Barber-Say Syndrome

A number sign (#) is used with this entry because of evidence that Barber-Say syndrome (BBRSAY) is caused by heterozygous mutation in the TWIST2 gene (607556) on chromosome 2q37.

Description

Barber-Say syndrome is a rare congenital condition characterized by severe hypertrichosis, especially of the back, skin abnormalities such as hyperlaxity and redundancy, and facial dysmorphism, including macrostomia, eyelid deformities, ocular telecanthus, abnormal and low-set ears, bulbous nasal tip with hypoplastic alae nasi, and low frontal hairline (summary by Roche et al., 2010).

Clinical Features

Barber et al. (1982) described a patient with a previously unreported pattern of multiple congenital anomalies consisting of macrostomia, ectropion, atrophic skin, marked hypertrichosis, and growth retardation.

Cesarino et al. (1988) described a male infant with bilateral lid agenesis and total keratinization of the cornea and conjunctiva with macrostomia, psychomotor retardation, forehead hypertrichosis, ocular hypertelorism, thin lips, abnormal auricles and nose, and other findings. They considered this patient's disorder to be distinct from the ablepharon-macrostomia syndrome (AMS; 200110) and proposed the designation 'lid agenesis-macrostomia-psychomotor retardation-forehead hypertrichosis syndrome.' Gorlin (1991) concluded also that this probably represents a disorder distinct from the ablepharon-macrostomia syndrome and pointed to another case reported by Barber et al. (1982). It was commented that the hairy forehead and some of the facial features resemble Cornelia de Lange syndrome (122470), although it is clearly a distinct disorder.

David et al. (1991) reported an 11-year-old boy with hypertelorism, exophthalmia, bilateral partial agenesis of the lids with ectropion, abnormal ears, macrostomia with thin lips, prognathism, redundant facial skin giving an aged appearance, atrophic thoracic skin and hypoplastic nipples, and marked hypertrichosis over the forehead, neck, and back. David et al. (1991) reviewed 5 previously reported similar cases (McCarthy and West, 1977; Barber et al., 1982; Hornblass and Reifler, 1985; Cesarino et al., 1988) and concluded that their own patient and that of Barber et al. (1982) had the same condition, and that the patient described by Cesarino et al. (1988) could be considered to represent a variant of the same syndrome.

Martinez Santana et al. (1993) reported a girl, born of healthy first-cousin parents, who presented with severe hypertrichosis, macrostomia, ectropion, and atrophic skin. The authors noted that this patient was the third to be reported with Barber-Say syndrome, after the reports of Barber et al. (1982) and David et al. (1991).

Sod et al. (1997) reported a 5-year-old boy with macrostomia, hypertelorism, atrophic skin, and severe hypertrichosis, all features of Barber-Say syndrome. The child did not have ectropion, however, and in general the phenotype was less severe than that in previously reported cases.

Mazzanti et al. (1998) presented a case of Barber-Say syndrome and suggested that the syndrome is definably separate from disorders such as ablepharon-macrostomia syndrome. Their patient was an 8-year-old girl whom they had followed from the age of 1 year. She had lax, redundant skin, ectropion, bulbous nose, macrostomia, and absence of mammary glands. Some of the anomalies noted at birth worsened with age: ectropion, bulbous and long nose, macrostomia, and skin laxity. Teeth were present, but with delayed eruption. Mazzanti et al. (1998) pointed out that this syndrome and AMS share distinctive clinical manifestations that involve the same structure of the skin and adnexa. The authors hypothesized that they may derive from a 'defective regulation of the same gene.'

Dinulos and Pagon (1999) reported mother-to-son transmission of the Barber-Say syndrome, a finding that strongly supports dominant inheritance. The characteristic facial changes, small ears, hirsutism, and redundant skin were consistent with the findings in 5 reported cases. The mother also had cleft palate and mild conductive hearing loss. Her son had a shawl scrotum, primary hypospadias, and mild hearing loss. The findings in this family are compatible with either autosomal dominant or X-linked inheritance.

Stevens and Sargent (2002) stated that the ablepharon-macrostomia and Barber-Say syndromes appear to be distinct disorders. Features common to both syndromes are macrostomia, abnormal ears and nose, hypoplastic nipples, sparse eyebrows and eyelashes, and redundant skin. Distinguishing features include ablepharon in AMS versus ectropion in Barber-Say syndrome and marked hypertrichosis in Barber-Say syndrome. In addition, genital abnormalities are much more severe in AMS.

Tenea and Jacyk (2006) reported a 1-week-old South African male infant, born to healthy nonconsanguineous parents, who had generalized hypertrichosis, most pronounced over the midback, and dysmorphic facies, including bilateral ectropion, hypertelorism, macrostomia, abnormally shaped ears, bulbous nose, and sparse eyebrows and eyelashes. He also exhibited nipple hypoplasia, transposition of the scrotum (shawl scrotum), clubfeet, short neck, and skin laxity. Skin biopsy from his right thigh showed atrophic, slightly orthohyperkeratotic epidermis, and a thin reticular layer of dermis. Staining for elastic fibers showed a reduction in number as well as fragmentation.

Haensel et al. (2009) described a 7-year-old girl, born of nonconsanguineous parents, who had unequivocal features of Barber-Say syndrome but also had bilateral microblepharon. She was first seen at 2 years of age due to generalized hypertrichosis, especially of the back. She also had hypertrichosis of the face, forearms, and lower legs, a triangular face, telecanthus, bilateral microblepharon, bulbous nose, macrostomia, thin lips, small teeth, cup-shaped ears, small tortuous external auditory canals, and mild hearing impairment. She had inverted nipples, swollen snout-shaped labia majora, and dry skin. Growth and proportions were normal, but she was mentally retarded, with vocabulary and speech perception corresponding to 3.75 years at age 7.2 years. Haensel et al. (2009) stated that this was the first report of microblepharon in a patient with Barber-Say syndrome and that this finding supported the hypothesis that Barber-Say syndrome and ablepharon-macrostomia syndrome may represent the same syndrome.

Roche et al. (2010) reported a father and daughter with Barber-Say syndrome. The father presented all the characteristics of the disorder but was less severely affected than his daughter. She had hypertrichosis of the face with low anterior hairline and broad, sparse eyebrows, low-set ears with a small external auditory meatus and abnormally formed conchae, flat nose with a bulbous tip and hypoplastic, flaring nostrils, and macrostomia with thin vermilion and mild micrognathia. Skin tags were present at the orbital rim and corner of the mouth; teeth were present but eruption was delayed. Her skin was atrophic and redundant with deep folds, most pronounced on the abdominal wall and forehead, with prominent subcutaneous veins on the trunk and limbs. Severe hypertrichosis was generalized, but particularly pronounced over her back and neck, and she had inverted and hypoplastic nipples. Her genitalia were normal. Hearing tests and psychomotor development were normal in both father and daughter; no cytogenetic abnormalities were found and array CGH was also normal. Roche et al. (2010) reviewed the clinical features of the 11 previously reported cases.

Martins et al. (2010) reported a 7-year-old girl with BBRSAY who was referred to their dentistry center for evaluation of malocclusion and delayed eruption of most primary teeth. Detailed oral examination showed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed tooth eruption, and malocclusion. Histopathologic evaluation of the patient's gingival tissue revealed abundant collagen deposition and absence of elastic fibers, which the authors noted is associated with laxity in the skin. Martins et al. (2010) proposed that lack of elastic fibers in gingival tissue can cause rigidity of the gingiva, which consequently becomes an obstacle for completed tooth eruption. Noting that the primary features of BBRSAY seem to derive from a developmental abnormality of the skin and adnexa, and that the ectodermal structures in this patient were 'impressively compromised,' Martins et al. (2010) suggested that BBRSAY should be considered an ectodermal dysplasia.

Molecular Genetics

After identifying a heterozygous mutation in the TWIST2 gene (E75K; 607556.0004) in patients with ablepharon-macrostomia syndrome (AMS; 200110), the features of which closely overlap those of BBRSAY, Marchegiani et al. (2015) analyzed TWIST2 in 12 individuals with BBRSAY and detected heterozygosity for 2 different missense mutations also involving codon 75 in 11 of the patients: 9 patients, including 8 who were previously reported (David et al., 1991; Martinez Santana et al., 1993; Tenea and Jacyk, 2006; Martins et al., 2010; Roche et al., 2010), were heterozygous for an E75Q mutation (607556.0005); and 2 patients, 1 of whom was originally reported by Mazzanti et al. (1998), were heterozygous for an E75A substitution (607556.0006). The remaining patient, a girl with BBRSAY who was originally reported by Haensel et al. (2009), was heterozygous for a 6-bp duplication at codons 77 and 78 (607556.0007). All 4 mutations are located in the basic domain of the protein, and molecular analyses suggested that the mutations alter the DNA-binding activity of TWIST2, leading to both dominant-negative and gain-of-function effects. Analysis of affected and unaffected skin from the mildly affected father reported by Roche et al. (2010) revealed mosaicism for the E75Q TWIST2 mutation.