ABCD syndrome
Encyclopedia
ABCD syndrome is the acronym for albinism
, black lock, cell migration disorder of the neurocytes of the gut and sensorineural deafness. It has been found to be caused by mutation in the endothelin B receptor gene (EDNRB).
in the EDNRB gene causes ABCD syndrome. This helped scientists discover that it is the same as type IV Waardenburg syndrome, also known as Shah-Waardenburg Syndrome
.
, and she did not react to noise.” The albinism is interesting in this diagnosis because the skin of an affected individual is albino pale besides the brown patches of mispigmented skin. The “black locks” described and seen in clinical pictures of the infants are thick patches of black hair above the ears that form a half circle reaching to the other ear to make a crest shape.
As identified in this first case study and stated in a dictionary of dermatologic syndromes, ABCD syndrome has many notable features, including “snow white hair in patches, distinct black locks of hair, skin white except brown macules, deafness, irises gray to blue, nystagmus, photophobia
, poor visual activity, normal melanocytes in pigmented hair and skin, and absent melanocytes in areas of leukoderma.” Individuals have the blue/gray irises typical of people affected by blindness. The C of ABCD syndrome is what distinguishes this genetic disorder from BADS and it involves cell migration disorder of the neurocytes of the gut. This characteristic occurs when nerve cells do not function correctly in the gut, which results in aganglionosis: The intestines’ failure to move food along the digestive tract. Deafness or being unresponsive to noise due to very low quality of hearing was reported in every case of ABCD syndrome. The characteristics of ABCD syndrome are clearly evident in an inflicted individual.
No longer considered a separate syndrome, ABCD syndrome is today considered to be a variation of Shah-Waardenburg type IV. P.J. Waardenburg syndrome
(WS) is described as “the combination of sensorinerual hearing loss, hypopigmentation of skin and hair, and pigmentary disturbances of the irides.” Hearing loss and deafness, skin mispigmentation and albinism, and pigmentary changes in irises are the similarities between WS and ABCD. According to a dictionary of dermatologic syndromes, Waardenburg syndrome has many notable features, including “depigmentaion of hair and skin - white forelock and prematuring graying of hair, confluent thick eyebrows, heterochromic irides or hypopigmentation of iris, laterally displacy inner canthi, congenital sensorinerual deafness, broad nasal root, autosomal dominant disorder, and other associated findings, including black forelocks.”
material testing methods and this discovery changed the view of ABCD syndrome completely. A homozygous mutation means that there was an identical mutation on both the maternal and paternal genes. The identifying clinical report stated the test was done by scanning the Kurdish family for mutations in the EDNRB gene and the EDN3 gene by using a test called denaturing gradient gel electrophoresis
. The electrophoresis test takes advantage of electrical currents and differences in melting points of fragments of DNA or RNA to move them based on their molecular weight; the differences in mobility of the fragments then can be analyzed to determine different sequences and to detect individual alleles. Different nucleotides in DNA are codes for certain proteins, which are formed by different patterns of the base pairs adenine, thymine, guanine, and cytosine. The combination of adenine and thymine and guanine and cytosine align on the double strands of DNA. The test results found “an aberrant DGGE pattern of exon 3 of the EDNRB gene. The mutation was determined to be a homozygous C to T base pair transition at the amino acid level, causing a premature stop in gene translation.” This specialized testing enables geneticists to recognize the gene mutation that is the cause of ABCD syndrome.
New findings introduced an important break in the beliefs about ABCD syndrome because the endotherlin B gene is a gene involved in Shah-Waardenburg syndrome. The endothelin receptor B produces Waardenburg syndrome type IV. Researchers began discussing the possibility that ABCD syndrome was in fact not a syndrome; rather it was a type of another syndrome known as Waardenburg. Discovering that the same gene is involved in ABCD and Waardenburg syndrome is important because researchers can now look further into ways to fix this crucial gene.
atically and can be confirmed through genetic testing. If the diagnosis is not made early enough, complications can arise from
Hirschsprung's disease
.
is treated in time, ABCD sufferers live otherwise healthy lives. If it is not found soon enough, death often occurs in infancy. For those suffering hearing loss, it is generally regressive and the damage to hearing increases over time. Digestive problems from the colostomy and reattachment may exist, but most cases can be treated with laxatives. The only other debilitating symptom is hearing loss, which is usually degenerative and can only be treated with surgery or hearing aids.
(1886–1979) brought about the idea of Waardenburg syndrome when he examined two deaf twins. Waardenburg decided to define the syndrome with the six major symptoms that patients most commonly had.
When scientists further investigated the syndrome, they realized that patients exhibited a wider range of symptoms of this disease in different combinations. This helped them distinguish forms of Waardenburg syndrome. Their evaluation consisted of specifying Waardenburg syndrome type I (WS1), type II (WS2), type III (WS3), and type IV (WS4).
In 1995, a case study was performed of a Kurdish family. Scientists completed a molecular analysis with DNA strands of the patients diagnosed with ABCD syndrome. Their task was to scan the sequences to find a mutation in the EDNRB gene, one of the most important protein-coding genes. When they completed the scan they “found a homozygous C to T transition resulting, at the amino acid level, in a premature stop codon.” Then, they went back and defined that Shah-Waardenburg syndrome consisted majorly of “mutations in the ENDRB or END3 gene,” along “with [some] SOX10 mutations.” Therefore, the researchers confirmed that ABCD syndrome was a form of Shah-Waardenburg syndrome. The genetic tests that they performed on the patients DNA helped in identifying the appropriate diagnosis.
In 2002, Whitkop and other scientists examined patients born with white hair, some black locks, and depigmented skin; he diagnosed them as having black lock albinism deafness syndrome (BADS). Those who were closely working with this case suggested that it was an autoimmune disorder rather than a genetic defect. However, soon after, they had a patient who was one of fourteen children of Kurdish parents. The pedigree they examined revealed autosomal-recessive inheritance which led to cell migration of the neurocytes in the gut and, therefore, they redefined the syndrome as ABCD syndrome. This revealed “a homozygous nonsense mutation in the EDNRB gene” meaning that ABCD syndrome was not a separate entity but rather the same as Shah-Waardenburg syndrome.
Albinism
Albinism is a congenital disorder characterized by the complete or partial absence of pigment in the skin, hair and eyes due to absence or defect of an enzyme involved in the production of melanin...
, black lock, cell migration disorder of the neurocytes of the gut and sensorineural deafness. It has been found to be caused by mutation in the endothelin B receptor gene (EDNRB).
Classification
ABCD syndrome is defined as albinism, black lock, cell migration disorder of the neurocytes of the gut, and deafness. It was initially misdiagnosed and later discovered that a homozygous mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the EDNRB gene causes ABCD syndrome. This helped scientists discover that it is the same as type IV Waardenburg syndrome, also known as Shah-Waardenburg Syndrome
Waardenburg syndrome
Waardenburg syndrome Waardenburg syndrome Waardenburg syndrome (also Waardenburg Shah Syndrome, Waardenburg-Klein syndrome, Mende's syndrome II, Van der Hoeve-Halbertsma-Waardenburg syndrome, Ptosis-Epicanthus syndrome, Van der Hoeve-Halbertsma-Gualdi syndrome, Waardenburg type Pierpont,[5] Van...
.
Characteristics
In the beginning, medical officials defined ABCD syndrome by the four key characteristics of the syndrome. In the first case study of the Kurdish girl, researches described her as having “albinism and a black lock at the right temporo-occiptital region along Blaschko lines, her eyelashes and brows were white, the irises in her eyes appeared to be blue, she had spots of retinal depigmentationDepigmentation
Depigmentation is the lightening of the skin, or loss of pigment. Depigmentation of the skin can be caused by a number of local and systemic conditions. The pigment loss can be partial or complete...
, and she did not react to noise.” The albinism is interesting in this diagnosis because the skin of an affected individual is albino pale besides the brown patches of mispigmented skin. The “black locks” described and seen in clinical pictures of the infants are thick patches of black hair above the ears that form a half circle reaching to the other ear to make a crest shape.
As identified in this first case study and stated in a dictionary of dermatologic syndromes, ABCD syndrome has many notable features, including “snow white hair in patches, distinct black locks of hair, skin white except brown macules, deafness, irises gray to blue, nystagmus, photophobia
Photophobia
Photophobia is a symptom of abnormal intolerance to visual perception of light. As a medical symptom photophobia is not a morbid fear or phobia, but an experience of discomfort or pain to the eyes due to light exposure or by presence of actual physical photosensitivity of the eyes, though the term...
, poor visual activity, normal melanocytes in pigmented hair and skin, and absent melanocytes in areas of leukoderma.” Individuals have the blue/gray irises typical of people affected by blindness. The C of ABCD syndrome is what distinguishes this genetic disorder from BADS and it involves cell migration disorder of the neurocytes of the gut. This characteristic occurs when nerve cells do not function correctly in the gut, which results in aganglionosis: The intestines’ failure to move food along the digestive tract. Deafness or being unresponsive to noise due to very low quality of hearing was reported in every case of ABCD syndrome. The characteristics of ABCD syndrome are clearly evident in an inflicted individual.
No longer considered a separate syndrome, ABCD syndrome is today considered to be a variation of Shah-Waardenburg type IV. P.J. Waardenburg syndrome
Waardenburg syndrome
Waardenburg syndrome Waardenburg syndrome Waardenburg syndrome (also Waardenburg Shah Syndrome, Waardenburg-Klein syndrome, Mende's syndrome II, Van der Hoeve-Halbertsma-Waardenburg syndrome, Ptosis-Epicanthus syndrome, Van der Hoeve-Halbertsma-Gualdi syndrome, Waardenburg type Pierpont,[5] Van...
(WS) is described as “the combination of sensorinerual hearing loss, hypopigmentation of skin and hair, and pigmentary disturbances of the irides.” Hearing loss and deafness, skin mispigmentation and albinism, and pigmentary changes in irises are the similarities between WS and ABCD. According to a dictionary of dermatologic syndromes, Waardenburg syndrome has many notable features, including “depigmentaion of hair and skin - white forelock and prematuring graying of hair, confluent thick eyebrows, heterochromic irides or hypopigmentation of iris, laterally displacy inner canthi, congenital sensorinerual deafness, broad nasal root, autosomal dominant disorder, and other associated findings, including black forelocks.”
Causes and DNA testing
Researchers in the past 20 years have determined that a gene mutation, specifically a homozygous mutation in the EDNRB gene, is the cause of ABCD syndrome. The advancement of technology led to new DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
material testing methods and this discovery changed the view of ABCD syndrome completely. A homozygous mutation means that there was an identical mutation on both the maternal and paternal genes. The identifying clinical report stated the test was done by scanning the Kurdish family for mutations in the EDNRB gene and the EDN3 gene by using a test called denaturing gradient gel electrophoresis
Gel electrophoresis
Gel electrophoresis is a method used in clinical chemistry to separate proteins by charge and or size and in biochemistry and molecular biology to separate a mixed population of DNA and RNA fragments by length, to estimate the size of DNA and RNA fragments or to separate proteins by charge...
. The electrophoresis test takes advantage of electrical currents and differences in melting points of fragments of DNA or RNA to move them based on their molecular weight; the differences in mobility of the fragments then can be analyzed to determine different sequences and to detect individual alleles. Different nucleotides in DNA are codes for certain proteins, which are formed by different patterns of the base pairs adenine, thymine, guanine, and cytosine. The combination of adenine and thymine and guanine and cytosine align on the double strands of DNA. The test results found “an aberrant DGGE pattern of exon 3 of the EDNRB gene. The mutation was determined to be a homozygous C to T base pair transition at the amino acid level, causing a premature stop in gene translation.” This specialized testing enables geneticists to recognize the gene mutation that is the cause of ABCD syndrome.
New findings introduced an important break in the beliefs about ABCD syndrome because the endotherlin B gene is a gene involved in Shah-Waardenburg syndrome. The endothelin receptor B produces Waardenburg syndrome type IV. Researchers began discussing the possibility that ABCD syndrome was in fact not a syndrome; rather it was a type of another syndrome known as Waardenburg. Discovering that the same gene is involved in ABCD and Waardenburg syndrome is important because researchers can now look further into ways to fix this crucial gene.
Screening
Screening generally only takes place among those displaying several of the symptoms of ABCD, but a study on a large group of institutionalized deaf people in Columbia revealed that 5.38% of them were Waardenburg patients. Because of its rarity, none of the patients were diagnosed with ABCD (Waardenburg Type IV). Nothing can be done to prevent the disease.Diagnosis
The occurrence of WS has been reported to be one in 45,000 in Europe. The diagnosis can be made prenatally by ultrasound due to the phenotype displaying pigmentary disturbances, facial abnormalities, and other developmental defects. After birth, the diagnosis is initially made symptomSymptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
atically and can be confirmed through genetic testing. If the diagnosis is not made early enough, complications can arise from
Hirschsprung's disease
Hirschsprung's disease
Hirschsprung's disease , or congenital aganglionic megacolon is a serious medical problem where the enteric nervous system is missing from the end of the bowel. The enteric nervous system is a complex network of neurons and glia that controls most aspects of intestinal function...
.
Treatment
Treatment for the disease itself is nonexistent, but there are options for most of the symptoms. For example, one suffering from hearing loss would be given hearing aids, and those with Hirschsprung’s disorder can be treated with a colostomy.Prognosis
If the Hirschsprung's diseaseHirschsprung's disease
Hirschsprung's disease , or congenital aganglionic megacolon is a serious medical problem where the enteric nervous system is missing from the end of the bowel. The enteric nervous system is a complex network of neurons and glia that controls most aspects of intestinal function...
is treated in time, ABCD sufferers live otherwise healthy lives. If it is not found soon enough, death often occurs in infancy. For those suffering hearing loss, it is generally regressive and the damage to hearing increases over time. Digestive problems from the colostomy and reattachment may exist, but most cases can be treated with laxatives. The only other debilitating symptom is hearing loss, which is usually degenerative and can only be treated with surgery or hearing aids.
History
Dutch ophthalmologist Petrus Johannes WaardenburgPetrus Johannes Waardenburg
Petrus Johannes Waardenburg was a Dutch ophthalmologist, geneticist, and pioneer in the application of genetics to ophthalmology...
(1886–1979) brought about the idea of Waardenburg syndrome when he examined two deaf twins. Waardenburg decided to define the syndrome with the six major symptoms that patients most commonly had.
- He defined “lateral displacement of the medial canthi combined with dystopia of the lacrimal punctum and blepharophimosis” referring to people with broader and flatter nasal bridges, which in turn leads to folds in the skin that cover the inner corners of the eye.
- Secondly, people who are born with a “prominent broad nasal root,” have a widened area between the eyes, causing them to have a flatter and wider face, along with eyes farther apart than normal.
- Thirdly, “hypertrichosis of the medial part of the eyebrows” is present, meaning excessive hair growth in the patients’ eyebrow region, most likely leading to a unibrowUnibrowA unibrow is a "confluence of eyebrows"; that is, the presence of abundant hair between the eyebrows, so that they seem to converge to form one long eyebrow. The condition of having a unibrow is synophrys.-Beauty culture:...
. - The fourth symptom, “white forelock,” was commonly seen as depigmented strands of hair
- “Heterochromia iridis” indicates that the patient has two different colored eyes or two colors in the same eyes.
- “Deaf-mutism”: People with the disorder are both deaf and mute.
When scientists further investigated the syndrome, they realized that patients exhibited a wider range of symptoms of this disease in different combinations. This helped them distinguish forms of Waardenburg syndrome. Their evaluation consisted of specifying Waardenburg syndrome type I (WS1), type II (WS2), type III (WS3), and type IV (WS4).
In 1995, a case study was performed of a Kurdish family. Scientists completed a molecular analysis with DNA strands of the patients diagnosed with ABCD syndrome. Their task was to scan the sequences to find a mutation in the EDNRB gene, one of the most important protein-coding genes. When they completed the scan they “found a homozygous C to T transition resulting, at the amino acid level, in a premature stop codon.” Then, they went back and defined that Shah-Waardenburg syndrome consisted majorly of “mutations in the ENDRB or END3 gene,” along “with [some] SOX10 mutations.” Therefore, the researchers confirmed that ABCD syndrome was a form of Shah-Waardenburg syndrome. The genetic tests that they performed on the patients DNA helped in identifying the appropriate diagnosis.
In 2002, Whitkop and other scientists examined patients born with white hair, some black locks, and depigmented skin; he diagnosed them as having black lock albinism deafness syndrome (BADS). Those who were closely working with this case suggested that it was an autoimmune disorder rather than a genetic defect. However, soon after, they had a patient who was one of fourteen children of Kurdish parents. The pedigree they examined revealed autosomal-recessive inheritance which led to cell migration of the neurocytes in the gut and, therefore, they redefined the syndrome as ABCD syndrome. This revealed “a homozygous nonsense mutation in the EDNRB gene” meaning that ABCD syndrome was not a separate entity but rather the same as Shah-Waardenburg syndrome.
External links
- GeneCard for EDNRB
- OMIM Genetic disorder catalog - Waardenburg syndrome