Nasodigitoacoustic syndrome
   HOME

TheInfoList



OR:

Nasodigitoacoustic syndrome, also called Keipert syndrome, is a rare
congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...
syndrome A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paired ...
first described by J.A. Keipert and colleagues in 1973. The syndrome is characterized by a misshaped nose, broad thumbs and halluces (the big toes),
brachydactyly Brachydactyly (Greek βραχύς = "short" plus δάκτυλος = "finger"), is a medical term which literally means "short finger". The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an in ...
,
sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII). SNHL accounts for about 90% of rep ...
, facial features such as
hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as ...
(unusually wide-set eyes), and
developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, c ...
. It is believed to be inherited in an
X-linked recessive X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
manner, which means a
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
tic
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
causing the disorder is located on the
X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
, and while two copies of the mutated gene must be inherited for a female to be born with the disorder, just one copy is sufficient to cause a male to be born with the disorder. Nasodigitoacoustic syndrome is likely caused by a mutated gene
located In geography, location or place are used to denote a region (point, line, or area) on Earth's surface or elsewhere. The term ''location'' generally implies a higher degree of certainty than ''place'', the latter often indicating an entity with an ...
on the X chromosome between positions Xq22.2–q28. The incidence of the syndrome has not been determined, but it is considered to affect less than 200,000 people in the United States, and no greater than 1 per 2,000 in Europe. It is similar to Keutel, Muenke,
Rubinstein Rubinstein is a surname of German and Yiddish origin, mostly found among Ashkenazi Jews; it denotes "ruby-stone". Notable persons named Rubinstein include: A–E * Akiba Rubinstein (1880–1961), Polish chess grandmaster * Amnon Rubinstein (born ...
and Teunissen–Cremers syndrome.


Characteristics

Nasodigitoacoustic syndrome is congenital and is characterized by a number of nasal, facial and cranial features. These include a broad and high, sometimes depressed nasal bridge (top of the nose, between the eyes) and a flattened nasal tip. This can give the nose a shortened, arch-like appearance.
Hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition the distance between the inner eye corners as ...
(unusually wide-set eyes), prominent frontal bones and
supraorbital ridge The brow ridge, or supraorbital ridge known as superciliary arch in medicine, is a bony ridge located above the eye sockets of all primates. In humans, the eyebrows are located on their lower margin. Structure The brow ridge is a nodule or crest ...
(the eyebrow ridge), bilateral
epicanthic fold An epicanthic fold or epicanthus is a skin fold of the upper eyelid that covers the inner corner (medial canthus) of the eye. However, variation occurs in the nature of this feature and the possession of "partial epicanthic folds" or "slight ...
s (an extra flap of skin over the eyelids), a broad forehead and an overall enlarged head circumference have also been observed. A bulging of the upper lip with an exaggerated
cupid's bow The Cupid's bow is a facial feature where the double curve of a human upper lip is said to resemble the bow of Cupid, the Roman god of erotic love. The peaks of the bow coincide with the philtral columns giving a prominent bow appearance to the ...
shape,Gorlin (1995). p. 208 and
maxillary hypoplasia Maxillary hypoplasia, or maxillary deficiency, is an underdevelopment of the maxillary bone, bones of the upper jaw. It is associated with Crouzon syndrome, Angelman syndrome, as well as Fetal alcohol syndrome. It can also be associated with Cleft ...
(underdevelopment of the
upper jaw The maxilla (plural: ''maxillae'' ) in vertebrates is the upper fixed (not fixed in Neopterygii) bone of the jaw formed from the fusion of two maxillary bones. In humans, the upper jaw includes the hard palate in the front of the mouth. The t ...
) with retraction have also been reported. Several anomalies affecting the digits (fingers and toes) have been observed with the syndrome. A broadening of the thumbs and big toes ( halluces) was reported in two brothers. The broadening was apparent in all
distal phalanges The phalanges (singular: ''phalanx'' ) are digital bones in the hands and feet of most vertebrates. In primates, the thumbs and big toes have two phalanges while the other digits have three phalanges. The phalanges are classed as long bones. ...
of the fingers, although the pinkies were unaffected yet appeared to be clinodactylic (warped, or bent toward the other fingers). Additional reports described this broadness of the thumbs and big toes, with
brachydactyly Brachydactyly (Greek βραχύς = "short" plus δάκτυλος = "finger"), is a medical term which literally means "short finger". The shortness is relative to the length of other long bones and other parts of the body. Brachydactyly is an in ...
(shortness) in the distal phalanges of the other digits except the pinkies in affected individuals. On
X-rays An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 Picometre, picometers to 10 Nanometre, nanometers, corresponding to frequency, ...
of a two-year-old boy with the disorder, the brachydactyly was shown to be caused by shortening of
epiphyses The epiphysis () is the rounded end of a long bone, at its joint with adjacent bone(s). Between the epiphysis and diaphysis (the long midsection of the long bone) lies the metaphysis, including the epiphyseal plate (growth plate). At the join ...
(
joint A joint or articulation (or articular surface) is the connection made between bones, ossicles, or other hard structures in the body which link an animal's skeletal system into a functional whole.Saladin, Ken. Anatomy & Physiology. 7th ed. McGraw ...
-ends) of the distal phalanges. The broadness and brachydactyly of the big toes in particular may give them a stunted, rounded and stub-like appearance.Gorlin (1995). illustration, p. 209. The auditory, or "acoustic" abnormalities observed with the syndrome include
sensorineural hearing loss Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve (cranial nerve VIII). SNHL accounts for about 90% of rep ...
and hoarseness. Two affected Turkish brothers with a mild form of this hearing loss, and a hoarse voice were reported. A laryngoscopic examination of both brothers revealed swelling of the
vocal cords In humans, vocal cords, also known as vocal folds or voice reeds, are folds of throat tissues that are key in creating sounds through vocalization. The size of vocal cords affects the pitch of voice. Open when breathing and vibrating for speech ...
, and a malformed
epiglottis The epiglottis is a leaf-shaped flap in the throat that prevents food and water from entering the trachea and the lungs. It stays open during breathing, allowing air into the larynx. During swallowing, it closes to prevent aspiration of food int ...
. Sensorineural-associated
hearing impairment 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 spoken l ...
and hoarseness was also observed in a 10-year-old girl and her father, and in a number of other cases. Other characteristics seen with the syndrome include
developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech, c ...
,
growth retardation Delayed milestone, also called developmental delays, is used to describe the condition where a child does not reach one of these stages at the expected age. However, in most cases, a wide variety of ages can be considered normal, and not a cause fo ...
,
pulmonary stenosis Pulmonic stenosis, is a dynamic or fixed obstruction of flow from the right ventricle of the heart to the pulmonary artery. It is usually first diagnosed in childhood. Signs and symptoms Cause Pulmonic stenosis is usually due to isolated valvula ...
(an obstruction of blood-flow from the
right ventricle A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the upper ...
of the
heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...
to the
pulmonary artery A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and t ...
) with associated
dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathing, breathe well enough. The American Thoracic Society defines it as "a subjective experience of brea ...
(shortness of breath), and
renal agenesis Renal agenesis is a medical condition in which one (unilateral) or both (bilateral) fetal kidneys fail to develop. Unilateral and bilateral renal agenesis in humans, mice and zebra fish has been linked to mutations in the gene GREB1L. It has also ...
(failure of the
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
s to develop during the
fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...
period).
Undescended testes Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek language, Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tra ...
,
hyperactivity Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
and
aggressive behavior Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...
have also been noted.


Genetics

Nasodigitoacoustic syndrome is thought to be caused by a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
in a gene on the
X chromosome The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
. A 2007 study concluded, based on analysis of
microsatellite A microsatellite is a tract of repetitive DNA in which certain DNA motifs (ranging in length from one to six or more base pairs) are repeated, typically 5–50 times. Microsatellites occur at thousands of locations within an organism's genome. ...
markers (small gene sequences found in common among individuals having the same ethnicity, ancestry or genetic disease) of the family described by Keipert, that this gene was likely
located In geography, location or place are used to denote a region (point, line, or area) on Earth's surface or elsewhere. The term ''location'' generally implies a higher degree of certainty than ''place'', the latter often indicating an entity with an ...
on the long arm of the X chromosome between positions Xq22.2–q28. This is not definitive, however, and no specific gene has been named. The syndrome is strongly believed to be inherited in an
X-linked recessive X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
manner. When a female carries a mutated gene on one of her two copies of the X chromosome, there is a 50% chance of passing the mutation on to her children. Much like her, a daughter inheriting this mutation will be a carrier, but will not herself have the associated disease. However, a son who inherits the mutation will have the disease; this is because males have only one copy of the X chromosome and therefore could only express the disease mutation. This form of inheritance for Nasodigitoacoustic syndrome is not yet absolute, though, as a girl has been reported with the disorder. It is suggested that further analysis is needed for the inheritance to be formally established. The mutations causing this syndrome have been mapped to the glypican 4 (''
GPC4 Glypican-4 is a protein that in humans is encoded by the ''GPC4'' gene. Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the gly ...
'') gene.Amor DJ, Stephenson SEM, Mustapha M, Mensah MA, Ockeloen CW, Lee WS, Tankard RM, Phelan DG, Shinawi M, de Brouwer APM, Pfundt R, Dowling C, Toler TL, Sutton VR, Agolini E, Rinelli M, Capolino R, Martinelli D, Zampino G, Dumić M, Reardon W, Shaw-Smith C, Leventer RJ, Delatycki MB, Kleefstra T7, Mundlos S, Mortier G, Bahlo M, Allen NJ, Lockhart P (2019) Pathogenic variants in GPC4 cause Keipert syndrome. Am J Hum Genet This gene is located on the long arm of
chromosome X The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex-d ...
(Xq26.2).


Diagnosis

The constellation of anomalies seen with nasodigitoacoustic syndrome result in a distinct diagnosis. The diagnostic criteria for the disorder are broad distal phalanges of the thumbs and big toes, accompanied by a broad and shortened nose, sensorineural hearing loss and developmental delay, with predominant occurrence in males.


Classification

Nasodigitoacoustic syndrome is similar to several syndromes that share its features. Brachydactyly of the distal phalanges, sensorineural deafness and pulmonary stenosis are common with
Keutel syndrome Keutel syndrome (KS) is a rare autosomal recessive genetic disorder characterized by abnormal diffuse cartilage calcification, hypoplasia of the mid-face, peripheral pulmonary stenosis, hearing loss, short distal phalanges (tips) of the fingers an ...
. In
Muenke syndrome Muenke syndrome, also known as FGFR3-related craniosynostosis, is a human specific condition characterized by the premature closure of certain bones of the skull during development, which affects the shape of the head and face. First described by M ...
, developmental delay, distal brachydactyly and sensorineural hearing loss are reported; features of Teunissen-Cremers syndrome include nasal aberrations and broadness of the thumbs and big toes, also with brachydactyly. Broad thumbs and big toes are primary characteristics of Rubinstein syndrome.


Management

A number of features found with nasodigitoacoustic syndrome can be managed or treated. Sensorineural hearing loss in humans may be caused by a loss of
hair cell Hair cells are the sensory receptors of both the auditory system and the vestibular system in the ears of all vertebrates, and in the lateral line organ of fishes. Through mechanotransduction, hair cells detect movement in their environment. ...
s (sensory receptors in the inner ear that are associated with hearing). This can be hereditary and/or within a syndrome, as is the case with nasodigitoacoustic syndrome, or attributed to infections such as viruses. For the management of sensorineural hearing loss,
hearing aid A hearing aid is a device designed to improve hearing by making sound audible to a person with hearing loss. Hearing aids are classified as medical devices in most countries, and regulated by the respective regulations. Small audio amplifiers su ...
s have been used. Treatments, depending upon the cause and severity, may include a
pharmacological Pharmacology is a branch of medicine, biology and pharmaceutical sciences concerned with drug or medication action, where a drug may be defined as any artificial, natural, or endogenous (from within the body) molecule which exerts a biochemica ...
approach (i.e., the use of certain
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
s), or surgical intervention, like a
cochlear implant A cochlear implant (CI) is a surgically implanted 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 improved speech und ...
. Pulmonary, or pulmonic stenosis is an often congenital narrowing of the pulmonary valve; it can be present in nasodigitoacoustic-affected infants. Treatment of this cardiac abnormality can require surgery, or non-surgical procedures like
balloon valvuloplasty Heart valve repair is a cardiac surgery procedure, carried out to repair one or more faulty heart valves. In some valvular heart diseases repair where possible is preferable to valve replacement. A mechanical heart valve is a replacement valve th ...
(widening the valve with a
balloon catheter A balloon catheter is a type of "soft" catheter with an inflatable "balloon" at its tip which is used during a catheterization procedure to enlarge a narrow opening or passage within the Human body, body. The deflated balloon catheter is positione ...
).


History and epidemiology

The syndrome was initially described in 1973 by James A. Keipert and associates. They reported of two brothers with broad distal phalanges, sensorineural hearing loss, and facial features consistent with what would become known as Keipert or "nasodigitoacoustic" syndrome. Although no specific rate of incidence has been determined, the syndrome is considered a
rare disease A rare disease is any disease that affects a small percentage of the population. In some parts of the world, an orphan disease is a rare disease whose rarity means there is a lack of a market large enough to gain support and resources for discove ...
by both the Office of Rare Diseases (ORDR) at the
National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
, and
Orphanet Orphanet is a knowledge base dedicated to rare diseases as well as corresponding diagnosis, orphan drugs, clinical trials and expert networks The website is managed by a network of academic establishments from 40 countries, led by Inserm. It co ...
. This suggests, respectively, that nasodigitoacoustic syndrome affects less than 200,000 people in the U.S., or affects no greater than 1 per 2,000 people in Europe.


References


Publications

*


External links


Nasodigitoacoustic syndrome listing at the Office of Rare Diseases website

Keipert syndrome - Orphanet
{{X-linked disorders Syndromes Rare diseases Congenital disorders X-linked recessive disorders