Nasolabial fold discontinuity during speech as a possible extended cleft phenotype.

Objective : This exploratory research sought to extend the cleft phenotype by identifying movement-related soft tissue appearance changes in the midfacial region in individuals with cleft lip/palate or those with genetic susceptibility to cleft lip/palate (unaffected relatives). The cleft phenotype (clinically identified orofacial cleft or subclinical orbicularis oris defect) was hypothesized to be associated with movement related appearance changes in the midfacial region, e.g., with furrowing and dimpling during speech. Design : Changes in the appearance of skin in the midfacial region, including a newly identified phenotypic feature, nasolabial fold (NLF) discontinuity, were described and compared across groups. Participants : Individuals with cleft lip (n  =  42), unaffected relatives of persons with a cleft (n  =  57) and healthy controls (n  =  41) were compared. Results : Frequencies of NLF discontinuity differed across cleft, relative, and control groups. NLF discontinuities were observed more frequently in individuals with a cleft phenotype (overt cleft or previously identified orbicularis oris muscle defect) than in those with no underlying muscular defect (Fisher exact test, P  =  .014). Conclusion : Results suggest that the appearance of facial soft tissue during movement of the midface is moderated at least in part by underlying cleft risk factors, indicating certain facial movements as candidate physical markers for extension of the cleft phenotype.

Whorl patterns on the lower lip are associated with nonsyndromic cleft lip with or without cleft palate.

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect due to both genetic and environmental factors. Whorl lip print patterns are circular grooves on the central upper lip and/or the left and right lower lip. To determine if whorls are more common in families with CL/P than in controls, the Pittsburgh Orofacial Cleft Study collected lip prints from over 450 subjects, that is, individuals with CL/P, their relatives, and unrelated controls-from the U.S., Argentina, and Hungary. Using a narrow definition of lower-lip whorl, the frequency of whorls in the U.S. sample was significantly elevated in cleft individuals and their family members, compared to unrelated controls (14.8% and 13.2% vs. 2.3%; P = 0.003 and 0.001, respectively). Whorls were more frequent in CL/P families from Argentina than in CL/P families from the U.S. or Hungary. If these results are confirmed, whorl lip print patterns could be part of an expanded phenotypic spectrum of nonsyndromic CL/P. As such, they may eventually be useful in a clinical setting, allowing recurrence risk calculations to incorporate individual phenotypic information in addition to family history data.

AXIS inhibition protein 2, orofacial clefts and a family history of cancer.

BACKGROUND: Cancer and congenital malformations occasionally may have a common etiology. The authors investigated whether families with one or more members affected by orofacial clefts (that is, families segregating orofacial clefts) had an increased cancer incidence when compared with control families. METHODS: The authors assessed 75 white families with nonsyndromic cleft lip with or without cleft palate (CL/P) and 93 white control families regarding a history of cancer. They used chi(2) and Fisher exact tests to determine significant differences. They then performed molecular studies with genes in which mutations have been independently associated with both cancer and craniofacial anomalies in a total of 111 families with CL/P. RESULTS: The families with CL/P reported a family history of cancer more often than did control families (P <.001), and they had higher rates of specific cancer types: colon (P <.001), brain (P = .003), leukemia (P = .005), breast (P = .009), prostate (P = .01), skin (P = .01), lung (P = .02) and liver (P = .02). The authors detected overtransmission of AXIS inhibition protein 2 (AXIN2) in CL/P probands (P = .003). CONCLUSION: Families segregating CL/P may have an increased susceptibility to cancer, notably colon cancer. Furthermore, AXIN2, a gene that when mutated increases susceptibility to colon cancer, also is associated with CL/P. CLINICAL IMPLICATIONS: People who are at a higher risk of developing disease need to adopt a healthier lifestyle, including avoiding exposure to risk factors that may interact with their genotypes.

Orbicularis oris muscle defects as an expanded phenotypic feature in nonsyndromic cleft lip with or without cleft palate.

Nonsyndromic cleft lip+/-cleft palate is a complex disease with a wide phenotypic spectrum; occult defects of the superior orbicularis oris muscle may represent the mildest subclinical form of the lip portion of the phenotype. This study used high-resolution ultrasonography to compare the frequency of discontinuities in the OO muscle in 525 unaffected relatives of individuals with nonsyndromic cleft lip+/-cleft palate versus 257 unaffected controls. OO muscle discontinuities were observed in 54 (10.3%) of the non-cleft relatives, compared to 15 (5.8%) of the controls-a statistically significant increase (P=0.04). Male relatives had a significantly higher rate of discontinuities than male controls (12.0% vs. 3.2%; P=0.01); female relatives also had a higher rate of discontinuities than female controls, but the increase was not statistically significant (8.9% vs. 7.4%; P=0.56). These data confirm the hypothesis that subepithelial OO muscle defects are a mild manifestation of the cleft lip phenotype. Identification of subepithelial OO muscle defects may be important in a clinical setting, as a means of providing more accurate recurrence risk estimates to relatives in cleft families. Furthermore, the expansion of the cleft lip+/-cleft palate phenotypic spectrum should improve the power of genetic studies.

Candidate genes for oral-facial clefts in Guatemalan families.

Nonsyndromic cleft lip +/- cleft palate (CL/P) is a complex trait of unknown etiology. Most genetic studies of CL/P define affection status in a way that ignores subtle subclinical manifestations, resulting in a potential loss of statistical power. This study investigated 10 candidate genes in 155 individuals from 25 Guatemalan CL/P families. High-resolution ultrasound images of the orbicularis oris (OO) muscle were obtained. CL/P was present in 28 family members; an additional 10 had subcutaneous OO muscle defects. Family-based association studies were performed for both narrow (CL/P only) and broad (CL/P plus OO muscle defects) definitions of affection status. PVRL1 was significantly associated under both definitions (P = 0.04, narrow; P = 0.02, broad). Association with JAG2 improved from P = 0.09 under the narrow definition to P = 0.04 under the broad definition. Broadening the oral-facial cleft phenotype to include subclinical variants may improve power in genetic studies.

Demographic and prenatal factors of patients with cleft lip and cleft palate. A pilot study.

BACKGROUND: Cleft lip, or CL, and cleft palate, or CP, are common congenital abnormalities. Birth prevalence ranges from one in every 500 to 1,000 in the white population and one in every 2,000 births in the African-American population. Etiologic and genetic factors contributing to CL and CP development are unknown though extensive research has been conducted. The authors conducted this pilot study to investigate a study design that could allow for an evaluation of such etiologic factors by providing the required estimate of the projected magnitude of differences between cases and controls. METHODS: The authors obtained pregnancy history data from the mothers of 137 consecutive patients at the University of Pittsburgh Cleft Palate-Craniofacial Center. The authors investigated the differences between sex or cleft status and family history of clefts, birth order, maternal age at birth and first-trimester maternal smoking and alcohol consumption. RESULTS: None of the factors showed any significant differences by sex or cleft type (P > or = .07) in the pilot data. Power estimates ranged from 12 to 71 percent. The sample size needed to obtain power of 80 percent would be 250 for variables with two categories and 480 for variables with three categories. CONCLUSIONS: There is no evidence that the factors contribute to either sex or cleft status differences. Further investigations are needed, and they should include a larger, more diverse sample of at least 250 cases, a matched control group and a focus on mothers of newborns. CLINICAL IMPLICATIONS: This study lays the groundwork for a better understanding of the etiology of CL and CP-common birth defects that present challenges for long-term dental management.