Mandibulofacial dysostosis with microcephaly (MFDM) is a disorder that causes abnormalities of the head and face.  People with this disorder often have an unusually small head at birth, and the head does not grow at the same rate as the rest of the body, so it appears that the head is getting smaller as the body grows (progressive microcephaly). Affected individuals have developmental delay and intellectual disability that can range from mild to severe. Speech and language problems are also common in this disorder.

Facial abnormalities that occur in MFDM include underdevelopment of the middle of the face and the cheekbones (midface and malar hypoplasia) and an unusually small lower jaw (mandibular hypoplasia, also called micrognathia). The external ears are small and abnormally shaped, and they may have skin growths in front of them called preauricular tags. There may also be abnormalities of the ear canal, the tiny bones in the ears (ossicles), or a part of the inner ear called the semicircular canals. These ear abnormalities lead to hearing loss in most affected individuals. Some people with MFDM have an opening in the roof of the mouth (cleft palate), which may also contribute to hearing loss by increasing the risk of ear infections. Affected individuals can also have a blockage of the nasal passages (choanal atresia) that can cause respiratory problems.

Heart problems, abnormalities of the thumbs, and short stature are other features that can occur in MFDM. Some people with this disorder also have blockage of the esophagus (esophageal atresia). In esophageal atresia, the upper esophagus does not connect to the lower esophagus and stomach. Most babies born with esophageal atresia (EA) also have a tracheoesophageal fistula (TEF), in which the esophagus and the trachea are abnormally connected, allowing fluids from the esophagus to get into the airways and interfere with breathing. Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening condition; without treatment, it prevents normal feeding and can cause lung damage from repeated exposure to esophageal fluids.

MFDM is a rare disorder; its exact prevalence is unknown. More than 60 affected individuals have been described in the medical literature.

MFDM is caused by mutations in the EFTUD2 gene. This gene provides instructions for making one part (subunit) of two complexes called the major and minor spliceosomes. Spliceosomes help process messenger RNA (mRNA), which is a chemical cousin of DNA that serves as a genetic blueprint for making proteins. The spliceosomes recognize and then remove regions called introns to help produce mature mRNA molecules.

EFTUD2 gene mutations that cause MFDM result in the production of little or no functional enzyme from one copy of the gene in each cell. A shortage of this enzyme likely impairs mRNA processing. The relationship between these mutations and the specific symptoms of MFDM is not well understood.

Genetic Testing Information

• Genetic Testing Registry: Mandibulofacial dysostosis-microcephaly syndrome

Genetic and Rare Diseases Information Center

• Mandibulofacial dysostosis-microcephaly syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• MANDIBULOFACIAL DYSOSTOSIS, GUION-ALMEIDA TYPE; MFDGA

Scientific Articles on PubMed

• PubMed

• Guion-Almeida ML, Zechi-Ceide RM, Vendramini S, Ju Nior AT. A new syndrome with growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate. Clin Dysmorphol. 2006 Jul;15(3):171-174. doi: 10.1097/01.mcd.0000220603.09661.7e. Citation on PubMed
• Lehalle D, Gordon CT, Oufadem M, Goudefroye G, Boutaud L, Alessandri JL, Baena N, Baujat G, Baumann C, Boute-Benejean O, Caumes R, Decaestecker C, Gaillard D, Goldenberg A, Gonzales M, Holder-Espinasse M, Jacquemont ML, Lacombe D, Manouvrier-Hanu S, Marlin S, Mathieu-Dramard M, Morin G, Pasquier L, Petit F, Rio M, Smigiel R, Thauvin-Robinet C, Vasiljevic A, Verloes A, Malan V, Munnich A, de Pontual L, Vekemans M, Lyonnet S, Attie-Bitach T, Amiel J. Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients. Hum Mutat. 2014 Apr;35(4):478-85. doi: 10.1002/humu.22517. Epub 2014 Mar 5. Citation on PubMed
• Lines M, Hartley T, MacDonald SK, Boycott KM. Mandibulofacial Dysostosis with Microcephaly. 2014 Jul 3 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK214367/ Citation on PubMed
• Lines MA, Huang L, Schwartzentruber J, Douglas SL, Lynch DC, Beaulieu C, Guion-Almeida ML, Zechi-Ceide RM, Gener B, Gillessen-Kaesbach G, Nava C, Baujat G, Horn D, Kini U, Caliebe A, Alanay Y, Utine GE, Lev D, Kohlhase J, Grix AW, Lohmann DR, Hehr U, Bohm D; FORGE Canada Consortium; Majewski J, Bulman DE, Wieczorek D, Boycott KM. Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am J Hum Genet. 2012 Feb 10;90(2):369-77. doi: 10.1016/j.ajhg.2011.12.023. Epub 2012 Feb 2. Citation on PubMed or Free article on PubMed Central
• Luquetti DV, Hing AV, Rieder MJ, Nickerson DA, Turner EH, Smith J, Park S, Cunningham ML. "Mandibulofacial dysostosis with microcephaly" caused by EFTUD2 mutations: expanding the phenotype. Am J Med Genet A. 2013 Jan;161A(1):108-13. doi: 10.1002/ajmg.a.35696. Epub 2012 Dec 14. Citation on PubMed or Free article on PubMed Central
• Wieczorek D, Gener B, Gonzalez MJ, Seland S, Fischer S, Hehr U, Kuechler A, Hoefsloot LH, de Leeuw N, Gillessen-Kaesbach G, Lohmann DR. 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 A. 2009 May;149A(5):837-43. doi: 10.1002/ajmg.a.32747. Citation on PubMed