Table 1 Differential diagnosis for CFW disorders

Mode of Inheritance

AR

AD

AD

AR

IC; AD (rare)

IC; AD (rare)

Phenotype MIM #

#601536

#600638

#214800

#614744

%157900

%164210

ORPHA #

69739/69737

45358

138

306530

570

141132

Distinguishing Clinical Features Summary

Limited horizontal gaze and sensorineural hearing loss are the most common features; CFW in ~ 20% of cases. Other specific features include carotid artery anomalies, conotruncal heart defects, and central hypoventilation

CFEOM and CFW are clinical characteristics of TUBB3 disease caused by p.E410K, R262H, or D417H mutations. Additional features include developmental delay, progressive axonal sensorimotor polyneuropathy, Kallman syndrome, vocal cord paralysis, cyclic vomiting, and/or congenital joint contractures

Unilateral or bilateral CFW seen in ~ 40%. Common features include coloboma, microphthalmia, choanal atresia, cranial nerve dysfunction, ear anomalies (external ear abnormalities, ossicular malformations, Mondini defect of the cochlea, temporal bone abnormalities, and/or absent or hypoplastic semicircular canals)

Bilateral CFW (100%); Full ocular motility; Strabismus (42%); Sensorineural hearing loss (90%)

Congenital, nonprogressive facial weakness with limitation in abduction of one or both eyes. Associated features may include other cranial nerve involvement, strabismus, hearing loss, club foot, limb reduction defects, other limb anomalies, Poland anomaly, developmental delay, and autism. For most persons with Moebius syndrome, the etiology is unknown

CFP seen in ~ 10–45% of affected individuals. Characterized by facial asymmetry, preauricular or facial tags, ear malformations, microtia/anotia, and hearing loss

Mode of Inheritance

AR

AR

AR

AR

AD, AR

AD, AR

AR

AD

XLR

Phenotype MIM #

#616325

#254300

#616326

#254940

#11700

#255310

#255200

#160150

#310400

ORPHA #

590

590

590

1358

597

2020

595

595

596

Distinguishing Clinical Features Summary

MUSK disease is characterized by early-onset muscle weakness with variable severity. Patients present with facial weakness, ptosis, ophthalmoplegia, episodic respiratory insufficiency and proximal muscle weakness

Clinical features of DOK7 disease include limb-girdle pattern of weakness, waddling gait, ptosis, facial weakness, but rare is ophthalmoparesis

RAPSN disease may present in neonates. Some affected individuals have weakness confined to facial and masticatory muscles. Arthrogryposis multiplex congenita seems to be particularly common in infants with truncating RAPSN mutations

Clinical features include facial weakness, full ocular movements, upturned/broad nasal tip, micro/retrognathia, normal cognition, delayed motor milestones, and generalized muscle hypoplasia. Additional occasional signs and symptoms are congenital contractures, growth failure, feeding problems, ptosis, cleft palate, gastro/jejunostomy, thin tubular neck, pectoralis hypoplasia, hypoglossia, scoliosis, pulmonary hypertension, and/or cryptorchidism

Characterized by muscle weakness and hypotonia. Symptoms may range from mild to severe. In early-onset disease, newborns may have respiratory insufficiency, facial weakness, and poor suck

Pathogenic variants in BIN1 have been described in a small group of individuals. Facial weakness may be present. The range of clinical severity is broad; presentation in infancy has been reported

Onset ranges from early (associated with severe disease) and late childhood or adulthood (associated with mild disease). Findings may include facial and extraocular muscle weakness, ptosis, and extremity weakness [Nance et al. 2012]. Of note, progressive weakness has been observed during the teen years and in adulthood in several individuals with a DNM2 pathogenic variant

Severe disease manifests prenatally with polyhydramnios and decreased fetal movement; newborns have profound weakness, hypotonia, and respiratory failure that usually requires ventilatory support. Facial and extraocular muscles are often involved resulting in myopathic facies and ophthalmoparesis, respectively. Motor milestones are significantly delayed and most affected males fail to achieve independent ambulation

Mode of Inheritance

AR

AD

AD

AD

AR

AD, AR

AR

AR

AD

AD, AR

XLR

Phenotype MIM #

N/A

#158900

#158901

#160900

#255995

#161800

#615348

#256030

#609285

#609284

#314580

ORPHA #

N/A

269

269

273

168572

607

607

607

607

607

3454

Distinguishing Clinical Features Summary

Affected individuals from four families with compound heterozygous pathogenic variants in SCN4A were reported to have symptoms of a congenital myopathy, and all were noted to have mild to moderate facial weakness that was either present at birth (3 of 4 families) or developed during the first few days of life (1 family). Associated features included moderate to severe hypotonia, reduced muscle bulk, and neck, axial, and limb weakness

Characterized by progressive muscle weakness involving the face, scapular stabilizers, upper arm, lower leg, and hip girdle. Most individuals become symptomatic in their teens, but severe infantile onset with muscle weakness at birth is possible

This is a more rare type of FSHD, and is clinically indistinguishable from type 1 due to DUX4 mutations

Congenital DM1 may include symptoms of CFW. Additional symptoms of affected neonates include hypotonia, positional malformations including club foot, and respiratory insufficiency

All reported patients had myopathic facies. Additional common features are congenital weakness, arthrogryposis, cleft palate, ptosis, short stature, kyphoscoliosis, club foot, and susceptibility to malignant hyperthermia provoked by anesthesia

The age of presentation of ACTA1 NM ranges from severe congenital myopathy to later childhood onset. Facial weakness may be present

Findings of NM8 (KLHL40) include severe congenital lethal disease or fetal akinesia. Contractures, fractures, respiratory failure, and swallowing difficulties may be present at birth. CFW was identified in all 26 individuals studied by Ravenscroft et al. (2013)

The phenotype of NM2 (NEB) typically includes infants presenting in the first year of life with hypotonia, limb weakness, facial weakness, feeding difficulty, and respiratory weakness. The muscle disease is either static or slowly progressive such that most affected individuals survive to adulthood and live independently. Less common presentations are: death in utero due to fetal akinesia; severe hypotonia and weakness; facial weakness with a poor suck and swallow at birth; or predominantly distal weakness in older individuals

TPM2 NM is generally associated with a typical congenital phenotype. The masticator (temporal) muscles and distal lower leg muscles are typically involved. CFW is typically present

TPM3 NM may cause a severe congenital, intermediate congenital, or childhood onset phenotype. CFW is typically present

Fetal akinesia is generally noted prenatally. Clinical features include arthrogryposis, delayed motor development, facial and bulbar weakness, and skeletal abnormalities

Mode of Inheritance

IC; AD

AD

IC; AD

AD

Phenotype MIM #

#125520

#603736

#248700

#608156

ORPHA #

1166

3047

2461

178303

Distinguishing Clinical Features Summary

Congenital hypoplasia of the depressor anguli oris muscle, congenital heart defects, microcephaly, intellectual impairment

Severe blepharophimosis, an immobile mask-like face, severe hypotonia and feeding problems, dislocated patellae, structural cardiac defects, pointed teeth, hypothyroidism, severe intellectual impairment

Mask-like face with blepharophimosis, micrognathia, cleft palate, low-set ears, kyphoscoliosis, joint contractures, Dandy-Walker malformation with hydrocephalus, vertebral abnormalities, intellectual impairment

Blepharophimosis, tight-appearing glistening facial skin, an abnormal hair pattern with an upswept frontal hairline, sparse arched eyebrows, flat and broad nose, long philtrum, distinctive ears, and a happy demeanor