Facial Defects as Major Feature

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.

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.

Etiology

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.

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.

Etiology

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.

Comment

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.

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.

Etiology

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.

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.

Comment

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

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.

Etiology

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.