Mandibulofacial dysostosis with microcephaly syndrome, also known as growth delay-intellectual disability-mandibulofacial dysostosis-microcephaly-cleft palate syndrome, mandibulofacial dysostosis, guion-almeida type, or simply as MFDM syndrome is a rare

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders ...

which is characterized by

developmental delays Global developmental delay is an umbrella term used when children are significantly delayed in two or more areas of development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, cognitive ...

intellectual disabilities Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

, and craniofacial dysmorphisms.

Signs and symptoms

People with this condition are usually born with congenital

microcephaly Microcephaly (from Neo-Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it m ...

, the type of microcephaly individuals with this condition exhibit ''progressive microcephaly'', this condition gives the appearance that the head is getting smaller as one ages, this is not true whatsoever; what is actually happening is that the head does not grow at the same rate as the rest of the body. Other craniofacial dysmorphisms include malar hypoplasia, midface and

cheekbone In the human skull, the zygomatic bone (from ), also called cheekbone or malar bone, is a paired irregular bone, situated at the upper and lateral part of the face and forming part of the lateral wall and floor of the orbit (anatomy), orbit, of t ...

hypoplasia,

micrognathia Micrognathism is a condition where the jaw is undersized. It is also sometimes called mandibular hypoplasia. It is common in infants, but is usually self-corrected during growth, due to the jaws' increasing in size. It may be a cause of abnorma ...

, and small abnormally-shaped ears. In some individuals with MFDM syndrome, preauricular tags are present. Patients (especially the ones with the difference that was mentioned beforehand) have a higher risk of having anomalies in the

ear canal The ear canal (external acoustic meatus, external auditory meatus, EAM) is a pathway running from the outer ear to the middle ear. The adult human ear canal extends from the auricle to the eardrum and is about in length and in diameter. S ...

, the auditory ossicles, or

semicircular canals The semicircular canals are three semicircular interconnected tubes located in the innermost part of each ear, the inner ear. The three canals are the lateral, anterior and posterior semicircular canals. They are the part of the bony labyrinth, ...

. These abnormalities (with the exception of the preauricular tags) end up in

hearing loss Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spo ...

in some to most cases. There are also oral and respiratory anomalies present within the condition,

cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...

s and

choanal atresia Choanal atresia is a congenital disorder where the back of the nasal passage (choana) is blocked, usually by abnormal bony or soft tissue (membranous) due to failed hole development of the nasal fossae during prenatal development. It causes persi ...

aren't uncommon findings. Choanal atresia in particular can end up causing breathing difficulties to the patient. Occasional findings include

short stature Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ...

, heart and thumb defects,

esophageal atresia Esophageal atresia is a congenital medical condition (birth defect) that affects the alimentary tract. It causes the esophagus to end in a blind-ended pouch rather than connecting normally to the stomach. It comprises a variety of congenital anat ...

, and

tracheoesophageal fistula A tracheoesophageal fistula (TEF, or TOF; see spelling differences) is an abnormal connection (fistula) between the esophagus and the trachea. TEF is a common congenital abnormality, but when occurring late in life is usually the sequela of surgica ...

. These last two symptoms are highly fatal, and may end up in

premature death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose shor ...

if left untreated.

Complications

Unilateral choanal atresia can cause neo-natal breathing difficulties and posteriorly mouth breathing, which, although not especially life-threatening, can be deprimental and cause symptoms such as narrow face, tired eyes, etc. Bilateral choanal atresia can cause respiratory distress and, in most cases,

arrest An arrest is the act of apprehending and taking a person into custody (legal protection or control), usually because the person has been suspected of or observed committing a crime. After being taken into custody, the person can be question ...

. Esophageal atresia and tracheoesophageal fistula can be deadly if they are left untreated. The latter causes an abnormal connection between the esophagus and the trachea, which causes esophageal fluids to enter the airways and cause respiratory problems. The combination of both esophageal atresia and tracheoesophageal fistula is especially life-threatening due to feeding difficulties and recurrent esophageal fluid exposure-associated lung damage.

Causes

This condition is caused by inherited autosomal recessive mutations in the

EFTUD2 116 kDa U5 small nuclear ribonucleoprotein component is a protein that in humans is encoded by the ''EFTUD2'' gene. Disease associations Heterozygous loss-of-function mutations in ''EFTUD2'' cause Mandibulofacial Dysostosis with Microcephaly ...

gene. These mutations can either be

missense In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn al ...

, splice-site, or the result of a

microdeletion In genetics, a deletion (also called gene deletion, deficiency, or Deletion anomaly, deletion mutation) (sign: delta (letter), Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA rep ...

. This gene is essential for the formation of

spliceosomes A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specif ...

, which helps in producing and maturing messenger RNA. The mutations involved in MFDM cause EFTUD2 enzymes with little to no function, which likely impairs the process of maturing mRNA.

Diagnosis

It can be diagnosed by a thorough examination of the patient's symptoms and

genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...

Treatment

Treatment is done on the symptoms themselves: * For craniofacial dysmorphisms: correctional surgeries such as oromaxillofacial surgery,

dentistry Dentistry, also known as dental medicine and oral medicine, is the branch of medicine focused on the Human tooth, teeth, gums, and Human mouth, mouth. It consists of the study, diagnosis, prevention, management, and treatment of diseases, dis ...

service, etc. * For developmental delays: occupational and speech/language therapy. * For respiratory abnormalities:

intubation Intubation (sometimes entubation) is a medical procedure involving the insertion of a tube into the body. Most commonly, intubation refers to tracheal intubation, a procedure during which an endotracheal tube is inserted into the trachea to supp ...

tracheostomy Tracheotomy (, ), or tracheostomy, is a surgical airway management procedure which consists of making an incision on the front of the neck to open a direct airway to the trachea. The resulting stoma (hole) can serve independently as an airway ...

. * For hearing loss:

cochlear implant A cochlear implant (CI) is a surgically implanted Neuroprosthetics, neuroprosthesis that provides a person who has moderate-to-profound sensorineural hearing loss with sound perception. With the help of therapy, cochlear implants may allow for imp ...

, bone-anchored hearing aids.

Prevalence

Around 100 cases have been described in the medical literature.

History

This disorder was discovered in the year 2000, when Guion-Almeida et al., described 2

Brazil Brazil, officially the Federative Republic of Brazil, is the largest country in South America. It is the world's List of countries and dependencies by area, fifth-largest country by area and the List of countries and dependencies by population ...

ian brothers with growth delays,

trigonocephaly Trigonocephaly is a congenital condition due to premature Synostosis, fusion of the metopic suture (), leading to a triangular forehead. The premature merging of the two frontal bones leads to transverse growth restriction and parallel growth ex ...

, preauricular tags, and

. They did a follow-up on these patients and 2 new ones: Brazilian siblings of the opposite sex (male and female), they found additional findings they had failed to describe before: zygomatic arc hypoplasia, and

. They had severe

speech Speech is the use of the human voice as a medium for language. Spoken language combines vowel and consonant sounds to form units of meaning like words, which belong to a language's lexicon. There are many different intentional speech acts, suc ...

language delay Language is a structured system of communication that consists of grammar and vocabulary. It is the primary means by which humans convey meaning, both in spoken and signed forms, and may also be conveyed through writing. Human language is ...

, they found this to be part of a brand new autosomal recessive mandibulofacial dysostosis entity.

References

{{reflist Autosomal recessive disorders Neurogenetic disorders Rare diseases