About growth retardation-rieger anomaly

What is growth retardation-rieger anomaly?

SHORT syndrome is a condition in which affected individuals have multiple birth defects in different organ systems. The term SHORT is an acronym with each letter representing one of the common findings in affected persons:

(S)= short stature
(H)= hyperextensibility of joints and/or hernia (inguinal)
(O)= ocular depression
(R) =Rieger anomaly
(T) =teething delay

Other characteristics common in SHORT syndrome are a triangular face, small chin with a dimple, a loss of fat under the skin (lipodystrophy), abnormal position of the ears, hearing loss and delayed speech.

What are the symptoms for growth retardation-rieger anomaly?

Ocular signs and symptoms

Ocular features of ARS usually occur in both eyes. The main ocular signs include an underdeveloped iris (iris hypoplasia), displacement of the pupil of the eye so that it is not centered (corectopia), one or more full thickness tears in the iris of the eye and an opaque ring around the outer edge of the cornea (posterior embryotoxon). Other features include adhesions in the front of the eye, between the iris and the edge of the cornea.

Glaucoma is a group of diseases in which the eye’s optic nerve is damaged. This damage is often secondary to increased pressure within the eyeball. Glaucoma is seen in approximately 50% of patients with ARS and can lead to complete permanent blindness if not treated. Fluid in the eye normally drains out of the eye through the angle formed by the junction of the iris and the cornea. Defects in the formation of the angle of the eye and/or adhesions that block this drainage route that are associated with ARS can lead to glaucoma.

Systemic signs and symptoms

Systemic signs include dental abnormalities including a congenital condition in which fewer teeth than normal are present (hypodontia), a tooth or teeth that are smaller than normal (microdontia), six or more missing teeth (oligodontia), complete absence of teeth (anodontia) and/or cone-shaped teeth.

Other characteristics include craniofacial abnormalities resulting in a prominent forehead, face that appears to be flattened, widely spaced eyes (hypertelorism), broad flat bridge of the nose, under-developed Bones of the upper jaw, thin upper lip and/or a protruding lower lip.

Some patients with ARS may also present with failure of the skin around the navel to decrease in size after birth (a condition that is sometimes mistaken for an umbilical hernia) and very rarely an unusually small anal opening (anal stenosis). Rarely, a patient may in fact present with umbilical hernia — a protrusion of intestine through a Weakness in the abdominal wall around the navel.

Other rare manifestations include a congenital abnormality in which the urethra in males opens from a different location than its usual one on the head of the penis (hypospadias), abnormalities of the pituitary gland — an important hormone-producing gland found in the brain, arachnoid cysts — fluid-filled balloons under one of the membranes covering the brain and spinal cord, growth delay, heart defects and hearing abnormalities.

What are the causes for growth retardation-rieger anomaly?

ARS is caused by changes (mutations) in several different genes and follows an autosomal dominant pattern of inheritance.

Dominant genetic disorders typically occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. The word ”autosomal” means that the genetic disorder is not associated with one of the sex chromosomes, but rather with the non-sex (or autosomal) chromosomes.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.

Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 4q25-q26” refers to a region between bands 25 and 26 on the long arm of chromosome 4. Chromosome 13q14 refers to a site at band 14 on the long arm of chromosome 13. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Several genetic studies have found two main genes associated with ARS: FOXC1 and PITX2. A wide spectrum of mutations in these genes contributes to the development of the disease. However, the genetic cause of ARS remains unclear in around 60% of patients.

There are three types of ARS. ARS type I is associated with mutations in the PITX2 gene on chromosome 4 (4q25), whereas ARS type III is associated with mutations in the FOXC1 gene on chromosome 6 (6p25). ARS type II has been associated with chromosome 13 (13q14), but a specific gene is not yet identified. Typically, patients who present with associated systemic abnormalities tend to have a PITX2 mutation, whereas patients who only present with ocular features, sometimes alongside heart defects and hearing loss, tend to have a FOXC1 mutation. Other genetic changes are also rarely associated with ARS: deletion of the PAX6 gene on chromosome 11 (11p13) as well as deletion of the chromosome 16q23-q24 region.

PTXI2 and FOXC1 are both genes that code for transcription factors that control other genes to regulate steps in embryonic development. The mechanism of ARS is not fully clear, but it is believed that the structural abnormalities seen in ARS originate from defects in the development and functions of cells that form the eye.

ARS has also been reported to be associated with of gain of function mutations or extra copies of genes. This might increase the activity of proteins involved in the development of the eyes.

What are the treatments for growth retardation-rieger anomaly?

Treatment

The main course of treatment in ARS is the management of glaucoma (if present) with medications, usually consisting of eye drops. These medications are mainly used to lower the pressure inside the eyeball (intra-ocular pressure). If eyedrops are not sufficient to control the glaucoma, surgery could be considered.

For the non-ocular features of ARS, effective coordination of care with other healthcare professionals is important for complete evaluation and treatment.

With age, certain patients with an uncentered pupil (corectopia) or multiple full thickness holes in the eye may experience an increased intolerance for light (photophobia). For these patients, special eye lenses may be beneficial.

Genetic counseling may also be helpful for patients and their families.

What are the risk factors for growth retardation-rieger anomaly?

Axenfled-Rieger syndrome/growth retardation-rieger anomaly is an autosomal dominant disorder. Unlike recessive disorders, these disorders do not need the causative mutations in the respective gene to be homozygous, which means even a single defective allele in a genotype reflects on the phenotype.

  • Characteristically, the disorder causes ocular abnormalities and exhibits systemic conditions, including dental abnormalities, craniofacial anomalies, cardiac defects, anal stenosis, and hypospadias.
  • It is estimated that Axenfeld-Rieger Syndrome occurs in about 1 in 1/50,000 newborns worldwide.
  • It affects people from different ethnic origins, including the Middle East as well as European, Asian, African, and South and North American populations.
  • Axenfeld-Rieger syndrome affects both males and females in about equal numbers and is usually diagnosed in infants and children.

    •Genetic disorders cannot be suppressed epigenetically from developing. However, it is possible to alleviate the symptoms, secondary diseases, or infections.

    Risk factors for Axenfled-Rieger disorder are
    1. Transferring the defective gene(s) from the affected parent to the next generation.
    2. Exposure to mutagenic agents, such as Ultraviolet rays and alkylating agents
    3. Unhealthy habits that harm the eyes worsen the conditions
    4. Diets that cause bowel obstructions

    Genetic counseling is the best way to prevent the inheritance of the disease, for inheritance is the most probable cause.
Symtpoms
Gradual loss of vision,Pain in eyes due to ocular dysfunctions,Aesthetic concerns and inferiority complex due to facial and dental abnormalities,Constipation,Uneasiness and bleeding during bowel movement due to anal stenosis
Conditions
Correctopia(pupil shifted off-center),Polycoria(multiple pupils),Hypertelorism(widely spaced eyes),Relatively flat nasal bridge,Dental abnormalities including microdontia(unusually small teeth) or oligodontia(fewer than normal teeth),Redundant periumbilical skin(extra folds of skin around belly button),Heart defects,Hypospadias(the opening of the urethra on the underside of the penis),Anal stenosis(narrowing of the anus),Malfunctioning of pituitary gland that can result in slow growth
Drugs
"Prostaglandin analogues: Latanoprost, travoprost, tafluprost, unoprostone, brimatopros,β-Adrenergic blockers: Timolol, levobunolol, carteolol, metipranolol, betaxolol,α-Adrenergic agonists: Brimonidine, apraclonidine,Carbonic anhydrase inhibitors: Dorzolamide, brinzolamide, acetazolamide,Cholinergic agonists: Pilocarpine, carbachol
"

Is there a cure/medications for growth retardation-rieger anomaly?

Rieger anomaly is one of the component terms given to a spectrum of disorders collectively called Axenfeld-Rieger syndrome, a rare genetic disorder, caused by mutations in at least two genes, namely FOXC1 AND PITX2.
These mutations interfere with the early development at the stage of the neural crest. Hence, the disease manifestations appear later in childhood or adolescence.
Currently, there is no treatment for the disease at its root cause. But the symptoms can be managed.
The disease primarily causes multiple ocular dysfunctions, leading to glaucoma wherein the fluid pressure in the eyeballs increases, finally leading to blindness, if left untreated. Therefore, the only course of treatment is the management of glaucoma.
Reduction of intraocular pressure is the only way to manage glaucoma either using drugs or surgically.
Classes of topical medications approved, and respective drugs are as follows
1. Prostaglandin analogues: Latanoprost, travoprost, tafluprost, unoprostone, brimatopros.
2. β-Adrenergic blockers: Timolol, levobunolol, carteolol, metipranolol, betaxolol.
3. α-Adrenergic agonists: Brimonidine, apraclonidine.
4. Carbonic anhydrase inhibitors: Dorzolamide, brinzolamide, acetazolamide.
5. Cholinergic agonists: Pilocarpine, carbachol.
Surgical treatments:
1. Trabeculectomy
2. Deep sclerectomy
3. Viscocanalostomy
4. Goniotomy
5. Trans-scleral diode cyclophotocoagulation
A few scientific literatures claim that growth hormones alleviate the symptoms, but there is no experimental evidence to support them.

Symtpoms
Gradual loss of vision,Pain in eyes due to ocular dysfunctions,Aesthetic concerns and inferiority complex due to facial and dental abnormalities,Constipation,Uneasiness and bleeding during bowel movement due to anal stenosis
Conditions
Correctopia(pupil shifted off-center),Polycoria(multiple pupils),Hypertelorism(widely spaced eyes),Relatively flat nasal bridge,Dental abnormalities including microdontia(unusually small teeth) or oligodontia(fewer than normal teeth),Redundant periumbilical skin(extra folds of skin around belly button),Heart defects,Hypospadias(the opening of the urethra on the underside of the penis),Anal stenosis(narrowing of the anus),Malfunctioning of pituitary gland that can result in slow growth
Drugs
Prostaglandin analogues: Latanoprost, travoprost, tafluprost, unoprostone, brimatopros,β-Adrenergic blockers: Timolol, levobunolol, carteolol, metipranolol, betaxolol,α-Adrenergic agonists: Brimonidine, apraclonidine,Carbonic anhydrase inhibitors: Dorzolamide, brinzolamide, acetazolamide,Cholinergic agonists: Pilocarpine, carbachol

Video related to growth retardation-rieger anomaly