Ectrodactyly-Ectodermal Dysplasia-Cleft Syndrome
Encyclopedia
Ectrodactyly–ectodermal dysplasia–cleft syndrome, or EEC, and also referred to as EEC syndrome (also known as "Split hand–split foot–ectodermal dysplasia–cleft syndrome") is a rare form of ectodermal dysplasia
, an autosomal dominant disorder inherited as an genetic
trait
. EEC is characterized by the triad of ectrodactyly
, ectodermal dysplasia, and Facial Clefts. Other features noted in association with EEC include vesicoureteral reflux
, recurrent urinary tract infection
s, obstruction of the nasolacrimal duct
, decreased pigmentation of the hair
and skin
, missing or abnormal teeth, enamel hypoplasia
, absent punctae in the lower eyelid
s, photophobia
, occasional cognitive impairment and kidney
anomalies, and conductive hearing loss
.
Ectodermal dysplasia describes abnormalities of structures derived from the embryonic ectoderm
. These abnormalities affect both the superficial ectodermal layer, as well as the mesectodermal layer constituted by the neural crest.
. In addition, abnormalities of ectodermal derivatives, neuroectodermal derivatives, and mesectodermal derivatives are often found. The ectodermal derivative abnormalities can affect the epidermis including mammary, pituitary and sweat glands, as well as hairs, dental enamel, nails, lens, and the internal ear. Neuroectodermal derivatives that can be affected include sensory placodes, cutaneous pigmental cells, and hair buds. Mesectodermal derivatives affected can include the dermis
, hypodermis
, dentin
, head muscles and conjunctival cells, cervicofacial vascular endothelial cells, and part of the maxillofacial skeleton.
The hypohydrotic symptoms of ectodermal dysplasia described above are evidenced not only in the skin of affected individuals, but also in their phonation
and voice
production. Because the vocal folds
may not be as hydrated as is necessary during the adduction phase of vocal fold vibration (due to lack of lubrication), a complete seal may not be accomplished between the folds and mucosal wave movement may be disrupted. This results in air escapement between the folds and the production of breathy voice, which often accompanies the skin abnormalities of ectodermal dysplasia.
and velopharyngeal incompetence. Because of this, compensatory articulation strategies including retruded articulation and glottal compensation are often incorporated into the patient's speech. Articulation
is further impaired by the numerous dental anomalies, including missing or malformed teeth found in EEC syndrome.
Language
deficits are also associated with EEC syndrome and are attributed to two factors. Conductive hearing loss
due to ossicular anomalies is often encountered in patients with EEC syndrome, which can have significant impacts on language acquisition. Also, the impaired cognitive functioning that sometimes accompanies EEC can inhibit language acquisition.
, mesoderm
, and endoderm
. It is from these three types of cells that all body organs originate. In general terms, ectodermal cells generate the skin
, spinal cord
, and teeth (as well as the numerous derivatives mentioned above). Mesodermal cells generate blood
vessels, muscle
and bone
, and endodermal cells generate the lungs, the digestive system and the urinary system.
There are two layers of mesoderm; intraembryonic and extraembryonic. As the intraembryonic layer grows laterally, it becomes continuous with the extraembryonic layer, forming the chorion (contributing to the blood supply). At the same time during embryonic development, the ectoderm begins to thicken and fold upward, forming the neural folds, which eventually meet to form the neural tube and neural crest. Because these two events occur at roughly the same time in embryological development, abnormalities found in this syndrome can involve not only the ectodermal cells, but also disruption to development in the mesectodermal layer constituted by the neural crest.
"What these structures have in common is that their development and morphogenesis depends on the signaling between specialized ectodermal cells and the underlying mesoderm. Epithelial-mesenchymal interactions between the apical ectodermal ridge (AER) and the underlying mesenchyme, denoted the progress zone, are required for normal morphogenesis of the limb.
includes 22 pairs of autosomal or non-sex chromosomes and one pair of sex chromosomes, constituting a total of 46 chromosomes. During reproduction, each parent contributes 23 chromosomes; 22 autosomal chromosomes and one sex chromosome. As stated above, EEC syndrome is an autosomal dominant disorder. This means that there is an abnormal gene on one of the autosomal (non-sex) chromosomes from either parent. Because the gene is dominant, only one parent must contribute the abnormal gene for the child to inherit the disease and the contributing parent will usually have the disease, due to the expression of the dominant gene in the parent. Some characteristics of autosomal dominant inheritance patterns include a vertical transmission pattern, meaning that the disease phenotype is seen in generation after generation. Also, the recurrence risk is 50% and there are an equal number of affected males and females. Though we can calculate the chance of inheritance of the gene, the degree of expression cannot be calculated.
Genetics research relating to EEC has made great strides in recent years, but many findings are currently being debated in the literature. chromosome 19
, within the region of D19S894 and D19S416 has been postulated as the locus for the abnormalities found in EEC syndrome. This is supported by reports (though conflicting) regarding an association of cleft lip +/- palate on locus 19q, which suggests that EEC could be an allelic variant.
More recently, the p63 gene has been targeted in numerous studies. Interestingly, the p63 gene is a homologue of the tumor suppressor gene p53, though this is not indicative that patients with EEC are more likely to develop tumors. p63 mutations have been implicated in other human malformation conditions as well, including AEC or Hay–Wells syndrome, limb–mammary syndrome, ADULT syndrome, and non-syndromic split hand–split foot malformation. When comparing the data for these syndromes, each syndrome has a distinct pattern and type of mutations, with extensive genotype–phenotype correlations. Brunner and colleagues found that most of the p63 mutations associated with EEC "involve amino acid substitutions in the DNA binding domain common to all known p63 isoforms". The findings of their study propose that the most frequently mutated arginine codons associated with EEC are 204, 227, 279, 280, and 304, with these five amino acid mutations accounting for 75% of all reported cases of EEC syndrome. Other studies have had similar findings. One study found three of the five listed amino acid mutations in their subjects and noted that when 200 control chromosomes were tested, these three mutant alleles were not present.
. The frameshift mutation introduces a premature stop codon that affected the α isotope, but does not affect the β and γ isotopes of p63. From this, it can be concluded that mutant p63α isotopes seem to play a major role in the pathogenesis of EEC syndrome. Interestingly, it seems that p63α is the predominant p63 isotope in epithelial basal cell layers, which are the cell type often associated with the anomalies found in patients with EEC syndrome.
This striking data offers convincing support for the p63 gene hypothesis. This study is also cited in the demonstration that the growth and patterning of the underlying mesenchyme is highly dependent on the apical ectodermal ridge of the limbs, as well as the maxillary and mandibular branchial ectoderm that are so prominently disturbed in these mice. All of these findings are consistent with the clinical presentation of EEC in humans and may explain the association of limb malformation and clefting that are found in this syndrome.
Ectodermal dysplasia
Ectodermal dysplasia is not a single disorder, but a group of syndromes all deriving from abnormalities of the ectodermal structures. More than 150 different syndromes have been identified. Despite some of the syndromes having different genetic causes the symptoms are sometimes very similar...
, an autosomal dominant disorder inherited as an genetic
Genetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
trait
Trait (biology)
A trait is a distinct variant of a phenotypic character of an organism that may be inherited, environmentally determined or be a combination of the two...
. EEC is characterized by the triad of ectrodactyly
Ectrodactyly
Ectrodactyly, sometimes referred to as the “Lobster-Claw Syndrome” involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand/split foot malformation...
, ectodermal dysplasia, and Facial Clefts. Other features noted in association with EEC include vesicoureteral reflux
Vesicoureteral reflux
Vesicoureteral reflux is an abnormal movement of urine from the bladder into ureters or kidneys. Urine normally travels from the kidneys via the ureters to the bladder...
, recurrent urinary tract infection
Urinary tract infection
A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
s, obstruction of the nasolacrimal duct
Nasolacrimal duct
The nasolacrimal duct carries tears from the lacrimal sac into the nasal cavity. Excess tears flow through nasolacrimal duct which drains into the inferior nasal meatus...
, decreased pigmentation of the hair
Hair
Hair is a filamentous biomaterial, that grows from follicles found in the dermis. Found exclusively in mammals, hair is one of the defining characteristics of the mammalian class....
and skin
Human skin
The human skin is the outer covering of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals,...
, missing or abnormal teeth, enamel hypoplasia
Hypoplasia
Hypoplasia is underdevelopment or incomplete development of a tissue or organ. Although the term is not always used precisely, it properly refers to an inadequate or below-normal number of cells. Hypoplasia is similar to aplasia, but less severe. It is technically not the opposite of hyperplasia...
, absent punctae in the lower eyelid
Eyelid
An eyelid is a thin fold of skin that covers and protects an eye. With the exception of the prepuce and the labia minora, it has the thinnest skin of the whole body. The levator palpebrae superioris muscle retracts the eyelid to "open" the eye. This can be either voluntarily or involuntarily...
s, 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...
, occasional cognitive impairment and kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
anomalies, and conductive hearing loss
Conductive hearing loss
Conductive hearing loss occurs when there is a problem conducting sound waves anywhere along the route through the outer ear, tympanic membrane , or middle ear ....
.
Ectrodactyly
Ectrodactyly involves the deficiency or absence of one or more central digits of the hand or foot and is also known as split hand–split foot malformation (SHFM). The hands and feet of people with ectrodactyly are often described as "claw-like" and may include only the thumb and one finger (usually either the little finger, ring finger, or a syndactyly of the two) with similar abnormalities of the feet.Ectodermal dysplasia describes abnormalities of structures derived from the embryonic ectoderm
Ectoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
. These abnormalities affect both the superficial ectodermal layer, as well as the mesectodermal layer constituted by the neural crest.
Ectodermal dysplasia
Ectodermal dysplasia is characterized by absent sweat glands resulting in dry (hypohydrotic), often scale-like skin, sparse and usually coarse scalp hair that is often blonde, sparse eyebrows and eyelashes, and small brittle nailsNail (anatomy)
A nail is a horn-like envelope covering the dorsal aspect of the terminal phalanges of fingers and toes in humans, most non-human primates, and a few other mammals. Nails are similar to claws, which are found on numerous other animals....
. In addition, abnormalities of ectodermal derivatives, neuroectodermal derivatives, and mesectodermal derivatives are often found. The ectodermal derivative abnormalities can affect the epidermis including mammary, pituitary and sweat glands, as well as hairs, dental enamel, nails, lens, and the internal ear. Neuroectodermal derivatives that can be affected include sensory placodes, cutaneous pigmental cells, and hair buds. Mesectodermal derivatives affected can include the dermis
Dermis
The dermis is a layer of skin between the epidermis and subcutaneous tissues, and is composed of two layers, the papillary and reticular dermis...
, hypodermis
Hypodermis
The hypodermis, also called the hypoderm, subcutaneous tissue, or superficial fascia is the lowermost layer of the integumentary system in vertebrates. Types of cells that are found in the hypodermis are fibroblasts, adipose cells, and macrophages...
, dentin
Dentin
Dentine is a calcified tissue of the body, and along with enamel, cementum, and pulp is one of the four major components of teeth. Usually, it is covered by enamel on the crown and cementum on the root and surrounds the entire pulp...
, head muscles and conjunctival cells, cervicofacial vascular endothelial cells, and part of the maxillofacial skeleton.
The hypohydrotic symptoms of ectodermal dysplasia described above are evidenced not only in the skin of affected individuals, but also in their phonation
Phonation
Phonation has slightly different meanings depending on the subfield of phonetics. Among some phoneticians, phonation is the process by which the vocal folds produce certain sounds through quasi-periodic vibration. This is the definition used among those who study laryngeal anatomy and physiology...
and voice
Voice
Voice may refer to:* Human voice* Voice control or voice activation* Writer's voice* Voice acting* Voice vote* Voice message-In film:* Voice , a 2005 South Korean film* The Voice , a 2010 Turkish horror film directed by Ümit Ünal...
production. Because the vocal folds
Vocal folds
The vocal folds, also known commonly as vocal cords, are composed of twin infoldings of mucous membrane stretched horizontally across the larynx...
may not be as hydrated as is necessary during the adduction phase of vocal fold vibration (due to lack of lubrication), a complete seal may not be accomplished between the folds and mucosal wave movement may be disrupted. This results in air escapement between the folds and the production of breathy voice, which often accompanies the skin abnormalities of ectodermal dysplasia.
Facial clefting
There is much discrepancy in the literature regarding the exact nature of the facial clefting involved in EEC. Some authors claim that the clefting involved in EEC is always cleft lip +/- palate and use this marker as a means of distinguishing EEC from other syndromes, such as AEC syndrome (ankyloblepharon, ectodermal dysplasia, and clefting) in which other types of clefting are found. Other authors include cleft palate only (CPO) in conjunction with ectrodactyly and ectodermal dysplasia as sufficient for a diagnosis of EEC.Speech deficits
The speech deficits associated with EEC syndrome are numerous. The clefting often causes hypernasal speechHypernasal speech
Rhinolalia , aperta = open, is the medical term for hypernasal speech. The other terms are hyperrhinolalia and open nasality. Hypernasality is a disorder of nasal speech when the sound of the voice is different, an abnormal resonance...
and velopharyngeal incompetence. Because of this, compensatory articulation strategies including retruded articulation and glottal compensation are often incorporated into the patient's speech. Articulation
Manner of articulation
In linguistics, manner of articulation describes how the tongue, lips, jaw, and other speech organs are involved in making a sound. Often the concept is only used for the production of consonants, even though the movement of the articulars will also greatly alter the resonant properties of the...
is further impaired by the numerous dental anomalies, including missing or malformed teeth found in EEC syndrome.
Language
Language
Language may refer either to the specifically human capacity for acquiring and using complex systems of communication, or to a specific instance of such a system of complex communication...
deficits are also associated with EEC syndrome and are attributed to two factors. Conductive hearing loss
Conductive hearing loss
Conductive hearing loss occurs when there is a problem conducting sound waves anywhere along the route through the outer ear, tympanic membrane , or middle ear ....
due to ossicular anomalies is often encountered in patients with EEC syndrome, which can have significant impacts on language acquisition. Also, the impaired cognitive functioning that sometimes accompanies EEC can inhibit language acquisition.
Embryology
The ectodermal dysplasia associated with EEC syndrome arises from abnormalities in the embryonic ectoderm, as described above. Very early in embryonic development, the embryonic stem cells differentiate into three types of cells: the ectodermEctoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
, mesoderm
Mesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
, and endoderm
Endoderm
Endoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and mesoderm , with the endoderm as the intermost layer...
. It is from these three types of cells that all body organs originate. In general terms, ectodermal cells generate the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
, spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, and teeth (as well as the numerous derivatives mentioned above). Mesodermal cells generate blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
vessels, muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
and bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
, and endodermal cells generate the lungs, the digestive system and the urinary system.
There are two layers of mesoderm; intraembryonic and extraembryonic. As the intraembryonic layer grows laterally, it becomes continuous with the extraembryonic layer, forming the chorion (contributing to the blood supply). At the same time during embryonic development, the ectoderm begins to thicken and fold upward, forming the neural folds, which eventually meet to form the neural tube and neural crest. Because these two events occur at roughly the same time in embryological development, abnormalities found in this syndrome can involve not only the ectodermal cells, but also disruption to development in the mesectodermal layer constituted by the neural crest.
"What these structures have in common is that their development and morphogenesis depends on the signaling between specialized ectodermal cells and the underlying mesoderm. Epithelial-mesenchymal interactions between the apical ectodermal ridge (AER) and the underlying mesenchyme, denoted the progress zone, are required for normal morphogenesis of the limb.
Current research
Current research regarding EEC syndrome is focused on the genetic components contributing to the presented traits found in patients with EEC. A normal human karyotypeKaryotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
includes 22 pairs of autosomal or non-sex chromosomes and one pair of sex chromosomes, constituting a total of 46 chromosomes. During reproduction, each parent contributes 23 chromosomes; 22 autosomal chromosomes and one sex chromosome. As stated above, EEC syndrome is an autosomal dominant disorder. This means that there is an abnormal gene on one of the autosomal (non-sex) chromosomes from either parent. Because the gene is dominant, only one parent must contribute the abnormal gene for the child to inherit the disease and the contributing parent will usually have the disease, due to the expression of the dominant gene in the parent. Some characteristics of autosomal dominant inheritance patterns include a vertical transmission pattern, meaning that the disease phenotype is seen in generation after generation. Also, the recurrence risk is 50% and there are an equal number of affected males and females. Though we can calculate the chance of inheritance of the gene, the degree of expression cannot be calculated.
Genetics
Genetics research relating to EEC has made great strides in recent years, but many findings are currently being debated in the literature. chromosome 19
Chromosome 19 (human)
125px|rightChromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active...
, within the region of D19S894 and D19S416 has been postulated as the locus for the abnormalities found in EEC syndrome. This is supported by reports (though conflicting) regarding an association of cleft lip +/- palate on locus 19q, which suggests that EEC could be an allelic variant.
More recently, the p63 gene has been targeted in numerous studies. Interestingly, the p63 gene is a homologue of the tumor suppressor gene p53, though this is not indicative that patients with EEC are more likely to develop tumors. p63 mutations have been implicated in other human malformation conditions as well, including AEC or Hay–Wells syndrome, limb–mammary syndrome, ADULT syndrome, and non-syndromic split hand–split foot malformation. When comparing the data for these syndromes, each syndrome has a distinct pattern and type of mutations, with extensive genotype–phenotype correlations. Brunner and colleagues found that most of the p63 mutations associated with EEC "involve amino acid substitutions in the DNA binding domain common to all known p63 isoforms". The findings of their study propose that the most frequently mutated arginine codons associated with EEC are 204, 227, 279, 280, and 304, with these five amino acid mutations accounting for 75% of all reported cases of EEC syndrome. Other studies have had similar findings. One study found three of the five listed amino acid mutations in their subjects and noted that when 200 control chromosomes were tested, these three mutant alleles were not present.
Mutations
The mutations found in EEC are missense mutations, meaning that there is a single amino acid change in the protein, as opposed to premature termination of protein synthesis, known as a nonsense mutationNonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
. The frameshift mutation introduces a premature stop codon that affected the α isotope, but does not affect the β and γ isotopes of p63. From this, it can be concluded that mutant p63α isotopes seem to play a major role in the pathogenesis of EEC syndrome. Interestingly, it seems that p63α is the predominant p63 isotope in epithelial basal cell layers, which are the cell type often associated with the anomalies found in patients with EEC syndrome.
Genetic expression
EEC can be both familial and sporadic, both cases relating back to abnormalities of the p63 gene. This means that in some cases, EEC expresses de novo in a child of unaffected parents (sporadic) due to spontaneous mutation, in addition to the existing autosomal dominant inherited form. There seems to be significant interfamilial and intrafamilial variability in expressivity, more noticeably between rather than within families. Because of this variability, it is possible that there is more than one genetic locus involved in the actual manifestation of the syndrome in any given person. Other notably proposed sections of the involved chromosome include 3q27, and more highly disputed areas, including 7q11.2–q21.3Knockout mice
A study supports the hypothesis of the p63 gene as the locus for the mutations associated with EEC syndrome. The study is known as the p63 knockout mice study, in which the phenotypes of p63-deficient mice are described. The description of the mice is as follows:P63-deficient mice lack all squamous epithelia and their derivatives, including hair, whiskers, teeth, as well as the mammary, lacrimal, and salivary glands. Particularly striking are severe limb truncations with forelimbs showing a complete absence of the phalanges and carpals, and variable defects of ulnae and radiae and hindlimbs that are lacking altogether…The p63 mutations act in a dominant fashion in humans, giving rise to a phenotype that resembles that of p63 knockout mice.
This striking data offers convincing support for the p63 gene hypothesis. This study is also cited in the demonstration that the growth and patterning of the underlying mesenchyme is highly dependent on the apical ectodermal ridge of the limbs, as well as the maxillary and mandibular branchial ectoderm that are so prominently disturbed in these mice. All of these findings are consistent with the clinical presentation of EEC in humans and may explain the association of limb malformation and clefting that are found in this syndrome.