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Mandibulofacial Dysostosis with Microcephaly

Synonyms: Mandibulofacial Dysostosis, Guion-Almeida Type; MFDGA

, MD, , MSc, and , PhD, MD.

Author Information

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Summary

Clinical characteristics.

Mandibulofacial dysostosis with microcephaly (MFDM) is characterized by malar and mandibular hypoplasia; microcephaly (congenital or postnatal onset); malformations of the pinna, auditory canal, and/or middle ear (ossicles and semi-circular canals) with associated conductive hearing loss; and distinctive facial features (metopic ridge, up- or downslanting palpebral fissures, prominent glabella, broad nasal bridge, bulbous nasal tip, and everted lower lip). Associated craniofacial malformations may include cleft palate, choanal atresia, and facial asymmetry. Intellectual disability is a prominent feature. Major extracranial malformations include: esophageal atresia (~40%), congenital heart disease (~40%), and thumb abnormalities (~25%). Short stature is present in approximately one third of individuals.

Diagnosis/testing.

The diagnosis of MFDM is suspected in individuals with characteristic clinical findings, and confirmed in virtually all affected persons by identification of a heterozygous pathogenic variant or deletion in EFTUD2.

Management.

Treatment of manifestations: Individualized treatment of craniofacial manifestations is managed by a multidisciplinary team which may include: plastic surgery, otolaryngology, dentistry, orthodontics, oromaxillofacial surgery, and occupational and speech/language therapy. Newborn infants may have airway compromise at delivery due to choanal atresia and/or mandibular hypoplasia, requiring intubation and/or tracheostomy for initial stabilization. Esophageal atresia is managed surgically. Cardiac defects are managed by pediatric cardiology and/or cardiac surgery. Treatment of hearing loss is individualized, and may involve conventional hearing aid(s), bone-anchored hearing aid(s), and/or cochlear implant(s). Occupational, physical, and/or speech/language therapies are involved as needed to optimize developmental outcome.

Surveillance: Periodic growth and developmental assessment (preferably by a pediatrician) with inquiry into symptoms of seizures and obstructive sleep apnea; routine follow up by audiology.

Pregnancy management: Management of an affected fetus should include a detailed (‘level II’) fetal ultrasound examination and consultation(s) with high-risk obstetrics and/or neonatology, as needed. The delivering team should be aware of the potential for neonatal airway compromise. Polyhydramnios, if present, should prompt urgent postnatal evaluation for esophageal atresia.

Genetic counseling.

MFDM is inherited in an autosomal dominant manner. While most affected individuals have a de novo heterozygous EFTUD2 pathogenic sequence variant or deletion, familial recurrence can result from either germline mosaicism or inheritance of the variant from a parent with a milder phenotype. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.

Diagnosis

Suggestive Findings

The diagnosis of mandibulofacial dysostosis with microcephaly (MFDM) should be suspected in individuals with three or more of the following five major features:

  • Mandibulofacial dysostosis, a developmental disorder of the first and second branchial arches, is characterized by malar and maxillary hypoplasia. Associated anomalies may include midline cleft palate, choanal atresia, ear anomalies (see Characteristic malformations of the external and/or middle ear), and/or lacrimal atresia. CT imaging of the skull may demonstrate zygomatic arch clefts in some individuals.
  • Microcephaly (defined here as occipitofrontal circumference [OFC] ≥2 SD below mean) may be either primary (i.e., congenital; present a birth) or secondary (i.e., postnatal onset). Intellectual disability, which may be mild, moderate, or severe, is present in virtually all affected individuals.
  • Characteristic malformations of the external and/or middle ear
    • External ears are anomalous in virtually all affected individuals. Typical findings (Figure 1) include microtia (grades I-III), deficiency of the superior helix and antihelix, preauricular tags (~50%), and auditory canal atresia/stenosis (~75%). The posterior-inferior margin of the lobule may have a right-angle (‘squared-off’) configuration, which, if present, is quite characteristic.
    • Middle ear structures (ossicles, semicircular canals) are absent and/or malformed in some individuals; this is best assessed by temporal bone CT [Gordon et al 2012, Luquetti et al 2013, Voigt et al 2013].
    • Most (~75%) affected persons have hearing loss, which is typically conductive (~80%).
  • Esophageal atresia/tracheoesophageal fistula (EA/TEF) is present in about 40% of affected individuals reported to date [Gordon et al 2012, Voigt et al 2013]. EA/TEF is typically type C (the most common type), in which the upper esophageal pouch ends blindly and the lower esophageal pouch connects abnormally to the trachea (distal tracheoesophageal fistula). Laryngotracheal anomalies (tracheomalacia, posterior laryngotracheoesophageal clefts) may be seen in association with EA/TEF.
  • Characteristic dysmorphic features (Figure 2), which are distinct from those of the other mandibulofacial and acrofacial dysostoses (see Differential Diagnosis), are recognizable by early childhood. In addition to malar and maxillary hypoplasia, microcephaly, and the typical ear anomalies described above, they include: metopic ridge, prominent glabella, broad nasal bridge with prominent ridge and bulbous tip, large oral aperture, everted lower lip, and/or (frequently) facial asymmetry. Particularly characteristic photographs are available; see Guion-Almeida et al [2006], Guion-Almeida et al [2009], Lines et al [2012], Voigt et al [2013], and Lehalle et al [2014].
Figure 1. . Range of external ear findings in MFDM.

Figure 1.

Range of external ear findings in MFDM. Microtia may be of any degree, and is frequently accompanied by preauricular tag(s) and/or auditory canal atresia/stenosis. The superior helix is relatively deficient. The posterior-inferior rim of the lobule may (more...)

Figure 2. . Typical craniofacial features of MFDM.

Figure 2.

Typical craniofacial features of MFDM. These include: micrognathia, malar hypoplasia, a relatively high nasal root with prominent ridge, everted lower lip, and (frequently) facial asymmetry. Characteristic ear malformations, present in essentially all (more...)

Establishing the Diagnosis

MFDM is confirmed in individuals with a heterozygous pathogenic variant in EFTUD2.

The two approaches to molecular genetic testing are:

  • Sequence analysis of EFTUD2, either as a single gene or as part of a multi-gene panel, if available;
  • Deletion analysis; appropriate for persons in whom EFTUD2 sequencing does not demonstrate a pathogenic variant.

Note: In individuals in whom the diagnosis of MFDM is strongly suspected, but genetic testing of EFTUD2 is inconclusive, a clinical diagnosis of MFDM may still be appropriate. However, given the high sensitivity of EFTUD2 testing, other disorders in the differential diagnosis should first be carefully considered.

Table 1.

Summary of Molecular Genetic Testing Used in Mandibulofacial Dysostosis with Microcephaly

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method 2
EFTUD2Sequence analysis 352/57 (~91%)
Deletion/duplication analysis 45/57 (~9%) 5
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.
3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

Excluding cytogenetically visible deletions

Clinical Characteristics

Clinical Description

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising craniofacial skeletal anomalies, microcephaly, abnormalities of the ears and hearing, and, in some instances, extracranial malformations (esophageal atresia, congenital heart defects, thumb anomalies) and/or short stature [Guion-Almeida et al 2006, Guion-Almeida et al 2009, Wieczorek et al 2007, Wieczorek et al 2009]. Intellectual disability is present in virtually all individuals; microcephaly is present in nearly 90%, and is of secondary (postnatal) onset in about one third.

The major clinical features of 63 persons (from 57 families) with a heterozygous EFTUD2 pathogenic variant or deletion are summarized in Table 2 and discussed below.

Table 2.

Clinical Features of Mandibulofacial Dysostosis with Microcephaly

Feature# of Persons Reported w/Feature / # Assessed for Feature 1Estimated Frequency 1
(95% CI) 2
Microtia / dysplastic pinna(e)56 / 5798% (91%-100%)
Developmental delay55 / 5698% (90%-100%)
Micrognathia / mandibular hypoplasia55 / 5993% (84%-98%)
Malar hypoplasia42 / 4691% (79%-98%)
Microcephaly 354 / 6189% (78%-95%) 4
Hearing loss41 / 5377% (64%-88%)
Auditory canal atresia or stenosis30 / 4863% (47%-76%)
Facial asymmetry24 / 4553% (38%-68%)
Preauricular tag25 / 5645% (31%-58%)
Congenital heart disease 523 / 5443% (29%-57%)
Esophageal atresia / tracheoesophageal fistula22 / 5441% (28%-55%)
Cleft palate22 / 5838% (26%-52%)
Choanal atresia19 / 5336% (23%-50%)
Thumb anomalies 614 / 5227% (16%-41%)
Epilepsy11 / 5022% (12%-36%)
Zygomatic arch cleft 77 / 7Unknown 8
Absent/malformed semicircular canals13 / 19Unknown 8
Absent/malformed middle ear ossicles5 / 8Unknown 8
Renal anomalies 96 / 14Unknown 8
Spine anomalies 109 / 53Unknown 8
Epibulbar dermoid1 / 11Unknown 8
1.

Bernier et al [2012], Lines et al [2012], Lehalle et al [2014], Gandomi et al [2015]; includes patients from Gordon et al [2012], Luquetti et al [2013], Need et al [2012], Voigt et al [2013]. Given the small number of reported cases and the likelihood of case-selection bias, estimates should be regarded as provisional.

2.

95% confidence interval (binomial)

3.

Occipitofrontal circumference two or more standard deviations below mean.

4.

Excludes cases 9 and 12 (with normocephaly) from Gordon et al [2012], both of whom have partial clinical features and intronic changes of uncertain significance. If these two cases are included, the resulting frequency is 54/63 (86%).

5.

Typically atrial and/or ventricular septal defect

6.

Typically proximally placed; uncommonly, preaxial polydactyly or hypoplasia

7.

Best assessed by cranial CT with 3D reconstruction

8.

Feature not specifically assessed in the majority of published cases

9.

Including unilateral renal agenesis, vesicoureteric reflux, and ureteropelvic junction obstruction

10.

Including scoliosis, kyphosis, hemivertebrae, and cervical segmentation anomalies

Mandibulofacial dysostosis. In a minority of newborns, upper airway compromise resulting from (1) obstruction due to severe micrognathia and/or (2) choanal atresia may require intubation and/or tracheostomy for airway stabilization. Airway concerns are analogous to those seen in Treacher-Collins syndrome. Tracheostomy can generally be reversed in childhood.

Cleft palate in MFDM occurs as a Pierre-Robin sequence, and is characterized by a midline bony defect without accompanying cleft lip. Submucous clefting has also been described. Choanal atresia is generally osseous, being either unilateral or bilateral; choanal stenosis is also frequent.

Microcephaly is present in about 90% of reported individuals, and may be primary (congenital: ~2/3) or secondary (postnatal: ~1/3). Of reported individuals for whom measurements are available, the median head circumference was -1.875 SD at birth (n=22; range: -3.5 to +1 SD), decreasing to -4 SD in toddlers age one to three years (n=10; range: -5.3 SD to +1 SD) [Gordon et al 2012, Lines et al 2012, Luquetti et al 2013, Voigt et al 2013].

Intellectual disability remains a consideration in individuals whose head circumference falls within the normal range [Luquetti et al 2013, Lehalle et al 2014].

Although MRI usually reveals a structurally normal brain (apart from microcephaly), CNS malformations reported on rare occasion have included undergyration, cerebral atrophy, cerebellar and pontine hypoplasia, olfactory bulb agenesis, and (in one case) exencephaly [Lehalle et al 2014].

Intellectual disability has been found in all but one individual reported in the literature [Voigt et al 2013]. Among 30 persons on whom data are available, the degree of intellectual disability was reported as: ‘mild’ (~40%), ‘moderate’ (~50%), or ‘severe’ (~10%) [Gordon et al 2012, Lines et al 2012, Luquetti et al 2013, Voigt et al 2013].

Affected children are ambulatory but show delayed motor development, taking first steps at a median age of 24 months (n=20; range 13-60 months).

Among those who are verbal, the median reported age at first words is 24 months (n=11; range 12-30 months); however, some affected persons remain nonverbal into adult life. Assessment of language skills may be confounded by the presence of hearing loss and/or cleft palate.

Developmental data in the few affected adults identified to date suggest a broad range of outcomes, with some affected persons living semi-independently and/or pursuing gainful employment, while others are nonverbal and need extensive assistance with daily activities [Authors, unpublished data].

Ear malformations and hearing loss. Hearing loss is generally conductive (~80%) rather than sensorineural or mixed, and is likely to result from malformation or absence of the middle ear ossicles, auditory canal atresia, or both. Although hearing loss is expected to be anatomical and, therefore nonprogressive, detailed clinical data regarding the severity and course of hearing loss in MFDM have not been specifically reported.

With individualized treatment (see Management), functional hearing is generally retained.

Esophageal atresia/tracheoesophageal fistula (EA/TEF) may be suspected antenatally because of polyhydramnios or absent stomach echolucency, or neonatally in the context of unexplained respiratory distress and/or failed nasogastric tube placement. A type ‘C’ (blind-ending esophagus with distal tracheoesophageal fistula) configuration is typical.

Management entails surgical repair in early infancy. EA/TEF is discussed in further detail in Esophageal Atresia/Tracheoesophageal Fistula Overview.

Associated findings

  • Cardiac anomalies are present in 40% of individuals. Hemodynamically insignificant atrial and ventricular septal defects are the most common; tetralogy of Fallot, patent ductus arteriosus, and aortic arch abnormalities (e.g., coarctation) have also been reported [Need et al 2012, Lehalle et al 2014].
  • Short stature is present in approximately one third of individuals.
  • Thumb anomalies (proximally placed, duplicated, or hypoplastic thumbs) are seen in about 25% of individuals.
  • A range of additional malformations, including cryptorchidism, renal anomalies, vertebral and rib anomalies, scoliosis, and lacrimal system abnormalities have each been reported in a minority of patients (Table 2) [Lines et al 2012, Lehalle et al 2014].

Genotype-Phenotype Correlations

Detailed genotype-phenotype correlations remain to be established. Given the relatively small number of individuals reported to date, there is a strong likelihood of case-ascertainment bias in the existing clinical literature, and the full spectrum of EFTUD2 phenotypes has yet to be determined.

Individuals with microdeletions encompassing EFTUD2 and contiguous genes may have additional features including cortical migration defects, symphalangism, and/or radioulnar synostosis [Park et al 1992, Dallapiccola et al 1993, Khalifa et al 1993, Gandomi et al 2015].

Penetrance

MFDM is highly penetrant but variably expressive. Features may be subclinical in some affected individuals, as in the case of a non-mosaic, intellectually normal mother of two affected children, in whom the only reported clinical finding was unilateral zygomatic cleft [Voigt et al 2013].

Nomenclature

The descriptive term ‘mandibulofacial dysostosis with microcephaly (MFDM)’ is synonymous with the eponym ‘mandibulofacial dysostosis, Guion-Almeida type’ [Guion-Almeida et al 2009].

Some have suggested that MFDM be classified as an acrofacial dysostosis rather than a mandibulofacial dysostosis [Voigt et al 2013]. This is predominantly a clinical (rather than pathophysiological) distinction based on the presence of limb anomalies in the former category, and their absence in the latter.

Prevalence

The prevalence of MFDM has not been established. At least 63 cases caused by mutation or microdeletion of EFTUD2 have been reported to date (Table 2 and references therein).

MFDM is a pan ethnic disorder with no recognized racial or ethnic predisposition.

Differential Diagnosis

Treacher Collins syndrome (TCS) is a ‘pure’ (i.e., isolated) mandibulofacial dysostosis with variable expressivity. Most inheritance is autosomal dominant; the cause is a heterozygous pathogenic variant in one of three genes (TCOF1, POLR1D, and POLR1C) that encode an RNA polymerase I transcription factor and two subunits of RNA polymerases I and III, respectively [Treacher Collins Syndrome Collaborative Group 1996, Dauwerse et al 2011].

Intellect and occipitofrontal circumference (OFC) are usually in the average range. Malformations in TCS are limited to first and second branchial arch-derived structures; cardiac and esophageal malformations are not associated. Uncommonly, intellectual disability (without microcephaly) may be present in individuals with either (1) a history of neonatal airway compromise or (2) microdeletions encompassing TCOF1 and adjacent genes [Vincent et al 2014].

Although the mandibulofacial dysostosis of MFDM can resemble that of TCS, MFDM differs slightly in that palpebral fissures are not consistently downslanting. Lower lid clefts, absent eyelashes, and lacrimal system anomalies may be seen in either condition.

Nager acrofacial dysostosis (OMIM) combines mandibulofacial dysostosis with preaxial (typically upper) limb defects, with or without other extracranial malformations [McDonald & Gorski 1993]. OFC and intelligence are typically normal.

Inheritance is autosomal dominant; the cause is a heterozygous pathogenic variant in SF3B4, which encodes the spliceosomal protein (splicing factor 3B subunit 4) [Bernier et al 2012].

Miller acrofacial dysostosis (OMIM) combines mandibulofacial dysostosis with postaxial limb defects, with or without other extracranial malformations. OFC and intelligence are typically normal [Donnai et al 1987]. Inheritance is autosomal recessive; the cause is biallelic pathogenic variants in DHODH, which encodes an enzyme involved in pyrimidine biosynthesis [Ng et al 2010].

CHARGE syndrome shares several major findings with MFDM, including microcephaly, ear anomalies (of pinna, ossicles, and semicircular canals), choanal atresia, tracheoesophageal fistula, and/or congenital heart defects. Ocular coloboma and Mondini malformation of the cochlea, which are key findings in CHARGE, are not reported features of MFDM. Because choanal atresia and ear anomalies comprise two of four major clinical diagnostic criteria for CHARGE syndrome, the potential for diagnostic confusion exists: of the 31 individuals reported with MFDM for whom detailed (individual) clinical and molecular data are available, 12/31 (39%) meet criteria for ‘probable/possible’ CHARGE syndrome; none meet ‘definite’ criteria [Gordon et al 2012, Lines et al 2012, Luquetti et al 2013, Voigt et al 2013].

Approximately 65%-70% of persons with CHARGE syndrome have a heterozygous pathogenic variant in CHD7, which encodes a chromodomain protein involved in TCOF1-mediated transcription of ribosomal RNA [Zentner et al 2010]. In these individuals inheritance is autosomal dominant, with a high proportion of de novo pathogenic variants.

Craniofacial microsomia (CFM) is a first- and second-arch malformation spectrum encompassing several phenotypes, including oculo-auriculo-vertebral (OAV) syndrome and Goldenhar syndrome. CFM most frequently occurs as a simplex case (i.e., occurrence in a single individual in a family) with unknown etiology; recurrence risks are empiric.

CFM shares several major features with MFDM including preauricular tags, microtia, aural atresia, hearing loss, and – notably – facial asymmetry, which is present in approximately 65% of persons with CFM and also a frequent finding in MFDM.

The spectrum of orofacial clefting differs between the two conditions: midline cleft palate is typical of MFDM, while CFM can be associated with any type of orofacial cleft, including lateral oral clefts. Although various extracranial anomalies may occur in either condition, vertebral anomalies in particular should suggest CFM.

At least two persons with an EFTUD2 pathogenic variant were diagnosed with ‘bilateral OAV syndrome’ prior to the recognition of MFDM as a distinct syndrome [Authors, personal observation].

Diamond-Blackfan anemia (DBA). Approximately one third of individuals with DBA, a disorder of ribosome biogenesis, exhibit mandibulofacial dysostosis-like craniofacial anomalies with or without cleft palate, anomalous thumbs, cardiac anomalies, and/or growth retardation [Ball et al 1996]. The presence of craniofacial malformations in DBA confirms the role of ‘ribosomal stress’ in the pathogenesis of mandibulofacial dysostosis, a pathway well-elucidated in the TCS mouse model [Dixon et al 2006, Jones et al 2008].

DBA has been associated with mutation of any of eleven autosomal genes that encode ribosomal proteins, as well as GATA1 on the X chromosome. A pathogenic variant in one of these twelve genes is identified in approximately 55% of individuals with DBA. Except when mutation of GATA1 is the cause, DBA is inherited in an autosomal dominant manner.

Craniofacial anomalies are reported to be more common in DBA with mutation of certain genes, specifically RPL5 and RPL11 [Gazda et al 2008, Quarello et al 2010].

Tracheoesophageal fistula is a feature of several other recognized conditions, including Feingold syndrome and VACTERL association; clinical differentiation is generally straightforward. See Esophageal Atresia / Tracheoesophageal Fistula Overview for details.

Management

Evaluations Following Initial Diagnosis

To establish medical needs and extent of disease in an individual diagnosed with mandibulofacial dysostosis with microcephaly (MFDM), the following evaluations are recommended:

  • In newborns: airway assessment for evidence of upper-airway obstruction with or without choanal atresia and urgent evaluation for possible esophageal atresia
  • Examination for midline cleft palate, and referral to multidisciplinary cleft palate team as required
  • Cardiology and/or echocardiographic assessment for structural heart defects
  • Renal ultrasound examination
  • Developmental assessment
  • Other evaluations as dictated by the specific clinical situation (e.g., skeletal x-ray for scoliosis)
  • Clinical genetics consultation

Treatment of Manifestations

Mandibulofacial dysostosis

  • Neonates with airway compromise at delivery may require intubation and/or tracheostomy for initial stabilization.
  • Treatment of craniofacial manifestations is individualized and managed by a multidisciplinary team, which may include: oromaxillofacial surgery, plastic surgery, otolaryngology, dentistry/orthodontics, occupational and speech/language therapy.

Intellectual disability. Occupational, physical, and/or speech/language therapies are involved as needed to optimize developmental outcome.

Hearing loss. Treatment is individualized and may involve conventional hearing aid(s), bone-anchored hearing aid(s), and/or cochlear implant(s). See Hereditary Hearing Loss and Deafness Overview.

Esophageal atresia is managed as for nonsyndromic forms of EA, the definitive management being surgical. See Esophageal Atresia/Tracheoesophageal fistula Overview.

Cardiac defects are managed in a routine manner.

Thumb anomalies. Preaxial polydactyly, if present, may be treated surgically; other thumb anomalies are not generally functionally significant.

Short stature is managed expectantly. Of note, the response to human growth hormone has not been specifically reported.

Surveillance

Surveillance includes monitoring of development by a physician with expertise in the disorder (typically a pediatrician). Clinical follow up should include measurement of growth parameters as well as specific enquiry into symptoms of seizures and obstructive sleep apnea.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Manifestations of MFDM in an affected fetus may include intrauterine growth restriction (IUGR), polyhydramnios, increased nuchal translucency, and/or fetal structural anomalies (e.g., cardiac and renal defects). Management of an affected fetus should include a detailed (‘level II’) fetal ultrasound assessment, and consultation(s) with high-risk obstetrics and/or neonatology, as appropriate for the clinical situation.

The delivery room team should be aware of the possible need for intubation in the event of airway compromise.

Polyhydramnios, if present, should prompt urgent postnatal evaluation for esophageal atresia.

Therapies Under Investigation

Studies of the Treacher-Collins syndrome (TCS) mouse show the craniofacial anomalies in that model to be p53-dependent [Jones et al 2008]. Although the role of p53 as a tumor suppressor protein makes it an unlikely therapeutic target, blockade of other proapoptotic genes downstream of p53 has been suggested as an alternative approach [Trainor et al 2009].

Search Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Mandibulofacial dysostosis with microcephaly (MFDM) is inherited in an autosomal dominant manner. Most cases are caused by a de novo EFTUD2 pathogenic variant.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to sibs of the proband (at conception) is 50%.
  • If the pathogenic variant found in the sib apparently occurred de novo, (i.e., is absent from the leukocyte DNA of both parents), the risk to sibs is low, but greater than the general population risk because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with mandibulofacial dysostosis with microcephaly has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals, as well as to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the EFTUD2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible options. The phenotype of affected offspring cannot be accurately predicted based on the results of prenatal molecular genetic testing (see Penetrance).

Fetal ultrasound examination. Because the sensitivity of prenatal ultrasound for detection of MFDM has not been assessed, molecular genetic testing is the recommended mode of prenatal diagnosis.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AmeriFace: The Cleft/Craniofacial Advocates
    PO Box 751112
    Las Vegas NV 89136
    Phone: 888-486-1209 (toll-free 24 hours); 702-769-9264
    Fax: 702-341-5351
    Email: info@ameriface.org
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free)
    Email: contactCCA@ccakids.com
  • Cleft Palate Foundation (CPF)
    1504 East Franklin Street
    Suite 102
    Chapel Hill NC 27514-2820
    Phone: 800-242-5338 (toll-free); 919-933-9044
    Fax: 919-933-9604
    Email: info@cleftline.org
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • National Institute of Dental and Craniofacial Research (NIDCR)
    Bethesda MD 20892-2190
    Phone: 866-232-4528 (toll-free); 301-496-4261
    Fax: 301-480-4098
    Email: nidcrinfo@mail.nih.gov
  • World Craniofacial Foundation
    7777 Forest Lane
    Suite C-616
    Dallas TX 75230
    Phone: 800-533-3315
    Fax: 972-566-3850
    Email: sue@worldcf.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Mandibulofacial Dysostosis with Microcephaly: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Mandibulofacial Dysostosis with Microcephaly (View All in OMIM)

603892ELONGATION FACTOR Tu GTP-BINDING DOMAIN-CONTAINING 2; EFTUD2
610536MANDIBULOFACIAL DYSOSTOSIS, GUION-ALMEIDA TYPE; MFDGA

Molecular Genetic Pathogenesis

EFTUD2 encodes a small GTPase that is one of several subunits belonging to the U5 small nuclear ribonucleoprotein particle (snRNP) [Fabrizio et al 1997]. The U5 snRNP is a component of the major and minor spliceosome, two large macromolecular machines that mediate canonic (U2-dependent) and minor (U12-introns) intron splicing [Wahl et al 2009]. The Saccharomyces cerevisiae homologue of EFTUD2, Snu114p, is essential for (1) the dissociation of the U4 and U6 RNAs during pre-spliceosomal activation and (2) subunit disassembly and recycling after catalytic splicing is complete [Fabrizio et al 1997, Bartels et al 2002, Small et al 2006]. Apart from a putative defect in pre-RNA processing, the downstream pathogenesis of MFDM is poorly understood, and remains to be studied in a suitable model organism.

Gene structure. EFTUD2 comprises 27 coding exons (plus alternate, noncoding first exons) and is differentially spliced. The canonic transcript is 4.5 kb in length with an open reading frame of 2919 nucleotides (NM_004247.3). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Reported EFTUD2 pathogenic variants include missense, nonsense, frameshift, and splice-site variants, as well as whole or partial gene deletions, consistent with haploinsufficiency as the underlying mechanism [Lines et al 2012].

Normal gene product. EFTUD2 is 972 amino acids in length (NP_004238.3) and contains a GTP-binding domain and several other conserved domains homologous to the translational elongation factor EF-2 [Fabrizio et al 1997]. The N-terminus of the protein contains an acidic domain of unknown function.

Abnormal gene product. The majority of pathogenic variants result in deletion or premature truncation of the EFTUD2 reading frame [Lines et al 2012]. Missense substitutions are uncommon, accounting for only 9/56 reported EFTUD2 pathogenic variants [Lehalle et al 2014]. Missense alleles are suspected to result in loss of EFTUD2 protein function based on their phenotypic similarity to truncating variants, but have not been characterized from a functional standpoint.

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Chapter Notes

Acknowledgments

The authors wish to gratefully acknowledge the contribution of the patients and their families.

Revision History

  • 3 July 2014 (me) Review posted live
  • 21 January 2014 (ml) Original submission
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