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.

The following is a list of symptoms that have been associated with Roberts syndrome:

- Bilateral Symmetric Tetraphocomelia- a birth defect in which the hands and feet are attached to shortened arms and legs

- Prenatal Growth Retardation

- Hypomelia (Hypoplasia)- the incomplete development of a tissue or organ; less drastic than aplasia, which is no development at all

- Oligodactyly- fewer than normal number of fingers or toes

- Thumb Aplasia- the absence of a thumb

- Syndactyly- condition in which two or more fingers (or toes) are joined together; the joining can involve the bones or just the skin between the fingers

- Clinodactyly- curving of the fifth finger (little finger) towards the fourth finger (ring finger) due to the underdevelopment of the middle bone in the fifth finger

- Elbow/Knee Flexion Contractures- an inability to fully straighten the arm or leg

- Cleft Lip- the presence of one or two vertical fissures in the upper lip; can be on one side (unilateral) or on both sides (bilateral)

- Cleft Palate- opening in the roof of the mouth

- Premaxillary Protrusion- upper part of the mouth sticks out farther than the lower part of the mouth

- Micrognathia- small chin

- Microbrachycephaly- smaller than normal head size

- Malar Hypoplasia- underdevelopment of the cheek bones

- Downslanting Palpebral Fissures- the outer corners of the eyes point downwards

- Ocular Hypertelorism- unusually wide-set eyes

- Exophthalmos- a protruding eyeball

- Corneal Clouding- clouding of the front-most part of the eye

- Hypoplastic Nasal Alae- narrowing of the nostrils that can decrease the width of the nasal base

- Beaked Nose- a nose with a prominent bridge that gives it the appearance of being curved

- Ear Malformations

- Intellectual disability

- Encephalocele (only in severe cases)- rare defect of the neural tube characterized by sac-like protrusions of the brain

Mortality is high among those severely affected by Roberts syndrome; however, mildly affected individuals may survive to adulthood

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 clinical presentation of HFM is quite variable. The severity may depend on the extent of the area with an insufficient blood supply "in utero", and the gestational age of the fetus at which this occurs. In some people, the only physical manifestation may be a small and underdeveloped external ear. In more severe cases, multiple parts of the face may be affected. Some people with HFM may have sensorineural hearing loss and decreased visual acuity or even blindness.

Goldenhar syndrome can be thought of as a particularly severe form of HFM, in which extracranial anomalies are present to some extent. Some of the internal organs (especially the heart, kidneys, and lungs) may be underdeveloped, or in some cases even absent altogether. The affected organs are typically on the same side as the affected facial features, but bilateral involvement occurs in approximately 10% of cases. Deformities of the vertebral column such as scoliosis may also be observed in Goldenhar syndrome.

While there is no universally accepted grading scale, the OMENS scale (standing for Orbital, Mandible, Ear, Nerves and Soft tissue) was developed to help describe the heterogeneous phenotype that makes up this sequence or syndrome.

Intellectual disability is not typically seen in people with HFM.

Most of the signs of MWS are present during the neonatal period. The most common signs at this state are multiple congenital joint contractures, dysmorphic features with mask-like face, blepharophimosis, ptosis, micrognathia, cleft or high arched palate, low-set ears, arachnodactyly, chest deformation as pectus, kyphoscoliosis and absent deep tendon reflexes are frequent minor malformations have also been described and consist of renal anomalies, cardiovascular abnormalities, hypospadias, omphalomesenteric duct, hypertriphic pyloric stenosis, duodenal bands, hyoplastic right lower lobe of the lung, displacement of the larynx to the right and vertebral abnormalities, cerebral malformations.

- 75% of children with MWS have blepharophimosis, small mouth, micrognathia, kyphosis/scoliosis, radio ulnar synostose and multiple contractures.

- They have severe developmental delay; congenital joint contractures and blepharophimosis should be present in every patient

- 2 out of 3 of the following signs should be manifested: post natal growth, mask-like faces, retardation, and decreased muscular mass.

- Some may require additional signs such as; micrognathia, high arched or cleft palate, low set ears, kyphoscoliosis.

- The symptoms of MWS are normally diagnosed during the newborn period

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.

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

The natural history of MWS is not well known: many patients died in infancy and clinical follow-up has been reported in few surviving adults. However, diagnosis may be more difficult to establish in adults patients, such as: blepharophimosis, contractures, growth retardation, and developmental delay, whereas minor face anomalies are less noticeable as the patient grows older. Throughout the development of the patient from young child to older adult changes the behavior drastically, from kindness to restless and hyperactive to aggressive.

Aneuploidy is often fatal, but in this case there is "X-inactivation" where the effect of the additional gene dosage due to the presence of extra X chromosomes is greatly reduced.

Much like Down syndrome, the mental effects of 49,XXXXY syndrome vary. Impaired speech and behavioral problems are typical. Those with 49,XXXXY syndrome tend to exhibit infantile secondary sex characteristics with sterility in adulthood and have some skeletal anomalies. Skeletal anomalies include:

- Genu valgum

- Pes cavus

- Fifth finger clinodactyly

The effects also include:

- Cleft palate

- Club feet

- Respiratory conditions

- Short or/and broad neck

- Low birth weight

- Hyperextensible joints

- Short stature

- Narrow shoulders

- Coarse features in older age

- Hypertelorism

- Epicanthal folds

- Prognathism

- Gynecomastia (rare)

- Muscular hypotonia

- Hypoplastic genitalia

- Cryptorchidism

- Congenital heart defects

- A very round face in infancy

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.

The condition is also known by various other names:

- Lateral facial dysplasia

- First and second branchial arch syndrome

- Oral-mandibular-auricular syndrome

- Otomandibular dysostosis

- Craniofacial microsomia

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 three most common symptoms of Opitz G/BBB syndrome (both type I & II) are hypertelorism (exceptionally wide-spaced eyes), laryngo-tracheo-esophalgeal defects (including clefts and holes in the palate, larynx, trachea and esophagus) and hypospadias (urinary openings in males not at the tip of the penis) (Meroni, Opitz G/BBB syndrome, 2012). Abnormalities in the larynx, trachea and esophagus can cause significant difficulty breathing and/or swallowing and can result in reoccurring pneumonia and life-threatening situations. Commonly, there may be a gap between the trachea and esophagus, referred to as a laryngeal cleft; which can allow food or fluid to enter the airway and make breathing and eating a difficult task.

Genital abnormalities like a urinary opening under the penis (hypospadias), undescended testes (cryptorchidism), underdeveloped scrotum and a scrotum divided into two lobes (bifid scrotum) can all be commonplace for males with the disease.

Developmental delays of the brain and nervous system are also common in both types I and II of the disease. 50% of people with Opitz G/BBB Syndrome will experience developmental delay and mild intellectual disability. This can impact motor skills, speech and learning capabilities. Some of these instances are likened to autistic spectrum disorders. Close to half of the people with Opitz G/BBB Syndrome also have a cleft lip (hole in the lip opening) and possibly a cleft palate (hole in the roof of the mouth), as well. Less than half of the people diagnosed have heart defects, imperforate anus (obstructed anal opening), and brain defects. Of all the impairments, female carriers of X-linked Type I Opitz G/BBB Syndrome usually only have ocular hypertelorism.

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.

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.

Little is known about the natural history of Roberts syndrome due to its wide clinical variability. The prognosis of the disease depends on the malformations, as the severity of the malformations correlates with survival. The cause of death for most fatalities of Roberts syndrome have not been reported; however, five deaths were reportedly due to infection.

The following are observations that have been made in individuals with cytogenetic findings of PCS/HR or ESCO2 mutations:

- The symptom of prenatal growth retardation is the most common finding and can be moderate to severe. Postnatal growth retardation can also be moderate to severe and correlates with the degree of severity of limb and craniofacial malformations.

- In limb malformations, the upper limbs are typically more severely affected than the lower limbs. There have been many cases of only upper limb malformation.

- In hand malformations, the thumb is most often affected, followed by the fifth finger (the little finger). In severe cases, the patient may only have three fingers and in rare cases only one.

- In craniofacial malformations, mildly affected individuals will have no abnormalities of the palate. The most severely affected will have a fronto-ethmoid-nasal-maxillary encephalocele.

- The severity of limb malformations and craniofacial malformations is correlated.

- Other abnormalities can occur in different parts of the body, including:

- Heart- atrial septal defects, ventricular septal defects, patent ductus arteriosus

- Kidneys- polycystic kidney, horseshoe kidney

- Male Genitals- enlarged penis, cryptorchidism

- Female Genitals- enlarged clitoris

- Hair- sparse, silvery-blonde scalp hair

- Cranial Nerve Paralysis, Moyamoya disease, Stroke, Intellectual disability

This classification is based on the morphologic characteristics of FND, that describes a variety of phenotypes

Both of these classifications are further described in table 1. This table originates from the article ‘Acromelic frontonasal dysplasia: further delineation of a subtype with brain malformations and polydactyly (Toriello syndrome)', Verloes et al.

The main characteristics of 49,XXXXX are intellectual disability, short stature and craniofacial abnormalities. Other physical traits include the following:

- Small head

- Ear abnormalities

- Widely spaced eyes with upward slanting palpebral fissures and epicanthal folds

- Short neck

- Broad nose with a depressed nasal bridge

- Hyperextension of the elbows

- Dental abnormalities and cleft palate

- Clinodactyly of the 5th finger

- Deformities of the feet

- Heart defects

This syndrome is associated with microcephaly, arthrogryposis and cleft palate and various craniofacial, respiratory, neurological and limb abnormalities, including bone and joint defects of the upper limbs, adducted thumbs, camptodactyly and talipes equinovarus or calcaneovalgus. It is characterized by craniosynostosis, and myopathy in association with congenital generalized hypertrichosis.

Patients with the disease are considered intellectually disabled. Most die in childhood. Patients often suffer from respiratory difficulties such as pneumonia, and from seizures due to dysmyelination in the brain's white matter. It has been hypothesized that the Moro reflex (startle reflex in infants) may be a tool in detecting the congenital clapsed thumb early in infancy. The thumb normally extends as a result of this reflex.

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.

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.

X-linked type I Opitz G/BBB Syndrome is diagnosed on clinical findings, but those findings can vary greatly: even within the same family. Manifestations of X-linked type I are classified in the frequent/major findings and minor findings that are found in less than 50% of individuals.

The three major findings that suggest a person has X-linked Type I Opitz G/BBB Syndrome:

1. Ocular hypertelorism (~100% cases)

2. Hypospadias (85-90% cases)

3. Laryngotracheoesophageal abnormalities (60-70%)

Minor findings found in less than 50% of individuals:

1. Developmental delay (especially intellectually)

2. Cleft lip/palate

3. Congenital heart defects

4. Imperforate (blocked) anus

5. Brain defects (especially corpus callosum)

In 1989, Hogdall used ultrasonographs to diagnose X-linked Type I Opitz G/BBB Syndrome after 19 weeks of pregnancy, by identifying hypertelorism (widely-spaced eyes) and hypospadias (irregular urinary tract openings in the penis).

There is also molecular genetic testing available to identify mutations leading to Opitz G/BBB Syndrome. X-linked Type I testing must be done on MID1, since this is the only gene that is known to cause Type I Opitz G/BBB Syndrome. Two different tests can be performed: sequence analysis and deletion/duplication analysis. In the sequence analysis a positive result would detect 15-50% of the DNA sequence mutated, while a deletion/duplication positive result would find deletion or duplication of one or more exons of the entire MID1 gene.

Associated symptoms range from things such as colobomas of the eyes, heart defects, ichthyosiform dermatosis, intellectual disability, and ear abnormalities. Further symptoms that may be suggested include characteristic facies, hearing loss, and cleft palate.

Popliteal pterygium syndrome (PPS) is an inherited condition affecting the face, limbs, and genitalia. The syndrome goes by a number of names including the "popliteal web syndrome" and, more inclusively, the "facio-genito-popliteal syndrome". The term PPS was coined by Gorlin "et al.." in 1968 on the basis of the most unusual anomaly, the popliteal pterygium (a web behind the knee).

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.