Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes.

Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries-a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5' untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5' UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.

Assessing nonacceptance of the facial appearance in adult patients after complete treatment of their rare facial cleft.

BACKGROUND: Treatment of patients with severe congenital facial disfigurements is aimed at restoring an aesthetic and functional balance. Besides an adequate level of satisfaction, an individual's acceptance of facial appearance is important to achieve because nonacceptance is thought to lead to daily psychological struggles. This study objectified the prevalence of nonacceptance among adult patients treated for their severe facial clefts, evaluated risk factors, and developed a screening tool. METHODS: The study included 59 adults with completed treatment for their severe facial cleft. All the patients underwent a semistructured in-depth interview and filled out the Body Cathexis Scale. RESULTS: Nonacceptance of facial appearance was experienced by 44% of the patients. Of the nonaccepting patients, 72% experienced difficulties in everyday activities related to their appearance versus 35% of the accepting patients. Acceptance did not correlate with objective severity or bullying in the past. Risk factors for nonacceptance were high self-perceived visibility, a troublesome puberty period, and an emotion-focused coping strategy. Also, the presence of functional problems was shown to be highly associated. CONCLUSIONS: The objective severity of the residual deformity did not correlate with the patients' acceptance of their facial appearance, but the self-perceived visibility did correlate. The process of nonacceptance resembles the process seen in patients with body dysmorphic disorders. Surgical treatment is no guarantee for an improvement in acceptance and is therefore discouraged for patients who match the risk factors for nonacceptance unless it solves a functional problem. The authors therefore recommend screening patients for nonacceptance and considering psychological treatment before surgery is performed. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors at www.springer.com/00266.

Defense mechanisms in congenital and acquired facial disfigurement: a clinical-empirical study.

It is of clinical interest to investigate the degree to which patients with facial disfigurement use defense styles. Therefore, 59 adults born with rare facial clefts, 59 patients with facial deformities acquired at an adult age, and a reference group of 141 adults without facial disfigurements completed standardized questionnaires. There was a significant difference between the group with and the group without disfigurements on immature defense styles, with the disfigured group using the immature style more frequently. There was a trend for the nondisfigured group to use more mature defense styles. No difference between congenital and acquired groups was seen on individual types of defense style. Self-esteem had the strength to differentiate mature and immature defense styles within our disfigured groups. The association of low self-esteem and the utilization of immature defense styles suggests that professional help may tailor treatment on discussing immature defense style and problems triggering or maintaining this style.

Adults with congenital or acquired facial disfigurement: impact of appearance on social functioning.

This study evaluates the impact of congenital and acquired facial disfigurement on social functioning in adults and whether this differs from adults without facial disfigurement. Moreover, the predictive value of objective and subjective appearance on social functioning is explored. Fifty-nine adults with severe congenital facial disfigurement, 59 adults with traumatically acquired facial deformities in adulthood, and 120 adults without facial disfigurement, completed the Scale for Interpersonal Behaviour, Social Avoidance and Distress Scale, and Visual Analogue Scale for facial appearance satisfaction. The impact of congenital and acquired facial disfigurement on social functioning in adults is similar and significantly differed from the reference group. The level of stress evoked by interpersonal behaviour, and social anxiety and distress were not significantly different between the groups. Only the patient's subjective appearance was a predictor of social functioning. Avoiding stress caused by stigmatization and uncertainty about reactions of others, leads to less frequent interpersonal behaviour in adults with facial disfigurement. The fact whether the deformity is congenital or acquired in adulthood has no influence on social functioning. Patient's satisfaction with facial appearance is more important than the objective severity of the deformity; in this context realistic expectations of the patient considering additional surgery are important.

Long-term results after 40 years experience with treatment of rare facial clefts: Part 1--Oblique and paramedian clefts.

BACKGROUND: Oblique and paramedian rare facial clefts impose a major reconstructive challenge and long-term assessments of the outcomes remain scarce. This study provides new details regarding surgical techniques and timing, influence of growth, and difficulties of this pathology on the long-term; a guideline for surgical treatment is given. METHODS: Twenty-nine adults with an oblique or paramedian facial cleft and surgically treated in the authors' unit between 1969 and 2009, were included. The long-term evaluation was based on series of photographs, 3D-CT's, X-rays, operation data, and was specified per facial area. RESULTS: The mean number of performed operations per patient was 10.6 (range: 1-26). Vertical dystopia is not caused by previous surgery, but by growth deficiencies of the maxilla. In all patients with vertical dystopia, its presence and severity were clear at the age of five, and it should ideally be treated shortly after that age. In mild cases grafting seems sufficient, but in more severe cases orbital translocation is necessary. Costochondral grafts showed the best long-term results in both orbital and nasal reconstructions. Major nose reconstruction is best delayed until adolescence. For an optimal final result in selected cases, correction of midface hypoplasia at adolescence is necessary. CONCLUSION: The three-dimensional underdevelopment of the midface region plays a central role in the deformities of most patients, but is complex and difficult to correct. The provided guideline should help to minimize the number of operations and ameliorate long-term results.

Long-term results after 40 years experience with treatment of rare facial clefts: Part 2--Symmetrical median clefts.

BACKGROUND: Median facial clefts are reconstructive challenges, requiring multiple operations throughout life. Long-term results are often still far from ideal and could be improved. Due to surgical intervention and diminished intrinsic growth potential, surgical results may change from initially good into a progressively disappointing outcome. If, however, the ideal timing and type of surgery are known, in combination with the intrinsic growth potential, the results can be ameliorated. A guideline for surgical treatment is given. METHODS: Twenty patients with a pure symmetrical median cleft were evaluated on intermediate and long-term surgical results. The final result was scored based on severity of the initial and the remaining facial deformities, and the need for revisional surgery. RESULTS: The long-term surgical outcome was initially good for each of the affected facial parts and the face in general, but worsened over time, especially in the zone of the nose. An adequate and stable result of hypertelorism correction was observed for both the orbital box osteotomy and medial faciotomy, even when performed at a young age. CONCLUSIONS: The intrinsic growth restriction is mainly localised in the central midface. This leads to a complex and often unpredictable growth of the maturing face. It makes it difficult to achieve perfect reconstructions. Caution with surgical interventions of the nose at a young age is required. Once the face has matured, a midface advancement and secondary nose correction should be considered for satisfactory projection. Early referral to a specialised centre is essential.