Overview of craniofacial clefts and holoprosencephaly

INTRODUCTION — Development of the face and cranium during embryogenesis is a complex and orchestrated process that involves cellular proliferation, differentiation, migration, and selective apoptosis. Facial clefts and holoprosencephaly (HPE) are conditions caused by the disturbance of these normal embryonic processes.

This topic gives an overview of facial clefts and HPE. It does not cover cleft lip and/or palate. Prenatal diagnosis and management of cleft lip and/or palate, other congenital anomalies of the head, and syndromes associated with craniofacial abnormalities are discussed in detail separately:

●(See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate".)

●(See "Congenital anomalies of the jaw, mouth, oral cavity, and pharynx".)

●(See "Congenital anomalies of the ear".)

●(See "Congenital anomalies of the larynx".)

●(See "Congenital anomalies of the nose".)

●(See "Congenital and acquired abnormalities of the optic nerve".)

●(See "Syndromes with craniofacial abnormalities".)

CRANIOFACIAL CLEFTS — Craniofacial clefts are deformations of the face and/or cranium caused by relative excesses or deficits of bone and/or soft tissue along linear anatomic planes [1,2].

Epidemiology — Although the exact incidence of craniofacial clefts is unknown, they are estimated to affect 1.4 to 4.9 newborns per 100,000 livebirths [1,3,4].

Embryology — More than one theory exists regarding the embryologic pathogenesis of craniofacial clefts. Fetal craniofacial development is a complex series of events that occurs between the third and eighth weeks of gestation. During the initial stages, five facial processes (one frontal, two maxillary, two mandibular) form and subsequently fuse (by the sixth week of gestation) to form the human face. The classic theory states that craniofacial clefts occur when the fusion process is disrupted. However, other theories propose that the pathogenesis is related to the infarction of primordial blood vessels, amniotic bands, failure of certain developmental zones of the face to develop completely, or errors in cellular migration, penetration, and differentiation [2].

Etiology — Although the precise etiology is unknown, multiple genetic and environmental factors may be involved. The environmental risk factors implicated include antenatal exposure to radiation, viral infections, metabolic abnormalities, and teratogenic compounds [2]. (See "Congenital anomalies: Causes".)

Classification of clefts — A classification system to describe the anatomic planes along which craniofacial clefts fall was first introduced in 1976 [1]. This classification system, which remains the standard, numbers clefts 0 through 14 and 30 based upon their location surrounding the orbit arranged in a counterclockwise direction. Clefts 0, 14, and 30 are located on the same vertical midline axis. Numbers 0 through 7 run inferior to the orbit (facial clefts) from medial to lateral, number 8 runs on the lateral portion of the orbit, and numbers 9 through 14 run superior to the orbit from lateral to medial (cranial clefts) (figure 1). Additionally, number 30 was assigned to a lower midline facial cleft involving the lower lip, chin, and mandible. The original intention was to further number mandibular paramedial clefts once identified; however, 15 through 29 were never assigned [5].

Clefts commonly involve both cranial and facial components and usually follow the same direction. Thus, clinicians should investigate the entire axis for additional malformation. When both occur together, the sum of the numbers assigned to each component involved will add up to 14 (eg, facial number 3 and cranial number 11). Locations of soft tissue and bone clefts do not always correspond exactly. Clefts tend to have greater soft tissue involvement when located medial to the infraorbital foramen and greater bony involvement when located lateral to this landmark [1]. Clefts may occur bilaterally but do not necessarily have an equal severity of each side. A common combination is bilateral clefts 6, 7, and 8, the physical findings associated with Treacher-Collins syndrome. Clefts 0 through 14 are described in the figure (figure 2). The most common clefts are described below.

Number 6 to 8 clefts — These lateral clefts tend to cause more bony destruction but less severe soft tissue defects compared with more medial clefts. Bony defects involve the zygomatic bone and mandible (figure 3). Varying soft tissue defects involving the ear may also be seen with the most lateral cleft, number 7. These clefts are most commonly present in patients with hemifacial microsomia and Treacher-Collins syndrome. (See "Syndromes with craniofacial abnormalities".)

Number 10 cleft — This cleft extends into the frontal bone near the middle one-third of the orbit and eyelid (figure 4). Inferolateral displacement of the orbit and globe are frequently present with significant defects. Orbital disfigurement may be caused by a mass effect due to a frontoorbital encephalocele, a defect in which the neural tube bulges into the orbit.

Number 14 cleft (frontonasal dysplasia) — In this cleft, the nose is often bifid. A midline encephalocele may be present, as well as telecanthus (figure 5). Although excessive distance between orbits may result from abnormal insertion of the canthal tendons, the bony orbits themselves are not excessively separated (hypertelorbitism) [6].

Problems associated with clefts

Airway/breathing — Defects involving the mandible may require respiratory support or tracheostomy placement.

Feeding and growth — Facial clefts may cause significant feeding difficulties and failure to thrive. Supplemental feeding through nasogastric or gastric feeding tubes may be required.

Vision — Clefts resulting in soft tissue deficiencies around the eye and eyelid may result in incomplete eye closure. Eye lubricants and/or surgical procedures may be required to provide protection to the eye.

Speech — Clefts involving the hard and/or soft palate may affect speech. Repair is recommended before 18 months of age.

Initial evaluation and referral — Most craniofacial clefts are diagnosed after birth. Defects require prompt consultation to a craniofacial surgeon and dedicated craniofacial team, if available. The craniofacial team generally consists of the following specialties: craniofacial surgery, neurosurgery, dentistry and/or orthodontics, speech therapy, psychology, otolaryngology, nutrition, ophthalmology, and clinical genetics. Additional diagnostic tests including radiographs and computed tomography (CT) scans may be required to better identify defects in bone, cartilage, and soft tissue to help make appropriate treatment recommendations. Genetic testing may also be warranted.

If a craniofacial cleft is suspected on prenatal ultrasound, a referral should be made to maternal-fetal medicine. Additional ultrasound evaluations may be required along with fetal magnetic resonance imaging (MRI) to further characterize the cleft, depending upon the severity. After the confirmed diagnosis of a craniofacial cleft, a referral to a dedicated craniofacial team should be promptly placed, as noted above. A neonatologist should be consulted if special precautions or services may be needed in the delivery room.

Treatment — The treatment of facial clefts can be complex and requires a multidisciplinary team [7]. Airway and breathing concerns should always be addressed first, providing supplemental oxygen or respiratory support if needed. Children who are unable to tolerate oral feeds may require nasogastric feeding or a surgically placed feeding tube.

The goals of reconstruction are to restore compromised skin, soft tissue, and bone in order to establish functional and aesthetic qualities to the face and cranium. Correction of encephaloceles, deficient corneal protection, or cleft lip deformities are addressed in the neonatal period, whereas other surgical procedures, orthognathic interventions, and revisional surgeries can be performed over the next several years and into adolescence.

The reconstructive process can be complicated. It often involves multistage procedures that consist of local flaps, tissue resection, fat injections, craniofacial osteotomies, cartilage and bone grafts, free flaps, tissue expansion, and techniques borrowed from other procedures, such as rhinoplasty and cleft lip/palate repair. Methods have been described to treat various Tessier clefts [1,8-10]. However, surgical plans must be individualized to the specific patient because there is a large degree of variability in presentation.

The prognosis of craniofacial clefts varies based upon the cleft severity, concurrent genetic syndromes, and additional anomalies.

HOLOPROSENCEPHALY — HPE is a developmental defect of the embryonic forebrain, or prosencephalon, that is commonly associated with midfacial defects. The defect results from incomplete development of central nervous system (CNS) structures and has a spectrum of presentations. There are three classic types (from the most to least severe CNS defects): alobar, semilobar, and lobar. In addition, there is a more recently described mild subtype, the middle interhemispheric (MIH) variant [11]. Severe forms are not compatible with life, but milder forms are potentially viable. These patients require a multidisciplinary approach to ensure both quality of life and survival.

Epidemiology — HPE is relatively rare. The overall prevalence in a multicenter study was 1.31 per 10,000 live and still births [12,13] and was reported in 1 out of 250 embryos leading to spontaneous abortions in another study [14].

Embryology — HPE results from incomplete development and separation of the midline CNS structures. In normal development, the disk-like neural plate invaginates to form a neural tube during the third embryonic week. Neural crest cells then organize along the neural tube and eventually move toward predetermined destinations. Following neural tube fusion at the midpoint, the process continues both rostrally and caudad to culminate in closure of rostral and caudal neuropores. Concurrently, the primordial brain divides into two hemispheres, and a frontal process takes form. When a disturbance of embryologic growth and development occurs at this stage, HPE may result.

Etiology — Although the exact etiology of HPE is not yet elucidated, the primary cause of the malformation is suspected to be heterogeneous, with both genetic and environmental components [15,16].

Multiple genes have been linked to HPE, including sonic hedgehog (SHH), zinc finger protein of the cerebellum 2 (ZIC2), sine oculis homeobox, drosophila, homolog of, 3 (SIX3), transforming growth factor beta-induced factor (TGIF), and others [17]. Chromosome abnormalities linked to HPE include trisomy 13, trisomy 18, and triploidy [16,18].

Environmental factors, such as maternal diabetes [19], retinoic acid [20], and drug and alcohol abuse [21] during early pregnancy, also have been implicated [22]. It is believed that the large number of possible combinations of these risk factor "hits" lead to the variable presentation of clinical severity [23].

Classification — HPE can present within a broad spectrum of clinical severity. A classification system divides HPE into subtypes based upon the degree of cerebral hemisphere separation: lobar, semilobar, and alobar [24]. An MIH variant of HPE has also been described [11].

●Lobar holoprosencephaly represents a mild form of the disease. Distinct right and left ventricles form, but cerebral continuity is present across the frontal cortex.

●Semilobar holoprosencephaly is distinguished by a partial separation of the forebrain.

●Alobar holoprosencephaly represents the most severe form, resulting from complete failure of the forebrain to divide into right and left hemispheres.

●The MIH variant is an unusual subtype of HPE in which the posterofrontal and parietal areas have midline continuity though the basal forebrain, and the anterior frontal lobes and occipital regions remain separated [25].

Clinical features — HPE represents a continuum of craniofacial and CNS defects. The severity of the facial defect generally correlates to the severity of the brain defect (figure 6). Very mild forms of HPE, or microform HPE, result in a spectrum of mild craniofacial anomalies with little to no CNS involvement or neurologic defects. Microform HPE may present inconspicuously with a single, central upper incisor. Mild forms of HPE, or MIH HPE, can present with microcephaly, microphthalmia, ocular hypotelorism, midfacial hypoplasia, and cleft lip with or without cleft palate [24,26]. Moderate to severe forms of HPE (lobar, semilobar, and alobar HPE) are associated with a greater degree of CNS involvement and more severe facial midline defects, such as a primitive nasal structure (proboscis), cyclopia (a single, midline eye), and midfacial clefting, as can be seen in the alobar subtype.

In addition, HPE (other than the microform) also is associated with some degree of intellectual disability or developmental delay because the malformations involve midline CNS structures. Other associated conditions include epilepsy, hydrocephalus, dystonia, movement disorder, autonomic dysfunction, and hypothalamic/pituitary dysfunction. The hypothalamic/pituitary dysfunction can manifest as arginine vasopressin deficiency (previously called central diabetes insipidus), growth hormone deficiency, adrenal hypoplasia, hypogonadism, or thyroid hypoplasia (table 1) [18,27]. Failure to thrive is common, especially in those severely affected. Feeding difficulties result from lethargy, seizures, axial hypotonia, poor suck and feeding abilities, oral-sensory dysfunction, vomiting, and aspiration risks [28].

Traditional subtypes are listed in order of severity, from least to most severe. All subtypes may exhibit relatively normal facial appearances with varying degrees of CNS and intellectual deficits. Incomplete penetrance and variable expressivity are typical of genetic forms of HPE.

Very mild HPE (microform HPE)

●Facial deformities – May exhibit a relatively normal facial appearance. It may also present as a single, central upper incisor; microcephaly; and narrow nasal bridge with a broad range of ophthalmologic anomalies [28].

●Effects on feeding, vision, and hearing – Depends upon the degree of facial involvement.

●Intellectual disability/developmental delay – Relatively no CNS involvement is present. Patients may exhibit minor developmental delay.

●Mortality – Microform HPE is often subclinical and has little to no effect on mortality.

Mild HPE (middle interhemispheric variant HPE)

●Facial deformities – May exhibit a relatively normal facial appearance. Patients may also present with closely spaced eyes and a depressed or narrow nasal bridge [28].

●Effects on feeding, vision, and hearing – Depends upon the degree of facial involvement.

●Intellectual disability/developmental delay – Patients may exhibit a range of developmental delays.

●Mortality – Mortality rates vary; however, long-term survival is possible in this mild form.

Moderate to severe HPE (lobar HPE, semilobar HPE)

●Facial deformities – A wide range of facial deformities are seen. Patients may exhibit a relatively normal facial appearance. They may also present with closely spaced eyes, a depressed nasal bridge, and a bilateral cleft lip with a medial process [28].

●Effects on feeding, vision, and hearing – Depends upon the degree of facial involvement.

●Intellectual disability/developmental delay – Patients may exhibit a range of developmental delays and intellectual deficits.

●Mortality – Approximately 50 percent of infants diagnosed with isolated lobar HPE will survive beyond 12 months of age [28].

Severe HPE (alobar HPE)

●Facial deformities – A wide range of facial deformities may be seen with the most severe deficits:

•Cyclopia – A single eye in a single orbit with a proboscis above the eye

•Cyclopia without the presence of a proboscis

•Ethmocephaly – Severe ocular hypotelorism with separate orbits and a proboscis in between the eyes

•Cebocephaly – Ocular hypotelorism with a single-nostril nose

Additional features may include absence of the premaxilla with a median cleft lip, ocular hypotelorism, and flat nose; bilateral cleft lip only; ocular hypotelorism only; or anophthalmia or microphthalmia. Patients may also exhibit a relatively normal facial appearance [28].

●Effects on feeding, vision, and hearing – Depends on the degree of facial involvement.

●Intellectual disability/developmental delay – Patients may exhibit a range of developmental delays and intellectual deficits. The most severe CNS deficits are seen in this subtype.

●Mortality – Infants with the most severe forms of alobar HPE, including cyclopia or ethmocephaly, typically do not survive beyond one week after birth. Approximately 50 percent of children with alobar HPE die between four to five months of age, and only 20 percent survive beyond the first year of life [28].

Referral — When HPE is suspected in utero, referral to maternal-fetal medicine should be performed for further evaluation. After confirmation of the diagnosis, referrals should be placed to a broad range of specialties depending on the clinical severity and availability. These may include the following: craniofacial surgery, neurosurgery, neurology, dentistry/orthodontics, speech therapy, clinical genetics, endocrinology, otolaryngology, ophthalmology, psychology, and nutrition specialists.

Diagnosis — Different imaging modalities are used to diagnose HPE depending on the severity of the condition and whether it is suspected prenatally or in the neonatal period. Patients with mild HPE are often not diagnosed until much later. In a series of 104 children with mild HPE, the mean age at diagnosis was not until four years of age, with 15 percent of patients diagnosed at 10 and 19 years of age [29].

Prenatal ultrasound (US) can detect the facial abnormalities that are seen with severe HPE, especially the alobar subtype, within the first trimester; however, milder forms of the condition may go unnoticed. Fetal magnetic resonance imaging (MRI) has been used to provide better characterization of the more subtle malformations identified on prenatal US during the third trimester of pregnancy and assists in appropriate referrals and recommendations [28].

In infants with suspected HPE, neuroimaging criteria have been established for the assessment of HPE. The imaging modality of choice is high-resolution MRI scans, which include thin-section image sequences in three orthogonal planes (axial, sagittal, and coronal) [27,29]. Imaging is important for diagnosis and case management because the severity of the brain malformation generally correlates with the degree of neurologic problems and life expectancy [11,30].

Management — Severe HPE is not compatible with life, and these children generally do not survive beyond early infancy. In such cases, referral to a clinical geneticist for comprehensive genetic assessment and counseling for the afflicted family is recommended to discuss the nature of the condition and the possibility of recurrence, which can vary from very low (<1 percent; eg, trisomy 13) to high (up to 50 percent if a parent has an autosomal-dominant genetic disorder; eg, SHH mutation) [31].

Milder forms of HPE are more compatible with life, and diagnosis should prompt a medical and genetic workup to rule out syndromic HPE, as well as the other associated conditions (eg, epilepsy, hydrocephalus, dystonia, movement disorder, autonomic dysfunction, and hypothalamic/pituitary dysfunction). The initial medical evaluation for patients with HPE may include serum electrolytes, cortisol, adrenocorticotropin hormone, thyroid-stimulating hormone, free T4, and insulin-like growth factor 1 (table 1) [27]. Chromosomal abnormalities are seen in approximately 25 to 50 percent of patients with HPE [28]. Chromosomal analysis is recommended in all cases and can be important in the management of neonates and infants with HPE. In a population-based case-control study, survival beyond one year of age was decreased in patients with cytogenetic abnormalities (2 percent versus 30 to 54 percent among patients without cytogenic abnormalities) [21]. (See "Evaluation of patients with polyuria" and "Diagnosis of growth hormone deficiency in children" and "Clinical manifestations and diagnosis of adrenal insufficiency in children" and "Approach to the patient with delayed puberty" and "Clinical features and detection of congenital hypothyroidism".)

Children with milder forms of HPE can have craniofacial defects, hydrocephalus, and/or feeding issues that may require surgical intervention in infancy. However, consideration must be given to the risks, benefits, and estimated life expectancy of the child. Alobar forms may not be compatible with life or present with a limited life expectancy. Milder forms of HPE, on the other hand, are more compatible with life, displaying a clinical spectrum with survival into adulthood possible. Thus, it is important that clinicians educate families about the spectrum of the disease and clinical outcomes.

The degree of patient care required generally differs based upon the severity of the condition. In many situations, a multidisciplinary approach is the best. Long-term cognitive and physical treatment is often necessary in these children with HPE. The Carter Neurocognitive Assessment tool is used for the assessment of performance and developmental growth of children with compromised language and motor skills including patients with HPE [32]. Physical and occupational therapy also may be helpful in patients with motor dysfunction.

Oral motor dysfunction is a frequent manifestation of HPE. Children may suffer from oropharyngeal dysphagia with an increased risk of aspiration. Patients may require occupational and speech evaluations. Supplemental nutrition through the placement of feeding tubes may ultimately be required. Additionally, poor CNS regulation may result in gastric and colonic dysmotility and gastroesophageal reflux requiring promotility medications and antireflux procedures.

Brain malformations may predispose patients to seizures. Antiepileptic medications and close neurology follow-up may be required. Hydrocephalus may also be present, necessitating the placement of ventriculoperitoneal shunts. Additional referrals to ophthalmology and otolaryngology may be indicated depending upon the clinical manifestations and severity of HPE.

Resources — The National Organization for Rare Disorders (NORD) provides information on HPE for patients and their families.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Syndromes with craniofacial anomalies".)

SUMMARY

●Craniofacial clefts and holoprosencephaly (HPE) occur when normal development of the fetal face and cranium is interrupted. (See 'Introduction' above.)

●The precise mechanism of craniofacial clefting is uncertain. Multiple environmental and genetic factors may contribute. (See 'Embryology' above.)

●According to the Tessier classification, facial clefts are numbered from 0 to 14, plus 30 (figure 1 and figure 2). Clefts have facial and/or cranial components. Clefts commonly involve both cranial and facial components and usually follow the same direction. Thus, clinicians should investigate the entire axis for additional malformation. (See 'Classification' above.)

●Clinically significant facial clefts include:

•Number 6 to 8 (occur in hemifacial microsomia and Treacher Collins syndrome) (figure 3)

•Number 10 (extend into the frontal bone near the middle one-third of the orbit and eyelid) (figure 4)

•Number 14 (median cleft face syndrome, frontonasal dysplasia) (figure 5)

●The reconstructive process for facial clefts can be complex and must be individualized to the clinical case. (See 'Treatment' above.)

●HPE results from incomplete development and septation of the midline central nervous system (CNS) structures and is commonly associated with midfacial defects. (See 'Embryology' above.)

●HPE has wide phenotypic variance and a broad spectrum of clinical severity, ranging from a primitive nasal structure and midline eye to mild hypotelorism (figure 6). (See 'Clinical features' above.)

●Outcomes for HPE vary based upon the severity of the malformation. The most severe forms are not compatible with life, and survival beyond early infancy is rare. Patients with the mildest forms of HPE may survive into adulthood. (See 'Management' above.)

●Referral to a team of specialists is indicated if craniofacial clefting and/or HPE is identified. (See 'Initial evaluation and referral' above and 'Referral' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Patrick Cole, MD; Larry H Hollier, Jr, MD; and Angela Volk, MD, who contributed to earlier versions of this topic review.