Distal 18q- is a

genetic condition 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 chromosomal abnormality. Although polygenic disorders ...

caused by a deletion of genetic material within one of the two copies of

chromosome 18 Chromosome 18 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 18 spans about 80 million base pairs (the building material of DNA) and represents about 2.5 percent of the total DNA in ...

. The deletion involves the distal section of 18q and typically extends to the tip of the long arm of chromosome 18.

Presentation

Distal 18q- causes a wide range of medical and developmental concerns, with significant variation in severity due to the variation in breakpoints reported in individuals with distal 18q-. Current research is focused on establishing genotype-phenotype correlations to enable predictive genotyping.

Congenital anomalies

Heart abnormalities are present in 25–35% of people with distal 18q-. The majority of these defects are septal. Congenital orthopedic anomalies are also relatively common, particularly rocker-bottom feet or

clubfoot Clubfoot is a birth defect where one or both feet are rotated inward and downward. Congenital clubfoot is the most common congenital malformation of the foot with an incidence of 1 per 1000 births. In approximately 50% of cases, clubfoot aff ...

Cleft lip and 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 ...

are relatively common in people with distal 18q-. Kidney abnormalities have also been reported and include

horseshoe kidney Horseshoe kidney, also known as ''ren arcuatus'' (in Latin), renal fusion or super kidney, is a congenital disorder affecting about 1 in 500 people that is more common in men, often asymptomatic, and usually diagnosed incidentally. In this disorder ...

hydronephrosis Hydronephrosis describes hydrostatic dilation of the renal pelvis and calyces as a result of obstruction to urine flow downstream. Alternatively, hydroureter describes the dilation of the ureter, and hydronephroureter describes the dilation of t ...

polycystic kidney Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a genetic disorder in which the renal tubules become structurally abnormal, resulting in the development and growth of multiple cysts within the kidney. These cy ...

, and absent kidney. Boys with distal 18q- may have genital anomalies, the most frequent being

cryptorchidism Cryptorchidism, also known as undescended testis, is the failure of one or both testes to descend into the scrotum. The word is from Greek () 'hidden' and () 'testicle'. It is the most common birth defect of the male genital tract. About 3% of ...

and

hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...

Neurologic

Hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

is a common finding. Around 10% of people with distal 18q- have

seizures An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or neural oscillation, synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much o ...

MRI abnormalities

Dysmyelination Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to Insulator (electricity), insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The ...

is a common finding in people with distal 18q-, present in about 95%.

Hypoplasia Hypoplasia (from Ancient Greek ὑπo- ''hypo-'' 'under' + πλάσις ''plasis'' 'formation'; adjective form ''hypoplastic'') is underdevelopment or incomplete development of a tissue or organ.corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental mam ...

is also a common finding.

Vision

Strabismus Strabismus is a vision disorder in which the eyes do not properly align with each other when looking at an object. The eye that is focused on an object can alternate. The condition may be present occasionally or constantly. If present during a ...

and

nystagmus Nystagmus is a condition of involuntary (or voluntary, in some cases) eye movement. Infants can be born with it but more commonly acquire it in infancy or later in life. In many cases it may result in reduced or limited vision. Due to the invol ...

are prevalent in distal 18q-. Changes in the

optic nerve In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...

, as well as

colobomas A coloboma (from the Greek , meaning defect) is a hole in one of the structures of the eye, such as the iris, retina, choroid, or optic disc. The hole is present from birth and can be caused when a gap called the choroid fissure, which is presen ...

, are also fairly common.

Myopia Near-sightedness, also known as myopia and short-sightedness, is an eye disease where light focuses in front of, instead of on, the retina. As a result, distant objects appear blurry while close objects appear normal. Other symptoms may include ...

has been reported in some individuals.

Ear and sinus infections

Due to changes in facial structures, infants, toddlers, and children with distal 18q- often have poor drainage from the

middle ear The middle ear is the portion of the ear medial to the eardrum, and distal to the oval window of the cochlea (of the inner ear). The mammalian middle ear contains three ossicles, which transfer the vibrations of the eardrum into waves in the ...

s, leading to a build-up of fluid. This can in turn lead to recurrent

ear An ear is the organ that enables hearing and, in mammals, body balance using the vestibular system. In mammals, the ear is usually described as having three parts—the outer ear, the middle ear and the inner ear. The outer ear consists of ...

and

sinus infections Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, headac ...

Antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...

are typically required to treat these infections. In addition, the diagnosis of ear infections in children with 18q- is frequently complicated by

stenosis A stenosis (from Ancient Greek στενός, "narrow") is an abnormal narrowing in a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' ...

or atresia of the ear canals, a common finding in people with distal 18q-.

Hearing

People with distal 18q- frequently have conductive and/or sensorineural

hearing loss Hearing loss is a partial or total inability to Hearing, 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 Language ...

. The degree of hearing loss may vary from mild to severe.

Gastrointestinal

Individuals with distal 18q- may have problems with

reflux Reflux is a technique involving the condensation of vapors and the return of this condensate to the system from which it originated. It is used in industrial and laboratory distillations. It is also used in chemistry to supply energy to reactions ...

Hernias A hernia is the abnormal exit of tissue or an organ, such as the bowel, through the wall of the cavity in which it normally resides. Various types of hernias can occur, most commonly involving the abdomen, and specifically the groin. Groin herni ...

have also been reported.

Genitourinary

As mentioned above, males with distal 18q- may have

Hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...

and

chordee Chordee is a condition in which the head of the penis curves downward or upward, at the junction of the head and shaft of the penis. The curvature is usually most obvious during erection, but resistance to straightening is often apparent in the fl ...

have also been reported. Also, a variety of kidney malformations have been reported in infants with distal 18q-, as noted above. Additionally, vesicouretereral reflux has been diagnosed in several people with distal 18q-.

Orthopedics

As mentioned above, distal 18q- is associated with an increased incidence of clubfoot and rocker bottom feet. Also, a significant chance of developing

pes planus Flat feet (also called pes planus or fallen arches) is a postural deformity in which the arches of the foot collapse, with the entire sole of the foot coming into complete or near-complete contact with the ground. Sometimes children are born ...

pes cavus Pes cavus, also known as high arch, is a human foot type in which the sole of the foot is distinctly hollow when bearing weight. That is, there is a fixed plantar flexion of the foot. A high arch is the opposite of a flat foot and is somewhat l ...

exists. People with distal 18q- frequently have overlapping toes.

Scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...

and

genu varum Genu varum (also called bow-leggedness, bandiness, bandy-leg, and tibia vara) is a varus deformity marked by (outward) bowing at the knee, which means that the lower leg is angled inward ( medially) in relation to the thigh's axis, giving the ...

are also known orthopedic complications in children and adults with distal 18q-.

Growth

Children and adults with distal 18q- are often small for their age. Many people with distal 18q- have an abnormal response to growth hormone stimulation. Those who have been treated with

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in h ...

have responded well to the treatment.

Microcephaly Microcephaly (from New 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 ...

is also common in people with distal 18q-.

Thyroid

Hypothyroidism Hypothyroidism (also called ''underactive thyroid'', ''low thyroid'' or ''hypothyreosis'') is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as po ...

has been reported in some people with distal 18q-.

Immunology

Several people with distal 18q- have been diagnosed with low

IgA Iga may refer to: Arts and entertainment * Ambush at Iga Pass, a 1958 Japanese film * Iga no Kagemaru, Japanese manga series * Iga, a set of characters from the Japanese novel '' The Kouga Ninja Scrolls'' Biology * ''Iga'' (beetle), a gen ...

levels, resulting in an increased incidence of infections.

Psychiatry

An increased incidence of psychiatric conditions occurs within the distal 18q- population. In one study, nearly 60% had depressive symptoms, 60% had symptoms of an anxiety disorder, 25% had manic symptoms, and 25% had psychotic symptoms. However, this study included young patients, many of whom were too young to exhibit signs of certain psychiatric conditions. The typical age of onset for many of these conditions appears to be during the teen years. Thus, the results of this study may actually underestimate the true incidence of psychiatric conditions within this population. Outbursts, or anger issues, such as temper tantrums are also common.

Cognition and adaptive skills

97% of individuals possess some form of intellectual disability, ranging from moderate to severe cases. The intellectual development of individuals with distal 18q- vary quite widely. In one study of 46 individuals with distal 18q-, IQ ranged from 49 to 113, with most individuals falling in the mild to moderate range of intellectual disability. Some of those with IQ scores on the lower end of the spectrum probably actually had deletions encompassing the ''

TCF4 Transcription factor 4 (TCF-4) also known as immunoglobulin transcription factor 2 (ITF-2) is a protein that in humans is encoded by the TCF4 gene located on chromosome 18q21.2. Function TCF4 proteins act as transcription factors which will ...

'' gene. An increased incidence of

autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...

is seen within the distal 18q- population. In a recent study, 45 of 105 individuals evaluated fell into the "possible" or "very likely" levels of risk for autism. Adaptive skills may also be delayed in people with distal 18q-.

Dysmorphology

Common facial features include midfacial hypoplasia, short and downward- or upward-slanting palpebral fissures, epicanthic folds, and low-set ears with a prominent antihelix.

Genetics

Distal 18q- is a deletion of the long arm of chromosome 18. The majority of deletions have breakpoints between 45,405,887 and the tip of the chromosome. There are no common breakpoints, thus the size of the deletions vary widely. The largest deletion reported is 30.076 Mb, while the smallest deletion reported to cause a clinical phenotype is 3.78 Mb.

Diagnosis

Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of distal 18q- is usually made from a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints.

Prenatal diagnosis Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of ...

is possible using

amniocentesis Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is ne ...

chorionic villus sampling Chorionic villus sampling (CVS), sometimes called "chorionic ''villous'' sampling" (as "villous" is the adjectival form of the word "villus"), is a form of prenatal diagnosis done to determine chromosomal or genetic disorders in the fetus. It ent ...

Treatment

At present, treatment for distal 18q- is symptomatic, meaning the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, people with distal 18q- are suggested to undergo routine screenings for thyroid, hearing, and vision problems.

History

Distal 18q- was first described in 1964. Originally, it was called "De Grouchy syndrome" or "De Grouchy syndrome 2". Today, the preferred nomenclature for this condition is 18q-. Since this condition was originally described, researchers have clarified the size and nature of these deletions. In general, deletions of 18q fall into one of two categories: interstitial deletions, which typically have breakpoints between 18q11.2 (18.9 Mb) to 18q21.1 (43.8 Mb), and terminal deletions, which typically have a breakpoint distal to 18q21.1 (45.4 Mb) and extend to the end of the chromosome. If possible, it is preferable to indicate the general location of the deletion with the phrases " proximal 18q-" and "distal 18q-".

Research

Currently, research is focusing on identifying the role of the genes on 18q in causing the signs and symptoms associated with distal deletions of 18q. ''TCF4'' – In 2007, deletions of or point mutations in this gene were identified as the cause of Pitt-Hopkins syndrome. This is the first gene that has been definitively shown to directly cause a clinical phenotype when deleted. If a deletion includes the'' TCF4'' gene (located at 55,222,331-55,664,787), features of Pitt-Hopkins may be present, including abnormal corpus callosum, short neck, small penis, accessory and wide-spaced nipples, broad or clubbed fingers, and

sacral dimple A sacral dimple (also termed pilonidal dimple or spinal dimple) is a small depression in the skin, located just above the buttocks. The name comes from the sacrum, the bone at the end of the spine, over which the dimples are found. A sacral dimpl ...

. Those with deletions inclusive of ''TCF4'' have a significantly more severe cognitive phenotype. ''

TSHZ1 Teashirt zinc finger homeobox 1 is a protein that in humans is encoded by the TSHZ1 gene. Function This gene encodes a colon cancer antigen that was defined by serological analysis of recombinant cDNA expression libraries. The encoded protein ...

'' - Point mutations and deletions of this gene are linked with congenital aural atresia. Individuals with deletions inclusive of this gene have a 78% chance of having aural atresia. Critical regions – Recent research has narrowed the critical regions for four features of the distal 18q- phenotype down to a small segment of distal 18q, although the precise genes responsible for those features remain to be identified. The table below shows the established critical regions for four features of distal 18q-, as well as the

penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...

for each of those features. The penetrance figure represents the likelihood a person would have the feature given the critical region is deleted. Haplolethal regions - Two regions on chromosome 18 have never been found to be deleted. They are located between the

centromere The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers a ...

and 22,826,284 bp (18q11.2) and between 43,832,732 and 45,297,446 bp (18q21.1). The genes in these regions are thought to be lethal when deleted.

References

External links

{{Chromosomal abnormalities Autosomal monosomies and deletions Syndromes affecting the nervous system