Clinical diagnosis based on orofacial clefts and lip pits typically occurs shortly after birth. Certain defects may be difficult to diagnose, particularly a submucous cleft palate. This form of CP may not be detected except through finger palpation, as the mucosa covering the palate is intact, but the muscles underneath have lost their proper attachments. Feeding problems, impaired speech, and hearing loss are symptoms of a submucous cleft palate. Furthermore, approximately 15% of VWS cases with orofacial clefts, in the absence of prominent lip pits, cannot be easily distinguished from non-syndromic forms of orofacial clefting. Therefore, it is very important to closely examine these patients as well as their relatives for lip pits, especially when there is a family history of mixed clefting, in order to make the VWS diagnosis. Dentists may also play an important role in diagnosing cases not detected at birth, as they detect hypodontia commonly associated with VWS. The

patients most commonly lack the upper second premolars followed by the lower second premolars and upper lateral incisors. The absence of these teeth might play a role in the constricting of the dental arches.

The clinical signs seen in VWS are similar to those of popliteal pterygium syndrome (PPS), which is also an autosomal dominant disease. Approximately 46% of affected individuals have lip pits; other features include genital abnormalities, abnormal skin near nails, syndactyly of fingers and toes, and webbed skin. The disease is also caused by mutations in "IRF6"; however, they occur in the DNA-binding domain of "IRF6" and result in a dominant negative effect in which the mutated IRF6 transcription factor interferes with the ability of the wild type copy to function, in the case of a heterozygous individual.

This version of macrostomia is less severe because it does not affect the facial muscles and is not associated with any soft tissue or bone deformities. A small cleft(s) extends from the mouth and can be repaired surgically.

Clefts in this variant are slightly more severe than the ones seen in simple macrostomia. It also does not have bone deformities, but it does include minor soft tissue deformities. The defining feature is muscle diastasis which is separation of the masseter. This phenotype can also be partially corrected with surgery.

They are divided into three types based on their location:

- commissural pits, which are small pits near the labial commissure of the mouth,

- a pit in the upper lip, in which case it may be called a midline sinus of the upper lip, and

- pits in the lower lip, in which case it may be called a congenital sinus of the lower lip.

In some cases commissural pits have been reported in combination with preauricaluar pits, which are near the ear.

Chief markers of Goldenhar syndrome are incomplete development of the ear, nose, soft palate, lip, and mandible on usually one side of the body. Additionally, some patients will have growing issues with internal organs, especially heart, kidneys, and lungs. Typically, the organ will either not be present on one side or will be underdeveloped. Note that while it is more usual for there to be problems on only one side, it has been known for defects to occur bilaterally (approximate incidence 10% of confirmed GS cases).

Other problems can include severe scoliosis (twisting of the vertebrae), limbal dermoids, and hearing loss (see hearing loss with craniofacial syndromes), and deafness or blindness in one or both ears/eyes, Granulosa cell tumors may be associated as well.

The Pai Syndrome is a rare subtype of frontonasal dysplasia. It is a triad of developmental defects of the face, comprising midline cleft of the upper lip, nasal and facial skin polyps and central nervous system lipomas. When all the cases are compared, a difference in severity of the midline cleft of the upper lip can be seen. The mild form presents with just a gap between the upper teeth. The severe group presents with a complete cleft of the upper lip and alveolar ridge.

Nervous system lipomas are rare congenital benign tumors of the central nervous system, mostly located in the medial line and especially in the corpus callosum. Generally, patients with these lipomas present with strokes. However, patients with the Pai syndrome don’t. That is why it is suggested that isolated nervous system lipomas have a different embryological origin than the lipomas present in the Pai syndrome. The treatment of CNS lipomas mainly consists of observation and follow up.

Skin lipomas occur relatively often in the normal population. However, facial and nasal lipomas are rare, especially in childhood. However, the Pai syndrome often present with facial and nasal polyps. These skin lipomas are benign, and are therefore more a cosmetic problem than a functional problem.

The skin lipomas can develop on different parts of the face. The most common place is the nose. Other common places are the forehead, the conjunctivae and the frenulum linguae. The amount of skin lipomas is not related to the severity of the midline clefting.

Patients with the Pai syndrome have a normal neuropsychological development.

Until today there is no known cause for the Pai syndrome.

The large variety in phenotypes make the Pai syndrome difficult to diagnose. Thus the incidence of Pai syndrome seems to be underestimated.

The general presentation is of a skin-covered nodule, papule, or nodule of the skin surface, usually immediately anterior to the auricle. However, it may be anywhere within the periauricular tissues. Bilateral presentation can be seen.

Midfacial malformations can be subdivided into two different groups. One group with hypertelorism, this includes FND. The other with hypotelorism (a decreased distance between the eyes), this includes holoprosencephaly (failure of development of the forebrain). In addition, a facial cleft can be classified using the Tessier classification. Each of the clefts is numbered from 0 to 14. The 15 different types of clefts are then subdivided into 4 groups, based on their anatomical position in the face: midline clefts, paramedian clefts, orbital clefts and lateral clefts. FND is a midline cleft, classified as Tessier 0/14.

Besides this, the additional anomalies seen in FND can be subdivided by region. None of these anomalies are specific for the syndrome of FND, but they do occur more often in patients with FND than in the population. The anomalies that may be present are:

- Nasal: mild anomalies to nostrils that are far apart and a broad nasal root, a notch or cleft of the nose and accessory nasal tags.

- Ocular: narrowed eye slits, almond shaped eyes, epicanthal folds (extra eyelid tissue), epibulbar dermoids (benign tumors of the eye), upper eyelid colombas (full thickness upper eyelid defects), microphtalmos (one or two small eyes), congenital cataract and degeneration of the eye with retinal detachment.

- Facial: telecanthus (an increased distance between the corners of the eye), a median cleft of the upper lip and/or palatum, and a V-shaped hairline.

- Others: polydactyly (an excess of fingers or toes), syndactyly (fused fingers or toes), brachydactyly (short fingers and/or toes), clinodactyly (bending of the fifth fingers towards the fourth fingers), preauricular skin tags, an absent tragus, low set ears, deafness, small frontal sinuses, mental retardation, encephalocele (protrusion of the brain), spina bifida (split spine), meningoencephalocele (protrusion of both meninges), umbilical hernia, cryptorchidism (absence of one or two testes) and possibly cardiac anomalies.

The clefts of the face that are present in FND are vertical clefts. These can differ in severity. When they are less severe, they often present with hypertelorism and normal brain development.

Mental retardation is more likely when the hypertelorism is more severe or when extracephalic anomalies occur.

Van der Woude syndrome (VDWS) is a genetic disorder characterized by the combination of lower lip pits, cleft lip with or without cleft palate, and cleft palate alone (CP). The frequency of orofacial clefts ranges from 1:1000 to 1:500 births worldwide, and there are more than 400 syndromes that involve cleft lip with or without cleft palate. VWS is distinct from other clefting syndromes due to the combination of cleft lip and palate (CLP) and CP within the same family. Other features frequently associated with VWS include hypodontia in 10-81% of cases, narrow arched palate, congenital heart disease, heart murmur and cerebral abnormalities, syndactyly of the hands, polythelia, ankyloglossia, and adhesions between the upper and lower gum pads.

The association between lower lip pits and cleft lip and/or palate was first described by Anne Van der Woude in 1954. The worldwide disease incidence ranges from 1:100,000 to 1:40,000.

In some cases, cleft palate is caused by syndromes which also cause other problems:

- Stickler's Syndrome can cause cleft lip and palate, joint pain, and myopia.

- Loeys-Dietz syndrome can cause cleft palate or bifid uvula, hypertelorism, and aortic aneurysm.

- Hardikar syndrome can cause cleft lip and palate, Hydronephrosis, Intestinal obstruction and other symptoms.

- Cleft lip/palate may be present in many different chromosome disorders including Patau Syndrome (trisomy 13).

- Malpuech facial clefting syndrome

- Hearing loss with craniofacial syndromes

- Popliteal pterygium syndrome

- Treacher Collins Syndrome

Symptoms in people with Treacher Collins syndrome vary. Some individuals are so mildly affected that they remain undiagnosed, while others have moderate to severe facial involvement and life-threatening airway compromise. Most of the features of TCS are symmetrical and are already recognizable at birth.

The most common symptom of Treacher Collins syndrome is underdevelopment of the lower jaw and underdevelopment of the zygomatic bone. This can be accompanied by the tongue being retracted. The small mandible can result in a poor occlusion of the teeth or in more severe cases, trouble breathing or swallowing. Underdevelopment of the zygomatic bone gives the cheeks a sunken appearance.

The external ear is sometimes small, rotated, malformed, or absent entirely in people with TCS. Symmetric, bilateral narrowing or absence of the external ear canals is also described. In most cases, the bones of the middle ear and the middle ear cavity are misshapen. Inner ear malformations are rarely described. As a result of these abnormalities, a majority of the individuals with TCS have conductive hearing loss.

Most affected people also experience eye problems, including colobomata (notches) in the lower eyelids, partial or complete absence of eyelashes on the lower lid, downward angled eyelids, drooping of upper and lower eyelids, and narrowing of the tear ducts. Vision loss can occur and is associated with strabismus, refractive errors, and anisometropia. It can also be caused by severely dry eyes, a consequence of lower eyelid abnormalities and frequent eye infections.

Although an abnormally shaped skull is not distinctive for Treacher Collins syndrome, brachycephaly with bitemporal narrowing is sometimes observed. Cleft palate is also common.

Dental anomalies are seen in 60% of affected people, including tooth agenesis (33%), discoloration (enamel opacities) (20%), malplacement of the maxillary first molars (13%), and wide spacing of the teeth. In some cases, dental anomalies in combination with mandible hypoplasia result in a malocclusion. This can lead to problems with food intake and the ability to close the mouth.

Less common features of TCS may add to an affected person's breathing problems, including sleep apnea. Choanal atresia or stenosis is a narrowing or absence of the choanae, the internal opening of the nasal passages. Underdevelopment of the pharynx, can also narrow the airway.

Features related to TCS that are seen less frequently include nasal deformities, high-arched palate, macrostomia, preauricular hair displacement, cleft palate, hypertelorism, notched upper eyelid, and congenital heart defects.

The general public may associate facial deformity with developmental delay and intellectual disability, but more than 95% of people affected with TCS have normal intelligence. The psychological and social problems associated with facial deformity can affect quality of life in people with TCS.

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.

The several components or degrees of development range from an ear tag, preauricular appendage, preauricular tag, or accessory tragus, to supernumerary ears or polyotia. It is a relatively common congenital anomaly of the first branchial arch or second branchial arches. Other anomalies may be present concurrently, including cleft palate, cleft lip, or mandibular hypoplasia. There is a known association with Goldenhar syndrome (oculo-auriculo-vertebral syndrome) and with Wildervanck syndrome. There may also be an association with congenital cartilaginous rest of the neck.

A congenital lip pit or lip sinus is a congenital disorder characterized by the presence of pits and possibly associated fistulas in the lips. They are often hereditary, and may occur alone or in association with cleft lip and palate, termed Van der Woude syndrome.

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. People with this condition are frequently tongue-tied.

If the cleft does not affect the palate structure of the mouth, it is referred to as cleft lip. Cleft lip is formed in the top of the lip as either a small gap or an indentation in the lip (partial or incomplete cleft), or it continues into the nose (complete cleft). Lip cleft can occur as a one-sided (unilateral) or two-sided (bilateral) condition. It is due to the failure of fusion of the maxillary and medial nasal processes (formation of the primary palate).

A mild form of a cleft lip is a microform cleft. A microform cleft can appear as small as a little dent in the red part of the lip or look like a scar from the lip up to the nostril. In some cases muscle tissue in the lip underneath the scar is affected and might require reconstructive surgery. It is advised to have newborn infants with a microform cleft checked with a craniofacial team as soon as possible to determine the severity of the cleft.

The symptoms of phocomelia syndrome are undeveloped limbs and absent pelvic bones; however, various abnormalities can occur to the limbs and bones. Usually the upper limbs are not fully formed and sections of the "hands and arms may be missing." Short arm bones, fused fingers, and missing thumbs will often occur. Legs and feet are also affected similarly to the arms and hands. Individuals with phocomelia will often lack thigh bones, and the hands or feet may be abnormally small or appear as stumps due to their close "attachment to the body."

According to NORD, individuals carrying phocomelia syndrome will generally show symptoms of growth retardation previous to and after birth. The syndrome can also cause severe mental deficiencies in infants. Infants born with phocomelia will normally have a petite head with "sparse hair" that may appear "silvery-blonde." Hemangioma, the abnormal buildup of blood vessels, will possibly develop around the facial area at birth and the eyes may be set widely apart, a condition known as orbital hypertelorism. The pigment of the eyes will be a bluish white. Phocomelia can also cause: an undeveloped nose with slender nostrils, disfigured ears, irregularly petite jaws [also known as micrognathia], and a cleft lip with cleft palate. According to NORD, severe symptoms of phocomelia include:

- A fissure of the skull and a projecting brain known as (encephalocele)

- An accumulation of spinal fluid under the skull also known as hydrocephalus; causing vomiting and migraines

- An abnormally shaped uterus (bicornuate)

- Inability to clot blood efficiently due to a low amount of platelets running through the blood

- Malformations in the kidney and heart

- Shortened neck

- Abnormalities in the urethra

This syndrome is characterised by typical facial appearance, slight build, thin and translucent skin, severely adducted thumbs, arachnodactyly, club feet, joint instability, facial clefting and bleeding disorders, as well as heart, kidney or intestinal defects. Severe psychomotor and developmental delay and decreased muscle tone may also be present during infancy. Cognitive development during childhood is normal.

Ectodermal dysplasia is characterized by absent sweat glands resulting in dry (hypohydrotic), often scale-like skin, sparse and usually coarse scalp hair that is often blonde, sparse eyebrows and eyelashes, and small brittle nails. In addition, abnormalities of ectodermal derivatives, neuroectodermal derivatives, and mesectodermal derivatives are often found. The ectodermal derivative abnormalities can affect the epidermis including mammary, pituitary and sweat glands, as well as hairs, dental enamel, nails, lens, and the internal ear. Neuroectodermal derivatives that can be affected include sensory placodes, cutaneous pigmental cells, and hair buds. Mesectodermal derivatives affected can include the dermis, hypodermis, dentin, head muscles and conjunctival cells, cervicofacial vascular endothelial cells, and part of the maxillofacial skeleton.

The hypohydrotic symptoms of ectodermal dysplasia described above are evidenced not only in the skin of affected individuals, but also in their phonation and voice production. Because the vocal folds may not be as hydrated as is necessary during the adduction phase of vocal fold vibration (due to lack of lubrication), a complete seal may not be accomplished between the folds and mucosal wave movement may be disrupted. This results in air escapement between the folds and the production of breathy voice, which often accompanies the skin abnormalities of ectodermal dysplasia.

There is much discrepancy in the literature regarding the exact nature of the facial clefting involved in EEC. Some authors claim that the clefting involved in EEC is always cleft lip +/- palate and use this marker as a means of distinguishing EEC from other syndromes, such as AEC syndrome (ankyloblepharon, ectodermal dysplasia, and clefting) in which other types of clefting are found. Other authors include cleft palate only (CPO) in conjunction with ectrodactyly and ectodermal dysplasia as sufficient for a diagnosis of EEC.

Goldenhar syndrome (also known as oculo-auriculo-vertebral (OAV) syndrome) is a rare congenital defect characterized by incomplete development of the ear, nose, soft palate, lip, and mandible. It is associated with anomalous development of the first branchial arch and second branchial arch. Common clinical manifestations include limbal dermoids, preauricular skin tags, and strabismus.

The term is sometimes used interchangeably with hemifacial microsomia, although this definition is usually reserved for cases without internal organ and vertebrae disruption.

It affects between 1/3,500 and 1/26,000 live births, with a male:female ratio of 3:2.

TCS is often first suspected with characteristic symptoms observed during a physical exam. However, the clinical presentation of TCS can resemble other diseases, making diagnosis difficult. The OMENS classification was developed as a comprehensive and stage-based approach to differentiate the diseases. This acronym describes five distinct dysmorphic manifestations, namely orbital asymmetry, mandibular hypoplasia, auricular deformity, nerve development, and soft-tissue disease.

Orbital symmetry

- O0: normal orbital size, position

- O1: abnormal orbital size

- O2: abnormal orbital position

- O3: abnormal orbital size and position

Mandible

- M0: normal mandible

- M1: small mandible and glenoid fossa with short ramus

- M2: ramus short and abnormally shaped

1. 2A: glenoid fossa in anatomical acceptable position

2. 2B: Temperomandibular joint inferiorly (TMJ), medially, anteriorly displaced, with severely hypoplastic condyle

- M3: Complete absence of ramus, glenoid fossa, and TMJ

Ear

- E0: normal ear

- E1: Minor hypoplasia and cupping with all structures present

- E2: Absence of external auditory canal with variable hypoplasia of the auricle

- E3: Malposition of the lobule with absent auricle, lobular remnant usually inferior anteriorly displaced

Facial nerve

- N0: No facial nerve involvement

- N1: Upper facial nerve involvement (temporal or zygomatic branches)

- N2: Lower facial nerve involvement (buccal, mandibular or cervical)

- N3: All branches affected

Soft tissue

- S0: No soft tissue or muscle deficiency

- S1: Minimal tissue or muscle deficiency

- S2: Moderate tissue or muscle deficiency

- S3: Severe tissue or muscle deficiency

Clinical expressions of PPS are highly variable, but include the following:

- Limb findings: an extensive web running from behind the knee down to the heel (90%), malformed toenails, and webbed toes.

- Facial findings: cleft palate with or without cleft lip (75%), pits in the lower lip (40%), and fibrous bands in the mouth known as syngnathia (25%).

- Genital findings (50%): hypoplasia of the labia majora, malformation of the scrotum, and cryptorchidism.

Ectrodactyly, split hand, cleft hand, derived from the Greek "ektroma" (abortion) and "daktylos" (finger) involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand/split foot malformation (SHFM). The hands and feet of people with ectrodactyly are often described as "claw-like" and may include only the thumb and one finger (usually either the little finger, ring finger, or a syndactyly of the two) with similar abnormalities of the feet.

It is a rare form of a congenital disorder in which the development of the hand is disturbed. It is a type I failure of formation – longitudinal arrest. The central ray of the hand is affected and usually appears without proximal deficiencies of nerves, vessels, tendons, muscles and bones in contrast to the radial and ulnar deficiencies. The cleft hand appears as a V-shaped cleft situated in the centre of the hand. The digits at the borders of the cleft might be syndactilyzed, and one or more digits can be absent. In most types, the thumb, ring finger and little finger are the less affected parts of the hand. The incidence of cleft hand varies from 1 in 90,000 to 1 in 10,000 births depending on the used classification. Cleft hand can appear unilateral or bilateral, and can appear isolated or associated with a syndrome.

Split hand/foot malformation (SHFM) is characterized by underdeveloped or absent central digital rays, clefts of hands and feet, and variable syndactyly of the remaining digits. SHFM is a heterogeneous condition caused by abnormalities at one of multiple loci, including SHFM1 (SHFM1 at 7q21-q22), SHFM2 (Xq26), SHFM3 (FBXW4/DACTYLIN at 10q24), SHFM4 (TP63 at 3q27), and SHFM5 (DLX1 and DLX 2 at 2q31). SHFM3 is unique in that it is caused by submicroscopic tandem chromosome duplications of FBXW4/DACTYLIN. SHFM3 is considered 'isolated' ectrodactyly and does not show a mutation of the tp63 gene.

PRS is characterized by an unusually small mandible (micrognathia), posterior displacement or retraction of the tongue (glossoptosis), and upper airway obstruction. Incomplete closure of the roof of the mouth (cleft palate) is present in the majority of patients, and is commonly U-shaped.