Facial Defects as Major Feature

Moebius Sequence

Sixth and Seventh Nerve Palsy

The basic features of Moebius sequence are mask-like facies with sixth and seventh cranial nerve palsy, usually bilaterally. Minimal diagnostic criteria include congenital nonprogressive facial palsy, abduction deficits, and full vertical motility. Necropsy cases implicate at least four modes of developmental pathology in the genesis of the problem. These are (1) hypoplasia to absence of the central brain nuclei, (2) destructive degeneration of the central brain nuclei (most common type), (3) peripheral nerve involvement, and (4) myopathy. Thus, Moebius sequence is a phenotype produced by multiple mechanisms. Both genetic and environmental factors have been implicated. The cause is unknown in most cases; however, classic Moebius sequence is virtually always a sporadic event.


  • Growth. Postnatal growth deficiency in cases with more extensive cranial nerve involvement or cleft palate.

  • Performance. Speech impediment; hearing loss, most frequently the result of chronic otitis media; intellectual and/or social delay (52%).

  • Craniofacial. Micrognathia, secondary to a neuromuscular deficit in early movement of the mandible leads to a U-shaped cleft palate or cleft uvula in one-third of cases (Robin sequence), ptosis, protruding auricle, expressionless facies.

  • Neurologic. Obligate sixth and seventh nerve palsy, more extensive cranial nerve involvement, including the third, fourth, fifth, ninth, tenth, and twelfth cranial nerves. In cases with more extensive cranial nerve involvement, the tongue may be limited in mobility and/or small.

  • Eyes. Refractive errors (42%), adduction deficit (83%), volitional Bell’s phenomenon (43%), intorsion with fixation (42%), near normal convergence, dysinnervation (41%) manifest as excessive tearing when eating or with attempted lateral gaze.

  • Limbs. Clubfoot (41%).

  • Other . Hypodontia, splenogonadal fusion, bilateral vocal cord paralysis, limb reduction defects, syndactyly, Poland anomaly (20%), Klippel-Feil sequence, scoliosis (14%).

Occasional Abnormalities

Hip dysplasia, arthrogryposis

Natural History

The majority of affected individuals are cognitively normal. Although autism was once thought to occur in 25% of cases, it is probably much less frequent than that. Intellectual disability has been estimated to occur in 10% to 15% of cases. The expressionless face and speech impediments create problems in acceptance and social adaptation, which have been demonstrated on standardized measures of child behavior. Studies of self-perception, however, document resilience in this population. Facial reanimation procedures are worthwhile to consider in affected individuals.

The Moebius sequence is most commonly a sporadic occurrence in an otherwise normal family. In most of those cases, insufficient blood supply to structures supplied by the developing primitive subclavian artery lead to the variable features seen in this disorder. Evidence that a number of affected individuals have been born to women who experienced events during pregnancy that could cause transient ischemic/hypoxic insults to the fetus suggests that this disorder may be owing to any event that interferes with the uterine/fetal circulation. Prenatal misoprostol exposure is an example. A number of single gene mutations have been documented in mostly atypical cases of Mobius sequence including TUBB3 (congenital fibrosis of the extraocular muscles (CFEOM) type 3 associated with vertical gaze deficiency), KIF21A (ophthalmoplegia, CFEOM1), HOXB1 (multiple affected family members with strabismus some of whom do not meet minimum diagnostic criteria), Other single genes implicated in sporadic cases include PLXND1 and REV3L.


  • Moebius PJ: Ueber engeborene doppelseitige Abducens-Facialis-Laehmung, Munch Med Wochenschr 35:91, 1888.

  • Henderson JL: The congenital facial diplegia syndrome: Clinical features, pathology, and aetiology: A review of sixty-one cases, Brain 62:381, 1939.

  • Bouwes-Bavinck JN, Weaver DD: Subclavian artery supply disruption sequence: Hypothesis of a vascular etiology for Poland, Klippel-Feil, and Möbius anomalies, Am J Med Genet 23:903, 1986.

  • Lipson AH, et al: Moebius syndrome: Animal model—human correlations and evidence for a brainstem vascular etiology, Teratology 40:339, 1989.

  • St. Charles S, et al: Mobius sequence: Further in vivo support for the subclavian artery supply disruption sequence, Am J Med Genet 47:289, 1993.

  • Vargas FR, et al: Prenatal exposure to misoprostol and vascular disruption defects—a case-control study, Am J Med Genet 95:302, 2000.

  • Strömland K, et al: Mobius sequence—a Swedish multidiscipline study, Eur J Paediatr Neurol 6:35, 2002.

  • Briegel W: Self-perception of children and adolescents with Mobius sequence. Res Dev Disabil 33:54, 2012.

  • MacKinnon S, et al: Diagnostic distinctions and genetic analysis of patients diagnosed with Moebius syndrome, Ophthalmology 121:1461, 2014.

  • Tomas-Roca L, et al: De novo mutations PLXND1 and REV3L cause Mobius syndrome, Nat Commun 6:7199, 2015.

  • K McClure P, et al: Mobius syndrome: A 35-year single institution experience, J Pediatr Orthop 37:e446, 2017.

  • Domantovsky I, et al: Long-term outcomes of smile reconstruction in Mobius syndrome, Plast Reconstr Surg 141:e868, 2018.

  • Briegel W, et al: Psychological adjustment of young subjects with Mobius sequence and their primary caregivers’ strain and life satisfaction: First longitudinal data, Res Dev Disabil 85:42, 2019.

    FIGURE 1

    Moebius sequence.

    A–E, Affected children at various ages showing high nasal bridge, micrognathia with limited mandibular movement, small mouth with downturned corners, expressionless facies with deficit of lateral gaze, and mild ptosis.

    D and E, From Strömland K, et al: Eur J Paediatr Neurol 6:35, 2002.

Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (Familial Blepharophimosis Syndrome)

Inner Canthal Fold, Lateral Displacement of Inner Canthi, Ptosis

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), predominantly a dysplasia of the eyelids, was described by Vignes in 1889; subsequently more than 200 families have been reported. Two clinical types have been delineated: type I, associated with premature ovarian failure, transmitted primarily through males; and type II, without a gonadal phenotype, transmitted by both males and females.


  • Eyes. Inverted inner canthal fold between the upper and lower lid (epicanthus inversus), short palpebral fissures, lateral displacement of inner canthi (telecanthus), ptosis of eyelids, fibrosis of the levator palpebrae muscle, strabismus (20%), amblyopia, eyebrows increased in their vertical height and arched, absent (52%) or hypoplastic (33%) lacrimal glands with reduced tear production, lateral displacement of the inferior punctum.

  • Nose. Low nasal bridge

  • Ears. Incomplete development, cupping.

  • Endocrine. Females with type I have menstrual irregularities or amenorrhea, infertility, and elevated gonadotropin levels, hypoplastic uterus, streak ovaries.

  • Other. Variable hypotonia in early life.

Occasional Abnormalities

Intellectual disability; cardiac defect; congenital hydronephrosis; ocular abnormalities, including nystagmus (6%), microphthalmia, microcornea, hypermetropia, trichiasis, colobomas of the optic disc, trabecular dysgenesis, congenital optic nerve hypoplasia, cataract, persistent fetal vasculature and nystagmus; endometrial carcinoma; granulosa cell tumor.

Natural History

Eyelid reconstruction is indicated for cosmetic reasons and to improve ocular function. Amblyopia is most frequently associated with asymmetric ptosis, although it also occurs when the ptosis is bilateral. Although most women with type I have a normal menarche and initially may be fertile, they soon develop ovarian resistance to gonadotropins or true premature ovarian failure. In at least one case primary ovarian failure has been documented in early childhood. Cryopreservation of eggs could be considered for females with type I BPES.


There is an autosomal dominant inheritance pattern for both type I and type II. Mutations in the forkhead transcription factor gene 2 ( FOXL2 ) located at 3q22.3, which have been documented in 72% of cases, are responsible for both types. Larger genomic rearrangements, including deletions involving FOXL2, account for 10% to 15%, and deletions outside the transcription unit of FOXL2 account for 5% of cases. Finally, cytogenetically visible apparently balanced translocations or interstitial deletions involving chromosome 3q22 account for approximately 2% of cases. In the majority of these latter cases, non-BPES features, such as intellectual disability, microcephaly, and growth delay, have been present, which suggests that the gene responsible for the additional features is located contiguous to FOXL2. It is important to distinguish between the types in order to provide counseling to affected individuals and their families relative to reproductive capabilities and menstrual irregularities, including amenorrhea in females with type I. With the exception of infertility in females, the two types are indistinguishable clinically. FOXL2 is a small, single exon gene containing a 14 copy alanine repeat. Mutations that truncate the protein product before the polyalanine tract tend to result in type I phenotypes, whereas, expansions of the polyalanine tract lead to type II phenotypes. Separating the two types requires a combination of molecular testing and careful family history. If the affected individual, either male or female, is a member of a family in which the disorder has been transmitted only through males, it is most likely type I, whereas if transmission has occurred through both males and females, it is type II.

For those individuals with BPES and intellectual disability who are negative for cytogenetic rearrangements involving FOXL2 testing for mutations in KAT6B and ADNP should be considered.


  • Vignes A: Epicanthus héréditaire, Rev Gen Ophthalmol (Paris) 8:438, 1889.

  • Sacrez R, et al: Le blépharophimosis compliqué familial: Étude des membres de la famille Blé, Ann Pediatr (Paris) 10:493, 1963.

  • Kohn R, Romano PE: Blepharoptosis, blepharophimosis, epicanthus inversus, and telecanthus—a syndrome with no name, Am J Ophthalmol 72:625, 1972.

  • Zlotogora J, Sagi M, Cohen T: The blepharophimosis, ptosis and epicanthus inversus syndrome: Delineation of two types, Am J Hum Genet 35:1020, 1983.

  • Dawson EL, et al: The incidence of strabismus and refractive error in patients with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). Strabismus 11:173, 2003.

  • Fokstuen S, et al: FOXL2 -mutations in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES): Challenges for genetic counseling in female patients, Am J Med Genet A 117A:143, 2003.

  • Beysen D, et al: FOXL2 mutations and genomic rearrangements in BPES, Hum Mutat 30:158, 2009.

  • Yu HC, et al: An individual with Blepharophimosis-Ptosis-Epicanthus Inversus syndrome (BPES) and additional features expands the phenotype associated with mutations in KAT6B. Am J Med Genet A 164A:950, 2014.

  • Takenouchi T, et al: Further evidence that a blepharophimosis syndrome phenotype is associated with a specific class of mutation in the ADNP gene, Am J Med Genet A 173A:1631, 2017.

  • Duarte AF, et al: Lacrimal gland involvement in blepharophimosis-ptosis-epicanthus inversus syndrome, Ophthalmology 124:399, 2017.

    FIGURE 1

    Blepharophimosis syndrome.

    A–C, Mother and infant son.

    Courtesy Dr. Lynne M. Bird, Rady Children’s Hospital, San Diego, California.

Ohdo/Say/Barber/Biesecker/Young-Simpson Syndrome

This disorder, often referred to as the Say/Barber/Biesecker/Young-Simpson (SBBYS) type of Ohdo syndrome was described in 1987 by Say and Barber. Over 50 cases now have been reported. It is one of five blepharophimosis-intellectual disability syndromes that Verloes clinically classified in 2006.


  • Performance. Severe global developmental delay. Marked delay in speech and language acquisition, with receptive better than expressive language. Hypotonia. Feeding and swallowing problems. Hearing difficulties, both sensorineural and conductive.

  • Facial. Blepharophimosis. Ptosis. Epicanthal folds. Mask-like face. Broad, flat nasal bridge, with bulbous nasal tip. Microstomia, with thin, tented upper lip. Micrognathia. Low-set ears with narrow external auditory canals.

  • Ocular. Variable defects, including myopia, strabismus, nystagmus, and optic disc hypoplasia.

  • Dental. Irregularities, including flat, pointed, or with gaps between the teeth and yellow discoloration. Delayed eruption of primary and secondary teeth. Retention of primary teeth.

  • Cardiac. Defects, including atrial and ventricular septal defects, patent ductus arteriosus, tetralogy of Fallot, right-sided aorta, pulmonary stenosis, and pulmonary atresia with hypoplastic right ventricle.

  • Skeletal. Joint hyperextensibility, including joints of hands and elbows. Stiffness of knees and ankles. Long, slightly broad thumbs and great toes. Overriding toes. Pes planus.

  • Other. Abnormal thyroid function resulting from agenesis/hypoplasia in about 20% of cases. Cryptorchidism.

Occasional Abnormalities

Cleft palate. Athetoid movements. Mirror images. Absence seizures. Periventricular and deep cerebral white matter lesions on MRI. Umbilical hernia. Vesicoureteric reflux on renal ultrasound. Ambiguous genitalia. Scoliosis. Talipes equinovarus. Pectus excavatum. Knee contractures. Postaxial polydactyly.

Natural history

Feeding difficulties and poor suck frequently occur in the neonatal period. Persistent drooling is common. Significant delay in walking is the rule. Communication skills are markedly delayed and range from only vocalization to short sentences. The majority of affected children have attended special education programs. With increasing age the chin becomes more pointed, the nose becomes larger, and the lower lip becomes more everted. Frequent respiratory infections have occurred in the first years of life. Affected children have been described as placid, affectionate, and able to enjoy a variety of activities. However, temper tantrums and self-injury occurred in some.


Mutations in the histone acetyltransferase gene, KAT6B , on chromosome 10q22 are responsible for this disorder. This disorder occurs sporadically in otherwise normal families. Recurrence risk is thus negligible.


Genitopatellar syndrome (GPS) has a clinically similar phenotype with a number of overlapping features. As opposed to the SBBYS phenotype, the classic features of GPS include severe large joint contractures, patellar abnormalities, and ambiguous genitalia. In addition, agenesis of the corpus callosum, hydronephrosis, and congenital heart defects occur more frequently. The facial phenotype of GPS is less severe and far less distinctive than in SBBYS. Both disorders are caused by mutations in KATB6 . However, mutations resulting in GPS occur in the proximal portion of the last exon, whereas mutations resulting in SBBYS occur either throughout the gene or more distally in the last exon.


  • Verloes A, et al: Blepharophimosis-mental retardation (BMR) syndromes: A proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one X-Linked and one autosomal recessive, Am J Med Genet 140A: 1285–1296, 2006.

  • Day R, et al: A clinical and genetic study of the Say/Barber/ Bieseker/Young-Simpson type of Ohdo syndrome, Clin Genet 74: 434–444, 2008.

  • Clayton-Smith J, et al: Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say/Barber/Biesecker variant of Ohno syndrome, Am J Hum Genet 89:675–681, 2011.

  • Campeau PM, et al: The KAT6B-related disorders genitopatellar syndrome and Ohno/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms, Hum Mutat 33:1520–1525, 2012.

  • Gannon T, et al: Further delineation of the KAT6B molecular and phenotype syndrome, Eur J Hum Genet 23: 1165–1170, 2015.

    FIGURE 1

    Facial images of an affected girl at 2 and 9 months of age. Very short palpebral fissures are evident bilaterally at 2 months. At 9 months the appearance is more of asymmetric ptosis, greater on the left. Note the low nasal bridge, anteverted and bulbous tip, long smooth philtrum, thin vermillion of the upper lip, and downturned corners of mouth. The cheeks are prominent and the retrognathia improved with age. The metopic suture has become very prominent at 9 months with some bitemporal narrowing. The face has an immobile mask-like appearance.

    FIGURE 2

    Both hands show long thumbs. Both lower limbs are abnormally positioned with fixed contractures at the hips and knees, bilateral contractures at the ankles, and abnormal foot positions with severe hallux valgus. The deep creases over both knees reflect the patella are absent. The first toes are retracted and somewhat long.

Oculocerebrofacial Syndrome, Kaufman Syndrome

Short Upslanting Palpebral Fissures, Blepharophimosis, Micrognathia

The first report of this condition was a 1971 paper describing four affected siblings with a distinctive pattern of malformation, including intellectual disability, microcephaly, upslanting palpebral fissures, microcornea, optic atrophy, preauricular skin tags, and migrognathia. Jurenka and Evans (1979) published a fifth case and suggested the name Kaufman oculocerebrofacial syndrome. Since the identification of the cause of this disorder in 2012, there have been numerous reports of patients suggesting that the condition is not as rare as the paucity of prior reports might suggest. To date roughly 36 patients have been described, most of whom have had molecular confirmation of the diagnosis.


  • Growth. Mild prenatal onset growth deficiency; microcephaly; postnatal growth deficiency, although final adult height may be normal.

  • Performance. Poor neonatal transition, feeding issues, hypotonia, intellectual disability, absent speech, seizures, sensorineural hearing loss, conductive hearing loss.

  • Craniofacial. Brachycephaly; blepharophimosis; ptosis; upslanting palpebral fissures; broad, flared eyebrows; epicanthal folds; long philtrum; small mouth; thin vermillion, micrognathia.

  • Eyes. Microcornea, microphthalmia, iris coloboma, pale optic disc, optic atrophy. Refractive errors; strabismus.

  • Ears. Preauricular tags, stenotic external auditory canals, small ears, protruding ears.

  • Nose. Broad nasal tip, short anteverted nose.

  • Dental. Small teeth.

  • Gastrointestinal. Gastroesophageal reflux, constipation.

  • Genitourinary. Cryptorchidism, hypospadias, clitoromegaly,

  • Musculoskeletal. Scoliosis.

  • Limbs. Long, thin hands; polydactyly; fifth finger clinodactyly; small distal phalanges; overlapping toes; camptodactyly.

  • Skin. Sparse scalp hair.

  • Imaging. Agenesis or hypoplasia corpus callosum, shallow sella turcica, Chiari I malformation, small pituitary, ectopic pituitary, hypoplastic vermis, vertical clivus, absent distal phalanges, wide ribs.

Occasional Abnormalities

Cleft palate, Robin sequence, high arched palate, bifid uvula, corneal dermoid cyst, absent terminal phalanges, absent nails, severe hallux varus, cardiac defect, hypertrophic cardiomyopathy, intestinal malrotation, diastasis of rectus muscles, renal defects, including cysts, vesicoureteral reflux, and dilated calyces

Natural History

Intellectual disability varies, but is usually severe to profound. Most infants have prolonged neonatal hospitalizations owing to respiratory issues (stridor and laryngomalacia) and feeding issues. A significant portion has a critical airway that needs aggressive management (tracheostomy or mandibular distraction). Milestones are delayed. Most affected individuals walk and develop self-help skills, but speech is severely delayed. Recurrent respiratory infections and persistent obstructive sleep apnea require ongoing management.


Inheritance is autosomal recessive. Consanguinity has been a risk factor in a quarter of families. Homozygous or compound heterozygous inactivating mutations in UBE3B cause this condition. UBE3B encodes a ubiquitin protein ligase E3B that is involved in protein turnover and ubiquitin-mediated signaling. One target of UBE3B is branched chain alpha-ketoacid dehydrogenase kinase ( BCKDK ), disruption of which perturbs multiple metabolic pathways potentially impacting the phenotype in these patients.


  • Kaufman RL, et al: An oculocerebrofacial syndrome, Birth Defects OAS 7:135, 1971.

  • Jurenka SB, et al: Kaufman oculocerebrofacial syndrome: Case report, Am J Med Genet 3:15, 1979.

  • Basel-Vanagaite L, et al: Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual disability syndrome, Am J Hum Genet 91:998, 2012.

  • Yilmaz R, et al: Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients, Am J Med Genet 176A:187, 2018.

  • Cheon S, et al: The ubiquitin ligase UBE3B , disrupted in intellectual disability and absent speech, regulates metabolic pathways by targeting BCKDK, PNAS 116:3662, 2019.

  • Galaretta CI, et al: Further phenotypic characterization of Kaufman oculocerebrofacial syndrome: Report of five new cases and literature review, Clin Dysmorphol 28:175, 2019.

    FIGURE 1

    A 3-year-old girl. Note epicanthal folds, upslanting palpebral fissures, flat face, downturned corners of mouth, smooth philtrum, and single transverse palmar crease

    FIGURE 2

    A and B , A 17-year-old young man. Note short, upslanting palpebral fissures with blepharoptosis, smooth philtrum, and arched eyebrows

Robin Sequence (Pierre Robin Syndrome)

Micrognathia, Glossoptosis, Cleft Soft Palate; Primary Defect—Early Mandibular Hypoplasia

The single initiating defect of this disorder may be hypoplasia of the mandibular area before 9 weeks in utero, allowing the tongue to be posteriorly located and thereby impairing the closure of the posterior palatal shelves that must “grow over” the tongue to meet the midline. The mode of pathogenesis is depicted to the right. The rounded contour of the “cleft” palate in some of these patients (see illustration) is compatible with this mode of developmental pathology and differs from the usual inverted V shape of most palatal clefts. The finding of a displaced tongue (in the palatal cleft rather than on the floor of the mouth) on prenatal MRI studies in fetuses later confirmed to have Robin sequence (RS) supports the hypothesis that the cleft palate in RS is a function of mechanical interference owing to abnormal tongue position secondary to micrognathia.

Birth prevalence of RS in the literature has varied between 1 in 3900 and 1 in 122,400. Most studies are hampered by definitional issues as to what constitutes RS. More rigorous investigations have suggested a birth prevalence of 1 in 5,600 (Netherlands) and 1 in 14,000 (Denmark).

The focus of management in the newborn period should be treatment of upper airway obstruction and feeding problems. Currently no consensus exists as to the best approach to management. The tongue-based airway obstruction may require, in order of increasing invasiveness, prone positioning, nasal pharyngeal airway, nasal esophageal intubation, lip-tongue adhesion, mandibular distraction, and tracheostomy. Airway obstruction can lead to hypoxia, cor pulmonale, failure to thrive, and cerebral impairment. Mortality rates as high as 30% have been reported. Infants with RS as part of a syndrome are at much higher risk of death than those with isolated RS. Significant airway obstruction may develop over the first 2 months of life. Therefore, affected children should be monitored carefully during that period, focusing on the obstruction pathogenesis of the apnea and airway concerns in the condition. In that significant hypoxia may occur without obvious clinical signs of obstruction, serial polysomnography may be helpful over the first month to identify infants at significant risk. Feeding problems requiring nasogastric tube feeding or gastrostomy are common

In 38% of cases, the Robin sequence occurs in otherwise normal individuals, in whom the prognosis is very good if they survive the early period of respiratory obstruction. However, this disorder commonly occurs as one feature in a multiple malformation syndrome of genetic etiology, the most common of which is Stickler syndrome. The 62% of cases with a syndrome include 9% with a chromosome anomaly, 29% with a Mendelian disorder (half of whom have Sticker syndrome), and 24% undiagnosed. The fact that accurate diagnosis of a genetic syndrome is often difficult in the newborn period highlights the need for longitudinal follow-up of affected children.


  • Dennison WM: The Pierre Robin syndrome, Pediatrics 36:336, 1965.

  • Latham RA: The pathogenesis of cleft palate associated with the Pierre Robin syndrome, Br J Plast Surg 19:205, 1966.

  • Hanson JW, Smith DW: U-shaped palatal defect in the Robin anomalad: Developmental and clinical relevance, J Pediatr 87:30, 1975.

  • Paes EC, et al: Birth prevalence of Robin sequence in the Netherlands from 2000-2010: A retrospective population-based study in a large Dutch cohort and review of the literature, Am J Med Genet A 167A:1972, 2015.

  • Basart H, et al: Etiology and pathogenesis of Robin sequence in a large Dutch cohort, Am J Med Genet A 167A:1983, 2015.

  • Gomez O, et al: Pierre Robin sequence: An evidence-based treatment proposal, J Craniofac Surg 29:332, 2018.

  • Resnick CM, et al: Pathogenesis of cleft palate in Robin sequence: Observations from prenatal magnetic resonance imaging, J Oral Maxillofac Surg 76:1058, 2018.

  • Logjes RJH, et al: Mortality in Robin sequence: Identification of risk factors, Eur J Pediatr 177:781, 2018.

  • Resnick CM, et al: Early management of infants with Robin sequence: An international survey and algorithm, J Oral Maxillofac Surg 77:136, 2019.

    FIGURE 1

    A, Mode of pathogenesis of the Robin sequence. B, Note the severe micrognathia. C, Note the unusual rounded shape to palatal “cleft” in a patient with the Robin sequence, which is compatible with the incomplete closure of the palate having been secondary to the posterior displacement of the tongue.

Cleft Lip Sequence

Primary Defect—Closure of Lip

By 35 days of uterine age, the lip is normally fused, as illustrated in Figure 1 . A failure of lip fusion, as shown, may impair the subsequent closure of the palatal shelves, which do not completely fuse until the eighth to ninth week. Thus, cleft palate is a frequent association with cleft lip. Other secondary anomalies include defects of tooth development in the area of the cleft lip and incomplete growth of the ala nasi on the side of the cleft. There may be mild ocular hypertelorism, the precise reason for which is undetermined. Tertiary abnormalities can include poor speech and multiple episodes of otitis media, conductive hearing loss, and malocclusion.

Etiology and Recurrence Risk Counseling

The cause of this disorder is usually unknown. It is more likely to occur in males. The highest birth prevalence is in Asians and Native Americans (1 in 500), followed by Europeans (1 in 1000), and the lowest prevalence is in populations of African descent (1 in 2500). The more severe the defect is, the higher the recurrence risk is for future siblings. For a unilateral defect, the recurrence risk is 2.7%; for bilateral defect, it is 5.4%. The following are the general risk figures: unaffected parents with one affected child, 4% for future siblings; unaffected parents with two affected children, 10% for future siblings. If either the mother or father is affected, the risk for offspring is 4%. An affected parent with one affected child has a 14% risk for future offspring with the defect. As many as 15% of infants surviving the newborn period with cleft lip, with or without cleft palate and 42% of those with cleft palate alone have the defect as part of a broader pattern of altered morphogenesis. One should identify such individuals before using the previously mentioned figures for recurrence risk counseling. In addition, the underlying diagnosis may well have an impact on prognosis.


The identification of more than 20 common genetic risk variants for cleft lip/palate through genome-wide association studies and single nucleotide polymorphism heritability estimates support a polygenic threshold model of inheritance. Philtral width appears to be a relevant facial phenotype. In addition, prenatal exposure to valproic acid, maternal smoking and alcohol, and mycophenolate mofetil have been identified as environmental factors associated with cleft lip with or without cleft palate. The American Cleft Palate-Craniofacial Association has published parameters of care for individuals with facial clefts


  • Bixler D: Heritability of clefts of the lip and palate, J Prosthet Dent 33:100, 1975.

  • Carter CO, et al: A three generations family study of cleft lip with or without cleft palate, J Med Genet 19:246, 1982.

  • Shprintzen RJ, et al: Anomalies associated with cleft lip, cleft palate, or both, Am J Med Genet 20:585, 1985.

  • Jones MC: Facial clefting: Etiology and developmental pathogenesis, Clin Plast Surg 20:599, 1993.

  • Dixon MJ, et al: Cleft lip and palate: Understanding genetic and environmental factors, Nat Rev Genet 12:167, 2011.

  • Howe LJ, et al: Investigating the shared genetics of non-syndromic cleft lip/palate and facial morphology, PLOS Genet 14:e1007501, 2018.

    FIGURE 1

    Cleft lip sequence.

    Left, Normal embryo of 35 days. Right, Spontaneously aborted 35-day embryo with hypoplasia of the left lateral nasal swelling and, therefore, a cleft lip. 1, Lateral nasal swelling; 2, maxillary swelling; 3, medial nasal swelling; 4, nares; 5, mandibular swelling.

    Left and right, Courtesy Professor G. Töndury, University of Zurich

    FIGURE 2

    A–D, All gradations of cleft lip and its consequences occur, from an isolated unilateral cleft lip to a widely open cleft with secondary consequences of cleft palate, flared ala nasi, and mild ocular hypertelorism.

Van der Woude Syndrome (Lip Pit–Cleft Lip Syndrome)

Lower Lip Pit(s), with or without Cleft Lip, with or without Missing Second Premolars

Originally reported by Van der Woude in 1954, this disorder is the most common multiple malformation syndrome associated with cleft lip, with or without cleft palate, and accounts for roughly 2% of all cases. The incidence of Van der Woude syndrome (VdWs) is estimated between 1 in 35,000 to 1 in 100,000 births.


  • Craniofacial. Lower lip pits (80%); hypodontia, missing central and lateral incisors, canines, or bicuspids; cleft lip, with or without cleft palate, cleft palate alone, submucous cleft palate, cleft uvula.

Occasional Abnormalities

Oral synechiae, tongue-palate fusion, toe syndactyly, pyramidal fold of skin overlying nail of hallux, cryptorchidism.

Natural History

Surgical removal of the fistulas, which represent small accessory salivary glands or possibly ectopic parotid tissue, is recommended because they may produce a watery mucoid discharge that can be a nuisance for the individual. Missing permanent teeth are common. Intelligence and growth are normal. The American Cleft Palate-Craniofacial Association has published parameters of care for individuals with facial clefts.


This disorder has an autosomal dominant inheritance pattern. Mutations in or rarely deletions of interferon regulatory factor 6 ( IRF6 ), which is mapped to chromosome 1q32.2, account for 72% of cases. Mutations in IRF6 lead not only to Van der Woude syndrome, but also to the popliteal pterygium syndrome. Both disorders have been observed in the same family. Mutations in grainy head-like 3 ( GRHL3) , mapped to chromosome 1p36.11, account for another roughly 10% of VdWs cases. Cleft lip, with or without cleft palate, is twice as frequent as cleft palate in individuals with mutations in IRF6 , whereas, cleft palate is the more common phenotype in individuals with mutations in GRHL3 . If intellectual disability is present, search for a larger deletion on chromosome 1 encompassing one of these genes.


Jun 28, 2021 | Posted by in PEDIATRICS | Comments Off on Facial Defects as Major Feature

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