Barber–Say syndrome and Ablepharon–Macrostomia syndrome: An overview

Face

The general head shape in BSS and AMS are normal. Dolichocephaly was present at birth in three patients [McCarthy and West, 1977; Cesarino et al., 1988; Mazzanti et al., 1998] but the shape of the head became normal with time. Bitemporal narrowing and flat malae are present in both syndromes, protrusion of the maxilla (Fig. 5) occurs in three-quarters of all BSS patients, and becomes frequently more pronounced after infancy. There are excessive skin creases, both between eyebrows and running laterally to nose and mouth, in both entities. The somewhat older appearance compared to calendar age will in part be due to this (Fig. 1).

The main peri-ocular signs include peri-orbital fullness, hypertelorism, telecanthi, and “underdevelopment of eyelids,” typically mainly the lower one. If studied in more detail not the total eyelids are underdeveloped, but only the anterior parts (anterior lamella), which allows the medial and posterior lamella to protrude as in ectropion (Fig. 2) [Cruz et al., 1995]. In this respect, the eyelid abnormalities are limited to the skin part of the eyelids, and may be compared to forceps marks sign which can be present in Setleis syndrome. The term ablepharon is therefore in fact a misnomer, but for historical reasons we suggest to keep the term AMS unchanged. The anterior parts of the eyelids vary in their underdevelopment from being extremely small in AMS to minor reduction in size in BSS, to even less marked expression in a coloboma in a mosaic patient [Ferraz et al., 2000] and absence of eyelashes only of the medially lower lid [Marchegiani et al., 2015]. The underdeveloped anterior lamella causes ectropion, causing in turn lagophtalmus, which may need surgical correction [McCarthy and West, 1977; David et al., 1991; Price et al., 1991; Cruz et al., 1995; Ferraz et al., 2000; Stevens and Sargent, 2002; Brancati et al., 2004; Martins et al., 2010; Roche et al., 2010; Rohena et al., 2011; Feinstein et al., 2015; Marchegiani et al., 2015]. The continuous exposure may cause corneal clouding occurring in half of the patients with AMS. The cloudy cornea seem to become less marked after surgery [Jackson et al., 1988; Cruz et al., 2000; Stevens and Sargent, 2002; Brancati et al., 2004; Feinstein et al., 2015]. Visual impairments have been reported in almost one-third of patients. Photophobia may occur [Brancati et al., 2004; Rohena et al., 2011; Feinstein et al., 2015; Marchegiani et al., 2015]. A single AMS patient was found to have entropion [Stevens and Sargent, 2002]. Strabismus was also present in three BSS patients [Barber et al., 1982; David et al., 1991; Roche et al., 2010] and three AMS patients [McCarthy and West, 1977; Hornblass and Reifler, 1985; Jackson et al., 1988], and nystagmus was reported in BSS [David et al., 1991] and AMS as well [Hornblass and Reifler, 1985; Cruz et al., 1995].

The nasal bridge can be high, normal or flat, and is more frequently wide in AMS compared to BSS. In both entities distinctive signs are the broad ridge and tip, thick and flared alae nasi and small, anteverted nares. The columella can be broad [Barber et al., 1982; Mazzanti et al., 1998; Rohena et al., 2011], and may show a remarkable extension onto the philtrum. The philtrum itself is typically long. A striking feature is the unusually wide mouth occurring in almost all patients of both syndromes (Fig. 3). The cheeks protrude typically lateral of the corners of the mouth leading to a trait we indicate as cheek pads (Fig. 4), which is more frequent in AMS than in BSS. The upper vermillion is much more often thin in BSS patients compared to AMS patients, the lower vermilion is much less frequently thin in both entities. Cleft palate is only present in one patient [Dinulos and Pagon, 1999]. Thick gums have been present in four BSS patients [David et al., 1991; Martins et al., 2010; Marchegiani et al., 2015].

A small chin is present in more than one-third of patients in both syndromes, prognatia can occur in BSS [David et al., 1991; Dinulos and Pagon, 1999; Cortés et al., 2000], and also retrognatia has been described (Fig. 5) [Cesarino et al., 1988; Mazzanti et al., 1998]. The ears are typically low-set, small and mildly abnormally formed, with attached earlobes. These ear signs are more evident in AMS patients. Narrow ear canals have been reported far more frequently in BSS patients. Sometimes ears protrude in BSS [Dinulos and Pagon, 1999; Haensel et al., 2009; Marchegiani et al., 2015]. Impaired hearing has been reported several times, especially in AMS [Dinulos and Pagon, 1999; Stevens and Sargent, 2002; Brancati et al., 2004; Haensel et al., 2009; Martins et al., 2010].

Ectodermally Derived Structures

Genitalia

Abnormalities of the genitalia form part of both entities, but more frequently in AMS compared to BSS. Labia majora and scrotum are typically underdeveloped. Other signs are a small penis, hypospadias and undescended testes in males and small labia minora in females.

One female had hypospadias as well (opening of urethra in the upper vaginal wall) [Stevens and Sargent, 2002]. Genitalia have been described several times as ambiguous, but unfortunately details were not provided. Abnormally low position of the penis was reported twice [McCarthy and West, 1977; Cruz et al., 1995]. Whether this is the same as an anteriorly positioned anus that has been reported several times as well, is uncertain.

Other Characteristics

Visceral anomalies are infrequent. A single patient had mild right ventricular dilatation [Rohena et al., 2011] and another one a patent foramen ovale at birth [Feinstein et al., 2015]. The anterior abdominal wall is more frequently showing either an omphalocele or umbilical hernia in AMS (Fig. 7), and the umbilicus has also been described as unusually flat and up-ward pointing in AMS [McCarthy and West, 1977] or large [Stevens and Sargent, 2002]. In the limbs partial syndactyly of fingers occur in both entities, and camptodactyly almost exclusively in AMS. Other unusual manifestations have been laryngomalacia and tracheomalacia [David et al., 1991; Rohena et al., 2011], and a lipoma overlying the metopic suture [Stevens and Sargent, 2002].

Physical growth was reported to be normal in all patients except two who showed a decreased growth in height [Barber et al., 1982; Cesarino et al., 1988]. Cognition was normal in most patients but six showed delay [McCarthy and West, 1977; Barber et al., 1982; Hornblass and Reifler, 1985; Cesarino et al., 1988; Haensel et al., 2009; Marchegiani et al., 2015]. Whether the disturbed growth and development should be ascribed to the disorder or to other factors remains uncertain.

Differential Diagnosis

In the present study we did not include all patients published as having BSS and AMS. The patient reported by Ng and Rajguru [2006] was excluded only because the available information was too limited to be sure about the diagnosis. The authors did show a detail of the face showing the eyebrow, which had a shape unusual for BBS and would fit better Fraser syndrome, putting doubt about the diagnosis. We remained also in doubt about the patient reported by Sod et al. [1997] as the patient had no eye phenotype and there was not truly a wide mouth. It may be this patient has an unusually mild phenotype but without molecular confirmation it seems prudent to keep him separate for the time being.

Dinulos and Pagon [1999] published two cases hypothesizing a mother to son transmission of the disorder. The description and pictures of patient 1 are fitting well the diagnosis BSS but data on the child were insufficient to allow for a diagnosis and follow-up has proven to be impossible (personal communication 2015, Dr Marybeth Dinulos and Dr Darci Sternen). Because of this uncertainty we decided not to include this patient in the present overview.

The patient reported by Suga et al. [2014] showed a phenotype differing from BSS both in eye, face and body phenotype despite some overlap with BSS. At follow-up these differences have increased, and signs distinctive of BSS were noticed which; however, did not allow a clinical diagnosis up to now (personal communication 2015, Dr Kenichi Suga). Molecular analysis of TWIST2 failed to show a mutation. We concur with Dr Suga the patient must have another, as yet undiagnosed, entity.

Pellegrino et al. [1996] described a patient who had a complex rearrangement of 18q that caused at least a deletion of terminal 18q. This chromosome imbalance, the less marked eye signs, the presence of supernumerary nipples, cutis laxa, widely spread joint contractures, edema, and marked developmental delay and seizures make it unlikely that this patient should be diagnosed as having AMS. We remained uncertain about the patient reported by Amor and Savarirayan [2011] as the underdevelopment of the eyelids was less expressed, there was no hypertelorism, signs of the nose, mouth, and ears were much less clear compared to other patients, while the patient did have a significant developmental delay, seizures and cerebral anomalies at neuroradiology. The short palpebral fissures, laterally sparse eyebrows, entropion, everted lower lip, and large ears might in fact fit better a diagnosis of Setleis syndrome. The patient reported by Kallish et al. [2011] showed the phenotype of an acrofacial dysostosis, possibly Nager syndrome, and the differences to AMS were too significant to allow inclusion. The latter two patients [Amor and Savarirayan, 2011; Kallish et al., 2011] tested negatively for TWIST2 mutations [Marchegiani et al., 2015]. Lastly, the patient reported by Larumbe et al. [2011] clearly had severe congenital ichthyosis. One patient showing an overlap between Fraser syndrome and AMS was subsequently found to harbor a homozygous splice site mutation in FRAS1, confirming the diagnosis of Fraser syndrome [Cavalcanti et al., 2007; Schanze et al., 2013]. Fraser syndrome differs to BSS and AMS in the presence of cryptophthalmos, urinary tract defects, airway anomalies, and marked cutaneous syndactyly [Van Haelst et al., 2007].

The most important entity to differentiate from BSS and AMS is Setleis syndrome, which can also be caused by a TWIST2 mutation (Table IV). Setleis syndrome shows bitemporal narrowing with localized skin atrophy (forceps marks sign). Bitemporal narrowing is common in BSS and AMS too, and forceps marks sign has been described in three BSS patients. A further resemblance are the excessive skin creases although in Setleis syndrome these are predominantly present in the peri-orbital region. Eyelids can be markedly similar in the three entities, with the exception of entropion which is characteristic of Setleis syndrome. The broadness of the nose does not allow a firm differentiation between the three disorders, but the mouth differs: in Setleis syndrome there is a prominent and everted upper vermilion which is absent in AMS and BSS. In all three the mouth can be wide, but the cheek pads are infrequent in Setleis syndrome. The ectodermally derived structures in Setleis syndrome patients can be somewhat similar but typically these are less marked compared to BSS and AMS, and mamma anomalies have not been described. Also genital anomalies are less frequent and less marked, and the limb anomalies are mainly confined to underdevelopment of thenar and hypothenar in Setleis syndrome. We conclude the overlap between the three entities is significant but differentiation will in general be possible. We may expect that further patients will be described that show further overlap between the three syndromes, and we might need to conclude with time that BSS, AMS, and Setleis syndrome form in fact a spectrum of anomalies. The three patients reported with a phenotype resembling Setleis syndrome and in whom a duplication of the chromosome region 1p36.22p36.21 was found [Weaver et al., 2015], may be helpful in dissecting the mechanism(s) and gene(s) involved to explain the phenotype both in these patients as in patients with Setleis syndrome caused by TWIST2 mutations.

Verloes and Lesenfants [1977] described a single patient with macroblepharon, ectropion, hypertelorism, macrostomia syndrome (MEHM). A second case was reported by Corona-Rivera et al. [2013]. Both patients show facial characteristics remarkably similar to those in BSS and AMS consisting of hypertelorism, ectropion, corneal exposure, coloboma, broad nasal bridge, ridge and tip, anteverted nares, long and smooth philtrum, a thin upper vermilion, wide mouth, small mandible and zygomatic bones, and small ears. Visceral and limb anomalies are absent and growth and cognition are normal. Abnormalities of ectodermally derived structures are minimal (thick eyebrows, densely implanted eyelashes) or absent. It remains well possible that MEHM is allelic to BSS and AMS. Indeed a search for TWIST2 mutations has been initiated (personal communication 2015, Dr Alain Verloes).

Management

The face plays a central role in identity, attractiveness, and social interactions between humans. Of all physical handicaps, none is more devastating than facial disfigurement. It can severely affect social interactions and one's perception of self-image [De Sousa, 2008]. Patients with AMS and BSS will survive and most of them will have normal psychomotor development, but their aesthetic and social impairment, due to the craniofacial anomalies, will sometimes be very debilitating. Other manifestations, especially hypertrichosis, and underdeveloped mammae in females, may form another burden.

The eyelid anomalies in BSS and especially AMS can be very prominent, cause ectropion, and may result in corneal exposure with potential loss of vision. In severe ectropion with corneal exposure, surgical correction with skin grafts or local flaps with or without tarsorraphy is highly recommended. One may expect this to have excellent results as only the anterior lamella are abnormal but all other structures are normally formed. Indeed, in all reported surgical cases, this resulted in tremendous improvement of both aesthetics and functioning of the eyelids [McCarthy and West, 1977; David et al., 1991; Price et al., 1991; Cruz et al., 1995; Dinulos and Pagon, 1999; Stevens and Sargent, 2002; Brancati et al., 2004; Haensel et al., 2009; Martins et al., 2010; Rohena et al., 2011; Marchegiani et al., 2015]. In one patient amniotic membrane grafting was used [Feinstein et al., 2015].

For the other facial signs, it can be difficult to balance between on one hand timing of radical surgeries with best results in adolescence or early adulthood, leaving the growing face undisturbed as much as possible, and on the other hand the demands of the patients and their family, as they may insist on early surgical correction to look as normal as possible at a young age. Extensive surgery may have disastrous effects on craniofacial growth, resulting in a worse outcome on the long-term. A multidisciplinary approach by a team experienced in craniofacial anomalies, and an individualized treatment plan are essential for timing and optimizing functional and aesthetic outcome. Only case reports, often with limited information on exact surgical procedures to obtain a more natural facial appearance and no long-term follow up are published on individuals with AMC and BSS, so it remains hard to give clear guidelines for these problems. Reported surgical procedures include local flaps, face-lift procedures, forehead lifting, botox injections, fat grafting, orthognathic surgery, and nasal reconstruction with rib cartilage grafts [Mc Carthy and West, 1977; Mazzanti et al., 1998; Dinulos and Pagon, 1999; Stevens and Sargent, 2002; Brancati et al., 2004; Martins et al., 2010; Roche et al., 2010; personal observations N.R.]. In our opinion, such major procedures are best deferred until craniofacial growth is completed.

Hypertrichosis in BSS can be treated with laser therapy with good results, especially in patients with dark hair [Stevens and Sargent, 2002; Brancati et al., 2004; personal observations, unpublished]. The disadvantages are that multiple sessions are needed due to the growth cycles of hairs and that general anesthesia is needed in children as laser therapy can be very painful. Cosmetic mamma reconstructions using prostheses have been performed with good results [Stevens and Sargent, 2002; Brancati et al., 2004; personal observations N.R.].

No specific psychological help strategies have been described. The psycho-social impact of BSS and AMS can be marked due to the normal cognition but obviously different face and body appearance in both entities. No quality-of-life studies have been performed. It seems likely that full acceptance by their family and social context, offering access to plastic surgery without medicalization of the disorders, and providing psychological support from early age on to the patients, their parents and their sibs, will be major prerequisites for acceptance of the patients of the physical appearance and a high quality of life.