There are thousands of craniofacial disorders, each with a different etiology. All cases of orofacial clefts have an underlying genetic cause, ranging from multifactorial with an underlying genetic predisposition to chromosomal and single-gene etiologies. More than 50% of cases of Pierre Robin sequence are syndromic and 25% of craniosynostoses are syndromic. Clinical genetics evaluation is important for each patient with a craniofacial condition to make a proper diagnosis, counsel the family, and assist in management. This is an overview of the major components of the clinical genetics evaluation with a review of many syndromes associated with craniofacial disorders.
Key points
- •
Every child born with a craniofacial disorder should be evaluated by a clinical geneticist.
- •
Many craniofacial disorders have a genetic etiology, and large variety of genetic testing is available for testing affected individual and family members.
- •
Although many genetic disorders are common, many patients present with rare or unique conditions requiring specialized genetics evaluations and tests.
- •
All children with craniofacial disorders should be managed by an interdisciplinary craniofacial or cleft team.
Introduction
Congenital anomalies and disorders are those conditions that are present at birth and that require some level of medical intervention. These conditions occur in approximately 3% to 5% of all live births. Craniofacial conditions, including orofacial clefts, craniosynostoses, the mandibulofacial dysostoses, and craniofacial macrosomia, are among the most common birth congenital anomalies. Many of these conditions have a genetic etiology (chromosomal, single-gene disorders, or epigenetic mutation) or may be caused by teratogens. Because of this, it is important for each child born with a craniofacial condition to be evaluated and followed by a medical geneticist. The American Cleft Palate-Craniofacial Association in their Standards for Cleft Palate and Craniofacial Teams states, “The Team also must demonstrate access to refer to a neurosurgeon, an ophthalmologist, a radiologist, and a geneticist.” The role of the medical geneticist is to assist in making a diagnosis of any known genetic disorder or syndrome, assist families and craniofacial team members in understanding the natural history of any syndrome, and ensure that additional medical evaluations and interventions are performed as indicated. There are thousands of different causes for craniofacial conditions. Identifying the etiologies is important for understanding the cause of a particular condition and influencing the management of a particular disorder. Also, craniofacial conditions are chronic conditions and follow-up evaluations with a medical geneticist should be encouraged.
Introduction
Congenital anomalies and disorders are those conditions that are present at birth and that require some level of medical intervention. These conditions occur in approximately 3% to 5% of all live births. Craniofacial conditions, including orofacial clefts, craniosynostoses, the mandibulofacial dysostoses, and craniofacial macrosomia, are among the most common birth congenital anomalies. Many of these conditions have a genetic etiology (chromosomal, single-gene disorders, or epigenetic mutation) or may be caused by teratogens. Because of this, it is important for each child born with a craniofacial condition to be evaluated and followed by a medical geneticist. The American Cleft Palate-Craniofacial Association in their Standards for Cleft Palate and Craniofacial Teams states, “The Team also must demonstrate access to refer to a neurosurgeon, an ophthalmologist, a radiologist, and a geneticist.” The role of the medical geneticist is to assist in making a diagnosis of any known genetic disorder or syndrome, assist families and craniofacial team members in understanding the natural history of any syndrome, and ensure that additional medical evaluations and interventions are performed as indicated. There are thousands of different causes for craniofacial conditions. Identifying the etiologies is important for understanding the cause of a particular condition and influencing the management of a particular disorder. Also, craniofacial conditions are chronic conditions and follow-up evaluations with a medical geneticist should be encouraged.
The genetics evaluation
The purpose of the genetics evaluation is to
- •
Make a diagnosis
- •
Characterize natural history
- •
Establish appropriate follow-up evaluations and testing
- •
Determine recurrence risk and potential genetic testing for family
- •
Provide genetic counseling for family
Ideally, the genetics evaluation should be performed as early as possible, often soon after birth. Given the technical advances in prenatal diagnosis, prenatal genetic evaluation has become a common occurrence. The genetics evaluation differs from the typical medical evaluation with greater emphasis on prenatal and family histories.
Prenatal Evaluation
Congenital craniofacial conditions begin in utero. Therefore, obtaining a comprehensive pregnancy history is essential to understanding etiology, especially with regard to teratogen exposure, maternal illness, and prenatal testing. Teratogens are substances that interfere with normal embryologic and fetal development. Teratogens include medications and drugs, high-dose radiation, viruses, and maternal illnesses.
Maternal illnesses that are known to cause craniofacial anomalies are diabetes and maternal phenylketonuria. Women with diabetes, both type 1 diabetes mellitus and type 2 diabetes mellitus, have least a 2-fold risk for having a child with birth defects, the greatest risks associated with type 1 diabetes mellitus. The major birth defects are renal, vertebral, brain, and craniofacial anomalies. Craniofacial anomalies include cleft lip, cleft palate (CP), and Pierre Robin sequence (PRS). In my institution, maternal diabetes is among the most common causes of cleft lip with or without CP (CLP) and CP. Women who have phenylketonuria are unable to properly metabolize the amino acid phenylalanine. If an affected woman does not follow a phenylalanine-restricted diet, the elevated levels of the metabolites of phenylalanine can cause multiple anomalies, including microcephaly, ear anomalies, congenital heart defects, and CP. Maternal hyperthyroidism and Graves disease have been associated with neonatal craniosynostosis.
Prenatal testing is commonly performed, especially fetal ultrasound. Ultrasound is performed in midtrimester in most pregnancies in the United States. Cleft lip can be identified with routine ultrasound in approximately 75% of cases and diagnosis approaches 100% with high-resolution ultrasound. It is more difficult to diagnose CP by ultrasound; however, micrognathia and PRS can be diagnosed prenatally. For more complex cases, especially with those with multiple anomalies, fetal MRI scans are performed at several high-risk centers and can be useful for assessing severity of fetal structural and brain anomalies and have a direct impact on pregnancy management ( Fig. 1 ).
If fetal anomalies are suspected, prenatal genetic testing should be considered. Invasive testing includes amniocentesis, which can be performed from 14 weeks’ gestation to term, and chorionic villus sampling can be performed at 12 weeks’ gestation. These procedures are usually performed to obtain chromosome analysis, chromosomal microarray, fluorescence in situ hybridization (FISH), or single-gene sequencing analysis.
Teratogens
Teratogens are those exogenous substances or physical agents, which, if there is fetal exposure, can cause birth defects. Many teratogens cause craniofacial anomalies. These include but are not limited to
- •
Physical agents – amniotic bands, radiation
- •
Infectious agents
- •
Medications
- •
Maternal illnesses
- •
Tobacco
- •
Alcohol
- •
Toluene (solvent for glues and spray paints)
- •
Cocaine
Alcohol is a commonly used and potent teratogen. Exposed children are at risk for many serious birth defects, the most common being developmental delay and intellectual disability. Fetal alcohol syndrome and fetal alcohol spectrum disorder are associated with a large number of birth defects. Dysmorphic facial features are common as are microcephaly, brain anomalies, holoprosencephaly, limb anomalies, short stature, and behavior disorders. Craniofacial anomalies include CLP, CP, and PRS.
Isotretinoin is a medication prescribed for cystic acne. Although this is an extremely effective medication for treatment of acne, it is a potent teratogen. Isotretinoin can cause multiple anomalies, including microcephaly, brain anomalies, microtia, absent auditory canal, hearing loss, and congenital heart defects.
Valproic acid is an anticonvulsant with significant teratogenicity. This medication causes neural tube defects in approximately 1% of children exposed in utero. Other reported findings include facial dysmorphism, microcephaly, developmental delay and cognitive impairment, CP, and metopic craniosynostosis ( Fig. 2 ). Diphenyl hydantoin is another anticonvulsant that is teratogenic. It is associated with short stature, developmental disabilities, distal digital and nail hypoplasia, and craniofacial anomalies, including CLP and CP.
Methotrexate is used to treat malignancies, autoimmune disorders, molar pregnancies, and tubal pregnancies. It acts as a folic acid antagonist and interferes with nucleic acid synthesis (thymidine) and, therefore, is highly cytotoxic. Because of this, methotrexate is a potent teratogen and can cause multiple birth defects, including CLP, CP, craniosynostosis, digital anomalies, microcephaly, brain anomalies, and developmental disabilities.
Cigarette smoking, in addition to causing intrauterine growth restriction, can also cause birth defects. There is an association between cigarette smoking and gastroschisis. Cigarettes have also been shown to cause CLP and CP. It is estimated that 6.1% of oral clefts can be attributed to smoking during pregnancy. In addition, several genes have been identified, which have been associated with risk for CLP in women who smoke during pregnancy.
Medical History
Obtaining a comprehensive history is essential for genetic diagnosis. Data should include birth history, including length of gestation, birth weight, length, and head circumference. Any hospitalizations and surgeries should also be recorded as well as significant illnesses. Information regarding feeding and growth is also important, especially to establish if feeding problems are related to a CP or craniofacial anomaly or perhaps caused by underlying neurologic or other structural anomalies, such as a heart defect. Many genetic disorders, especially chromosomal conditions, are associated with poor growth.
Developmental history also gives important clues to diagnosis and management. Major parameters of development include speech and language development, gross motor skills, fine motor skills and personal–social development. For patients with craniofacial disorders, speech and language delays may indicate hearing deficits, whether from middle ear effusions with recurrent otitis media or possibly other structural neurologic problems causing conductive and/or sensorineural deafness. See Box 1 for essential components of the genetics medical history.
History of present illness
- •
Gestational age
- •
Type of delivery and complications
- •
Birth parameters: weight, length, and head circumference
- •
Other congenital anomalies or major illnesses
- •
Neonatal complications
- •
Early feeding and growth
Pregnancy history
- •
Maternal illnesses
- •
Maternal medications
- •
Exposure to other substance (alcohol, cigarettes, and history of substance abuse)
- •
Prenatal genetic testing (maternal screening tests, ultrasounds, and fetal chromosome or genetic testing)
Past medical history
- •
Major illnesses
- •
Hospitalizations
- •
Surgeries
- •
Feeding, nutrition, and growth
- •
Prior medical specialty evaluations
Comprehensive review of systems
- •
Ten-system review
- •
Overall health assessment
Developmental history
- •
Early developmental milestones
- •
Therapeutic interventions (early intervention, speech, physical, and occupational therapies)
- •
School performance
- •
Developmental and neuropsychological evaluations
Family history
- •
Four-generation pedigree
- •
Birth defects
- •
Pregnancy losses (miscarriages and stillbirths)
- •
Infant, childhood, and early adult deaths
- •
Infertility
- •
Consanguinity
Family History
A family history is an essential component of a genetics evaluation. Information from family history can provide information regarding hereditary disorders and birth defects. A pedigree is constructed, which is a pictorial representation of the family history. Usually information for at least 3 generations is obtained ( Fig. 3 ). Family history should include information about
- •
Birth defects
- •
Consanguinity
- •
Pregnancy loss (miscarriages and stillbirths)
- •
Developmental delay and intellectual disability
- •
Early or unexpected deaths and causes (if known)
- •
Mental illness and psychiatric disorders
- •
Early or unusual cancers
- •
Blindness
- •
Deafness
- •
Chromosome disorders
Physical Examination
A physical examination is an important component of any medical evaluation. The medical genetics physical examination differs from the typical physical examination because in addition to looking for typical findings, the genetics evaluation focuses on looking for atypical or dysmorphic physical features, which may give clues to a genetic or other syndromic disorder or possible etiology. Box 2 outlines many of the features that may be seen. Any physical examination should include growth parameters, height, weight, and head circumference and should be accompanied by growth percentiles and z scores. These data are essential for diagnosis of short stature, microcephaly, and failure to thrive, all of which may give critical clues to causes of craniofacial disorders and diagnoses.
- •
Growth parameters – including z scores and growth trends on standardized charts
- ○
Height
- ○
Weight
- ○
Head circumference
- ○
Arm span
- ○
Upper to lower segment ratios (for disproportionate short stature)
- ○
- •
Skin
- ○
Birth marks
- ○
Hemangiomas
- ○
Hyperpigmented or hypopigmented macules
- ○
Hair – alopecia, texture, or hypertrichosis
- ○
Nails – missing nails or dysplastic nails
- ○
- •
Head/craniofacial
- ○
Cranial shape – evidence of craniosynostosis, ridging of sutures, or plagiocephaly
- ○
Fontanelles
- ○
Inner canthal, interpupillary, and outer canthal distances (hypertelorism and hypotelorism)
- ○
Facial asymmetry
- ○
Palpebral fissures – length and epicanthic folds
- ○
Ear position – low set and posteriorly rotated
- ○
Ear shape, microtia, and anotia
- ○
External auditory canal (stenosis and atresia)
- ○
Preauricular skin tags or fistulae (ear pits)
- ○
Eye examination – red reflex, iris colobomas, epibulbar dermoids, extraocular movements, nystagmus, and ptosis
- ○
Nose – short, anteverted nares, shape of nasal tip, and flat or prominent nasal bridge
- ○
Upper lip – clefting, unilateral, bilateral, and midline
- ○
Lower lip – clefting and lip pits
- ○
Palate – clefting (V-shaped or U-shaped), bifid uvula, and SMCP
- ○
Dentition – abnormally shaped teeth and missing teeth
- ○
Tongue – lobulations, microglossia or macroglossia, and asymmetry
- ○
Oral synechiae
- ○
Mandible – micrognathia, asymmetry, and ankylosis
- ○
- •
Neck
- ○
Masses
- ○
Torticollis
- ○
Branchial clefts or cysts
- ○
- •
Chest
- ○
Symmetry
- ○
Chest size and shape
- ○
Lung auscultation
- ○
Intercostal and subcostal retractions
- ○
Pectus deformities
- ○
- •
Cardiovascular
- ○
Heart murmurs
- ○
Pulses (upper and lower extremities)
- ○
- •
Abdomen
- ○
Organomegaly
- ○
Masses
- ○
Bowel sounds
- ○
- •
Genitalia — male
- ○
Penis size
- ○
Hypospadias
- ○
Testes – cryptorchidism and testicular size
- ○
- •
Genitalia – female
- ○
Labial adhesions and fusion
- ○
Vaginal discharge
- ○
- •
Musculoskeletal
- ○
Limb deformities
- ○
Brachydactyly
- ○
Clinodactyly (incurving of fifth finger)
- ○
Contractures
- ○
Joint hypermobility
- ○
Syndactyly
- ○
Polydactyly
- ○
Broad thumbs and halluces
- ○
Scoliosis
- ○
- •
Neurologic
- ○
Muscle tone (hypertonia or hypotonia)
- ○
Strength
- ○
Gait
- ○
Cranial nerve abnormalities (facial palsy, hearing loss, abnormal eye movements)
- ○
Laboratory Analysis
There are more than 1000 different disorders that can cause craniofacial anomalies, CLP, and CP. The prenatal, medical, and family histories and the physical examination often give clues as to the specific diagnosis; it then becomes important to confirm the diagnosis if a genetic etiology is suspected. In an analysis of children born with CLP or CP at Cincinnati Children’s Hospital Medical Center, chromosomal anomalies were among the most common group of genetic conditions associated with orofacial clefts ( Fig. 4 ). There was no clustering of specific chromosome disorders, but several chromosome conditions are associated with CLP and CP, including trisomy 13, trisomy 18, and Wolf-Hirschhorn syndrome (deletion of the short arm of chromosome 4). Velocardiofacial syndrome, or deletion 22q11.2 syndrome, is caused by a microdeletion of the long arm of chromosome 22 and can be diagnosed with a specific fluorescent-tagged DNA sequence, which hybridizes to the specific sequence of chromosome 22 by a test, FISH. In 22q11.2 deletion syndrome, 1 of the 2 chromosome 22 homologues has a deletion of this critical region ( Fig. 5 ). Standard chromosome analysis is helpful for many conditions with additional or missing chromosomes or for identifying large chromosomal rearrangements. Chromosomal microarray is a more recently developed test that not only can identify large chromosomal rearrangements but also is able to identify small submicroscopic rearrangements. Microarray has many advantages over routine chromosome analysis, including the ability to identify rare chromosomal rearrangements and increase yield of diagnoses.
