Otocephaly, also known as agnathia–otocephaly complex, is a very rare and lethal

cephalic disorder Cephalic disorders () are Congenital disorder, congenital conditions that stem from damage to, or abnormal development of, the budding nervous system. Cephalic disorders are not necessarily caused by a single factor, but may be influenced by her ...

characterized by the absence of the

mandible In jawed vertebrates, the mandible (from the Latin ''mandibula'', 'for chewing'), lower jaw, or jawbone is a bone that makes up the lowerand typically more mobilecomponent of the mouth (the upper jaw being known as the maxilla). The jawbone i ...

( agnathia), with the ears fused together just below the chin (synotia). It is caused by a disruption to the development of the

first branchial arch The pharyngeal arches, also known as visceral arches'','' are transient structures seen in the Animal embryonic development, embryonic development of humans and other vertebrates, that are recognisable precursors for many structures. In fish, t ...

. It occurs in every 1 in 70,000 embryos.

Signs and symptoms

The disorder is characterised by the absence of the mandible (agnathia), with the ears fused together just below the chin (synotia). In addition to agnathia and synotia, other symptoms that may manifest in otocephaly include: * Facial/musculoskeletal ** Small (microglossia) or absent (aglossia) tongue ** Small (

microstomia Microstomia () is the medical condition of an abnormally small mouth. Congenital It is a feature of many craniofacial syndromes, including Freeman–Sheldon syndrome and Sheldon-Hall syndromes (or distal arthrogryposis multiplex congenita). It ...

) or absent (astomia) mouth **

Cyclopia Cyclopia (named after the Greek mythology characters cyclopes), also known as alobar holoprosencephaly, is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosen ...

with

proboscis A proboscis () is an elongated appendage from the head of an animal, either a vertebrate or an invertebrate. In invertebrates, the term usually refers to tubular arthropod mouthparts, mouthparts used for feeding and sucking. In vertebrates, a pr ...

** Median

cleft lip 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 nasal cavi ...

and

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 ...

* Neurological **

Holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...

Agenesis of the corpus callosum Agenesis of the corpus callosum (ACC) is a rare birth defect in which there is a complete or partial absence of the corpus callosum. It occurs when the development of the corpus callosum, the band of white matter connecting the two hemispheres ...

Anencephaly Anencephaly is the absence of a major portion of the brain, skull, and scalp that occurs during embryonic development. It is a cephalic disorder that results from a neural tube defect that occurs when the rostral (head) end of the neural tube ...

or other

neural tube defects Neural tube defects (NTDs) are a group of birth defects in which an opening in the spine or cranium remains from early in human development. In the third week of pregnancy called gastrulation, specialized cells on the dorsal side of the embry ...

* Organ systems **

Situs inversus ''Situs inversus'' (also called ''situs transversus'' or ''oppositus'') is a Congenital disorder, congenital condition in which the major Organ (anatomy), visceral organs are reversed or mirror image, mirrored from their normal positions. The norm ...

(full rotation of the internal organs) ** Cardiac anomalies ** Ambiguous genitalia ** Absence of glands

Grades

Sewall Wright Sewall Green Wright ForMemRS HonFRSE (December 21, 1889March 3, 1988) was an American geneticist known for his influential work on evolutionary theory and also for his work on path analysis. He was a founder of population genetics alongside ...

described twelve grades of otocephaly in

guinea pig The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy ( ), is a species of rodent belonging to the genus ''Cavia'', family Caviidae. Animal fancy, Breeders tend to use the name "cavy" for the ani ...

s. Grades 1 to 5 were isolated agnathia with no neurological defects. Grades 6 to 9 featured severe holoprosencephaly. Grades 10 to 12 featured aprosopus (absence of the face and most of the head) with absence of the prosencephalon and

mesencephalon The midbrain or mesencephalon is the uppermost portion of the brainstem connecting the diencephalon and cerebrum with the pons. It consists of the cerebral peduncles, tegmentum, and tectum. It is functionally associated with vision, hearing, mo ...

. One human case corresponding to a high Wright grade has been reported in

modern history The modern era or the modern period is considered the current historical period of human history. It was originally applied to the history of Europe and Western history for events that came after the Middle Ages, often from around the year 1500, ...

Cause

Otocephaly is generally a result of a

de novo mutation A de novo mutation (DNM) is any mutation or alteration in the genome of an individual organism (human, animal, plant, microbe, etc.) that was not inherited from its parents. This type of mutation spontaneously occurs during the process of DNA repl ...

in the gene ''

PRRX1 Paired related homeobox 1 is a protein that in humans is encoded by the ''PRRX1'' gene. Function The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functi ...

'' on the long arm of

chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which a ...

Autosomal trisomies A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes). Description and causes Most organisms that reprodu ...

, while prevalent in related conditions like cyclopia, are uncommon in otocephaly.

Development

During early

embryogenesis An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male ...

, many different organ systems begin development. Any disruption in these processes results in complex malformation, which usually results in death. The

will normally develop around the 23rd to 26th day of

gestation Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregn ...

, also known as Carnegie stage 10. Usually, failure of this will result in isolated agnathia, but otocephaly may occur in exceptional circumstances. After agenesis of the first branchial arch, no cure is possible.

Prognosis

Otocephaly describes a spectrum of various manifestations, ranging in severity from severe micrognathia as a part of the

Pierre Robin sequence Pierre Robin sequence (; abbreviated PRS) is a congenital defect observed in humans which is characterized by facial abnormalities. The three main features are micrognathia (abnormally small mandible), which causes glossoptosis (downwardly displ ...

to the

cyclopia Cyclopia (named after the Greek mythology characters cyclopes), also known as alobar holoprosencephaly, is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosen ...

holoprosencephaly Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to Prenatal development, develop into two Cerebral hemisphere, hemispheres, typically occurring between the 18th and 28th day of gestati ...

complex, which is invariably associated with fetal death or death immediately after birth. Otocephaly is classified into four groups: (1) agnathia alone; (2) agnathia with holoprosencephaly; (3) agnathia with situs inversus and

visceral In a multicellular organism, an organ is a collection of Tissue (biology), tissues joined in a structural unit to serve a common function. In the biological organization, hierarchy of life, an organ lies between Tissue (biology), tissue and an o ...

anomalies; and (4) agnathia with holoprosencephaly, situs inversus, and visceral anomalies. Other extracranial malformations include

, cephalocele, corpus callosum dysgenesis, renal ectopia, adrenal

hypoplasia Hypoplasia (; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.intrauterine growth restriction Intrauterine growth restriction (IUGR), or fetal growth restriction, is the poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...

, prematurity, and impaired ventilation.

Endotracheal intubation Tracheal intubation, usually simply referred to as intubation, is the placement of a flexible plastic tube into the trachea (windpipe) to maintain an open airway or to serve as a conduit through which to administer certain drugs. It is frequently ...

is difficult due to severe airway malformations, and only approximately 7 non-holoprosencephaly patients have survived beyond infancy. However, the less severe agnathia-otocephaly complex (AOC) has been successfully treated by extensive

reconstructive surgery Reconstructive surgery is surgery performed to restore normal appearance and function to body parts malformed by a disease or medical condition. Description Reconstructive surgery is a term with training, clinical, and reimbursement implicat ...

, including reconstruction of the mandible. Research indicates that a reasonable quality of life may even be achieved. However, the lack of musculature cannot be repaired with current therapies. This means swallowing is virtually impossible, so patients will depend on

enteral nutrition Enteral administration is food or pharmaceutical drug#Administration, drug administration via the human gastrointestinal tract. This contrasts with parenteral nutrition or drug administration (Greek ''para'', "besides" + ''enteros''), which occu ...

. Researchers are optimistic that transplantation may eventually allow more complete

reconstruction Reconstruction may refer to: Politics, history, and sociology *Reconstruction (law), the transfer of a company's (or several companies') business to a new company *''Perestroika'' (Russian for "reconstruction"), a late 20th century Soviet Union ...

of structures affected by AOC. In all cases, an expert team, family information, premature birth planning, early gastrostomy and tracheostomy, and a long-term treatment plan are essential to ensure proper patient management.

History

Otocephaly was first described in 1717 by Dutch scientist Theodor Kerckring. In 1933, evolutionary biologist Sewall Wright performed a study on otocephaly on guinea pigs and gave otocephaly its name. The name comes from the

Greek Greek may refer to: Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group *Greek language, a branch of the Indo-European language family **Proto-Greek language, the assumed last common ancestor of all kno ...

-derived

Neo-Latin Neo-LatinSidwell, Keith ''Classical Latin-Medieval Latin-Neo Latin'' in ; others, throughout. (also known as New Latin and Modern Latin) is the style of written Latin used in original literary, scholarly, and scientific works, first in Italy d ...

prefix ''oto-'' ("ear") and the suffix ''-cephaly'' ("head"). In 2018, Indian neonatologist Kanwar Singh and his associates described a particularly severe case of otocephaly with cyclopia, agnathia, complete astomia and synotia. They dubbed the resulting condition Kanwar syndrome.

References

External links

NINDS Overview
{{Congenital malformations and deformations of ear, face and neck Congenital disorders of eye, ear, face and neck