA4, FGFR2, FOXE1, FLG, NME1, SPINK1, SPARC, SLC19A1, RYK, RAD51C, PCNA, PAX7, PAX3, NME2, NHLH1, FN1, MYH9, MTRR, MTHFD1, MMP13, MMP1, MID1, HTC2, GNRHR, GABRB3, CBSL

Drugs

—

Interested in hearing about new therapies?

A number sign (#) is used with this entry because of evidence that orofacial cleft-11 (OFC11) is caused by heterozygous mutation in the BMP4 gene (112262) on chromosome 14q22.

For a phenotypic description and a discussion of genetic heterogeneity of nonsyndromic cleft lip with or without cleft palate, see OFC1 (119530).

Description

Congenital 'healed' cleft lip (CHCL) is an unusual anomaly consisting of a paramedian 'scar' of the upper lip with an appearance suggesting that a typical cleft lip was corrected in utero. The CHCL is frequently associated with an ipsilateral notch in the vermilion border and a 'collapsed' nostril (Castilla and Martinez-Frias, 1995).

Clinical Features

Castilla and Martinez-Frias (1995) presented 25 CHCL cases, 18 of which represented an isolated malformation found among the 3,950,715 births examined in 2 similar birth defect registries, 1 in Spain and 1 in Latin America. Like open cleft lip, of which it seems to be a variant, CHCL is most frequently seen among males (14/18 isolated cases), and preferentially affects the left side (10/18 cases). CHCL segregated with cleft lip in 1 family. The 5 CHCL cases with other congenital anomalies included 2 cases with hydrocephalus, 2 cases of the VACTERL association, and 1 infant with an atypical oblique facial cleft with single umbilical artery. CHCL may result from a defective fusion of the frontal nasal and maxillary processes (before week 7 of embryonic life), or from a spontaneously repaired open cleft lip, later on. In either way, these cases heal with a visual scar, and the pre-occurrence of CHCL in 2 families suggests a familial predisposition to this phenomenon.

Neiswanger et al. (2007) noted that the spectrum of severity in visible CL/P is broad, ranging from notches of the vermilion and/or grooves in the philtrum to complete unilateral and bilateral clefts of the lip and palate. Minimal or microform expressions of the CL/P phenotype, typically involving subtle defects of the lip, alveolar arch, and/or inferior nasal region, are at the mild end of the spectrum. Using high-resolution ultrasonography to examine the orbicularis oris muscle, Neiswanger et al. (2007) found that 10.3% of 525 noncleft relatives of patients with nonsyndromic cleft lip had discontinuity of the orbicularis oris muscle compared to 5.8% of 257 controls (p = 0.04). Male relatives had a significantly higher rate of discontinuity than male controls (12.0% vs 3.2%; p = 0.01); female relatives also had a higher rate of discontinuity than female controls, but the increase was not statistically significant. These data confirm the hypothesis that subepithelial defects in the orbicularis oris are a mild manifestation of the cleft lip phenotype.

Molecular Genetics

Suzuki et al. (2009) identified mutations in the BMP4 gene (see, e.g., 112262.0003-112262.0005) in children with cleft lip and cleft palate. The parents, who also carried the mutation, only had subtle defects in the orbicularis oris muscle on ultrasound. Overall, BMP4 mutations were identified in 1 of 30 patients with microform clefts, 2 of 87 patients with subepithelial defects in the orbicularis oris muscle, and 5 of 968 patients with overt cleft lip/palate. These results indicated that microforms and subepithelial defects in the orbicularis oris muscle are part of the spectrum of CL/P and should be considered during the clinical evaluation of families with clefts.

Animal Model

In mice, Liu et al. (2005) demonstrated that conditional inactivation of the Bmp4 gene (112262) in the facial primordia resulted in delayed fusion of the medial nasal process to form the lip, resulting in isolated cleft lip in all mouse embryos at 12 days after conception. However, cleft lip was only present in 22% of mouse embryos at 14.5 days after conception, indicating spontaneous repair or healing of cleft lip in utero.