A Framework for the Evaluation of Patients with Congenital Facial Weakness Bryn D

Webb et al. Orphanet J Rare Dis (2021) 16:158 https://doi.org/10.1186/s13023-021-01736-1

REVIEW Open Access A framework for the evaluation of patients with congenital facial weakness Bryn D. Webb1,2* , Irini Manoli3, Elizabeth C. Engle4,5,6 and Ethylin W. Jabs1,2

Abstract There is a broad diferential for patients presenting with congenital facial weakness, and initial misdiagnosis unfortu- nately is common for this phenotypic presentation. Here we present a framework to guide evaluation of patients with congenital facial weakness disorders to enable accurate diagnosis. The core categories of causes of congenital facial weakness include: neurogenic, neuromuscular junction, myopathic, and other. This diagnostic algorithm is presented, and physical exam considerations, additional follow-up studies and/or consultations, and appropriate genetic testing are discussed in detail. This framework should enable clinical geneticists, neurologists, and other rare disease special- ists to feel prepared when encountering this patient population and guide diagnosis, genetic counseling, and clinical care. Keywords: Congenital facial weakness, Facial paralysis, Clinical genetics, Clinical characterization

Clinical characteristics: congenital facial weakness CFW may be unilateral or bilateral and may be partial Congenital facial weakness (CFW) refers to decreased or complete (Fig. 2). Complete CFW refers to complete facial movement present at birth secondary to impaired absence of facial movement in all four quadrants of the function of facial musculature. CFW may be second- face (right upper quadrant, right lower quadrant, left ary to a defect in the motor nucleus of the facial nerve upper quadrant, and left lower quadrant). Patients with or the facial nerve itself (cranial nerve 7; CN7) (neuro- complete absence of facial movement on the left side genic), a defect at the neuromuscular junction, an inher- of the face may be described as having unilateral (left) ent muscular problem (myopathic), or other unknown or complete CFW. Similarly, patients with reduced facial mixed causes (Fig. 1). Congenital facial paralysis (CFP) movement on the left side of the face may be described is decreased (palsy/paresis) or absent (paralysis) facial as having unilateral (left) partial CFW. Clinical charac- movement present at birth that results specifcally from teristics of CFW may include: facial droop; absence of loss of facial nerve function. CFP may be caused by an forehead, nasolabial, or periorbital folds; lagophthal- abnormal developmental process or other causes, includ- mos (incomplete eyelid closure); open mouth posture or ing the most common cause of trauma, as in the case of u-shaped upper lip; drooling; and inability to make facial temporary or permanent CFP resulting from the use of expressions, wrinkle the forehead, whistle, and/or dif- forceps during delivery. Te diferential provided in this culties with articulation of labial consonants. review is useful after exclusion of post-traumatic CFP. An In some cases of CFW, recruitment of other muscu- appropriate history and temporary CFP are important lature can result in asymmetric synkinesis of facial and considerations for diagnosis of traumatic CFP. neck musculature. Most commonly, synkinesis afects the eye and facial muscles. During voluntary movement *Correspondence: [email protected] of the mouth, there may be involuntary eye closure, and 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA Full list of author information is available at the end of the article

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons. org/ licen ses/ by/4. 0/ . The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons.org/ publi cdoma in/ zero/1. 0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 2 of 17

ABDS/BSAS

CFEOM3A

CHARGE syndrome Neurogenic (CFP) Hereditary Congenital Facial Paresis (HCFP)

Moebius syndrome

Oculo-auriculo-vertebral spectrum

Congenital myasthenic syndrome 9

Neuromuscular Congenital myasthenic syndrome 10 Junction Congenital myasthenic syndrome 11

Carey-Fineman-Zitersyndrome

Central core disease/Multiminicoredisease Congenital Facial Weakness (CFW) Centronuclear/ Myotubular myopathy

Congenital myopathy-Zaharieva et al [2016]

Myopathic Facioscapulohumeralmuscular dystrophy (FSHD)

Myotonic Dystrophy, Type 1

Native American myopathy

Nemaline myopathy

ZC4H2-associated rare disorders

Asymmetric Crying Facies

KAT6B disorders Other Marden-Walker syndrome

Nablus mask-like facial syndrome Fig. 1 Diferential Diagnosis for CFW Disorders. CFW disorders may be due to neurogenic, neuromuscular junction, myopathic, or other causes during voluntary movement of the eye, there may be weakness may also be acquired, resulting from a diferent involuntary mouth or neck muscle movements [1]. set of etiologies including infection (Bell’s palsy), neopla- In diagnosing CFW, it is important to establish that sia, or neurodegeneration. the facial weakness indeed was present at birth, as facial Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 3 of 17

frst identifed in Native American families [2, 4]. BSAS and ABDS are characterized by horizontal gaze palsy in which there is absent to markedly restricted ocular abduction and adduction. In some cases the horizontal gaze palsy is accompanied by retraction of the globe and narrowing of the palpebral fssure on attempted adduction, consistent with the diagnosis of Duane syndrome type 3. Most individuals with BSAS and ABDS also have bilateral sensorineural hearing loss caused by an absent cochlea and rudimentary inner-ear development and absent or hypoplastic carotid arteries with a corre- sponding absence of the carotid canal through which the artery normally passes. Approximately 20% of patients with BSAS or ABDS have congenital facial palsy [5]. Some afected individuals also have intellectual disability, autism spectrum disorder, moderate-to-severe central hypoventilation, swallowing difculties, vocal cord paresis, conotruncal heart defects, macrocephaly, and Fig. 2 CFW seen in an adult female. This adult female with Moebius syndrome has CFW, often described as causing a “mask-like” facial malformations of inner ear bones and/or petrous bones. appearance. She has bilateral CFP and is more afected on her right Individuals with simplex isolated Duane syndrome have side not been found to harbor pathogenic variants in HOXA1 [2].

Congenital fbrosis of the extraocular muscles 3A Diferential diagnosis of congenital facial with or without extraocular involvement (CFEOM3A) weakness (ORPHA:45358) Tere is a broad diferential for disorders with a promi- Congenital fbrosis of the extraocular muscles 3 nent characteristic of CFW. Tis diferential includes (CFEOM3A) is a complex eye movement disorder with neurogenic, neuromuscular junction, myopathic, and ptosis and restricted vertical and horizontal gaze with or other unknown or mixed causes (Fig. 1). without congenital facial palsy and non-ocular manifestations caused by a heterozygous, pathogenic missense Neurogenic causes of congenital facial weakness variants in TUBB3, which encodes a beta-tubulin protein Tere are a wide variety of neurogenic causes of con- [6]. At least three specifc TUBB3 mutations are associ- genital facial weakness including Athabasacan brain stem ated with CFEOM and CFP (c.1228G > A;p.Glu410Lys; dysgenesis/Bosley-Salih-Alorainy syndrome, congenital c.785G > A;p.Arg262His; and c.1249G > C;p.Asp417His). fbrosis of the extraocular muscles (CFEOM) type 3A, Of these, the c.1228G > A;p.Glu410Lys variant is best CHARGE syndrome, hereditary congenital facial paresis, defned, and the disorder caused by this specifc muta- Moebius syndrome, and oculo-auriculo-vertebral spec- tion is known as the TUBB3 E410K syndrome. Features trum (Fig. 1 and Table 1). of the TUBB3 E410K syndrome (CFEOM3A, MIM #600638) include CFEOM, bilateral CFP, developmental Athabascan brain stem dysgenesis syndrome (ABDS) delay, progressive sensorimotor polyneuropathy, Kall- (ORPHA:69739)/ Bosley‑Salih‑Alorainy syndrome (BSAS) mann syndrome, stereotyped midface hypoplasia, and (ORPHA:69737) in some cases, vocal cord paralysis, tracheomalacia, and Athabascan brain stem dysgenesis syndrome (ABDS) and cyclic vomiting [7]. Patients with TUBB3 p.Arg262His Bosley-Salih-Alorainy (BSAS) syndrome are allelic HOX and p.Asp417His mutations present with CFEOM, CFP, gene disorders caused by recessive, pathogenic loss-of- developmental delay, progressive sensorimotor polyneu- function variants in the gene HOXA1. Te HOX genes ropathy, and congenital joint contractures [6]. are homeodomain containing proteins that are critical for anterior–posterior diferentiation in the developing CHARGE syndrome (ORPHA:138) embryo. In the developing vertebrate central nervous CHARGE syndrome is a CFW syndrome due to het- system, HOX genes function in hindbrain or rhomben- erozygous pathogenic variants in the gene CHD7, a cephalon development. BSAS was frst identifed in Saudi chromatin helicase protein. CHARGE is a mnemonic for Arabian and Turkish families [2, 3], while ABDS was coloboma, heart defects, choanal atresia, retarded growth Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 4 of 17 in ~ 10–45% of afected individuals. Characterized by facial asymmetry, or preauricular ear facial tags, malformations, microtia/anotia, and hearing loss Oculo-auriculo- vertebral spectrum N/A IC; AD (rare) %164210 141132 CFP seen - 2 nonprogressive nonprogressive facial weakness with limitation in abduction of one or both eyes. - fea Associated include may tures other cranial nerve involve ment, strabis - hearing mus, club foot, loss, limb reduction other defects, limb anomalies, anomaly, Poland developmental and autism. delay, most persons For with Moebius syndrome, the etiology is unknown Moebius syndrome PLXND1, REV3L IC; AD (rare) %157900 570 Congenital, Congenital, (100%); Full (100%); Full ocular motility; Strabismus (42%); Sensorineural hearing loss (90%) Hereditary congenital facial type 3 paresis HOXB1 AR #614744 306530 Bilateral CFW Bilateral - - bilateral CFW bilateral seen in ~ 40%. Common include features coloboma, microphthalmia, choanal atresia, cranial nerve dysfunction, ear anomalies (exter nal ear abnor ossicular malities, malformations, Mondini defect of the cochlea, bone temporal abnormalities, and/or absent or semi - hypoplastic canals) circular CHARGE syndrome CHD7 AD #214800 138 Unilateral or Unilateral - 1 are clinical are characteristics of TUBB3 disease caused by p.E410K, R262H, or D417H muta - Additional tions. include features developmental progressive delay, sensori - axonal polyneu - motor Kallman ropathy, vocal syndrome, paralysis, cord cyclic vomit and/or ing, congenital joint contractures Congenital fbrosis fbrosis Congenital of the extraocular muscles 3A with or without extraocular involvement TUBB3 AD #600638 45358 CFEOM and CFW tal gaze and tal gaze sensorineural hearing loss are the most com - mon features; CFW in ~ 20% Otherof cases. specifc features include carotid artery anomalies, conotruncal heart defects, and central hypoventilation Neurogenic CFW Neurogenic Athabaskan brainstem dysgenesis Bosley- syndrome/ Salih-Alorainy syndrome HOXA1 AR #601536 69739/69737 - horizon Limited - Diferential diagnosis for CFW disorders for diagnosis Diferential ance Clinical Features Clinical Features Summary 1 Table Disorder Gene Mode of Inherit Phenotype MIM # ORPHA # Distinguishing Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 5 of 17 - - manifests manifests with prenatally polyhydramnios and decreased movement; fetal newborns have weak profound hypotonia, ness, and respiratory that failure usually requires ventilatory support. Facial and extraocular often muscles are resulting involved in myopathic facies and ophthalmopare respectively. sis, Motor milestones signifcantly are and most delayed males afected achieve fail to independent ambulation MTM1 XLR #310400 596 Severe disease Severe - early (associated with severe disease) and childhood late or adulthood with (associated mild disease). may Findings include facial and extraocular muscle weak ptosis, ness, and extremity weakness [Nance et al. 2012]. Of note, progressive weakness has been observed during the teen and in years adulthood in individu - several als with a DNM2 pathogenic variant DNM2 AD #160150 595 Onset ranges from Onset ranges from - variants in BIN1 been have described in a small group of individuals. weakness Facial be present. may range of The clinical sever ity is broad; presentation in infancy has been reported Centronuclear/myotubular myopathy Centronuclear/myotubular BIN1 AR #255200 595 Pathogenic Pathogenic SEPN1 AD, AR AD, #255310 2020 hypotonia. Symptoms may range may Symptoms hypotonia. In early-onset severe. mild to from - respira newborns have disease, may tory facial weakness, insufciency, and poor suck Central core disease/ Multiminicore disease/ Multiminicore core Central disease RYR1 AD, AR AD, #11700 597 Characterized by muscle weaknessCharacterized by and - include facial weakness, full ocular movements, upturned/ nasal tip, broad - micro/retrog nathia, normal cognition, motor delayed milestones, and general - muscle ized hypoplasia. Additional occasional signs and symptoms congenital are contractures, growth feeding failure, problems, cleft ptosis, gastro/ palate, jejunostomy, thin tubular neck, pectoralis hypoplasia, - hypoglos sia, scoliosis, pulmonary hypertension, and/or cryptor chidism Myopathic CFW Carey-Fineman- syndrome Ziter MYMK AR #254940 1358 Clinical features Clinical features may present present may in neonates. Some afected individuals weaknesshave confned to facial and masti - catory muscles. Arthrogryposis multiplex con - genita seems to be particularly common in infants with truncating RAPSN muta - tions Congenital Congenital myasthenic 11 syndrome with associated acetylcholine receptor defciency RAPSN AR #616326 590 RAPSN disease of DOK7 disease include limb- pattern girdle of weakness, waddling gait, facial ptosis, weakness, but is ophthal - rare moparesis Congenital Congenital myasthenic 10 syndrome DOK7 AR #254300 590 Clinical features Clinical features - - - characterized early-by onset muscle weakness with variable severity. present Patients with facial weakness, pto ophthalmo sis, plegia, episodic plegia, respiratory insufciency and proximal muscle weak ness Congenital Congenital myasthenic 9 syndrome with associated acetylcholine receptor defciency Neuromuscular CFW Neuromuscular MUSK AR #616325 590 disease is MUSK HPO Term - (continued) ance Clinical Features Clinical Features Summary 1 Table gene Disorder Mode of Inherit Phenotype MIM # ORPHA # Distinguishing Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 6 of 17 - ZC4H2 rare associated disorders ZC4H2 XLR #314580 3454 TPM3 AD, AR AD, #609284 607 TPM2 AD #609285 607 NEB AR #256030 607 KLHL40 AR #615348 607 Nemaline myopathy ACTA1 AD, AR AD, #161800 607 Native Native American myopathy STAC3 AR #255995 168572 Myotonic Myotonic dystrophy, type 1 DMPK AD #160900 273 SMCHD1 AD #158901 269 Facioscapulohumeral Facioscapulohumeral muscular dystrophy DUX4 AD #158900 269 3 Myopathic CFW Congenital myopathy- Zaharieva et al. [2016] SCN4A AR N/A N/A HPO Term (continued) Inheritance MIM # 1 Table Disorder Gene Mode of Phenotype ORPHA # Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 7 of 17 - - - is gener ally noted prenatally. - Clinical fea include tures arthrogrypo delayed sis, motor develop ment, facial and bulbar weakness, and skeletal abnormali - ties - ZC4H2 rare associated disorders ZC4H2 Fetal akinesia Fetal - - may may cause a severe con - genital, inter mediate congen - or ital, child - hood onset pheno type. CFW is typically present TPM3 TPM3 NM - NM is generally associ - ated with a typical con - genital pheno type. The mastica - - (tem tor poral) muscles and distal leg lower muscles are typically involved. CFW is typically present TPM2 TPM2 - - - NM2 ( NEB ) typi - cally includes infants present ing in the frst with of life year limb hypotonia, weakness, facial - weakness, feed ing difculty, and respiratory weakness. The muscle disease is either static or - progres slowly such that sive most afected individuals survive adult to hood and live independently. common Less presentations death in are: due to utero akinefetal sia; severe and hypotonia weakness; facial weakness with a poor suck and at birth;swallow - or predomi nantly distal weakness in older individuals NEB The phenotypeThe of - of NM8 ( KLHL40 ) include severe congenital lethal disease or fetal akinesia. - Contrac tures, fractures, respiratory and failure, swallowing difculties be may present at birth. CFW was identifed in all 26 individuals studied by Raven et al. scroft (2013) KLHL40 Findings Findings - presenta tion of NM ACTA1 ranges from severe con - genital myopathy later to childhood onset. Facial weakness be may present Nemaline myopathy ACTA1 The age of The - - - - patients had myopathic facies. Additional common are features congenital weakness, arthro gryposis, cleft palate, shortptosis, stature, kyphoscolio club foot, sis, and suscep tibility to malignant hyper thermia by provoked anesthesia Native Native American myopathy STAC3 All reported - DM1 may DM1 may include symptoms of CFW. Additional symptoms of afected neonates include hypotonia, positional malfor mations includ - ing club and foot, respiratory insuf - ciency Myotonic Myotonic dystrophy, type 1 DMPK Congenital Congenital rare type rare of and FSHD, is clinically indistin - guishable type from 1 due to DUX4 mutations SMCHD1 This is a more more a is This - - - ized by by ized progressive muscle weakness involving the face, scapular stabilizers, upper arm, leg, lower and hip gir dle. Most dle. individuals become sympto matic in their teens, but severe infantile onset with muscle weakness at birth is possible Facioscapulohumeral Facioscapulohumeral muscular dystrophy DUX4 Character - - 3 individuals four from families with compound heterozygous pathogenic variants in SCN4A were reported have to of symptoms a congenital myopathy, and all were to noted mild have moderate to facial weak ness that was either present at birth (3 of 4 families) or developed during the days frst few (1 fam - of life - ily). Associ features ated included to moderate hypo severe reduced tonia, muscle bulk, and neck, and limb axial, weakness Myopathic CFW Congenital myopathy- Zaharieva et al. [2016] SCN4A Afected Afected HPO Term (continued) ing Clinical Features Summary Disorder Gene 1 Table Distinguish - Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 8 of 17 - glistening facial skin,glistening an abnormal hair hair frontal pattern with an upswept fat and eyebrows, sparse arched line, long philtrum, distinctive ears, nose, broad demeanor and a happy Nablus mask-like facial syndrome Nablus mask-like 8q22.1 AD #608156 178303 Blepharophimosis, tight-appearing tight-appearing Blepharophimosis, 5 syndrome rophimosis, micrognathia, micrognathia, rophimosis, ears, low-set cleft palate, kyphoscoliosis, joint Dandy- contractures, with malformation Walker vertebral hydrocephalus, intellectualabnormalities, impairment Marden-Walker Marden-Walker PIEZO2 IC; AD #248700 2461 Mask-like face with blepha - immobile mask-like face, face, immobile mask-like and feeding hypotonia severe patellae, dislocated problems, defects, structural cardiac hypothyroidism, teeth, pointed intellectual impairment severe disorders KAT6B KAT6B AD #603736 3047 Severe blepharophimosis, an blepharophimosis, Severe 4 facies the depressor anguli oris the depressor congenital heartmuscle, microcephaly, defects, intellectual impairment Mixed/unknown CFW cryingAsymmetric 22q11 IC; AD #125520 1166 Congenital hypoplasia of hypoplasia Congenital HPO Term (continued) = 26700687 [2016], PMID et al. Zaharieva Some cases of asymmetric crying with 22q11 deletion associated facies are syndrome Marden-Walker for is extremely rare in PIEZO2 variants pathogenic of potentially Identifcation for Moebius syndrome is extremely rare is extremely Moebius in PLXND1 or REV3L syndrome variants for pathogenic of potentially Identifcation Summary The name listed in OMIM is Congenital fbrosis of the extraocular muscles 3A with or without extraocular involvement; however, extraocular muscle involvement is required for the diagnosis for is required extraocular muscle involvement however, of the extraocular muscles 3A with or without extraocular involvement; fbrosis in OMIM is Congenital name listed The

isolated cases; N/A = not applicable; MIM Online Mendelian Inheritance IC = isolated in Man; ORPHA = Orphanet; HPO = Human recessive; XLR = X-linked recessive; AR = autosomal dominant; AD = autosomal Abbreviations: Phenotype Ontology 1 Table Disorder Gene 1 2 3 4 5 Mode of Inheritance Phenotype MIM # ORPHA # Distinguishing Clinical Features Distinguishing Clinical Features Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 9 of 17

and development, genital abnormalities, and ear anoma- clinical manifestations, which can include bilateral hori- lies. 39% of CHD7 mutation positive CHARGE syndrome zontal gaze palsy, other cranial nerve dysfunction, crani- patients were noted to have unilateral or bilateral CFW ofacial and limb deformities (e.g. Poland syndrome and [8]. Other notable clinical features include additional clubbed foot), mirror movements, sleep disorders, sei- cranial nerve dysfunction, impaired hearing, swallowing zures, and neurocognitive and social impairments. difculties, hypogonadotropic hypogonadism, orofacial For the majority of cases of Moebius syndrome, the clefts, and/or tracheoesophageal fstula. etiology is unknown. Both genetic and environmen- tal etiologies have been proposed. Additionally, prena- Hereditary Congenital Facial Paresis (HCFP) (ORPHA:306530) tal exposure to misoprostol and other agents has been Hereditary congenital facial paresis (HCFP) is a disorder known to be associated with a Moebius syndrome phe- with apparently isolated dysfunction of the facial nerve of notype [19, 20]. De novo heterozygous missense PLXND1 germline genetic etiology. HCFP type 3 (HCFP3) results variants were reported in three individuals with Moebius from recessive pathogenic loss-of-function variants in syndrome and variable dysmorphic features (including the HOXB1 gene [9]. At present, 17 afected individu- microcephaly, epicanthal folds, fat nasal bridge, micro- als from 6 separate families have been identifed [9–13]. gnathia, external ear defects, dental defects, clinodac- All 17 afected patients had bilateral CFW and were tyly, and low-set thumbs) [21]. However, one of these described as having masked-like facies. Eleven of 15 three individuals was noted to have a synonymous vari- patients or 73% were noted to have sensorineural hear- ant in PLXND1 that is not predicted to alter splicing and, ing loss (information unavailable for 2 patients). Seven therefore, is presumed not to afect gene function. Addi- of 17 or 41% of patients were noted to have esotropia. tionally, three individuals were reported with de novo, Patients had full ocular motility, and thus did not meet heterozygous missense variants in REV3L (two with the minimum diagnostic criteria for Moebius syndrome Moebius syndrome and one with isolated CFP without (see below). Dysmorphic features included midface a defect in ocular motility), suggesting that HCFP and retrusion (16 of 17 patients or 94%), upturned nasal tip Moebius syndrome may be allelic disorders. Analysis of (13 of 17 patients or 76%), smooth philtrum (12 of 17 Plxnd1 and Rev3l mutant mice revealed hypoplasia of the patients or 71%), and low-set ears (5 of 17 patients or facial motor nucleus [21]. To date confrmation of addi- 29%) [9–12]. Four afected members of one family har- tional cases of Moebius syndrome or CFW with muta- boring a homozygous HOXB1 c.66C > G;p.Tyr22* mutations in these genes has not been reported. tion and 3 members of a family harboring a homozygous c.296_302del;p.Y99Wfs*20 mutation were noted to have Oculo‑auriculo‑vertebral spectrum (ORPHA:141132) external ear/auricular malformations; these external ear Oculo-auriculo-vertebral spectrum is a developmental malformations have not been seen in the 4 other families disorder involving abnormal development of the frst who harbor diferent HOXB1 mutations [9–11, 13]. and second pharyngeal arches. Characteristic fndings Two additional genetic loci (HCFP1 (MIM %601471) include facial asymmetry resulting from maxillary and/ and HCFP2 (MIM %604185) have been reported in large or mandibular hypoplasia; preauricular or facial tags; ear autosomal dominant pedigrees with incomplete pene- malformations such as microtia, anotia, or aural atresia; trance [14–16]. Both loci are associated with unilateral or and hearing loss. Te phenotype is heterogeneous and bilateral facial palsy; some individuals with HCFP2 also ranges from subtle asymmetries to frank, bilateral crani- had hearing loss (a few cases associated with anomalous ofacial involvement with involvement of other organ formation of the petrous portion of the temporal bone). systems. Facial palsy (unilateral or bilateral involvement Ocular movements are reported to be normal [14, 16]. of either part or all branches of CN7) is observed in ~ 10–45% of afected individuals [22], and other cranial Moebius syndrome (ORPHA:570) nerve abnormalities may also be seen. Other craniofacial Due to discrepancies and confusion in the literature, malformations that may be present include cleft lip and/ Moebius syndrome was defned at the Scientifc Confer- or palate. Non-craniofacial malformations involving skel- ence on Moebius Syndrome in 2007 as congenital, non- etal, renal, and cardiac systems may be seen. Te etiology progressive facial weakness with limited abduction of one in most cases is currently unknown. or both eyes [17]. More recently, addition of the criterion of full ocular vertical motility to the minimum diagnostic Neuromuscular junction causes of congenital facial criteria was suggested [18]. Given the diagnostic crite- weakness ria, all persons with Moebius syndrome have CFW. Te Neuromuscular causes of congenital facial weakness CFW may be unilateral or bilateral as well as partial or include the congenital myasthenic syndromes, particu- complete. Moebius subjects can present with additional larly types 9, 10, and 11 (Table 1). Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 10 of 17

Congenital myasthenic syndrome (CMS), types 9, 10, and 11 abducens nerve palsy, a required feature for the diagnosis (ORPHA:590) of Moebius syndrome [31]. Congenital myasthenic syndromes are a group of disorders characterized by skeletal muscle weakness that Central core disease (ORPHA:597)/multiminicore disease worsens with exercise (myasthenia). Te defect is due (ORPHA:2020) to recessive loss-of-function mutations in genes that Central core disease and multiminicore disease may be encode proteins that function at the neuromuscular junc- caused by pathogenic variants in RYR1 or SEPN1. Central tion. While most congenital myasthenic syndromes may core disease is named due to the presence of disorgan- result in CFW, CFW is most typical in types 9, 10, and 11 ized areas of ‘central cores’ seen on muscle biopsy, while [23–25]. Additional associated features may include oph- multiminicore is named due to disorganized ‘minicores’. thalmoplegia with congenital myasthenic syndrome, type Mutations in RYR1 may cause autosomal recessive or 9 [26], respiratory muscle weakness with types 9, 10, and autosomal dominant central core disease, autosomal 11 [24, 27], and joint contractures and arthrogryposis, recessive minicore myopathy with external ophthalmo- particularly with type 11. Treatment with cholinesterase plegia, and autosomal recessive or autosomal dominant inhibitors may be helpful for congenital myasthenic syn- neuromuscular disease, congenital, with uniform type 1 drome, type 9, treatment with cholinesterase inhibitors fber. RYR1 encodes the skeletal muscle ryanodine recep- or amifampridine may be helpful for myasthenic syn- tor, which is a ligand-gated calcium channel important drome, type 11 [27], and treatment with ephedrine may in calcium signaling in the sarcoplasmic reticulum. For be helpful for congenital myasthenic syndrome type 10 autosomal dominant central core disease, onset is typi- [28]. cally at birth or early childhood with features of facial weakness and nonprogressive limb weakness, or in early Myopathic causes of congenital facial weakness childhood with nonprogressive limb weakness and hypo- CFW has been associated with both congenital myopa- tonia. Afected patients generally survive to adulthood. thies and muscular dystrophies. Te congenital myopa- Multiminicore myopathy due to recessive mutations in thies with CFW include Carey-Fineman-Ziter syndrome, RYR1 presents generally in infancy with external oph- central core disease/multiminicore disease, centro- thalmoplegia, limb weakness, and wasting of hip girdle nuclear/myotubular myopathy, congenital myopathy muscles similar to central core disease [32]. Additional reported by Zaharieva et al., Native American myopathy, features include bulbar, facial, or respiratory weakness, Nemaline myopathy, and ZC4H2-associated rare disor- and joint abnormalities including hyperlaxity, con- ders. Te muscular dystrophies include myotonic dystro- tractures, and arthrogryposis. Rare cases of autosomal phy, type 1 and infantile facioscapulohumeral muscular recessive inheritance, with homozygous or compound dystrophy (Table 1). heterozygous RYR1 mutations have been described presenting with severe congenital ophthalmoplegia and Carey‑Fineman‑Ziter syndrome (CFZS) (ORPHA:1358) facial weakness in the setting of only mild skeletal myo- Carey-Fineman-Ziter syndrome, also known as congeni- pathy. Tese patients were susceptible to malignant tal nonprogressive myopathy with Moebius sequence hyperthermia [33]. and Robin sequence, was frst described by Carey et al. Mutations in the selenoprotein N gene (SEPN1) have in 1982 in two siblings with Moebius sequence, Pierre been identifed in individuals with multiminicore dis- Robin sequence, hypotonia, growth delay, and normal ease, muscular dystrophy with rigid spine, and congeni- cognition. One sibling developed restrictive lung disease tal myopathy with fber-type disproportion. Homozygous and died of pneumonia at age 37 years [29, 30]. CFZS or compound heterozygous mutations in SEPN1 cause results from recessive mutations in the MYMK gene autosomal recessive multiminicore disease. Multimini- [31]. MYMK encodes myomaker, a protein necessary core disease is broadly classifed into four groups: clas- for fusion of myoblasts to form multinucleated myofb- sic form (75% of individuals); moderate form with hand ers [31]. Compound heterozygous MYMK mutations involvement (< 10%); antenatal form with arthrogryposis were identifed in the initial afected siblings reported multiplex congenita (< 10%); and ophthalmoplegic form by Carey et al., as well as 6 additional afected individu- (< 10%) [34]. Onset of the classic form is usually at birth als from 4 additional families. All 8 afected individuals or early in childhood with hypotonia, delayed motor had facial weakness, an upturned/broad nasal tip, micro/ milestones, scoliosis, and signifcant respiratory involve- retrognathia, delayed motor milestones, generalized ment. Most patients with multiminicore disease and muscle hypoplasia, and normal cognition. Some also SEPN1 mutations exhibit a variable degree of facial weak- had downslanting palpebral fssures, epicanthal folds, ness [34, 35]. fat nasal root, and mandibular hypoplasia. None had an Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 11 of 17

Centronuclear (ORPHA:595, 596)/ myotubular myopathy may be present. In FSHD, the muscle weakness is slowly Centronuclear/myotubular myopathy may be caused progressive and approximately 20% of afected individu- by homozygous or compound heterozygous pathogenic als eventually require a wheelchair. Life expectancy is not variants in the gene BIN1, heterozygous pathogenic vari- shortened. Te incidence is approximately 4 individuals ants in the gene DNM2, or hemizygous pathogenic vari- afected per 100,000 people [38]. ants in MTM1. Muscle biopsy in these conditions reveals Although some controversy remains, FSHD is likely small, rounded myofbers with increased percentages caused by inappropriate expression of the double home- of centrally located nuclei. Pathogenic variants in BIN1 obox-containing gene DUX4 in muscle cells. DUX4 lies have been described in a small group of individuals. BIN1 in the macrosatellite repeat D4Z4 on chromosome 4q35, encodes amphiphysin-2, which binds to DNM2 during which has a length between 11 and 100 repeat units on clathrin-dependent endocytosis [36]. Te range of clini- normal alleles. Approximately 95% of individuals with cal severity is broad, and CFW has been reported. FSHD have a D4Z4 allele of between one and ten repeat DNM2 encodes dynamin-2-protein, a large GTPase units. Te shortening of the D4Z4 allele causes chroma- protein involved in clathrin-dependent and clathrin- tin relaxation at the D4Z4 locus and DUX4 promoter and independent endocytosis and intracellular membrane thereby derepression of DUX4. Tis common form of trafcking. For DNM2 centronuclear/myotubular myo- FSHD is designated facioscapulohumeral muscular dys- pathy, the range of symptoms in afected individuals is trophy 1 (FSHD1). Molecular genetic testing measures broad, and severe disease may present with CFW. Find- the length of the D4Z4 allele [38]. ings may include facial and extraocular muscle weakness, ptosis, and extremity weakness [36]. Myotonic dystrophy, type 1 (DM1) (ORPHA:273) MTM1 encodes myotubularin, a tyrosine phosphatase Myotonic dystrophy type 1 (DM1) is a multisystem dis- protein required for muscle cell diferentiation. Myopa- order that afects skeletal and smooth muscle as well as thy due to MTM1 mutations is also known as X-linked the ocular, cardiovascular, endocrine, and central nerv- centronuclear myopathy (CNMX). In CNMX, muscle ous systems. Te clinical fndings, which span a con- weakness ranges from mild to severe (classic disease). tinuum from mild to severe, have been categorized into Te muscle disease of CNMX is not obviously progres- three overlapping phenotypes: mild, classic, and congeni- sive. CFW may be present in severe/classic disease. tal. Congenital DM1 is characterized by hypotonia and Female carriers of CNMX are generally asymptomatic. severe generalized weakness at birth, including CFW. Afected infants often have an inverted V-shaped upper Congenital myopathy‑ Zaharieva et al. [2016] lip, which is characteristic of signifcant facial diplegia. Recessive loss of function homozygous or compound Before birth polyhydramnios and reduced fetal move- heterozygous variants in SCN4A, which encodes sodium ment may be noted. Positional malformations such as voltage-gated channel, alpha subunit 4, have been club foot and respiratory insufciency leading to early reported to cause a spectrum of disease ranging from death may also occur. Intellectual disability is common. severe fetal hypokinesia to a ‘classical’ congenital myo- DM1 is caused by expansion of a CTG trinucleotide pathy. Afected individuals from four families with com- repeat in the non-coding region of DMPK. A normal pound heterozygous pathogenic variants in SCN4A were allele has 5–34 CTG repeats, a premutation allele has reported to have symptoms of a congenital myopathy, 35–49 CTG repeats, and a full penetrance allele has ≥ 50 and all were noted to have mild to moderate facial weak- CTG repeats. Congenital DM1 is associated with a repeat ness that was either present at birth (3 of 4 families with size of > 1000 CTG repeats. Generally, CTG repeat CFW) or developed during the frst few days of life (1 expansion causing congenital DM1 occurs when the family). Associated features included moderate to severe mother is transmitting the abnormal allele [39]. hypotonia, reduced muscle bulk, and neck, axial, and limb weakness [37]. Native American myopathy (NAM) (ORPHA:168572) Native American myopathy is an autosomal recessive Facioscapulohumeral muscular dystrophy (FSHD) condition originally identifed in the Lumbee Native (ORPHA:269) American population of North Carolina, which pre- Facioscapulohumeral muscular dystrophy (FSHD) type sents with features of congenital onset of muscle weak- 1 is an autosomal dominant condition caused by muta- ness, susceptibility to malignant hyperthermia, multiple tions in DUX4 [38]. FSHD typically presents before age joint contractures, ptosis, and dysmorphic features. All 20 years with weakness of the facial muscles and the reported patients had myopathic facies and hypoto- stabilizers of the scapula or the dorsifexors of the foot. nia and generalized weakness present from birth. Mus- Tere is extreme clinical variability. In some cases, CFW cle biopsies of afected individuals reveal a non-specifc Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 12 of 17

myopathic pattern. Afected Native American individuals pathogenic variants in TPM2 cause autosomal dominant with Native American myopathy were identifed to have nemaline myopathy 4 which accounts for < 1% of cases of a homozygous STAC3 pathogenic variant, c.1046G > C;p. nemaline myopathy. TPM2 nemaline myopathy is gen- Trp284Ser [40]. erally causative of a typical congenital phenotype and is Subsequently Native American myopathy also has been commonly associated with involvement of the masticator identifed in individuals of non-Lumbee Native American muscles and distal lower leg muscles. Afected patients descent and additional pathogenic variants other than typically have a myopathic face with facial diplegia. the p.Trp284Ser variant have now been identifed [41– TPM3 encodes alpha-tropomyosin, another thin fla- 43]. Native American myopathy has overlapping features ment component of the sarcomere. Biallelic pathogenic with Moebius and Carey-Fineman-Ziter syndromes [42]. variants and heterozygous pathogenic variants in TPM3 cause autosomal recessive or autosomal dominant nema- Nemaline myopathy (ORPHA:607) line myopathy, 1, respectively which accounts for ~ 2–3% Nemaline myopathy (NM) is named for the fnding on of cases of nemaline myopathy. TPM3 disease phenotypic muscle biopsy of abnormal rod-like structures within range includes severe congenital (autosomal recessive; muscle cells termed nemaline bodies [44]. It can be ~ 16% of cases), intermediate congenital, or childhood caused by pathogenic variants in multiple genes, includ- onset (autosomal dominant) types. Findings include ing ACTA1, KLHL40, NEB, TPM2, and TPM3. weakness that is predominantly proximal and general- ACTA1 encodes the skeletal muscle protein alpha- ized with or without facial weakness; hypotonia and actin, which forms the core of the thin flament of the depressed deep tendon refexes, with preserved sensation sarcomere that functions in muscle contraction. Biallelic and normal cognition; and feeding difculties related to pathogenic variants in ACTA1 cause autosomal recessive facial and bulbar weakness, respiratory difculties, recur- NM; heterozygous pathogenic variants cause autosomal rent infections or a weak cough related to restrictive lung dominant NM3. ACTA1 disease causes 20–25% of all disease from weakness of the respiratory muscles [44]. nemaline myopathy, but 50% of severe nemaline myopathy. Te age of presentation ranges from severe congeni- ZC4H2‑associated rare disorders (ZARD) (ORPHA:3454) tal myopathy to later childhood onset. Facial weakness ZC4H2-associated rare disorders includes a spectrum may be present. of disease with arthrogryposis multiplex and peripheral KLHL40, or kelch-like family member 40, is a protein and central nervous system involvement [47]. Tis spec- that is necessary for sarcomere structure and contractil- trum includes Wieacker-Wolf syndrome (WRWF), an ity [45]. Biallelic pathogenic variants in KLHL40 cause X-linked recessive condition caused by pathogenic vari- autosomal recessive nemaline myopathy 8. Findings are ants in ZC4H2. ZC4H2 encodes a zinc-fnger protein, severe congenital lethal disease or fetal akinesia. In addi- expressed in a variety of tissues. Boys with WRWF gener- tion to severe fetal akinesia or hypokinesia, contractures, ally had decreased fetal movements in utero and are born fractures, respiratory failure, and swallowing difculties with severe contractures. Additional clinical fndings at birth, facial weakness was present at birth in all 26 include delayed motor development, CFW, bulbar weak- individuals studied by Ravenscroft et al. [46]. ness, characteristic dysmorphic facial features (carp- NEB encodes nebulin, a cytoplasmic matrix protein like mouth, narrow palate, micrognathia, long philtrum, in skeletal muscle. Biallelic pathogenic variants in NEB upturned nares, and short neck), skeletal abnormalities cause autosomal recessive, nemaline myopathy 2, which such as hip dislocation, scoliosis, pes equinovarus, intel- accounts for about 50% of cases of nemaline myopathy. lectual disability, and Duane syndrome. Carrier females Te phenotype of the typical congenital form includes may exhibit mild features of the disorder due to skewed presentation within the frst year of life with hypotonia, X-chromosome inactivation [48]. limb weakness, facial weakness, feeding difculty, and respiratory weakness. Te muscle disease is either static Other, Including Unknown or Mixed Causes of Congenital or slowly progressive such that most afected individuals Facial Weakness survive to adulthood and live independently. Less com- Tere are other causes of CFW that are of other mon presentations are: death in utero due to fetal akine- unknown or mixed etiology. Tese types of CFW include sia; severe hypotonia and weakness; CFW with a poor asymmetric crying facies, KAT6B disorders, Marden- suck and swallow at birth; or predominantly distal weak- Walker syndrome, and Nablus mask-like facial syndrome. ness in older individuals [44]. TPM2 encodes beta-tropomyosin, a component of the Asymmetric crying facies (ACF) (ORPHA:1166) thin flament of the sarcomere, and is primarily expressed Asymmetric crying facies (ACF) describes newborns in slow, type 1 skeletal muscle fbers. Heterozygous with unilateral facial weakness noticed when the infant Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 13 of 17

cries. Primary (myopathic) or secondary (neurogenic) Consultations generally begin with a full medical his- agenesis or hypoplasia of the depressor anguli oris mus- tory (including family history) and physical examination. cle may cause developmental forms of asymmetric crying Family history assessment includes an extended pedigree facies, which is also known as congenital unilateral lower with attention to relatives with related craniofacial fnd- lip palsy (CULLP). ACF may be associated with heart ings and documentation of relevant fndings through defects and/or deletion 22q11 [49]. direct examination or review of medical records, including results of molecular genetic testing. Depending on KAT6B disorders (ORPHA:3047) the diagnosis, genetic testing may be indicated (Table 2). KAT6B disorders include Say-Barber-Biesecker-Young- Te medical history and physical examination are Simpson syndrome (SBBYSS), characterized by distinc- directed at identifying features associated with specifc tive facial features including severe blepharophimosis, an causes of congenital facial weakness (Table 1, Additional immobile, mask-like face, a bulbous nasal tip, and a small fle 1). Te consultant should obtain detailed informa- mouth with a thin upper lip; neurologic fndings includ- tion regarding the onset and severity of the CFW and ing severe hypotonia and feeding problems in infancy, the presence of additional symptoms. Past medical his- severe intellectual disability, delayed motor milestones, tory, including surgical history, should be obtained with and signifcantly impaired speech; and skeletal fndings special attention to any incidence of malignant hyper- including joint laxity, abnormally long thumbs and great thermia. A genetics evaluation should include dys- toes, and dislocated or hypoplastic patellae. Te mask- morphology assessment that may aid in narrowing the like facial appearance is due to bilateral CFW. Other diagnosis. A full cranial nerve examination should be common fndings are congenital heart defects (~ 50%), completed as well as an examination for signs and symp- dental anomalies (small and pointed teeth), and abnor- toms of primary muscle disease (preferably by a neurolo- malities of thyroid structure or function. To date, most gist or neuromuscular specialist). Ocular motility should individuals with a KAT6B-related disorder have had a de be assessed (preferably by an ophthalmologist or orthop- novo dominant pathogenic variant in the KAT6B gene, tist). Patients should receive audiology evaluation as well which encodes a histone acetyltransferase [50]. as a smell test to assess for anosmia. Endocrine evaluation should be performed if there are signs of delayed puberty, Marden‑Walker syndrome (MWKS) (ORPHA:2461) growth failure, or thyroid abnormalities. A developmen- Marden-Walker syndrome (MWKS) is characterized by tal assessment should be performed if developmental “immobile facies,” blepharophimosis, joint contractures delays are suspected, and feeding or speech therapy and including camptodactyly, scoliosis, cleft palate, dimin- other supportive services may be ofered to help with ished muscular bulk, developmental delay, and hind- physical and social impairments and improve the qual- brain malformations, most commonly Dandy-Walker ity of life of afected individuals. Additional work-up may malformation. For the majority of cases, the etiology is include assessment for congenital heart defect, skeletal unknown. One patient with MWKS has been identifed defects, dental or craniofacial anomalies, or other system with a de novo missense mutation (p.R2686C) in PIEZO2. involvement, guided by associated fndings. Mutations in PIEZO2 were also found in the phenotypi- CFP with or without strabismus, but without a limi- cally overlapping syndromes, Gordon syndrome or distal tation in horizontal or vertical ocular movement and arthrogryposis, type 3 (DA3) and distal arthrogryposis, without other major systemic involvement is suggestive type 5 (DA5) [51]. of HCFP and includes the HOXB1 syndrome as well as genetically undefned forms of autosomal dominant Nablus mask‑like facial syndrome (ORPHA:178303) CFP (HCFP1, HCFP2). Impairment in ocular abduc- Nablus mask-like facial syndrome is a contiguous gene tion, with full ocular vertical mobility, in association with deletion syndrome at chromosome 8q22.1 characterized CFW suggests a diagnosis of Moebius syndrome [18] or by blepharophimosis, tight-appearing glistening facial HOXA1 syndromes. CFP with both horizontal and ver- skin, an abnormal hair pattern with an upswept frontal tical gaze limitations and ptosis (i.e. CFEOM) may be hairline, sparse arched eyebrows, fat and broad nose, suggestive of TUBB3 syndromes and should prompt fur- long philtrum, distinctive ears, and a happy demeanor ther evaluations for associated peripheral axonal poly- [52–54]. neuropathy, endocrine work-up for Kallmann syndrome, and neurocognitive testing. CFP in combination with a Evaluation strategy for consultants coloboma, deafness, and/or a distinctive ear appearance Establishing a specifc cause of congenital facial weakness is suggestive of CHARGE syndrome. CFW in association enables accurate discussions of treatment, management, and prognosis and allows for precise genetic counseling. Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 14 of 17 - - microtia present, consider a diag - present, microtia ± disease nosis of oculo-auriculo-vertebral sonogram renal and order spectrum disorder and cervical x-ray akinesia or fetal syndromes consider Carey-Fineman-Ziter or RYR1 can myopathy sequencing with dele order family history, especially in the case of positive the suspected genes or D4Z4 allele contractiontion/duplication analysis for in the case of facioscapulohumeral muscular dystrophy testing some analysis and chromosomal microarray may be ofered. Consider whole Consider be ofered. may microarray some analysis and chromosomal sequencing exome drome or HCFP to assess for absence or hypoplasia of CN7 and other cranial absence or hypoplasia assess for or HCFP to drome nerves abnormalities of the corpus callosum, reveal (1, 3, 6, 8–11). MRI may pituitary olfactory gland, TUBB3 sulci and olfactory bulbs in individuals with E410K cular dystrophy consider diagnosis of Moebius syndrome or ABDS/BSAS of Moebius syndrome consider diagnosis myopathy core canals in the case of CHARGE syndrome and ABDS/BSAS canals in the case of CHARGE syndrome If characteristic of CHARGE syndrome consider a diagnosis CHARGE ear present, consider HCFP3 If present, ear anomalies are present, are and/or contractures If scoliosis, cleft Pierre-Robin palate, sequence, If personal or family history hyperthermia, of malignant Ameri- consider Native genes, If a single gene or few is suspected that is caused by a specifc diagnosis chromo a single gene is not suspected, caused by When a specifc diagnosis If facial asymmetry/hemifacial microsomia Brainstem/cranial nerve/orbitalBrainstem/cranial of Moebius MRI if considering syn - diagnosis EMG, nerve diferential conduction narrow studies to rule out seizures EEG to Consider abnormal muscle biopsy if limb muscles are Consider sleep studies depending on historyConsider of facioscapulohumeral mus - consider diagnosis If weakness of shoulder girdle, of asymmetric crying lip palsy is suggestive congenital lower Isolated facies be seen with CFEOM3 may neuropathy Peripheral If palsy with full vertical abduction gaze horizontal defcit or bilateral motility, be seen with CFEOM3, CMS9, and multimini - may and ptosis Ophthalmoplegia CT to assess for temporal bone abnormalities and/or hypoplastic semicircular CT semicircular bone abnormalities temporal and/or hypoplastic assess for to Echocardiogram Hormone testing Smell testing PT, OT, and ST as indicated OT, PT, X-rays Craniofacial exam by a craniofacial surgeon Craniofacial exam by Dental exam drome (associated with ABDS/BSAS) (associated drome vertebral spectrum disorder, and Moebius syndrome) vertebral spectrum disorder, with CFEOM3 and CHARGE) dental anomalies Assess for dysmorphic features for Assess Obtain family history intrauterine exposures for Assess Full cranial nerve anosmia and hearing for examination including testing Full movements and mirror of peripheral neuropathy presence for Assess or myotonia muscle weakness of myopathy and signs for Assess Assess extraocular movements and for presence of ptosis presence extraocular and for Assess movements in Duane syn - found such as globe retraction aberrant movements for Assess Assess for possible hearing bone/ear anomalies loss and temporal for Assess Assess for congenital heart for with BSAS/ABDS, oculo-auriculo- (associated Assess defect Assess for hypogonadotropic hypogonadism/ Kallmann hypogonadism/ (associated syndrome hypogonadotropic for Assess Assess for developmental delays developmental for Assess Assess for scoliosis, limb length discrepancy, and need for orthotics and need for limb length discrepancy, scoliosis, for Assess Assess for orofacial clefting, Pierre Robin sequence, palatal and tongue defects, defects, palatal and tongue Robin sequence, Pierre clefting, orofacial for Assess Evaluation and examination recommended for patients with congenital facial weakness for and examination recommended Evaluation Rehabilitation referral 2 Table with CFW: all patients For Dysmorphology geneticist exam by Neurology exam Neurology Ophthalmology exam For some patients with CFW: some patients For ENT referral Cardiology referral Cardiology Endocrinology referral Developmental pediatrics referral Orthopedics/Physical Medicine and Craniofacial Team/Dental referral Craniofacial Team/Dental Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 15 of 17

with facial asymmetry, microtia, preauricular tags or Abbreviations ABDS: Athabascan brain stem dysgenesis; ACF: Asymmetric crying facies; pits, micrognathia, aural atresia, or conductive hearing BSAS: Bosley-Salih-Alorainy syndrome; CFEOM: Congenital fbrosis of the loss is suggestive of oculo-auriculo-vertebral spectrum extraocular muscles; CFP: Congenital facial paralysis; CFW: Congenital facial disorder. Isolated congenital lower lip palsy is consistent weakness; CFZS: Carey-Fineman-Ziter syndrome; CMS: Congenital myasthenic syndrome; CN7: Cranial nerve 7; DM1: Myotonic dystrophy, type 1; FSHD: with a diagnosis of asymmetric crying facies. If history of Facioscapulohumeral muscular dystrophy; HCFP: Hereditary congenital facial malignant hyperthermia is present, a diagnosis of Native paresis; MWKS: Marden-Walker syndrome; NAM: Native American myopathy; American Myopathy or other congenital myopathies like SBBYSS: Say-Barber-Biesecker-Young-Simpson syndrome; CNMX: X-linked centronuclear myopathy; ZARD: ZC4H2-Associated rare disorders. RYR1 should be considered. MRI of cranial nerves may reveal absence or hypoplasia Supplementary Information of the facial nerve. Axial and sagittal oblique T2-SPACE The online version contains supplementary material available at https://doi. MRI series is recommended for evaluation of the facial org/10.1186/s13023-021-01736-1. nerve. MRI of facial muscles may reveal absence or hypoplasia. Muscle ultrasound and MRI may help diferentiate Additional fle 1. Clinical Features of CFW Disorders. amongst the congenital myopathies based on the distribution of afected muscle groups. Additionally, electro- Acknowledgements myogram may aid in the diagnosis of myasthenia or a The authors acknowledge the Moebius Syndrome Research Consortium for congenital myopathy as well as help identify an appro- their assistance, and the authors thank the Moebius Syndrome Foundation priate site for muscle biopsy. Nerve conduction studies for their support. B.D.W. is a clinical geneticist, clinical molecular geneticist, and pediatrician specializing in genetic studies of rare, congenital anomalies. may also be used to help narrow the diferential. Creatine She is Co-Director of the Cleft and Craniofacial Program at the Icahn School kinase levels may be elevated in cases of myopathy. of Medicine at Mount Sinai. I.M. is a clinical and biochemical geneticist and pediatrician with a focus on clinical and translational research in rare genetic Genetic testing syndromes and inborn errors of metabolism. She works at the National Human Genome Research Institute of the National Institutes of Health. E.C.E. is Molecular genetic testing approaches may include a a child neurologist and neurogeneticist at Boston Children’s Hospital and Har- combination of gene-targeted testing (multi-gene panel vard Medical School, whose research focuses on the phenotypic, genetic, and molecular defnition of disorders altering cranial nerve and muscle develop- or single-gene testing) and genomic testing (compre- ment. E.W.J. is a medical geneticist at the Icahn School of Medicine at Mount hensive genomic sequencing or chromosomal micro- Sinai with a clinical focus in dysmorphology and a clinical, translational, and array analysis [CMA]). Gene-targeted testing requires basic research interest in developmental genetics, in particular craniofacial disorders. the clinician to narrow in on a particular diagnosis and hypothesize which gene(s) are likely involved. Chromo- Authors’ contributions somal microarray (CMA) may be considered in patients B.D.W. wrote the manuscript. I.M., E.C.E, and E.W.J. edited the manuscript. All authors read and approved the fnal manuscript. with distinguishing, multiple phenotypic features suggestive of a contiguous gene deletion syndrome. Whole Funding exome sequencing (WES) and whole-genome sequenc- This work was supported by NIH grant U01HD079068. ing (WGS) may be considered if the phenotype alone is Availability of data and materials insufcient to support gene-targeted testing. In some Not applicable. instances where the genetic etiology for a particular diagnosis is currently unknown, genetic testing may not be Declarations indicated at this time. Ethics approval and consent to participate Not applicable. Conclusions Te diferential diagnosis for congenital facial weakness Consent for publication Consent to publish the photograph of the patient in Fig. 2 was obtained. conditions is quite broad and extensive. Te clinician must be knowledgeable regarding the many neurogenic, Competing interests neuromuscular junction, and myopathic causes of con- None. genital facial weakness as well as other unknown or Author details mixed causes to make an accurate diagnosis. Medical his- 1 Department of Genetics and Genomic Sciences, Icahn School of Medicine 2 tory, physical examination, and additional testing as indi- at Mount Sinai, New York, NY, USA. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. 3 Medical Genomics and Meta- cated are necessary to narrow in on the correct diagnosis. bolic Genetics Branch, National Human Genome Research Institute, National Depending on the cause of the congenital facial weak- Institutes of Health, Bethesda, MD, USA. 4 Department of Neurology, Boston 5 ness, confrmatory genetic testing may be available. Children’s Hospital, Harvard Medical School, Boston, MA, USA. Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA. 6 Howard Hughes Medical Institute, Chevy Chase, MD, USA. Webb et al. Orphanet J Rare Dis (2021) 16:158 Page 16 of 17

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