Clinical characteristics.

Mandibulofacial dysostosis with microcephaly (MFDM) is characterized by malar and mandibular hypoplasia, microcephaly (congenital or postnatal onset), intellectual disability (mild, moderate, or severe), malformations of the external ear, and hearing loss that is typically conductive. Associated craniofacial malformations may include cleft palate, choanal atresia, zygomatic arch cleft (identified on cranial CT scan), and facial asymmetry. Other relatively common findings (present in 25%-35% of individuals) can include cardiac anomalies, thumb anomalies, esophageal atresia/tracheoesophageal fistula, short stature, spine anomalies, and epilepsy.

Diagnosis/testing.

The diagnosis of MFDM is confirmed in a proband with typical clinical findings and a heterozygous pathogenic variant in EFTUD2 identified by genetic testing.

Management.

Treatment of manifestations: Individualized treatment of craniofacial manifestations is managed by a multidisciplinary team which may include: oromaxillofacial surgery, plastic surgery, otolaryngology, dentistry/orthodontics, 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/tracheoesophageal fistula, cardiac defects, renal anomalies, and thumb anomalies are treated in a routine manner. Short stature is managed expectantly. Treatment of hearing loss is individualized, and may involve conventional hearing aid(s), bone-anchored hearing aid(s), and/or cochlear implant(s). Early individualized educational and therapy plans are devised as needed to optimize developmental outcome.

Surveillance: Annual growth assessment and periodic developmental assessment with evaluation for obstructive sleep apnea and epilepsy as needed.

Genetic counseling.

MFDM is an autosomal dominant disorder. Most individuals diagnosed with MFDM to date are presumed to have the disorder as the result of a de novo EFTUD2 pathogenic variant; in some individuals, the causative pathogenic variant was inherited from a parent with a milder phenotypic presentation. If a parent of the proband has the pathogenic variant identified in the proband, the risk to sibs of the proband (at conception) is 50%. Once the causative EFTUD2 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible.

Suggestive Findings

Mandibulofacial dysostosis with microcephaly (MFDM) should be suspected in individuals with mandibulofacial dysostosis (a developmental disorder of the first and second branchial arches characterized by malar and maxillary hypoplasia) in the context of one or more additional features, including:

• Microcephaly (defined here as occipitofrontal circumference ≥2 SD below mean), which 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
• Characteristic malformations of the external ear (see Figure 1), which include microtia (grades I-III), deficiency of the superior helix and antihelix, preauricular tags, and auditory canal atresia/stenosis. The posterior-inferior margin of the lobule may have a right-angle ("squared-off") configuration.
• Hearing loss, typically conductive

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...)

Establishing the Diagnosis

The diagnosis of MFDM is established in a proband with typical clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in EFTUD2 identified by genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous EFTUD2 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the clinical phenotype of MFDM varies, individuals with highly characteristic clinical findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with an atypical or nonspecific clinical phenotype overlapping other inherited syndromes are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising craniofacial skeletal anomalies, microcephaly, developmental delay / intellectual disability, abnormalities of the ears and hearing, and, in some instances, extracranial malformations (esophageal atresia, congenital heart defects, thumb anomalies), and/or short stature.

To date, 126 individuals have been identified with a pathogenic variant in EFTUD2 [Gordon et al 2012, Lines et al 2012, Need et al 2012, Luquetti et al 2013, Voigt et al 2013, Lehalle et al 2014, Deml et al 2015, Gandomi et al 2015, Sarkar et al 2015, Smigiel et al 2015, Huang et al 2016, Vincent et al 2016, Bick et al 2017, Matsuo et al 2017, McDermott et al 2017, Rengasamy Venugopalan et al 2017, Williams et al 2017, Paderova et al 2018, Yu et al 2018, Lacour et al 2019, Silva et al 2019, Wu et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.

Mandibulofacial dysostosis is characterized by malar and maxillary hypoplasia.

Accompanying findings in MFDM include micrognathia/mandibular hypoplasia, cleft palate, and/or choanal abnormality.

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

Zygomatic arch cleft has been identified in ten of 19 individuals assessed (best done with cranial CT with 3-D reconstruction).

Characteristic dysmorphic features (Figure 2), distinct from those seen in 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 in this section, features 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.

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...)

Microcephaly is present in about 87% of reported individuals (n=33; median -3.5 SD; range -0.2 SD to -6.5 SD) [Huang et al 2016]. Cephalic growth curves for MFDM are published [Huang et al 2016]. In some instances, individuals have exhibited apparent cephalic "catch-up" growth, resulting in a normal adult occipitofrontal circumference despite microcephaly in childhood. Individuals whose head circumference falls within the normal range have also been reported to have intellectual disability [Luquetti et al 2013, Lehalle et al 2014].

Developmental delay and/or intellectual disability are present in almost all individuals. 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 26 months (n=38; range 13-60 months) [Huang et al 2016].

Among those who are verbal, the median reported age at first words is 27 months (n=32; range 12 months to 5.6 years); some affected persons remain nonverbal into adult life [Huang et al 2016]. Assessment of language skills may be confounded by the presence of hearing loss and/or cleft palate.

To date there have been no detailed or cross-sectional studies of long-term neuropsychological outcomes in MFDM. Developmental data in the few affected adults identified to date suggest a broad range of outcomes, with some affected persons achieving semi-independent living with paid employment [Huang et al 2016], whereas others are nonverbal and require extensive assistance with daily activities [Authors, unpublished data].

Ear malformations and hearing loss

• External ear malformations. External ears are anomalous in virtually all affected individuals. Typical findings (see Figure 2) include microtia (grades I-III), deficiency of the superior helix and antihelix, preauricular tags, and auditory canal atresia/stenosis. The posterior-inferior margin of the lobule may have a right-angle ("squared-off") configuration.
• Middle/inner ear malformations. 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].
• Hearing loss. Hearing loss is typically conductive (~60%) as opposed to sensorineural or mixed, and is likely to result from malformation or absence of the middle ear ossicles, auditory canal atresia, or both.

Other relatively common findings

• Cardiac anomalies are present in 35% 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].
• Thumb anomalies (proximally placed, duplicated, or hypoplastic thumbs) are seen in about 35% of individuals.
• Esophageal atresia / tracheoesophageal fistula (EA/TEF) is present in about 35% of affected individuals. 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. It 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.
• Short stature is present in 30% of individuals. Height growth curves for MFDM are published [Huang et al 2016].
• Spine anomalies include scoliosis, kyphosis, hemivertebrae, and cervical segmentation anomalies.
• Epilepsy is present in 26% of individuals. Detailed clinical data regarding the type of epilepsy have not been specifically reported. Matsuo et al [2017] report one individual with recurrent seizures for which EEG demonstrated occasional spike discharges originating from the right frontal area.

Additional malformations (low frequency)

• Other CNS abnormalities. Although brain MRI imaging data is limited, in most cases individuals have a structurally normal brain (apart from microcephaly). The CNS malformations reported on rare occasion have included undergyration, cerebral atrophy, cerebellar and pontine hypoplasia, olfactory bulb agenesis, and (in 1 individual) exencephaly [Lines et al 2012, Lehalle et al 2014, Huang et al 2016, Matsuo et al 2017, Lacour et al 2019, Silva et al 2019].
• Renal anomalies include unilateral renal agenesis, vesicoureteric reflux, and ureteropelvic junction obstruction.
• Other. Cryptorchidism, lacrimal system abnormalities, and epidermal dermoid have each been reported in one or a few individuals [Lines et al 2012, Luquetti et al 2013, Lehalle et al 2014].

Genotype-Phenotype Correlations

No genotype-phenotype correlations for EFTUD2 have been identified.

Individuals with microdeletions encompassing EFTUD2 and contiguous genes may have additional features or more severe intellectual disability [Lines et al 2012, 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 two non-mosaic, intellectually normal mothers – each with two affected children – in whom the only reported clinical findings were unilateral zygomatic cleft and facial asymmetry [Voigt et al 2013] and mild facial asymmetry and a preauricular tag [McDermott et al 2017].

Nomenclature

The descriptive term "mandibulofacial dysostosis with microcephaly" 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 pathophysiologic) distinction based on the presence of limb anomalies in the former category, and their absence in the latter.

In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], MFDM is referred to as EFTUD2-related mandibulofacial dysostosis with microcephaly (Guion-Almeida type) and included in the craniofacial dysostoses group.

Prevalence

The prevalence of MFDM has not been established. At least 126 cases caused by mutation of EFTUD2 have been reported to date (see Table 2 and references cited in Clinical Description).

Mandibulofacial Dysostosis

Craniofacial Microsomia

Craniofacial microsomia (CFM) is a first- and second-arch malformation spectrum encompassing several phenotypes, including oculo-auriculo-vertebral (OAV) syndrome and Goldenhar syndrome (OMIM 164210). CFM most frequently occurs as a simplex case (i.e., in a single individual in a family) with unknown etiology; recurrence risks are empiric.

CFM shares several major features with mandibulofacial dysostosis with microcephaly (MFDM), including preauricular tags, microtia, aural atresia, hearing loss, and – notably – facial asymmetry, present in approximately 65% of persons with CFM and also a frequent finding in MFDM (58%).

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].

Tracheoesophageal Fistula

Tracheoesophageal fistula is a feature of several other recognized conditions, including Feingold syndrome and VACTERL association (OMIM 192350); clinical differentiation is generally straightforward.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mandibulofacial dysostosis with microcephaly (MFDM), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There are no published management guidelines to date for MFDM.

Esophageal atresia / tracheoesophageal fistula, cardiac defects, renal anomalies, and thumb anomalies are treated in a routine manner. Short stature is managed expectantly. Of note, the response to human growth hormone has not been specifically reported.

Surveillance

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Mandibulofacial dysostosis with microcephaly (MFDM) is an autosomal dominant disorder often caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• More than 80% of individuals diagnosed with MFDM to date are presumed to have the disorder as the result of a de novo EFTUD2 pathogenic variant [Huang et al 2016].
• In 12 of 64 individuals diagnosed with MFDM, the causative pathogenic variant was inherited from a parent with a milder phenotypic presentation [Gordon et al 2012, Voigt et al 2013, Lehalle et al 2014, Huang et al 2016].
• Molecular genetic testing and clinical evaluation are recommended for the parents of a proband with an apparent de novo EFTUD2 pathogenic variant (i.e., the proband is the only family member known to have MFDM).
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The incidence of parental germline mosaicism in MFDM is 6% [Huang et al 2016]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.
• The family history of some individuals diagnosed with MFDM may appear to be negative because of a failure to recognize the disorder in family members because of milder manifestations of the disorder in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of the proband (at conception) is 50%. Although MFDM is thought to be highly penetrant, intrafamilial clinical variability is observed, and a sib who inherits an EFTUD2 pathogenic variant may be more or less severely affected than the proband [Huang et al 2016].
• If the proband has a known MFDM-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.
• If the parents have not been tested for the EFTUD2 pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for MFDM because of the possibility of subclinical manifestations of the disorder in a heterozygous parent or the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with MFDM has a 50% chance of inheriting the EFTUD2 pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the EFTUD2 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the EFTUD2 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing are possible. 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. Many of the characteristic findings in MFDM have a low probability of detection by antenatal ultrasound.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular 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 spliceosomes, two large macromolecular machines that mediate canonic (U2-dependent) and minor (U12-introns) intron splicing [Wahl et al 2009]. The Saccharomyces cerevisiae homolog 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]. An EFTUD2 haploinsufficient zebrafish model displayed abnormal brain development with neuronal apoptosis. No other systems were affected. RNA sequencing and functional analyses demonstrated RNA splicing deficiency which led to inadequate nonsense-mediated RNA decay and activation of the p53 pathway [Lei et al 2017].

Mechanism of disease causation. 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].

Author Notes

Matthew Lines, MD; matthew.lines@albertahealthservices.ca

Taila Hartley, MSc; thartley@cheo.on.ca

Stella K MacDonald, BSc; smacdonald@cheo.on.ca

Kym M Boycott, PhD, MD; kboycott@cheo.on.ca

Acknowledgments

The authors wish to gratefully acknowledge the patients and their families from around the world who have contributed to the understanding of this condition. Our knowledge of MFDM has been facilitated by research support from the Care4Rare Canada Consortium.

Revision History

• 6 April 2023 (sw) Revision: "EFTUD2-Related Mandibulofacial Dysostosis with Microcephaly (Guion-Almeida Type)" added as a synonym; Nosology of Genetic Skeletal Disorders: 2023 Revision [Unger et al 2023] added to Nomenclature
• 12 November 2020 (ha) Comprehensive update posted live
• 3 July 2014 (me) Review posted live
• 21 January 2014 (ml) Original submission

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