SNOMEDCT: 718575002; ORPHA: 920; DO: 0060550;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q37.3 | Ablepharon-macrostomia syndrome | 200110 | Autosomal dominant | 3 | TWIST2 | 607556 |
A number sign (#) is used with this entry because of evidence that ablepharon-macrostomia syndrome (AMS) is caused by heterozygous mutation in the TWIST2 gene (607556) on chromosome 2q37.
Ablepharon-macrostomia syndrome (AMS) is a congenital ectodermal dysplasia characterized by absent eyelids, macrostomia, microtia, redundant skin, sparse hair, dysmorphic nose and ears, variable abnormalities of the nipples, genitalia, fingers, and hands, largely normal intellectual and motor development, and poor growth (summary by Marchegiani et al., 2015).
McCarthy and West (1977) reported 2 unrelated male children with absent eyelids, eyebrows, and eyelashes; fusion defects of the mouth; rudimentary external ears; ambiguous genitalia; absent or rudimentary nipples; coarse, dry skin with redundant skin folds; and delayed development of expressive language. Jackson et al. (1988) provided follow-up at age 12 years on the second case of McCarthy and West (1977). They pointed out another feature of the disorder, namely, absence of the zygomatic arches.
Hornblass and Reifler (1985) described a 10-day-old infant with total absence of the upper and lower eyelids, failure of lip fusion resulting in an enlarged, fish-like mouth, abnormally shaped ears and nose, absence of lanugo, ventral hernia, and ambiguous genitalia. They reconstructed the eyelids in a 3-stage procedure and later the child underwent successful reconstruction of the mouth. Hornblass and Reifler (1985) drew attention to the presence of vestigial eyelid structures, suggesting that the true nature of the eyelid deformity in this syndrome may be severe microblepharon rather than ablepharon.
Price et al. (1991) reported a male infant who was born with shallow orbits with inadequate eyelids, hypertelorism, large square mouth, protrusion of maxilla, and malformed, low-set ears. Skin was wrinkled and hairless, and eyelashes and eyebrows were absent. Genitalia were ambiguous. Periorbital skin biopsies taken during reconstructive surgery showed no specific abnormality, and collagen studies were normal. His parents were nonconsanguineous, and there was no family history of congenital anomalies.
Ferraz et al. (2000) described an infant with ablepharon-macrostomia syndrome, the sister of a previously reported affected female (Cruz et al., 1995). Manifestations of the syndrome included severe shortness of the eyelids, low nasal bridge with hypoplastic and anteverted nostrils, macrostomia, small ears, absence of nipples, and absence of lanugo. The father had more mild abnormalities of the eyelids, eyebrows, and ears. The authors suggested that this family supports autosomal dominant inheritance with variable expression.
Stevens and Sargent (2002) reported 3 new cases, gave a 10-year follow-up of a newborn reported in an abstract by Markouizos et al. (1990), and reviewed the findings in the 4 other reported cases. All of the patients had absent hair, brows, and lashes, absent or short eyelids, macrostomia, ear anomalies, redundant skin, and abnormal genitalia. Many had persistent visual problems, often related to early corneal exposure. Hearing loss, poor hair growth, finger contractures, and growth retardation were also chronic problems. Developmental impairment was present in two-thirds of patients but was usually mild. Their series included the first reported adult patient, a 27-year-old woman. She had no scalp hair, eyelids, eyebrows, or eyelashes at birth. She had macrostomia and tiny 'rosebud' ears. There was camptodactyly and mild syndactyly of fingers 2 to 5 bilaterally and ambiguous genitalia.
Because of distinctive clinical manifestations that are shared in common by AMS and Barber-Say syndrome (209885), some have suggested that they may represent defects in the same gene (Mazzanti et al., 1998).
Stevens and Sargent (2002) suggested that their experience provided evidence that AMS is distinct from Barber-Say syndrome. Common features of the 2 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. Genital abnormalities are much more severe in AMS.
Brancati et al. (2004) contributed to the characterization of the AMS phenotype in adulthood. They reported an Italian woman in whom the diagnosis was made at the age of 46 years. At birth, absent eyelashes and eyebrows, with slight and asymmetric vertical shortening of upper and lower eyelids, and abnormal ears with rudimentary cartilage were described. At the age of 14 years, when surgical repair of the eyelids was performed, alae nasi and malar hypoplasia, absent zygomatic arches, macrostomia, and small chin were noted. At 22 years of age, chin and breast hypoplasia were treated by plastic surgery, and hypoplasia of the zygomatic arches was remodeled some months later, by implantation of subcutaneous prostheses. At 31 years of age, surgical reconstruction of external ears was attempted. On evaluation at age 46 years, the findings included partial cutaneous syndactyly with camptodactyly of the fifth fingers, particularly on the left. Other finger bone anomalies included short left third, fourth, and fifth and right fourth and fifth metacarpal bones. Audiograms showed bilateral high frequency hearing loss. Developmental milestones were considered normal as well as intelligence at the time of examination. Menarche occurred at 12 years of age. The findings were compared to those in 13 other patients: 11 aged newborn to 12 years, one aged 25 years (Ferraz et al., 2000), and one aged 27 years (Stevens and Sargent, 2002).
Marchegiani et al. (2015) restudied the AMS family originally reported by Rohena et al. (2011). Extensive craniofacial phenotyping of the affected daughter revealed harlequin-shaped eyebrows with absence of the distal third, hypoplastic nasal dorsum with no projection of the nasal tip, absent columella, hypoplastic ala nasi, macrostomia, CL II malocclusion with 50% overbite, Brodie bite, conical teeth, and long uvula. The macrostomia was characterized by deficient lateral development of the vermilion border and an inability to raise the oral commissures on smiling, suggesting discontinuity of the orbicularis oris muscle. Electron microscopy of skin biopsies from the affected father and daughter showed thin, disrupted elastic fibers with areas of amorphous deposits along abnormally oriented collagen fibers and adjacent areas of microfibrillar proliferation. Masson-trichrome staining revealed abnormal reticulodermal collagen patterns in both patients, whereas elastic fiber staining was within normal limits.
Rohena et al. (2011) reported AMS in a newborn female and her 22-year-old father and suggested autosomal dominant inheritance of the disorder. Marchegiani et al. (2015) confirmed autosomal dominant inheritance of the AMS in this family.
Possible autosomal recessive inheritance was proposed because of a postulated relationship to the disorder in monozygotic twins from a consanguineous marriage: one twin had bilateral cryptophthalmos and the other had cryptophthalmos on the left and ablepharon on the right (Azevedo et al., 1973).
Pellegrino et al. (1996) described a male infant with ablepharon-macrostomia syndrome and a complex rearrangement and partial deletion of chromosome 18; the final karyotype, based on molecular cytogenetic analysis, was 46,XY,-18,+[del(18)(q21.3q23),inv(18)(q12.3q21.2)]. The authors stated that this was the first AMS patient to be reported with an abnormal karyotype, and that he lacked the typical features of the 18q deletion syndrome (601808). Pellegrino et al. (1996) suggested that the gene(s) for ablepharon-macrostomia syndrome might lie on chromosome 18 in the region of this patient's deletion or inversion breakpoints.
Using DNA from a father and daughter with AMS, originally reported by Rohena et al. (2011), Marchegiani et al. (2015) performed exome sequencing and identified heterozygosity for a missense mutation in the TWIST2 gene (E75K; 607556.0004) that was not found in an in-house exome cohort or in public variant databases. Targeted sequencing revealed heterozygosity for the same E75K mutation in 8 more individuals with AMS from 6 unrelated, previously reported families (Price et al., 1991; Cruz et al., 1995; Ferraz et al., 2000; Stevens and Sargent, 2002; Brancati et al., 2004). Analysis of TWIST2 in individuals with Barber-Say syndrome (BSS; 209885), the features of which closely overlap those of AMS, revealed heterozygosity for 2 different missense mutations also involving codon 75, E75Q (607556.0005) and E75A (607556.0006), as well as 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 3 mildly affected AMS patients with variable skin pigmentation (Ferraz et al., 2000; Brancati et al., 2004; Rohena et al., 2011) revealed mosaicism for the TWIST2 E75K mutation.
Azevedo, E. S., Biondi, J., Ramalho, L. M. Cryptophthalmos in two families from Bahia, Brazil. J. Med. Genet. 10: 389-392, 1973. [PubMed: 4774831] [Full Text: https://doi.org/10.1136/jmg.10.4.389]
Brancati, F., Mingarelli, R., Sarkozy, A., Dallapiccola, B. Ablepharon-macrostomia syndrome in a 46-year-old woman. Am. J. Med. Genet. 127A: 96-98, 2004. [PubMed: 15103726] [Full Text: https://doi.org/10.1002/ajmg.a.20658]
Cruz, A. A. V., Guimaraes, F. C., Obeid, H. N., Ferraz, V. E. F., Noce, T. R., Martinez, F. E. Congenital shortening of the anterior lamella of all eyelids: the so-called ablepharon macrostomia syndrome. Ophthal. Plast. Reconstr. Surg. 11: 284-287, 1995. [PubMed: 8746822] [Full Text: https://doi.org/10.1097/00002341-199512000-00012]
Ferraz, V. E. F., Melo, D. G., Hansing, S. E., Cruz, A. A. V., Pina-Neto, J. M. Ablepharon-macrostomia syndrome: first report of familial occurrence. Am. J. Med. Genet. 94: 281-283, 2000. [PubMed: 11038439] [Full Text: https://doi.org/10.1002/1096-8628(20001002)94:4<281::aid-ajmg3>3.0.co;2-s]
Hornblass, A., Reifler, D. M. Ablepharon macrostomia syndrome. Am. J. Ophthal. 99: 552-556, 1985. [PubMed: 4003491] [Full Text: https://doi.org/10.1016/s0002-9394(14)77956-5]
Jackson, I. T., Shaw, K. E., del Pinal Matorras, F. A new feature of the ablepharon macrostomia syndrome: zygomatic arch absence. Brit. J. Plast. Surg. 41: 410-416, 1988. [PubMed: 3293678] [Full Text: https://doi.org/10.1016/0007-1226(88)90084-7]
Marchegiani, S., Davis, T., Tessadori, F., van Haaften, G., Brancati, F., Hoischen, A., Huang, H., Valkanas, E., Pusey, B., Schanze, D., Venselaar, H., Vulto-van Silfhout, A. T., and 35 others. Recurrent mutations in the basic domain of TWIST2 cause ablepharon macrostomia and Barber-Say syndromes. Am. J. Hum. Genet. 97: 99-110, 2015. [PubMed: 26119818] [Full Text: https://doi.org/10.1016/j.ajhg.2015.05.017]
Markouizos, D., Siddiqi, U., Siddiqi, S., Raziuddin, K., Nangia, B. Ablepharon macrostomia syndrome: report of a case and clinical delineation. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A66 only, 1990.
Mazzanti, L., Bergamaschi, R., Neri, I., Perri, A., Patrizi, A., Cacciari, E., Forabosco, A. Barber-Say syndrome: report of a new case. Am. J. Med. Genet. 78: 188-191, 1998. [PubMed: 9674915]
McCarthy, G. T., West, C. M. Ablepheron (sic) macrostomia syndrome. Dev. Med. Child Neurol. 19: 659-672, 1977. [PubMed: 913905] [Full Text: https://doi.org/10.1111/j.1469-8749.1977.tb07999.x]
Pellegrino, J. E., Schnur, R. E., Boghosian-Sell, L., Strathdee, G., Overhauser, J., Spinner, N. B., Stump, T., Grace, K., Zackai, E. H. Ablepharon macrostomia syndrome with associated cutis laxa: possible localization to 18q. Hum. Genet. 97: 532-536, 1996. [PubMed: 8834257] [Full Text: https://doi.org/10.1007/BF02267081]
Price, N. J., Pugh, R. E., Farndon, P. A., Willshaw, H. E. Ablepharon macrostomia syndrome. Brit. J. Ophthal. 75: 317-319, 1991. [PubMed: 2036354] [Full Text: https://doi.org/10.1136/bjo.75.5.317]
Rohena, L., Kuehn, D., Marchegiani, S., Higginson, J. D. Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome. Am. J. Med. Genet. 155A: 850-854, 2011. [PubMed: 21595001] [Full Text: https://doi.org/10.1002/ajmg.a.33900]
Stevens, C. A., Sargent, L. A. Ablepharon-macrostomia syndrome. Am. J. Med. Genet. 107: 30-37, 2002. [PubMed: 11807864] [Full Text: https://doi.org/10.1002/ajmg.10123]