Alternative titles; symbols
SNOMEDCT: 711543008; ORPHA: 79113; DO: 0080196;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.31 | Mandibulofacial dysostosis, Guion-Almeida type | 610536 | Autosomal dominant | 3 | EFTUD2 | 603892 |
A number sign (#) is used with this entry because the Guion-Almeida type of mandibulofacial dysostosis (MFDGA) is caused by heterozygous mutation in the EFTUD2 gene (603892) on chromosome 17q21.
Mandibulofacial dysostosis with microcephaly is a rare syndrome comprising progressive microcephaly, midface and malar hypoplasia, micrognathia, microtia, dysplastic ears, preauricular skin tags, significant developmental delay, and speech delay. Many patients have major sequelae, including choanal atresia that results in respiratory difficulties, conductive hearing loss, and cleft palate (summary by Lines et al., 2012).
Guion-Almeida et al. (2000) reported 2 Brazilian boys with mental and growth retardation, microcephaly, trigonocephaly, preauricular skin tags, and cleft palate. Guion-Almeida et al. (2006) reevaluated these patients and reported 2 additional patients, a Brazilian boy and girl. In addition to the features noted by Guion-Almeida et al. (2000), all 4 patients had zygomatic arch hypoplasia and accentuated micrognathia, and all had severe language and speech delay. Guion-Almeida et al. (2006) concluded that this combination of signs represents a novel form of mandibulofacial dysostosis.
Ozkan et al. (2006) reported a male infant with esophageal atresia and distal tracheoesophageal fistula, micrognathia, U-shaped cleft palate, low-set right ear with microtia, glossoptosis, and right congenital radioulnar synostosis. The authors stated that the association of Pierre Robin sequence (261800) with congenital radioulnar synostosis and esophageal atresia had not previously been reported.
Wieczorek et al. (2007) described a sister and brother with esophageal atresia, microcephaly, hypoplasia of the zygomatic arch, microcephaly, micrognathia, cup-shaped ears, congenital heart defect, and mental retardation. The brother was more severely affected, with more pronounced facial dysmorphism, progression of microcephaly with age, and bilateral absence of the zygomatic arch. Their mother was mildly affected, with only right-sided hypoplasia of the zygomatic complex with partial aplasia of the zygomatic arch.
Wieczorek et al. (2009) reported 3 unrelated patients with sporadic occurrence of a mandibulofacial dysostosis syndrome with microcephaly and developmental delay. The children were born to unrelated parents of Turkish, German, and Spanish origin, respectively. Microcephaly (-2.2 to 3.7 SD) was apparent at birth, as were microtia, upturned nose, choanal atresia, malar hypoplasia, and micrognathia. Ears were dysplastic or hypoplastic with atresia or stenosis of the external auditory canal resulting in conductive hearing loss, preauricular tags, and hypoplasia of the upper part of the helix. Choanal atresia resulted in breathing difficulties. One patient had downslanting palpebral fissures and 2 had upslanting palpebral fissures. One had mild pulmonary stenosis, and another had atrial septal defect and cleft palate. All had delayed psychomotor development. Brain MRI of 1 patient at age 12 months showed delayed myelination, and bone scan at age 15 months showed retarded bone age. This patient developed seizures at age 7 years. Another patient had short neck and slender fingers with proximally located thumbs. Molecular studies excluded mutations in the TCOF1 (606847), HOXA2 (604685), and CHD7 (608892) genes in all patients. Wieczorek et al. (2009) noted similarities between these patients and the 2 sisters reported by Megarbane et al. (2005) (see 221300) and the sister and brother described by Wieczorek et al. (2007), although none of the sibs had choanal atresia.
Lines et al. (2012) reported follow-up of the patients reported by Guion-Almeida et al. (2006) and those of Wieczorek et al. (2009), as well as 7 additional patients with a similar phenotype. The patients ranged in age from 1 to 13 years; none had a family history of the disorder. Most were full-term infants, with microcephaly at birth, which progressed after birth to -3.0 to 6 SD. Other common features included malar hypoplasia, micrognathia, oblique palpebral fissures, and microtia, usually resulting in conductive hearing loss. Preauricular tags were found in most. Six patients had choanal atresia, 6 patients had a cleft palate, and 1 had bifid uvula. All had mild to moderate global developmental delay, with delayed walking and delayed or absent speech. Five developed seizures. More variable features included cardiac septal defects (6), proximally placed thumbs (4), and cryptorchidism (2).
Vincent et al. (2016) sequenced the EFTUD2 gene in 11 patients with suspected MFDM or MFD Guion-Almeida type 1 and identified mutations in 4 of those patients. All 4 patients had microcephaly, intellectual disability, malar and mandibular hypoplasia, deafness, and downward slanting palpebral fissures. Of 2 patients examined, both had microtia. One patient presented with esophageal atresia and 1 with complex cardiac malformation involving an atrial septal defect, patent ductus arteriosus, and bicuspid aortic valve. Notably, none of them had coloboma of the lower lid, projection of scalp hair onto the lateral cheek, renal malformation, or anomaly of the limbs.
Lines et al. (2012) found that all 12 molecularly confirmed cases of MFDM occurred de novo. However, Guion-Almeida et al. (2009) reported 1 instance of a Brazilian mother and son with variable manifestations of a similar disorder; molecular analysis was not performed. The boy had microcephaly, mandibulofacial dysostosis, S-shaped palpebral fissures, unusual ears with skin tags, micrognathia, cleft palate, and mental retardation with speech delay. The ears were small and cup-shaped with an atretic meatus, and he had conductive hearing loss. He had respiratory difficulties at birth. His mother had a similar craniofacial phenotype, with microcephaly, S-shaped palpebral fissures, zygomatic arch hypoplasia, micrognathia, malformed ears, and preauricular skins tags, but without cleft palate, mental retardation, or speech delay. However, in infancy she had mild motor developmental delay and learning difficulties.
In 12 unrelated patients with mandibulofacial dysostosis with microcephaly, Lines et al. (2012) identified heterozygous de novo mutations in or deletions involving the EFTUD2 gene (see, e.g., 603892.0001-603892.0005). A range of mutations, including deletion, frameshift, splice site, nonsense, and missense mutations, were identified, consistent with haploinsufficiency as the disease mechanism. The mutations were found by exome capture and high-throughput sequencing of 4 unrelated affected individuals, followed by analysis of EFTUD2 in 8 additional patients. All 3 patients reported by Wieczorek et al. (2009) had mutations, as did the 2 Brazilian patients reported by Guion-Almeida et al. (2006).
Because of the overlap in features between the Nager type of acrofacial dysostosis (AFD1; 154400), which is caused by mutation in the SF3B4 gene (605593), and MFDM, Bernier et al. (2012) analyzed the EFTUD2 gene in AFD patients who were negative for mutation in SF3B4 and identified a nonsense mutation in EFTUD2 in 1 patient (603892.0006). The authors noted that in retrospect the patient exhibited microcephaly, suggesting that MFDM rather than Nager syndrome was the appropriate diagnosis.
Need et al. (2012) performed whole-exome sequencing in 12 unrelated patients with unexplained and apparently genetic conditions, along with their unaffected parents. In 2 of the trios, in which the offspring had microcephaly, facial dysmorphism, dysplastic ears, and hearing loss, among other features, Need et al. (2012) identified a splice site and a frameshift insertion/deletion in the EFTUD2 gene, respectively. Analysis of mRNA from the proband with the splice site mutation and his parents did not reveal altered splicing or expression level. Need et al. (2012) concluded that EFTUD2 was a leading candidate for explaining the conditions in these children, and noted that both showed similarities to the patients studied by Lines et al. (2012).
Gordon et al. (2012) analyzed the EFTUD2 gene in 3 groups of patients: 17 cases with isolated esophageal atresia, 19 cases with oculoauriculovertebral spectrum (OAVS; see 164210), and 14 patients with mandibulofacial dysostosis and esophageal atresia and/or microcephaly. No mutations were found in the first 2 groups, but 10 of the patients in the last group had pathogenic EFTUD2 mutations (see, e.g., 603892.0007 and 603892.0008) or deletions. Of the 10 patients with pathogenic EFTUD2 mutations, 8 presented with esophageal atresia as a component of the phenotype; Gordon et al. (2012) concluded that esophageal atresia is an additional malformation caused by heterozygous EFTUD2 loss-of-function mutations. The authors noted that microcephaly might not be a consistent feature in this syndrome and proposed designating the entity 'MFD Guion-Almeida type.' They also suggested that the 2 patients with OAVS and esophageal atresia reported by Sutphen et al. (1995) (see hemifacial microsomia, 164210), and possibly the familial cases described by Wieczorek et al. (2007) and the patient reported by Ozkan et al. (2006), might represent additional cases of this syndrome.
Bernier, F. P., Caluseriu, O., Ng, S., Schwartzentruber, J., Buckingham, K. J., Innes, A. M., Jabs, E. W., Innis, J. W., Schuette, J. L., Gorski, J. L., Byers, P. H., Andelfinger, G., and 12 others. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am. J. Hum. Genet. 90: 925-933, 2012. [PubMed: 22541558] [Full Text: https://doi.org/10.1016/j.ajhg.2012.04.004]
Gordon, C. T., Petit, F., Oufadem, M., Decaestecker, C., Jourdain, A.-S., Andrieux, J., Malan, V., Alessandri, J.-L., Baujat, G., Baumann, C., Boute-Benejean, O., Caumes, R., and 20 others. EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia. J. Med. Genet. 49: 737-746, 2012. [PubMed: 23188108] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101173]
Guion-Almeida, M. L., Kokitsu-Nakata, N. M., Richieri-Costa, A. Mental and growth retardation, microtrigonocephaly, cleft palate and preauricular skin tags: a variant of the C syndrome or a new autosomal recessive syndrome? Braz. J. Dysmorph. Speech Hear. Disord. 3: 25-29, 2000.
Guion-Almeida, M. L., Vendramini-Pittoli, S., Passos-Bueno, M. R. S., Zechi-Ceide, R. M. Mandibulofacial syndrome with growth and mental retardation, microcephaly, ear anomalies with skin tags, and cleft palate in a mother and her son: autosomal dominant or X-linked syndrome? Am. J. Med. Genet. 149A: 2762-2764, 2009. [PubMed: 19921636] [Full Text: https://doi.org/10.1002/ajmg.a.32816]
Guion-Almeida, M. L., Zechi-Ceide, R. M., Vendramini, S., Tabith, A., Jr. A new syndrome with growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate. Clin. Dysmorph. 15: 171-174, 2006. [PubMed: 16760738] [Full Text: https://doi.org/10.1097/01.mcd.0000220603.09661.7e]
Lines, M. A., Huang, L., Schwartzentruber, J., Douglas, S. L., Lynch, D. C., Beaulieu, C., Guion-Almeida, M. L., Zechi-Ceide, R. M., Gener, B., Gillessen-Kaesbach, G., Nava, C., Baujat, G., and 16 others. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am. J. Hum. Genet. 90: 369-377, 2012. [PubMed: 22305528] [Full Text: https://doi.org/10.1016/j.ajhg.2011.12.023]
Megarbane, A., Chouery, E., Rassi, S., Delague, V. A new autosomal recessive oto-facial syndrome with midline malformations. Am. J. Med. Genet. 132A: 398-401, 2005. [PubMed: 15633182] [Full Text: https://doi.org/10.1002/ajmg.a.30479]
Need, A. C., Shashi, V., Hitomi, Y., Schoch, K., Shianna, K. V., McDonald, M. T., Meisler, M. H., Goldstein, D. B. Clinical application of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49: 353-361, 2012. [PubMed: 22581936] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100819]
Ozkan, K. U., Coban, Y. K., Uzel, M., Ergun, M., Oksuz, H. Pierre Robin sequence with esophageal atresia and congenital radioulnar synostosis. Cleft Palate Craniofac. J. 43: 317-320, 2006. [PubMed: 16681404] [Full Text: https://doi.org/10.1597/05-032.1]
Sutphen, R., Galan-Gomez, E., Cortada, X., Newkirk, P. N., Kousseff, B. G. Tracheoesophageal anomalies in oculoauriculovertebral (Goldenhar) spectrum. Clin. Genet. 48: 66-71, 1995. [PubMed: 7586653] [Full Text: https://doi.org/10.1111/j.1399-0004.1995.tb04057.x]
Vincent, M., Genevieve, D., Ostertag, A., Marlin, S., Lacombe, D., Martin-Coignard, D., Coubes, C., David, A., Lyonnet, S., Vilain, C., Dieux-Coeslier, A., Manouvrier, S., and 44 others. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet. Med. 18: 49-56, 2016. Note: Erratum: Genet. Med. 17: 686 only, 2015. [PubMed: 25790162] [Full Text: https://doi.org/10.1038/gim.2015.29]
Wieczorek, D., Gener, B., Gonzalez, M. J. M., Seland, S., Fischer, S., Hehr, U., Kuechler, A., Hoefsloot, L. H., de Leeuw, N., Gillessen-Kaesbach, G., Lohmann, D. R. Microcephaly, microtia, preauricular tags, choanal atresia and developmental delay in three unrelated patients: a mandibulofacial dysostosis distinct from Treacher Collins syndrome. Am. J. Med. Genet. 149A: 837-843, 2009. [PubMed: 19334086] [Full Text: https://doi.org/10.1002/ajmg.a.32747]
Wieczorek, D., Shaw-Smith, C., Kohlhase, J., Schmitt, W., Buiting, K., Coffey, A., Howard, E., Hehr, U., Gillessen-Kaesbach, G. Esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and mental retardation--new MCA/MR syndrome in two affected sibs and a mildly affected mother? Am. J. Med. Genet. 143A: 1135-1142, 2007. [PubMed: 17497718] [Full Text: https://doi.org/10.1002/ajmg.a.31752]