Mandibulofacial Dysostosis With Microcephaly
Summary
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.
Diagnosis
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 variant in EFTUD2 identified by genetic testing (see Table 1).
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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of MFDM, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of EFTUD2 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
- A multigene panel that includes EFTUD2 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders with similar craniofacial features or is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, other techniques (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis (see Table 1).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in MFDM
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| EFTUD2 | Sequence analysis 3 | 93% 4 |
| Gene-targeted deletion/duplication analysis 5 | 7% 4 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.
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]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
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.
Table 2.
Mandibulofacial Dysostosis with Microcephaly (MFDM): Frequency of Select Features
| Feature | % of Persons w/Feature | Comment | |
|---|---|---|---|
| Facial structural differences | Malar hypoplasia | 92% | |
| Micrognathia / Mandibular hypoplasia | 93% | ||
| Cleft palate | 43% | ||
| Choanal atresia | 30% | ||
| Facial asymmetry | 58% | ||
| Microcephaly | 87% | Occipitofrontal circumference ≥2 SD below mean | |
| Developmental delay / Intellectual disability | 97% | Severity varies (may be mild, moderate, or severe; critical sequelae (e.g. neonatal airway compromise, cardiac anomalies) may affect developmental outcome. | |
| Ear malformations & hearing loss | Microtia / Dysplastic pinna(e) | 97% | |
| Auditory canal atresia or stenosis | 68% | ||
| Preauricular tag | 50% | ||
| Hearing loss | 83% | ||
| Other findings | Cardiac anomalies | 35% | Typically atrial &/or ventricular septal defect |
| Thumb anomalies | 34% | Typically proximally placed; uncommonly, preaxial polydactyly or hypoplasia | |
| Esophageal atresia / Tracheoesophageal fistula | 33% | ||
| Short stature | 30% | ||
| Spine anomalies | 28% | Incl scoliosis, kyphosis, hemivertebrae, & cervical segmentation anomalies | |
| Epilepsy | 26% | ||
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 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 (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.
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).
MFDM is a pan ethnic disorder with no recognized racial or ethnic predisposition and no evidence of sex bias.
Differential Diagnosis
Mandibulofacial Dysostosis
Table 3.
Genes of Interest in the Differential Diagnosis of Mandibulofacial Dysostosis with Microcephaly
| Gene(s) | DiffDx Disorder | MOI | Clinical Characteristics of DiffDx Disorder Overlapping w/MFDM | Distinguishing Features |
|---|---|---|---|---|
| CHD7 1 | CHARGE syndrome (See CHD7 Disorder.) | AD | Microcephaly, ear anomalies, choanal atresia, TEF, CHD | Ocular coloboma & Mondini malformation are present in CHARGE but not in MFDM. |
| DHODH | Miller acrofacial dysostosis (OMIM 263750) | AR | MFD w/postaxial limb defects ± other extracranial malformations | OFC & intelligence are typically normal in Miller acrofacial dysostosis. |
| POLR1C POLR1D TCOF1 | Treacher Collins syndrome (TCS) | AD AR |
|
|
| RPL5 RPL11 RPL35A RPS10 RPS17 RPS19 RPS24 RPS26 3 | Diamond-Blackfan anemia (DBA) | AD (XL 4) | ~1/3 of persons exhibit MFD-like craniofacial anomalies ± cleft palate, anomalous thumbs, cardiac anomalies, &/or growth restriction. | Moderate-to-severe anemia in DBA |
| SF3B4 | Nager acrofacial dysostosis (OMIM 154400) | AD | MFD w/preaxial (typically upper) limb defects, ± other extracranial malformations | OFC & intelligence typically normal in Nager acrofacial dysostosis |
AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart defect; DiffDx = differential diagnosis; ID = intellectual disability; MFD = mandibulofacial dysostosis; MFDM = mandibulofacial dysostosis with microcephaly; MOI = mode of inheritance; OFC = occipitofrontal circumference; TEF = tracheoesophageal fistula; XL = X-linked
- 1.
The finding of a CHD7 pathogenic variant is not equivalent to a diagnosis of CHARGE syndrome; the phenotypic spectrum of heterozygous CHD7 pathogenic variants encompasses CHARGE syndrome as well as subsets of features that comprise the CHARGE syndrome phenotype.
- 2.
Intellectual disability (without microcephaly) may be present in individuals with either (a) a history of neonatal airway compromise or (b) microdeletions encompassing TCOF1 and adjacent genes [Vincent et al 2016].
- 3.
Listed genes represent the most common genetic causes of Diamond-Blackfan anemia (DBA); more than 20 genes are known to be associated with DBA (see Diamond-Blackfan anemia).
- 4.
DBA is most often inherited in an autosomal dominant manner; GATA1- and TSR2-DBA are inherited in an X-linked manner (GATA1 and TSR2 are less common genetic causes of DBA and are not included in the table).
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. See Esophageal Atresia/Tracheoesophageal Fistula Overview for details.
Management
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.
Table 4.
Recommended Evaluations Following Initial Diagnosis in Individuals with MFDM
| System/Concern | Evaluation | Comment |
|---|---|---|
| MFD |
| Important in newborns w/disorder |
| DD/ID | Developmental assessment | Incl adaptive, cognitive, & speech/language evals |
| Hearing loss | Audiologic eval | Assess for hearing loss. |
| EA/TEF | Urgent eval in newborns, esp in those w/history of polyhydramnios, unexplained respiratory distress, &/or failed nasogastric tube placement | |
| Cardiac anomaly | Echocardiogram & cardiologist eval | |
| Renal anomaly | Renal ultrasound | |
| Skeletal anomaly | Radiograph to assess for scoliosis, rib or thumb malformation as clinically indicated | |
| Short stature | Assess w/growth charts. | Height growth curves for MFDM are published. 1 |
| Genetic counseling | By genetics professionals 2 | To inform patients & their families re nature, MOI, & implications of disorder to facilitate medical & personal decision making |
| Family support/ resources | Assess:
|
DD/ID = developmental delay / intellectual disability; EA/TF = esophageal atresia / tracheoesophageal fistula; MFD = mandibulofacial dysostosis; MOI = mode of inheritance
- 1.
Huang et al [2016]
- 2.
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
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.