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Craniofacial cleft
Craniofacial cleft
Craniofacial cleft
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A facial cleft is an opening or gap in the face, or a malformation of a part of the face. Facial clefts is a collective term for all sorts of clefts. All structures like bone, soft tissue, skin etc. can be affected. Facial clefts are extremely rare congenital anomalies. There are many variations of a type of clefting and classifications are needed to describe and classify all types of clefting. Facial clefts hardly ever occur isolated; most of the time there is an overlap of adjacent facial clefts.[1]

Classifications

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There are different classifications about facial clefts. Two of the most used classifications are the Tessier classification[2] and the Van der Meulen classification.[3] Tessier is based on the anatomical position of the cleft and Van der Meulen classification is based on the embryogenesis.

Tessier classification

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Tessier classification. Left: boney clefts, Right: Soft tissue clefts.

In 1976 Paul Tessier published a classification on facial clefts based on the anatomical position of the clefts. The different types of Tessier clefts are numbered 0 to 14. These 15 different types of clefts can be put into 4 groups, based on their position:[4] midline clefts, paramedian clefts, orbital clefts and lateral clefts. The Tessier classification describes the clefts at soft tissue level as well as at bone level, because it appears that the soft tissue clefts can have a slightly different location on the face than the bony clefts.[citation needed]

Midline clefts

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The midline clefts are Tessier number 0 ("median craniofacial dysplasia"), number 14 (frontonasal dysplasia), and number 30 ("lower midline facial cleft", also known as "median mandibular cleft"). These clefts bisect the face vertically through the midline. Tessier number 0 bisects the maxilla and the nose, Tessier number 14 comes between the nose and the frontal bone. The Tessier number 30 facial cleft is through the tongue, lower lip and mandible. The tongue may be absent, hypoplastic, bifid, or even duplicated.[5] People with this condition may be tongue-tied.[5]

Paramedian clefts

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Tessier number 1, 2, 12 and 13 are the paramedian clefts. These clefts are quite similar to the midline clefts, but they are further away from the midline of the face. Tessier number 1 and 2 both come through the maxilla and the nose, in which Tessier number 2 is further from the midline (lateral) than number 1. Tessier number 12 is in extent of number 2, positioned between nose and frontal bone, while Tessier number 13 is in extent of number 1, also running between nose and forehead. Both 12 and 13 run between the midline and the orbit.[citation needed]

Orbital clefts

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Bilateral number 4 orbital clefts
Partial 3-11 orbital cleft

Tessier number 3, 4, 5, 9, 10 and 11 are orbital clefts. These clefts all have the involvement of the orbit. Tessier number 3, 4, and 5 are positioned through the maxilla and the orbital floor. Tessier number 9, 10 and 11 are positioned between the upper side of the orbit and the forehead or between the upper side of the orbit and the temple of the head. Like the other clefts, Tessier number 11 is in extent to number 3, number 10 is in extent to number 4 and number 9 is in extent to number 5.

Lateral clefts

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The lateral clefts are the clefts which are positioned horizontally on the face. These are Tessier number 6, 7 and 8. Tessier number 6 runs from the orbit to the cheek bone. Tessier number 7 is positioned on the line between the corner of the mouth and the ear. A possible lateral cleft comes from the corner of the mouth towards the ear, which gives the impression that the mouth is bigger. It's also possible that the cleft begins at the ear and runs towards the mouth. Tessier number 8 runs from the outer corner of the eye towards the ear. The combination of a Tessier number 6-7-8 is seen in the Treacher Collins syndrome. Tessier number 7 is more related to hemifacial microsomia and number 8 is more related to Goldenhar syndrome.

Van der Meulen classification

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Van der Meulen classification divides different types of clefts based on where the development arrest occurs in the embryogenesis. A primary cleft can occur in an early stage of the development of the face (17 mm length of the embryo). The developments arrests can be divided in four different location groups: internasal, nasal, nasalmaxillar and maxillar. The maxillar location can be subdivided in median and lateral clefts.

  • Internasal dysplasia
    Internasal dysplasia
  • Nasal dysplasia
    Nasal dysplasia
  • Nasomaxillary dysplasia
    Nasomaxillary dysplasia
  • Maxillary dysplasia
    Maxillary dysplasia

Internasal dysplasia

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Internasal dysplasia is caused by a development arrest before the union of the two nasal halves. These clefts are characterized by a median cleft lip, a median notch of the cupid's bow or a duplication of the labial frenulum. Besides the median cleft lip, hypertelorism can be seen in these clefts. Also sometimes there can be an underdevelopment of the premaxilla.

Nasal dysplasia

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Nasal dysplasia or nasoschisis is caused by a development arrest of the lateral side of the nose, resulting in a cleft in one of the nasal halves. The nasal septum and cavity can be involved, though this is rare. Nasoschisis is also characterized by hypertelorism.

Nasomaxillary dysplasia

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Nasomaxillary dysplasia is caused by a development arrest at the junction of the lateral side of the nose and the maxilla, which results in a complete or non-complete cleft between the nose and the orbital floor (nasoocular cleft) or between the mouth, nose and the orbital floor (oronasal-ocular cleft). The development of the lip is normal.

Maxillary dysplasia

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Maxillary dysplasia can manifest itself on two different locations in the maxilla: in the medial or the lateral part of the maxilla.

  • Median maxillary dysplasia is caused by a development failure of the medial part of the maxillary ossification centers. This results in secondary clefting of the lip, philtrum and palate. Clefting from the maxilla to the orbital floor has also been reported.
  • Lateral maxillary dysplasia is caused by a development failure of the lateral part of the maxillary ossification centers, which also results in secondary clefting of the lip and palate. Clefting of the lateral part of the lower eyelid is typical for lateral maxillary dysplasia.

Causes

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It is possible that facial clefts are caused by a disorder in the migration of neural crest cells.[6]

Another theory is that facial clefts are caused by failure of the fusion process and failure of inwards growth of the mesoderm.

Other theories are that genetics play a part in the development of facial clefts[7] or that they are caused by amniotic bands.[8]

Genetics

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Overview

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Around one in 700 individuals are born with craniofacial clefts.[9] There are multiple genetic and environmental factors which contribute to craniofacial development. Within craniofacial disorders and abnormalities, orofacial clefts, and specifically cleft lip (CL) and cleft palate (CP) are the most common in humans.[9] Occurrences of CL/P are most often (around seventy percent of cases) isolated and nonsyndromic, meaning they are not associated with a syndrome or inherited genetic conditions.[9][10] Around thirty percent occur with other structural variances, and over 500 syndromes have been identified in which clefting is a principal feature.[9][10] Clefting can result from teratogens, an agent that disrupts embryo development such as, radiation, maternal infection, chemicals, or drugs.[9][10] Chromosomal abnormalities or mutations at single gene loci have also contributed to clefting development.[9][10] Genetic causes are linked with most craniofacial syndromes, and CL/P and other orofacial clefts are recognized as heterogeneous disorders, meaning there are multiple recognized causes.[9][11] Orofacial clefts have great phenotypic diversity, and their associated genetic environments have called for vast research and investigation.

Environmental Interaction

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Craniofacial disorders have high variance in phenotypic expression, and researchers have suggested this variance could be due to interactions between the mutated/deviated genes and other genes, along with interactions with environmental factors.[12][13] Environmental causes have been found to contribute to craniofacial clefting, however, these are still influenced by and supported by genetic factors. Many studies, for example, have linked maternal smoking to increased CLP risk; however, the increased risk suggests that genes in metabolic pathways could still contribute to susceptibility or formation of CL/P.[14]

Development and Inheritance

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The craniofacial complex begins its progress in the fourth week of development, and results from neural crest cells migrating to form and fuse the facial primordia.[9][10] Failures or deviations in this process result in craniofacial clefts, either CL or CP.[6] The range of variation in phenotype aligns with ancestry.[9][14] Studies have found increased amounts of clefting in the relatives of patients with clefts, suggesting genetic factors are the underlying cause for CL/P.[9] Inheritance has a known and significant role in human craniofacial morphology. This is supported through cephalometric and anthropometric comparisons of family members including between triplets, twins, siblings, and parents and children.[15]

Genetic Experimentation

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Genetic factors of craniofacial clefting can be investigated and tracked through several methods including sequencing in humans, Genome-wide association studies (GWAs), fate mapping, expression analysis, and animal studies (knockout experiments or models with clefting from chemical mutagenesis).[16] Twin studies and familial clustering have also revealed that facial structure and formation are genetically linked. Several genes have been associated with craniofacial disorders through experimentation, including sequencing Mendelian clefting syndromes.[9] Over 25 loci have been identified as potential influencers of craniofacial clefts across populations.[12]

Linked Genes

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The transforming growth factor (TGF) family has provided multiple candidate genes linked with craniofacial development and malformation.[17][18][14][10] TGF is involved in cell migration, differentiation, and proliferation, as well as regulating the extracellular matrix.[17] Another gene that has been flagged as causal for craniofacial disorders, including CL/P, is interferon regulatory factor 6 or, IRF6.[9][14][19] Mutations in IRF6 cause Van der Woude syndrome, the most common clefting syndrome.[9] Ventral anterior homeobox 1, VAX1, and noggin, NOG, were identified with genome-wide significance for contributing to CL/P.[14] Additionally, mutations in SPECC1L have recently been identified as influential to facial structure formation, and as causal for syndromic facial clefting.[19][20] Nonsyndromic CL/P has been associated with the transcription factor forkhead box protein E1 (FOXE1), as mutations have resulted in cases of CL/P in mice.[10] Other genes which have been found to interact with or contribute to craniofacial clefting include FGFRs, TWIST, MSXs, GREM1, TCOF1, PAXs, MAFB, ABCA4, and WNT allowing great cause for more research into the genetic basis for craniofacial disorders.[11][18][12][13][14]

Prevention

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Because the cause of facial clefts still is unclear, it is difficult to say what may prevent children being born with facial clefts. It seems that folic acid contributes to lowering the risk of a child being born with a facial cleft.[21]

Treatment

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There is no single strategy for treatment of facial clefts, because of the large amount of variation in these clefts. Which kind of surgery is used depends on the type of clefting and which structures are involved. There is much discussion about the timing of reconstruction of bone and soft tissue. The problem with early reconstruction is the recurrence of the deformity due to the intrinsic restricted growth. This requires additional operations at a later age to make sure all parts of the face are in proportion.[22] A disadvantage of early bone reconstruction is the chance to damage the tooth germs, which are located in the maxilla, just under the orbit. The soft tissue reconstruction can be done at an early age, but only if the used skin flap can be used again during a second operation. The timing of the operation depends on the urgency of the underlying condition. If the operation is necessary to function properly, it should be done at early age. The best aesthetic result is achieved when the incisions are positioned in areas which attract the least attention (they cover up the scars). If, however, the function of a part of the face isn't damaged, the operation depends on psychological factors and the facial area of reconstruction.

The treatment plan of a facial cleft is planned right after diagnosis. This plan includes every operation needed in the first 18 years of the patient's life to reconstruct the face fully. The plan distinguishes between two types of anomalies: those which need to be treated to improve the health of the patient (like coloboma), and those which need to be treated to achieve better cosmetic results (like hypertelorism).

The treatment of the facial clefts can be divided into different areas of the face: the cranial anomalies, the orbital and eye anomalies, the nose anomalies, the midface anomalies and the mouth anomalies.

Treatment of the cranial anomalies

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The most common cranial anomaly seen in combination with facial clefts is encephalocele.

Encephalocele

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The treatment of encephalocele is based on surgery to repair the bony gap and provide adequate protection of the underlying brain. The question remains if the external brain tissue should be put back into the skull or if it is possible to cut off that piece of brain tissue, because its claimed that the external piece of brain tissue often isn't functional,[23] with the exception of a basal encephalocele, in which the pituitary gland can be found in the mouth.

Treatment of orbital / eye anomalies

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The most common orbital /eye anomalies seen in children with facial clefts are colobomas and vertical dystopia.

Coloboma

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The coloboma which occurs often in facial clefts is a cleft in the lower or upper eyelid. This should be closed as soon as possible, to prevent drought of the eye and a consecutive loss of vision.[24]

Vertical orbital dystopia

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Vertical orbital dystopia can occur in facial clefts when the orbital floor and/or the maxilla is involved in the cleft. Vertical orbital dystopia means that the eyes do not lay on the same horizontal line in the face (one eye is positioned lower than the other). The treatment is based on the reconstruction of this orbital floor, by either closing the boney cleft or reconstructing the orbital floor using a bone graft.[25]

Hypertelorism

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There are many types of operations which can be performed to treat a hypertelorism. 2 options are: box osteotomy and facial bipartition[26] (also referred to as a median fasciotomy). The goal of the box osteotomy is to bring the orbits closer together by removing a part of the bone between the orbits, to detach both orbits from the surrounding bone structures and move both orbits more to the centre of the face. The goal of the facial bipartition is not only to bring the orbits closer together, but also to create more space in the maxilla. This can be done by splitting the maxilla and the frontal bone, remove a triangular shaped piece of bone from the forehead and nasal bones and pulling the two pieces of forehead together. Not only will the hypertelorism be solved by pulling the frontal bone closer together, but because of this pulling, the space between the both parts of the maxilla will become wider.

  • Box Osteotomy
    Box Osteotomy
  • Facial Bipartition
    Facial Bipartition

Treatment of nasal deformities

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The main goal in the treatment of nasal deformities is to reconstruct the nose to get a functional and esthetically acceptable result. One treatment option is to reconstruct the nose with a forehead flap or reconstruct the nasal dorsum with a bone graft (e.g., a rib graft). Nasal reconstruction with a forehead flap is based on the rotation (repositioning) of a skin flap from the forehead to the nose. A possible downside of this reconstruction is that a second operation is often needed if the operation is performed at an early age, because the nose has a restricted growth in the cleft area. Repair of the wing of the nose often requires the inset of cartilage graft, commonly taken from the ear.[27]

Treatment of midface anomalies

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The treatment of soft tissue parts of midface anomalies is often a reconstruction from a skin flap of the cheek. This skinflap can be used for other operations in the further, as it can be raised again and transposed again. In the treatment of midface anomalies there are generally more operations needed. Bone tissue reconstruction of the midface often occurs later than the soft tissue reconstruction. The most common method to reconstruct the midface is by using the fracture/ incision lines described by René Le Fort. When the cleft involves the maxilla, it is likely that the impaired growth will result in a smaller maxillary bone in all 3 dimensions (height, projection, width).

Treatment of mouth anomalies

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There are several options for treatment of mouth anomalies like Tessier cleft number 2-3-7 . These clefts are also seen in various syndromes like Treacher Collins syndrome and hemifacial microsomia, which makes the treatment much more complicated. In this case, treatment of mouth anomalies is a part of the treatment of the syndrome.

See also

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Related articles

Syndromes

References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Craniofacial cleft

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Craniofacial clefts are rare congenital anomalies characterized by partial or total defects in the soft tissues, bones, or both within the craniofacial region, resulting from disruptions in the normal fusion of prominences during embryonic development between the 5th and 10th weeks of . These malformations can range from subtle notches to extensive gaps involving the , , eyes, cheeks, and , often accompanied by associated features such as colobomas (gaps in the eyelid or iris), (widened eye spacing), and skeletal deformities. Unlike more common orofacial clefts like cleft lip and palate, which occur in approximately 1 in 700 live births, craniofacial clefts are significantly rarer, with an estimated incidence of 1.4 to 4.9 per 100,000 live births globally. The Tessier classification system, developed by French surgeon Paul Tessier in the , provides a standardized numerical framework (types 0 through 14) for these clefts, based on their anatomical position relative to the sagittal midline and the orbits, linking soft tissue disruptions to underlying skeletal involvement. Types 0 to 7 primarily affect the facial structures, with type 0 representing a midline cleft involving the and , type 1 extending from the lip's to the nostril sill, type 2 to the nasal ala, type 3 from the to the medial (often with nasolacrimal issues), and type 4 from the lateral lip to the lower eyelid. Types 5 through 7 progress laterally across the , zygoma, and , while types 8 to 14 extend into the , involving the , temples, and even the occiput in type 14, frequently resulting in more severe neurocranial deformities. Clefts on opposite sides of the midline (e.g., 3 and 11) are numbered separately but may occur together, and oblique facial clefts (types 3, 4, and 7) are among the most commonly reported atypical variants. The etiology of craniofacial clefts is multifactorial, involving genetic predispositions, such as mutations affecting cell migration, alongside environmental influences like amniotic band disruption sequence or maternal exposures during critical embryogenic periods. While isolated cases predominate, some clefts associate with syndromes (e.g., in type 0), and prenatal diagnosis via or 3D imaging is increasingly feasible for early planning. Management requires a multidisciplinary approach, including craniofacial surgeons, ophthalmologists, and orthodontists, with staged reconstructive surgeries—often beginning in infancy—to address functional deficits (e.g., vision, feeding) and aesthetic restoration, though outcomes vary due to the clefts' complexity and rarity.

Overview

Definition and Characteristics

Craniofacial clefts are rare congenital malformations characterized by gaps or fissures in the craniofacial and overlying soft tissues, arising from incomplete fusion of the processes during early embryogenesis. These defects typically occur between the 4th and 7th weeks of , when neural crest-derived fails to migrate properly or when epithelial seams persist without proper breakdown, leading to disruptions in the normal merging of prominences that form the and . Unlike the more common orofacial clefts, which are confined to the and , craniofacial clefts extend to involve the , orbits, and , potentially affecting underlying structures such as through associated encephaloceles or meningoencephaloceles in severe midline cases. The characteristics of craniofacial clefts vary widely in severity and presentation, ranging from subtle oblique facial clefts that primarily disrupt the lower face to more extensive transverse craniofacial dysostosis involving the upper and orbits. They may occur unilaterally or bilaterally, with the latter often presenting greater and functional challenges, and are frequently accompanied by tissue deficiencies such as colobomas of the eyelids or nasal alae, duplications like accessory limbs or supernumerary structures, or displacements of facial features leading to or . These malformations not only create aesthetic distortions but also functional impairments, including ocular exposure, nasal airway obstruction, and feeding difficulties, due to the involvement of multiple tissue layers along predictable embryologic fusion lines. The detailed recognition of craniofacial clefts as distinct entities beyond typical lip and palate anomalies was pioneered by Paul Tessier, who in 1976 provided the first comprehensive anatomical description of these atypical facial clefts, emphasizing their extension into the cranium and the need for a systematic approach to their identification. This work highlighted their rarity and complexity, setting the foundation for modern understanding and management by linking soft tissue fissures to underlying skeletal deformities.80013-6)

Epidemiology and Incidence

Craniofacial clefts represent a rare group of congenital anomalies, with an estimated global incidence ranging from 1.43 to 4.85 per 100,000 live births. This prevalence is substantially lower than that of more common orofacial clefts, which affect approximately 1 in 700 live births worldwide. The rarity of craniofacial clefts underscores their classification as atypical facial malformations, distinct from the more frequently encountered cleft lip and palate. Demographic patterns indicate no strong sex predilection, with affected individuals showing a near-equal male-to-female ratio of approximately 1:1 across reported cases. The majority of cases, estimated at over 90%, occur sporadically without familial recurrence. Reported incidences vary by , with higher rates documented in certain Asian and African populations, potentially influenced by factors such as regional birth rates and diagnostic practices; underdiagnosis may occur elsewhere due to advanced prenatal screening and selective terminations in high-resource settings. Associated risk factors include and consanguineous parental unions, which have been linked to elevated occurrence in population studies, though geographic and socioeconomic influences also play a role without clear causal specificity. Diagnostic challenges contribute to imprecise estimates, as severe craniofacial clefts often result in early , leading to underreporting in vital registries. Additionally, misclassification as other craniofacial dysmorphisms or syndromic conditions can obscure accurate incidence data, particularly in resource-limited settings where comprehensive phenotyping is unavailable. These factors highlight the need for improved to better quantify the true burden of these anomalies.

Etiology

Genetic Factors

Craniofacial clefts exhibit a complex genetic , often sporadic and nonsyndromic, with most cases showing no clear familial pattern or single-gene cause. While recurrence risks in families are generally low, certain Tessier types are associated with genetic syndromes involving mutations that disrupt cell migration and facial prominence fusion during embryonic development. Syndromic forms occur in a minority of cases, linked to specific monogenic or chromosomal abnormalities with variable expressivity. Key associations include midline clefts (type 0), often part of caused by heterozygous mutations in ALX1, ALX3, or ALX4 genes, which regulate cranial development and lead to , nasal anomalies, and clefting via autosomal dominant inheritance. Lateral and oblique clefts (e.g., types 3, 4, 7) may rarely involve mutations in SPECC1L, as in oblique facial clefting-1 (OBLFC1), an autosomal dominant condition affecting facial process fusion. For types 6-8, (mandibulofacial dysostosis) is implicated, primarily due to mutations in TCOF1 (autosomal dominant, accounting for ~90% of cases), disrupting in -derived tissues and resulting in colobomas, ear anomalies, and mandibular hypoplasia alongside cleft-like defects. Other lateral clefts associate with or , potentially involving CHST14 or polygenic factors, though etiology remains incompletely understood. Genetic studies highlight over 40 susceptibility loci from broader orofacial cleft research, but for rare craniofacial clefts, the oligogenic model is less defined, with disruptions primarily affecting weeks 4-7 of when cells form facial structures. Animal models, such as with alx knockdowns, recapitulate frontonasal defects, underscoring pathways' role.

Environmental and Teratogenic Influences

Environmental and teratogenic influences contribute significantly to craniofacial clefts, particularly through interactions with genetic vulnerabilities that disrupt embryonic facial morphogenesis in the first trimester. These factors include maternal exposures, infections, and mechanical disruptions, many of which are preventable. Prominent teratogens include retinoids (e.g., 13-cis-retinoic acid/Accutane), which cause severe craniofacial malformations including clefts by altering cranial apoptosis and migration. Folic acid antagonists like inhibit pathways essential for , leading to midline and oblique facial defects when exposure occurs around 6-8 weeks gestation. Anticonvulsants such as are linked to fetal with and clefting. Maternal and alcohol use during early impair vascular supply and induce in facial , increasing risk for facial clefts, though specific associations with Tessier types are less quantified. A key mechanism for atypical oblique clefts is amniotic band disruption sequence, where ruptured strands cause mechanical tissue adhesions and asymmetric deformations. Maternal conditions like pregestational elevate risk via affecting embryonic and neural crest survival. may contribute through inflammatory pathways disrupting palate closure. Infections such as can lead to craniofacial anomalies, often with and midfacial hypoplasia. Gene-environment interactions, including polymorphisms in folate-related genes like MTHFR, can amplify teratogen effects via epigenetic changes in neural crest patterning. Periconceptional folic acid supplementation reduces orofacial cleft incidence and may benefit craniofacial cases by supporting during .

Pathogenesis

Embryonic Facial Development

The development of the craniofacial region begins in the fourth week of embryonic , when the primitive mouth, or , forms as a depression in the ventral surface of the , surrounded by the frontonasal prominence cranially and the first pair of es caudally. During weeks 4 to 6, facial prominences emerge from the proliferation of neural crest-derived : the frontonasal prominence gives rise to the and nasal structures, the maxillary prominences (from the first ) form the upper cheek, lateral upper lip, and secondary palate, and the mandibular prominences (also from the first arch) develop into the lower jaw. By week 7, paired lateral and medial nasal prominences appear within the frontonasal region, flanking the nasal placodes that indent to form nasal pits. Fusion of these prominences occurs progressively; for instance, the medial nasal and maxillary prominences merge by week 7 to form the and upper lip, while complete facial contouring, including palatal shelf elevation and fusion, is achieved by week 10. Central to these events is the migration of cranial cells (CNCCs), which delaminate from the dorsal starting around day 21 and invade the es and frontonasal area via defined pathways. CNCCs from rhombomeres 1-2 primarily populate the first , providing mesenchymal cells that differentiate into skeletal and connective tissues of the face, while those from rhombomeres 4-7 contribute to more caudal structures. The first divides into maxillary and mandibular processes, with the maxillary contributing to the midface and the mandibular to the lower face; subsequent arches (second to sixth) form additional pharyngeal structures but play lesser roles in visible facial morphology. Key processes include mesenchymal penetration, where CNCCs integrate into epithelial coverings to support prominence growth, and epithelial fusion, involving programmed at contact points between prominences to eliminate intervening and allow seamless merging. Anatomical precursors further shape the face: the frontonasal process, influenced by signaling, establishes the midline nasal and forehead regions, while optic vesicles evaginate from the by week 4 to induce orbital structures and interact with surrounding for eye placement. These developments are tightly regulated by molecular signaling pathways. Bone morphogenetic proteins (BMPs), expressed in the ventral arches, promote CNCC proliferation and skeletogenesis in structures like the and . Fibroblast growth factors (FGFs), particularly FGF8 and from the pharyngeal , drive CNCC survival, migration, and patterning of the branchial arches. Sonic hedgehog (SHH), secreted from the and midline facial , maintains CNCC viability and coordinates jaw and midline development. Disruptions in these coordinated processes underlie craniofacial anomalies such as clefts.

Mechanisms of Cleft Formation

Craniofacial clefts arise primarily from disruptions in the intricate processes of facial morphogenesis during embryonic development, with two longstanding theories explaining their formation: the failure of mesenchymal penetration and the failure of fusion. The failure of mesenchymal penetration theory posits that inadequate migration or proliferation of neural crest-derived mesenchymal cells prevents the ingrowth necessary to bridge epithelial seams between facial prominences, resulting in persistent gaps that evolve into clefts. In contrast, the classic failure of fusion model, proposed by Dursy and His, attributes clefts to the incomplete merging of adjacent facial processes, where epithelial contact occurs but subsequent breakdown of the epithelial wall fails due to insufficient underlying mesenchymal support, leading to tissue separation. These mechanisms often overlap, as deficiencies in mesenchymal tissue can precipitate both inadequate penetration and fusion failure, particularly in oblique or transverse cleft patterns that do not follow typical midline suture lines. Pathological processes further contribute to cleft formation through vascular insufficiency, excessive , and mechanical disruptions. Vascular disruption, often triggered by maternal infections or teratogens like , compromises blood supply to developing facial structures, leading to ischemic and subsequent tissue defects that manifest as clefts. Excessive , particularly of cranial neural crest cells (CNCCs), disrupts the cellular framework required for proper facial field development; for instance, heightened in migratory CNCCs can result in reduced tissue mass and incomplete closure of facial prominences. Additionally, amniotic band syndrome introduces mechanical tears via fibrous strands that entangle and constrict fetal parts, causing asymmetric craniofacial clefts through direct physical disruption rather than intrinsic developmental failure. Clefts typically propagate from initial soft tissue interruptions to underlying skeletal elements, following neuromeric patterns that distort adjacent developmental fields and produce oblique or transverse trajectories across the craniofacial skeleton. This progression often results in more pronounced bony defects than soft tissue ones, as mesenchymal deficiencies propagate inferiorly or laterally, affecting structures like the maxilla or orbits. Midline craniofacial clefts, in particular, are associated with holoprosencephaly, where failure of Sonic hedgehog (SHH) signaling impairs ventral forebrain patterning and midline facial integration, leading to fused cerebral hemispheres and severe prosencephalic defects.

Classification

Tessier Classification

The Tessier classification system, introduced by Paul Tessier in , provides a numerical framework for identifying and categorizing craniofacial clefts based on their precise anatomical locations relative to the , which serves as the central reference point. The system employs numbers from 0 to 14 to denote cleft positions in a circular manner around the orbits, starting at the median midline (No. 0, involving the and ) and proceeding laterally to the dorsal midline (No. 14, affecting the and ). This arrangement highlights the continuity between facial (Nos. 0–7) and cranial (Nos. 8–14) components of each cleft, emphasizing their extension through both soft tissues and underlying bone structures. An additional designation, No. 30, addresses rare midline mandibular clefts as a caudal extension of Nos. 0 and 14. Clefts are grouped into four primary categories according to their predominant anatomical involvement: oral-nasal (Nos. 0–3), which affect the midline and paramedian , , and ; oral-ocular (Nos. 4–6), involving the , zygoma, and inferior ; lateral facial (Nos. 7–9), extending to the lateral , , and ; and cranial (Nos. 10–14), which traverse the superior , , and skull base. For instance, No. 0 represents a midline cleft through the , nasal tip, and interincisor alveolus, often associated with a and , while No. 7 involves the oral commissure, duplicate maxillary elements, and external deformities, commonly seen in syndromes like Treacher Collins or . These groups underscore the variable severity and asymmetry, with clefts rarely occurring in isolation and frequently combining across numbers (e.g., Nos. 3 and 4 linking nasal and ocular defects). Clinically, the numbering correlates directly with affected structures and potential complications, guiding the identification of associated anomalies such as colobomas of the eyelids (e.g., in Nos. 3–5, disrupting the medial to middle inferior orbital rim), nasolacrimal duct obstruction (specific to No. 3), or cranial defects like encephaloceles (in No. 14). For example, No. 4 typically spares the nasolacrimal system but involves the medial lower eyelid and canine alveolus, leading to inferior displacement of the medial canthus and globe, whereas No. 10 affects the middle superior orbital rim and may cause temporal bone anomalies. This anatomical specificity aids in predicting functional impairments, including exposure keratopathy from eyelid defects or feeding difficulties from oral involvement. The primary advantages of the Tessier system lie in its utility for surgical planning, as it standardizes communication among multidisciplinary teams and delineates the three-dimensional pathways of deformities, enabling targeted reconstructions to restore , orbital alignment, and cavity separation. By focusing on location rather than , it facilitates individualized, staged interventions that minimize complications like recurrent herniation or asymmetry, particularly in complex cases involving multiple cleft numbers.

Van der Meulen Classification

The Van der Meulen classification, introduced in the early 1980s, provides a morphogenetic framework for craniofacial clefts by categorizing them as dysplasias arising from developmental arrests in specific processes during embryogenesis. Unlike purely anatomical systems, it emphasizes the chronological and topographical aspects of embryonic fusion failures, distinguishing between true clefts and broader hypoplastic or dysraphic anomalies to better reflect underlying . This approach integrates observations from embryologic studies and clinical cases to predict long-term skeletal growth patterns. The system delineates four primary dysplasias based on the affected facial prominences: internasal, nasal, nasomaxillary, and maxillary. Internasal dysplasia results from dysjunction between the frontal and nasal processes, leading to median clefts such as or severe often associated with frontal encephaloceles. Nasal dysplasia involves defects in the ala nasi or base, manifesting as nasal aplasia, , or duplication, and is relatively rare. Nasomaxillary dysplasia affects the fusion of nasal and maxillary processes, resulting in upper jaw involvement with orbital and nasal deformities, including incomplete or complete clefts extending to the eye. Maxillary dysplasia encompasses isolated clefts of the , potentially medial or lateral, with variable soft tissue involvement. Key to this classification is its focus on skeletal hypoplasia and tissue volume deficiencies rather than mere soft tissue gaps, enabling clinicians to anticipate growth disturbances such as midfacial retrusion or orbital asymmetry. By linking anomalies to specific embryonic stages—typically between the 4th and 7th weeks of gestation—it facilitates targeted prognostic assessments over descriptive labeling. In comparison to the Tessier classification, which relies on anatomical numbering (0–14) for cleft locations across soft and hard tissues, Van der Meulen's model prioritizes embryologic mechanisms to guide etiological understanding rather than spatial mapping.

Clinical Presentation

Cranial and Central Nervous System Anomalies

Craniofacial clefts often involve anomalies of the cranial vault and (CNS), arising from disruptions in early embryonic development that affect the and surrounding structures. These anomalies can range from subtle calvarial defects to profound malformations, impacting function and overall neurological health. In the Tessier classification, cranial clefts (numbers 8 through 14) frequently exhibit such involvement, with midline and paramedian variants showing the strongest associations. Encephalocele, a herniation of tissue and through a defect, represents one of the most common CNS anomalies in craniofacial clefts, particularly in Tessier clefts 10, 13, and 14. For instance, Tessier cleft 14, a median craniofacial cleft, commonly features herniation of intracranial contents through the frontal or fronto-nasal region, potentially extending to orbital structures in severe cases. This condition stems from incomplete closure of the anterior neuropore during embryogenesis, leading to a spectrum of severity from small, protrusions to large defects causing significant displacement. Craniosynostosis, the premature fusion of cranial sutures, is also frequently observed in association with craniofacial clefts, altering skull shape and potentially restricting brain growth. This anomaly is linked to the same neuroembryologic fields disrupted in cleft formation, as seen in Tessier clefts involving the frontal and orbital regions, where excess or deficient migration contributes to suture obliteration. , characterized by accumulation of leading to ventricular enlargement, occurs in select cases, such as certain Tessier type 3 clefts, often complicating midline defects and requiring vigilant monitoring. Patients with these CNS anomalies face elevated risks, including increased from or suture restriction, which can manifest as headaches, vomiting, or . Seizures affect approximately 25.5% of individuals with encephaloceles, attributed to cortical irritation or scarring at the herniation site. These complications are particularly prevalent in midline clefts, where embryologic overlaps between facial and neural structures heighten the likelihood of associated malformations. Early is essential for , revealing defects often tied to these cleft patterns.

Orbital and Ocular Features

Craniofacial clefts frequently involve the and ocular structures, leading to a range of deformities that disrupt normal eye positioning and function. , characterized by an increased interorbital distance, is a hallmark feature particularly in and paramedian clefts such as Tessier numbers 0, 1, 2, 13, and 14, resulting from abnormal bony separation of the orbits during embryogenesis. Vertical orbital dystopia, where the orbits are misaligned vertically due to defects in the orbital floor or roof, commonly accompanies these clefts and can cause hypoglobus or hyperglobus, exacerbating facial asymmetry. Colobomas, representing gaps in ocular tissues, are prevalent anomalies; upper colobomas occur in up to 42.5% of cases, while lower colobomas affect about 30%, often extending to the iris or fundus and associated with microcornea or . In Tessier clefts 3 and 4, medial orbital involvement predominates, featuring inferomedial colobomas, lacrimal duct anomalies, and severe globe defects including or , which may lead to orbital tissue exposure and through bony defects like the absent orbital floor. These clefts can extend to the in higher-number variants (e.g., Tessier 10), allowing meningeal or cerebral tissue herniation into the and contributing to further of orbital contents. Exposure keratopathy and corneal opacities arise from incomplete closure or , increasing the risk of ingress into the exposed ocular surface. Functionally, these features often result in significant ocular morbidity, with visual acuity classified as poor in 18% of affected eyes and fair in 11%, primarily due to , , optic nerve anomalies, or corneal scarring. is a common , driven by restrictive fibrosis or muscle involvement, as seen in cases of hypotropia, , or limited ductions. Such impairments necessitate early ophthalmologic evaluation to mitigate and preserve residual vision.

Nasal and Midfacial Deformities

Nasal deformities in craniofacial clefts often manifest as disruptions in the midline or paramedian structures, resulting from incomplete fusion of the frontonasal and maxillary prominences during embryogenesis. A , characteristic of Tessier No. 0 clefts, features a flattened nasal dorsum, shortened , and separated alar cartilages with widened , leading to a V-shaped or duplicated nasal tip. In severe midline cases, such as extreme Tessier 0 variants, a —a rudimentary, trunk-like nasal appendage—may protrude superiorly from the midline , often associated with underlying or encephaloceles. Nasal pyramid is common in Tessier 3 clefts, presenting as underdevelopment of the and alae, with colobomas or notching of the nasal sill. Midfacial involvement extends these defects to the central face, frequently incorporating and . , seen in Tessier 1 and 2 clefts, results in retrusion of the midface , contributing to a flattened profile and reduced nasal projection due to deficient bony support. , an increased intercanthal distance without true , arises from medial orbital wall disruptions in these clefts, often with inferior displacement of the medial canthi and widened nasal base. These features align with Tessier 1 (oblique facial cleft) and 2 (paramedian) classifications, where the cleft line traverses the nose and upper lip, exacerbating midfacial asymmetry. Functionally, these deformities can cause significant challenges in infancy, including airway obstruction from or narrowed nasal passages in Tessier 3 clefts, which may necessitate urgent intervention to prevent respiratory distress. Feeding difficulties arise from distorted nasal airflow and associated oral cleft extensions, impairing suckling coordination and increasing aspiration risk. Over time, unequal growth leads to progressive facial , with the affected midface lagging behind, potentially worsening nasal obstruction and aesthetic disproportion into childhood.

Oral and Mandibular Anomalies

Oral and mandibular anomalies in craniofacial clefts primarily manifest in the lower face, often involving disruptions to the , alveolus, and jaw structures, particularly in Tessier types 7 and 8. Oblique facial clefts in these classifications extend laterally from the oral commissure toward the ear, affecting the and alveolar with incomplete or complete separations that disrupt normal continuity. These clefts frequently include tissue bridges analogous to Simonart bands, which are fibrous connections spanning the defect and potentially influencing surgical repair complexity. Mandibular , characterized by underdevelopment of the jawbone, is a common associated feature, especially in Tessier 7, where it contributes to asymmetric growth and retrognathia. of the may also occur, leading to restricted mouth opening and further mandibular deformity due to fibrous or bony fusion. Tessier 7 and 8 clefts are notably associated with lateral facial involvement, where the oral defect integrates with ear malformations such as preauricular tags or , and extends to the mandibular border without crossing the midline. In Tessier 7, the cleft often incorporates the buccinator muscle and parotid region, resulting in macrostomia—a rare widening of the that exceeds normal commissural distance and alters oral sphincter function. This anomaly arises from failed fusion of the maxillary and mandibular processes during embryogenesis, commonly linked to syndromes like or , which exacerbate mandibular involvement. Type 8 clefts, while less extensive orally, may present with similar mandibular asymmetries when syndromic features are present. Dental anomalies, including supernumerary teeth or in the affected alveolus, frequently accompany these clefts, complicating occlusion. Functionally, these anomalies profoundly impact speech articulation due to diastasis and oral incompetence, often requiring early intervention to support development. Dentition is disrupted by alveolar irregularities, leading to malpositioned or missing teeth that hinder mastication and hygiene. Occlusal problems, such as class II or III , affect individuals with associated clefts, stemming from asymmetric mandibular growth and maxillary involvement, which can perpetuate feeding difficulties and facial asymmetry if untreated. These impacts underscore the need for coordinated orthodontic and surgical management to restore lower facial harmony.

Diagnosis

Prenatal Imaging and Screening

Prenatal imaging plays a crucial role in the antenatal detection of craniofacial clefts, which are rare congenital anomalies often classified under the Tessier system. Routine screening, particularly during the second trimester anomaly scan at 18-20 weeks of , is the primary modality for identifying these defects. Two-dimensional (2D) can visualize facial clefts with detection rates of 75-90% for orofacial clefts in recent studies, though rates for more complex craniofacial variants like Tessier clefts may be lower due to their rarity and subtlety. Due to their rarity, prenatal detection of Tessier clefts is uncommon, with many cases identified postnatally. Three-dimensional ( enhances diagnostic accuracy by providing surface-rendered images that better delineate cleft extent and associated soft tissue involvement, improving sensitivity to up to 89% for orofacial clefts in some studies when combined with 2D techniques, though lower for complex Tessier variants. For high-risk pregnancies, such as those with a family history of craniofacial anomalies, enhanced screening protocols are recommended, including targeted examinations, referral for to discuss recurrence risks and associated syndromic features, and such as chromosomal microarray analysis (CMA) to identify potential chromosomal anomalies. Fetal (MRI) serves as a complementary tool, particularly when findings are inconclusive or suggest brain involvement, offering detailed multiplanar views with diagnostic concordance rates of up to 89% for orofacial clefts and aiding in the assessment of anomalies. Key indicators of craniofacial clefts on imaging include direct visualization of the facial defect, such as widened mouth commissures in Tessier number 7 clefts, due to impaired fetal swallowing, and associated anomalies like limb defects or . Despite these advances, prenatal detection faces limitations, including operator dependency, acoustic shadowing that can mimic or obscure clefts leading to false positives, and reduced visualization in late gestation due to and . Overall detection rates for isolated craniofacial clefts remain variable, estimated at 50-70% in specialized centers, underscoring the need for multidisciplinary follow-up, including postnatal confirmation.

Postnatal Clinical and Radiographic Assessment

Upon birth, infants with suspected craniofacial clefts undergo immediate to evaluate the extent and of the cleft, including assessment of facial asymmetry, orbital positioning, nasal deformities, and oral structures. This clinical inspection also addresses functional concerns such as airway patency, feeding ability, and breathing stability, often revealing associated disruptions or skeletal misalignments. A multidisciplinary team, including craniofacial surgeons, neurosurgeons, plastic surgeons, and otolaryngologists, conducts the initial intake to document findings through detailed photographs and measurements for baseline records. , such as CMA, may be performed to evaluate for syndromic associations. Radiographic imaging is essential for confirming the and delineating the cleft's anatomical involvement. Plain X-rays serve as an initial screening tool to visualize gross and abnormalities in the craniofacial . Computed tomography (CT) scans, preferably with three-dimensional reconstruction, provide high-resolution details of bony defects, orbital involvement, and intracranial extensions, enabling precise mapping of the cleft pathway. (MRI) complements CT by assessing soft tissue anomalies, brain malformations, and neural structures, particularly in cases with suspected involvement. The Tessier classification system is applied postnatally to categorize the cleft by assigning a number from 0 to 14 based on its anatomical location relative to the and midline, using integrated data from clinical photographs, physical exams, and imaging scans. This numbering facilitates standardized documentation and guides subsequent evaluations by highlighting potential extensions into cranial or facial regions. For instance, a cleft involving the medial might be designated as Tessier number 3, confirmed through correlative CT and photographic evidence. Associated evaluations include ophthalmologic examination to assess vision, corneal exposure, and orbital , often requiring immediate protective measures like . If anomalies are suspected, (EEG) is performed to detect subclinical seizures. These checks ensure comprehensive identification of comorbidities without delaying core diagnostic processes.

Management

Multidisciplinary Team Approach

The management of craniofacial clefts necessitates a multidisciplinary team approach to address the multifaceted anatomical, functional, and challenges these conditions present. This model, recognized as the since 1938, coordinates specialists to deliver integrated treatment, ensuring timely interventions and holistic support across developmental stages. Core team members typically include plastic surgeons, who frequently lead coordination; neurosurgeons for cranial involvement; ophthalmologists for ocular anomalies; orthodontists for dental and maxillary alignment; speech-language pathologists for communication and feeding issues; and psychologists for emotional and behavioral support. Additional specialists, such as otolaryngologists (), geneticists, and social workers, contribute based on individual needs, with teams often convening in clinics for joint evaluations and post-clinic conferences to refine care plans. Care timelines emphasize neonatal stabilization, including initial feeding and respiratory assessments, followed by staged interventions from infancy through adolescence. Early surgeries and presurgical orthopedics occur in the first year, with follow-up peaks for speech therapy at ages 3-6 years, orthodontics at 8-14 years, and potential later procedures into adulthood; annual clinic visits, often aligned with the patient's birth month, facilitate ongoing monitoring and adjustments. Family involvement is integral, with teams providing counseling, education on condition management, and access to social services for logistical support like transportation and financial aid. Psychologists and coordinators offer emotional guidance, while support groups help families navigate long-term challenges; this engagement improves adherence and addresses barriers such as socioeconomic factors. Recent advances in integrated clinics, such as those verified by the as Level 1 Children's Surgery Centers, enhance outcomes through coordinated planning, resulting in more comprehensive care—for instance, children in team settings receive dental evaluations at rates of 82.3% compared to 61.7% with individual providers, and genetic counseling at 47.9% versus 26.2%.

Surgical Interventions

Surgical interventions for craniofacial clefts are typically staged to address and skeletal deformities progressively, allowing for facial growth while correcting functional and aesthetic deficits. These procedures are individualized based on the Tessier classification of the cleft, which guides the extent of involvement across facial structures. Timing of surgery varies by the severity and location of the cleft. repairs, such as for and nasal deformities, are often performed between 3 and 6 months of age to facilitate feeding and early development. Palatal and initial skeletal corrections occur around 6 to 12 months, while more complex bony reconstructions, including orbital and midfacial advancements, are deferred until 5 to 10 years to account for skeletal maturity. Life-threatening anomalies, like encephaloceles, require neonatal intervention to prevent complications such as infection or neurological compromise. Soft tissue reconstruction primarily employs rotation-advancement flaps to realign displaced tissues and close clefts, often combined with interdigitating flaps for naso-maxillary alignment. These techniques minimize scarring and restore in the and nasal regions, with grafts sometimes integrated for support in malar or orbital areas. Rigid fixation using plates or screws secures grafts to the maxillary , ensuring stability during healing. Bony interventions focus on osteotomies to reposition skeletal elements. For orbital hypertelorism and dystopia, procedures such as box osteotomy or spectacle osteotomy enable medial translocation of the orbits, correcting anti-mongoloid slant and elevating the globe with lateral orbital wall grafts. Encephalocele closure involves resection of protruded neural tissue followed by multilayer dural and soft tissue repair, often with nasal pyramid reconstruction. Midface advancement utilizes Le Fort III osteotomies or facial bipartition to expand maxillary volume and advance the midface, addressing severe deformities in Tessier types 3 and 7 clefts. These are secured with rigid internal fixation to promote bone healing. Recent advances since 2020 have enhanced precision through virtual surgical planning (VSP) and , which allow preoperative simulation of osteotomies and custom implant design using (CAD) software. Patient-specific 3D-printed implants, often from or polyetheretherketone (PEEK), improve anatomical fit in orbital and midfacial reconstructions, reducing operative time by 20-40% and revision rates. Endoscopic approaches, while more established for , are increasingly applied in select craniofacial cleft cases for minimally invasive access to cranial and orbital regions, minimizing blood loss and scarring. integration with 3D imaging further refines cleft severity assessment and planning, achieving up to 92.5% accuracy in prenatal predictions and intraoperative navigation errors as low as 2.4 mm.

Nonsurgical Supportive Care

Nonsurgical supportive care for patients with craniofacial clefts plays a crucial role in optimizing function, growth, and quality of life, often complementing surgical interventions through multidisciplinary approaches. These therapies address immediate challenges such as feeding difficulties, speech impairments, and psychosocial needs, while promoting long-term development. Orthodontic appliances, such as nasoalveolar molding (NAM), are employed presurgically to gently reshape the nasal cartilage, gums, and lip in infants with cleft lip and palate, thereby improving alignment and facilitating subsequent repairs. NAM typically involves custom-fitted acrylic appliances adjusted weekly by specialists, starting shortly after birth and continuing for several months until surgery. Speech therapy targets velopharyngeal insufficiency (VPI), a common issue where inadequate closure between the oral and nasal cavities leads to hypernasal speech and nasal air emission; therapists use techniques like oral-motor exercises and articulation training to enhance velopharyngeal function and compensatory speech patterns, often beginning in early childhood and continuing as needed. Nutritional support is essential for infants with craniofacial clefts, who often face challenges with sucking, , and airway due to anatomical defects. Specialized feeding techniques, including the use of squeezable bottles, specialty nipples, or nasogastric tubes, help ensure adequate caloric intake and prevent aspiration; for severe cases, temporary feeding tubes provide stable , reducing the need for analgesia and enabling earlier hospital discharge. Psychological care addresses the emotional toll of visible differences, including concerns and risks of , which can lead to and reduced in children with craniofacial anomalies. Interventions involve counseling by psychologists and social workers to build coping skills, foster , and support family dynamics, with long-term monitoring to track adjustment and intervene early against issues like depression. Adjunctive measures include prosthetics for unrepaired defects, such as palatal obturators that restore oral-nasal separation, improve speech, and enhance mastication in cases where is not feasible or delayed.

Prognosis and Long-Term Outcomes

Functional and Aesthetic Results

Functional outcomes following treatment for craniofacial clefts, such as those classified under the , show improvements in key areas like vision, speech, and feeding when early intervention is implemented. With multidisciplinary approaches starting in infancy, many patients achieve acceptable vision and speech development, particularly in cases where orbital involvement is addressed promptly to prevent complications like coloboma-related deficits. Feeding difficulties often improve post- in infancy, with many achieving independence in . Aesthetic results are enhanced through multi-stage reconstructions that restore and balance, leading to high levels of patient and parental satisfaction in adulthood, with rates around 71% reporting very positive outcomes. Independent observer evaluations confirm good aesthetic results in approximately 70% of cases, emphasizing reduced in the midface and orbital regions. These improvements are routinely assessed using validated measures like the FACE-Q Craniofacial Module, which captures satisfaction with appearance and health-related in children and young adults aged 8-29. Factors influencing these outcomes include the severity of the cleft—such as involvement of multiple Tessier numbers—and the timing of repairs, where early interventions yield superior functional and aesthetic results. Long-term follow-up involves annual multidisciplinary assessments up to age 18, monitoring growth, speech articulation, and facial harmony to optimize ongoing care and address any residual deficits.

Associated Complications and Syndromes

Craniofacial clefts, particularly those classified under the Tessier system, are associated with various postoperative and inherent complications that can impact patient health and . Surgical interventions for these clefts carry risks including , with reported rates in craniofacial procedures ranging from 2% to 9%. Scarring is a common issue, often manifesting as hypertrophic scars following cleft repair, with incidence varying widely from 1% to nearly 50% depending on surgical technique and patient factors. Relapse of deformities, such as oronasal fistulas or skeletal misalignment, occurs in a subset of cases post-palatoplasty, influenced by growth patterns and surgical timing. In cranial-involving clefts, neurological deficits may arise from associated anomalies or surgical proximity to neural structures, though major deficits are rare in well-managed cases. These clefts frequently link to underlying syndromes that exacerbate complications. (HPE), a forebrain malformation, is strongly associated with midline craniofacial clefts, leading to additional neurological impairments like developmental delays and seizures. Amniotic band syndrome often causes atypical oblique or transverse facial clefts through mechanical disruption in utero, resulting in asymmetric deformities and potential limb involvement. , a ciliopathy, presents with craniofacial clefts alongside digital anomalies and oral malformations, contributing to feeding difficulties and recurrent infections. Psychosocial complications are significant, with individuals experiencing elevated challenges. Similar to patients with cleft lip and palate, where depression rates are approximately twice as high compared to the general population, those with craniofacial clefts may face heightened risks stemming from concerns and , though specific data for these rarer conditions are limited. Educational delays are common, particularly in expressive , leading to underachievement and behavioral inhibition in school settings. Long-term neurodevelopmental outcomes, including potential cognitive delays and seizures, are a concern especially in clefts involving the cranium (Tessier types 8-14), due to associated anomalies; however, large-scale studies remain scarce, emphasizing the need for lifelong monitoring. Knowledge gaps persist regarding long-term outcomes, especially into adulthood, where data on persistent aesthetic and functional issues like nasal obstruction and remain limited from single-center studies. Longitudinal research post-2020 is needed to better understand lifelong impacts and optimize multidisciplinary care.

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