Mandibulofacial dysostosis can include various types of facial abnormalities and various degrees of severity. Possible symptomatology is broad and involves the following [8]:

Skull

Patients exhibit underdeveloped zygomatic bones, sinuses and lower jaw. The eyes are often set wide apart from each other (hyperteloric orbits) and air cells are absent from the mastoids. The cranial base is abnormally curved. The aforementioned defects are observed via radiographic imaging.

Face

The nose seems disproportionately bigger, although its actual size is regular. This is caused by underdeveloped zygomatic bones and supraorbital rims. The longitudinal opening of the eyelids follows a downwards- sloping course and the outer part of the lower lids may also feature a coloboma. A receding lower jaw is also observable. Hearing loss is frequently diagnosed in patients with mandibulofacial dysostosis and is a result of ear deformities. The external part of the ear may be abnormally shaped and, as far as the middle mechanism is concerned, the patient may exhibit meatal atresia, underdeveloped or absent incus and malleus, lack of the middle ear and monopodal stapedes. The development of fistulas connecting the tragus and the outer corner of the mouth are also observed.

Additionally, approximately 30% of patients exhibit a given inability of the soft palate to accomplish palatopharyngeal closure, which leads to a cleft palate. Parotid glands may not be present and the pharynx is markedly underdeveloped.

Mental abilities

Mandibulofacial dysostosis is not accompanied by cognitive impairment. However, the frequent and severe hearing loss due to hypoplastic ear particles often lead to a wrongly diagnosed lower intelligence.

Generally, the clinical picture of the disease features fluctuating and diverse symptomatology. Most prominent features are hearing loss of the conductive type, dysphagia due to a cleft palate, problems with vision and a backwards displacement of the tongue.

• Developmental Delay

  CHARGE syndrome was discussed because of ear anomalies, choanal atresia, and developmental delay in our patients. [ncbi.nlm.nih.gov]

  […] loss and speech delay. [ctgt.net]

• Plethora

  A plethora of other genetic mutations has since been documented, which are extremely particular to the members of each family. [symptoma.com]

• Atrial Septal Defect

  […] atresia Birth defect in which part of esophagus did not develop 0002032 Proximal placement of thumb Attachment of thumb close to wrist 0009623 Seizures Seizure 0001250 Ventricular septal defect Hole in heart wall separating two lower heart chambers 0001629 [rarediseases.info.nih.gov]

• Poor Feeding

  […] language development Speech and language delay Speech and language difficulties Speech delay [ more ] 0000750 Feeding difficulties Feeding problems Poor feeding [ more ] 0011968 Hypoplasia of the maxilla Decreased size of maxilla Decreased size of upper [rarediseases.info.nih.gov]

• Dysphagia

  Our proband was born at 36 weeks gestation with microcephaly, microcrania, cleft palate, severe retrognathia, oral and pharyngeal dysphagia, bilateral proximal radioulnar synostosis, 11 thoracic ribs, abnormal magnetic resonance imaging (MRI) findings [ncbi.nlm.nih.gov]

  Initial psychometric assessment of a functional oral intake scale for dysphagia in stroke patients. Arch Phys Med Rehabil. 2005;86(8):1516-20. PMID: 16084801 DOI: http://dx.doi.org/10.1016/j.apmr.2004.11.049 Furkim AM, Sacco ABF. [tinnitusjournal.com]

  Most prominent features are hearing loss of the conductive type, dysphagia due to a cleft palate, problems with vision and a backwards displacement of the tongue. [symptoma.com]

• Macrostomia

  ·dib·u·lo·fa·cial dys·os·to·sis ( man-dib'yū-lō-fā'shăl dis'os-tō'sis ) Variable syndrome of malformations primarily of derivatives of pharyngeal arch; characterized by bony defects or hypoplasia of malar and zygomatic bones, hypoplasia of mandible, macrostomia [medical-dictionary.thefreedictionary.com]

  […] hallmarks of the syndrome are a round, flat face, severe hypertelorism, downslanting palpebral fissures extending to the temples, a broad nasal base, anteverted nares, small, posteriorly rotated ears, a long, smooth philtrum, a thin upper lip, striking macrostomia [ncbi.nlm.nih.gov]

  Two other genes also are known to cause Treacher Collins syndrome: POLR1C and POLR1D 3. dental and mandibular retrognathia micrognathia macrostomia hypoplasia or aplasia of the condylar and coronoid processes of the mandible marked bowing of the lower [radiopaedia.org]

  Macrostomia. Cleft palate and or cleft lip with palatopharyngeal incompetence. Obliteration of the nasal frontal angle with narrow nares and hypoplasia of the alar cartilages. [neuroradiologyonthenet.blogspot.com]

• Receding Chin

  Persons with the condition have downslanting eyes ( antimongoloid palpebral fissures); absence of all or part of the lower lid; underdeveloped cheekbones that appear depressed; a prominent nose, wide mouth, and small receding chin; underdeveloped, malformed [medical-dictionary.thefreedictionary.com]

  Plastic surgery can correct the receding chin and other changes in face structure. Children with this syndrome typically grow to become functioning adults of normal intelligence. [medlineplus.gov]

  Affecting 1 in 50,000 people, the syndrome results in some or all of the following: a small lower jaw and receding chin (technically called micrognathia) a very large mouth eyes that slant downwards scanty eyelashes along the lower eyelid tiny, absent [news-medical.net]

• Discolored Enamel

  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. [en.wikipedia.org]

• Visual Impairment

  An instrument (ophthalmoscope) is used to visualize the interior of the eye to detect any possibility of visual impairment. [rarediseases.org]

  impairment Impaired vision Loss of eyesight Poor vision [ more ] 0000505 Wide nasal bridge Broad nasal bridge Broad nasal root Broadened nasal bridge Increased breadth of bridge of nose Increased breadth of nasal bridge Increased width of bridge of nose [rarediseases.info.nih.gov]

• Blepharospasm

  Malformed teeth Misshapen teeth Misshapened teeth [ more ] 0006482 Abnormality of the adrenal glands Adrenal abnormalities 0000834 Abnormality of the vertebral column Abnormal spine Abnormal vertebral column Abnormality of the spine [ more ] 0000925 Blepharospasm [rarediseases.info.nih.gov]

• Ear Deformity

  Middle ear deformities, while present in both, are more severe when associated with mandibulofacial dysostosis. [ncbi.nlm.nih.gov]

  Hearing loss is frequently diagnosed in patients with mandibulofacial dysostosis and is a result of ear deformities. [symptoma.com]

• Hearing Impairment

  Children with hearing impairment will need support in terms of hearing aids or cochlear implant as well as speech and language therapy. [gosh.nhs.uk]

  A similar form of hearing impairment occurs in about 50% of affected individuals. TCS cannot be cured, but certain treatments may address its symptoms. [gradesaver.com]

  The child's ears may be normal, or they may be small, malformed or missing altogether, and hearing impairment is often part of the syndrome. Most children with MFD have complications related to speech, hearing, vision, swallowing and breathing. [ucsfbenioffchildrens.org]

  Genetic Hearing Impairment Its Clinical Presentations Editor(s): Cremers, C.W.R.J. (Nijmegen) Smith, R.J.H. (Iowa City, IA) Audiometric Patterns in Types of Common Syndromic Deafness Marres H.A.M. [doi.org]

  Mental abilities Mandibulofacial dysostosis is not accompanied by cognitive impairment. However, the frequent and severe hearing loss due to hypoplastic ear particles often lead to a wrongly diagnosed lower intelligence. [symptoma.com]

• Hearing Problem

  This can cause hearing problems if the ear's internal structures are also underdeveloped. Meanwhile, if the jaw is small or underdeveloped, this can cause problems with feeding and breathing. [thesun.co.uk]

  Careful attention should be given to any hearing problem in order for the child to realise their full potential. Prevention Genetic counselling is recommended for prospective parents with a family history of Treacher Collins' syndrome. [patient.info]

  It depends on the problems your child has, or may have in the future. If your baby does have TCS, you’ll want to get her hearing checked. Deformed bones in the face can also make it hard for your child to breathe and eat. [webmd.com]

  Symptoms Frequent middle ear infections Growth problems, short arms and legs Hearing problems Mental deficiency Unusual looking face Signs and tests Your health care provider can usually diagnose this condition with a physical exam. [coordinatedhealth.com]

  Symptoms Symptoms of this disorder include: Frequent middle ear infections Growth problems, short arms and legs Hearing problems Mental deficiency The body being resistant to certain hormones, even though hormone levels are normal Unusual looking face [nicklauschildrens.org]

• Low Set Ears

  An exam of the infant may reveal a variety of problems, including: Abnormal eye shape Flat cheekbones Cleft palate or lip Small jaw Low-set ears Abnormally formed ears Abnormal ear canal Hearing loss Defects in the eye (coloboma that extends into the [medlineplus.gov]

  The common features are macrostomia, low-set ears and ear defects, high-arched palate, nasal deformity, teeth malocclusion, open bite and conductive hearing loss. [patient.info]

  ears Low set ears Lowset ears [ more ] 0000369 Malar flattening Zygomatic flattening 0000272 Micrognathia Little lower jaw Small jaw Small lower jaw [ more ] 0000347 Microtia Small ears Underdeveloped ears [ more ] 0008551 Morphological abnormality of [rarediseases.info.nih.gov]

• Hypertelorism

  The hallmarks of the syndrome are a round, flat face, severe hypertelorism, downslanting palpebral fissures extending to the temples, a broad nasal base, anteverted nares, small, posteriorly rotated ears, a long, smooth philtrum, a thin upper lip, striking [ncbi.nlm.nih.gov]

  Convert to ICD-10-CM : 756.0 converts approximately to: 2015/16 ICD-10-CM Q75.0 Craniosynostosis Or: 2015/16 ICD-10-CM Q75.2 Hypertelorism Or: 2015/16 ICD-10-CM Q75.9 Congenital malformation of skull and face bones, unspecified Approximate Synonyms Absence [icd9data.com]

  Hypertelorism. Preoperative appearance of patient with hypertelorism and maxillary retrusion. Hypertelorism. Preoperative appearance of patient with hypertelorism and maxillary retrusion. [emedicine.com]

  Facial abnormalities showing hypertelorism, maxillary hypoplasia, broad low nasal bridge, short upturned nose with anteverted nostrils and triangular mouth. Figure 2. [hormones.gr]

• Dysphasia

  […] the rear opening of the nasal cavity Obstruction of the rear opening of the nasal cavity [ more ] 0000453 Cleft palate Cleft roof of mouth 0000175 Cleft upper lip Harelip 0000204 Cryptorchidism Undescended testes Undescended testis [ more ] 0000028 Dysphasia [rarediseases.info.nih.gov]

Ultrasonographic scans conducted as part of the standard obstetrical prenatal care are able to detect facial disfigurement early during the course of pregnancy [9] [10]. A definitive diagnosis would require genetic testing of parents and fetal cells or amnic fluid, but the procedure has not been applied clinically as of yet.

Postpartum, a newborn must be thoroughly examined, if the physical examination causes suspicion to arise in the direction of mandibulofacial dysostosis. Oxygen saturation should be meticulously monitored, feeding capability must be ensured and tests conducted to diagnose hearing impairment are also mandatory. Postnatal genetic diagnosis may be an invaluable tool in cases of a doubtful diagnosis. The same pertains to craniofacial computerized tomography scans, plain radiographs and a magnetic resonance imaging scan: they can all contribute to the establishing of a definitive diagnosis and the successful assessment of surgical options. Imaging studies include:

• A full craniofacial computed tomography (CT) scan
• A cephalography, with a lateral and anteroposterior view
• MRI of the brain, to assess the auditory tract
• Panoramic radiographs
• Orthopantomography, to evaluate mandibular underdevelopment and temporomandibular joint irregularity

Treatment of mandibulofacial dysostosis is symptomatic and individualized [11].

The first step after diagnoses is to ensure oxygenation sufficiency and assess dysphagic phenomena [12]. A backwards positioning of the mandible can result in substantial airway obstruction; therapeutic measures vary depending on the degree of severity. The newborn may be positioned in a way that enables normal breathing, but if this method fails, intubation and tracheostomy may be mandatory to ensure breathing. Tracheostomy may be required for years before a normal airway can be achieved.

Young individuals who cannot feed receive gavage-mediated feeding or a gastrostomy. Hearing loss should be treated with proper aids, in order to allow for the normal mental development of the child and intrafamilial bonding.

The retropositioning of the tongue, which leads to airway obstruction can also be addressed in a more invasive manner. It is surgically attached to the lip and anterior mandible, do that it is positioned in a more forward location and releases the nasopharynx. Distraction osteogenesis is a procedure that can also be performed in order to lengthen the mandible. Incisions are made to the jaw postpartum and distraction instruments are used to achieve stretching. The process is considered successful when the mandible is stretched 10 millimeters and the instrumentation is removed. Various other surgical solutions are available, depending on the type of deformity, whether they are aesthetic procedures or aim at enhancing functionality.

Mandibulofacial dysostosis involves facial disfigurement with unimpaired intelligence. Severe cases may result in some type of disability, but surgical corrections can restore the greater part. Hearing function should be paid attention to and evaluated from a young age.

Mandibulofacial dysostosis is a genetic condition. Various genes have been identified, with TCOF1 being the predominant mutation in over 90% of the patients diagnosed with the disease [3] [4]. Ribosomal RNA formation is abnormal as a result of the mutation, which leads to a disfigured face, due to impairment of the proteins mediating the formation of the facial skeleton.

The specific pattern of inheritance depends on each individual's mutation. An abnormal TCOF1 or POLR1D gene (the latter being a less frequent mutation leading to the same phenotype) is passed down via an autosomal dominant pathway; this means that at least one parent is already affected by the disease. On the other hand, another mutation to the POLR1C gene is inherited via an autosomal recessive inheritance pattern and means that a child can be born with mandibulofacial dysostosis from two completely unaffected individuals.

Spontaneous mutations have also been observed; in fact, the majority of patients are descended from families with no other diseased member.

Mandibulofacial dysostosis affects 0.5 to 1 per 50,000 live births [5] and is usually detected postnatally. Embryos that are severely disfigured may be diagnosed during pregnancy with the aid of an ultrasonographic evaluation. Newborns with insignificant symptomatology may be diagnosed later in life, when the development of facial features makes abnormalities more prominent. 

Mandibulofacial dysostosis is a result of various mutations to the TFCO1, POLR1D and POLR1C genes. Over 90% of the patients exhibit mutations related to the TFCO1 genetic location, a mutation that is passed down to a person's offspring via an autosomal dominant pattern of inheritance; penetrance is almost always 100%. The majority of the cases, however, develop the disease as a result of a spontaneous mutation to the aforementioned genes.

The genetic location of the most clinically significant gene, TFCO1, is on chromosome 5. As of yet, 50 distinct mutations have been documented, including deletions, insertions and splicing mutations. The particular genetic locus is responsible for the regulation of the production of the treacle protein; the latter is itself responsible for the formation and shaping of the facial skeleton. The molecular pathophysiologic mechanism is believed to encompass a given haploinsufficiency, due to the premature insertion of termination codons in the reading frame [6] [7].

The condition cannot be prevented, as it is either inherited or a result of a spontaneous mutation. Genetic counseling is mandatory to parents descended from families with a history of the disease.

Mandibulofacial dysostosis (MFD) is a condition also known as Treacher-Collins syndrome and is inherited primarily via an autosomal dominant inheritance pattern. The first gene ever to be detected for this condition is the TCOF1 gene, responsible for the production of the nucleolar phosphoprotein Treacle [1]. A plethora of other genetic mutations has since been documented, which are extremely particular to the members of each family. The 5th chromosome is invariably implicated in the mutation process, according to genetic mapping carried out in many families with the condition and relatively small deleted regions can lead to the MFD syndrome.

However, more than half of the patients diagnosed with the disease are born into families with no prior medical history of mandibulofacial dysostosis, a fact which delineates the possibility of spontaneous mutations as well. The syndrome is characterized by extreme symptom variability: even though the penetrance of the abnormal gene is believed to be increased, there are family members who carry the mutation and display minimal symptomatology, even non-observable one. On the other hand, the mutation may be so intensely expressed in other newborns, that perinatal death might occur. The fluctuating clinical picture and characteristics associated with the disease indicate that not only genetics, but environmental factors and random variables play a significant role to each individual's phenotype [2].

Mandibulofacial dysostosis, otherwise known as Treacher Collins syndrome, is a congenital condition which leads to disfigured facial characteristics.

The disease is a result of genetic mutation. The gene that is most commonly involved is the TFCO1 gene on chromosome 5 and over 50 mutations have been tracked until now. This gene is responsible for the production of a protein, without which, facial characteristics cannot fully form. Mandibulofacial dysostosis most of the times occurs spontaneously, without any genetic family background (60% of the cases); in the rest of the cases it is inherited from the parents. There are two possible ways to inherit a defective gene: the autosomal recessive pattern and the autosomal dominant pattern. In cases of autosomal dominant inheritance, a parent is already affected by the condition and is they pass one defective gene to their offspring, the latter will also develop the disease. In the pattern of inheritance is the autosomal recessive one, both parents can be normal, but if they both carry a mutated gene and they both pass it down to their offspring, the child will be born with mandibulofacial dysostosis.

Most symptoms are observed simply with the eye and include underdeveloped cheek bones, abnormal ears, an opening in the roof of the mouth (cleft palate), eyes at an abnormally long distance from each other and a very small lower jaw. Sometimes the tongue is positioned backwards in the mouth; this feature alongside the small jaw may result in the obstruction of the airway. People with mandibulofacial dysostosis have normal intelligence but may have significant hearing loss.

The condition can be detected before birth. Chorionic villous sampling, amniocentesis and an ultrasonographic scan can help to diagnose the disease. After birth, a physical examination will reveal facial characteristics which are compatible with the syndrome.

Therapy is designed depending on the particular symptoms of each patient. Breathing problems are treated with a more convenient positioning of the newborn, with a tracheostomy or a surgical procedure which pulls the tongue forward, so that the airway is free. Hearing aids are used to restore hearing to a considerable degree and the cleft palate can also be surgically mended. Psychological support is of vital importance both to the children and their families.

1. Treacher Collins Syndrome Collaborative Group: Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nat Genet. 1996; 12: 130–136.
2. Dixon J, Dixon MJ. Genetic background has a major effect on the penetrance and severity of craniofacial defects in mice heterozygous for the gene encoding the nucleolar protein Treacle. Dev Dyn. 2004; 229: 907–914.
3. The Treacher Collins Syndrome Collaborative Group. Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. Nat Genet. 1996 Feb; 12(2):130-6.
4. Wise CA, Chiang LC, Paznekas WA, et al. TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region. Proc Natl Acad Sci U S A. 1997 Apr 1; 94(7):3110-5.
5. Fazen LE, Elmore J, Nadler HL. Mandibulo-facial dysostosis (Treacher-Collins syndrome). Am J Dis Child. 1967; 113: 405–410.
6. Lines MA, Huang L, Schwartzentruber J, et al. Haploinsufficiency of a Spliceosomal GTPase Encoded by EFTUD2 Causes Mandibulofacial Dysostosis with Microcephaly. Am J Hum Genet. 2012 Feb 10; 90(2):369-77.
7. Edwards SJ, Gladwin AJ, Dixon MJ. The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon. Am. J. Hum. Genet. 1997; 60:515-524.
8. Gorlin RJ, Cohen MM Jr, Hennekam RCM. Syndromes of the head and neck, 4th ed. Oxford University Press. 2001.
9. Nicolaides KH, Johansson D, Donnai D, et al. Prenatal diagnosis of mandibulofacial dysostosis. Prenat Diagn. 1984 May-Jun; 4(3):201-5.
10. Tolarova M, Zwinger A. The use of fetoscopy by inborn morphological anomalies. Acta Chir Plast. 1981; 23(3):139-51.
11. Thompson JT, Anderson PJ, David DJ. Treacher Collins Syndrome: Protocol Management From Birth to Maturity. J Craniofac Surg. 2009 Oct 29.
12. Hosking J, Zoanetti D, Carlyle A, et al. Anesthesia for Treacher Collins syndrome: a review of airway management in 240 pediatric cases. Paediatr Anaesth. 2012 Mar 7.