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.
Craniofrontonasal syndrome (CFNS) is an X-linked developmental malformation, caused by mutations in the EFNB1 gene, which have only been described since 2004. A genotype-phenotype correlation seems not to be present. As it is of major importance to adequately counsel patients with EFNB1 mutations and their parents, and to improve diagnosis of new patients, more information about the phenotypic features is needed. This study included 23 patients (2 male, 21 female) with confirmed EFNB1 mutations. All patients underwent a thorough physical examination and photographs were taken. If available, radiological images were also consulted. Hypertelorism, longitudinal ridging and/or splitting of nails, a (mild) webbed neck and a clinodactyly of one or more toes were the only consistent features observed in all patients. Frequently observed phenotypic features were bifid tip of the nose (91%), columellar indentation (91%) and low implantation of breasts (90%). In comparison with anthropometric data of facial proportions, patients with CFNS had a significantly different face in multiple respects. An overview of all phenotypic features is shown. Patients with EFNB1 mutations have a clear phenotype. This study will facilitate genetic counseling of parents and patients, and contribute to the diagnostic and screening process of patients with suspected CFNS.
BackgroundTreatment 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.MethodsThe 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.ResultsNonacceptance 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.ConclusionsThe 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 IIIThis 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.
BackgroundSmoking is a major cause of premature facial aging. Skin aging in general, often accompanied by wrinkling and furrowing, plays a significant role in the decision to undergo aesthetic surgery. Smoking may therefore be related to the demand for cosmetic surgery. This study aimed to compare smoking habits with respect to a standard cosmetic procedure (blepharoplasty) in the general population and to evaluate whether the age at surgery differs between smokers and nonsmokers.MethodsA questionnaire was sent to 517 patients with valid reports describing dermatochalasis of the upper eyelid who subsequently underwent an upper-eyelid correction in 2004. Smoking habits, socioeconomic status, and medical history were evaluated. The patients were classified as smokers, ex-smokers with at least 1 year of smoking cessation, and never-smokers.ResultsOf the 353 questionnaires (68.3 %) returned, 345 were eligible for statistical analysis. The smoking habits did not differ between the blepharoplasty group and the general population. However, the smokers underwent surgery an average of 3.7 years earlier than the ex-smokers (p = 0.0007) and 3.5 years earlier than the never-smokers (p = 0.006). No significant difference was observed between the ex-smokers and the never-smokers.ConclusionsThis is the first study to describe an association between smoking habits and an earlier need for upper-eyelid correction among ex- and never-smokers. The mechanism of skin restoration could result in a regenerative mechanism among ex-smokers, but further research is needed to support this hypothesis.Level of Evidence IIIThis 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.
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.
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