Symptoms and diagnosis
Microdeletion syndromes are an extensive group of diseases affecting various organs and systems. These diseases are caused by deletion of loss) of small chromosome regions, which are often not noticeable in standard cytogenetic analysis. Previously, most microdeletion syndromes were described as pathologies of unknown origin and were not even associated with “chromosomal breakdowns”, since it was not possible to conduct subtle and accurate genetic diagnostics.
Today, the variety of diagnostic methods is constantly increasing and, accordingly, the ability to identify many diseases is becoming more accessible.
IGR Medical Center provides the widest research panel in Ukraine on microdeletion diseases.
Chromosome 1p36 deletion syndrome
The frequency of the disease is 1: 5000 newborns. Chromosome 1p36 deletion syndrome (1p36 monosomy) is an autosomal dominant disease caused by terminal deletion of the short arm of chromosome 1. Deletion often occurs de novo. It is characterized by malformations, mental retardation, growth retardation, hypotension, seizures, speech retardation, hearing and vision impairment, craniofacial dysmorphisms, among which microcephaly, small, deep-set eyes, flat nose and nose, low-set small ears, small a mouth with lowered corners, a pointed chin, facial asymmetry and a large, late-closing fontanel. Children have a mental retardation (from moderate to severe), speech is severely affected (some patients know only a few words). The behavior is characterized by a quick-tempered temper, aggression towards others, self-harming behavior, and some children have autistic features. Symptoms may vary depending on the size of the deletion.
The frequency of this syndrome is 1: 50,000 births. Wolff-Hirschhorn syndrome is a syndrome caused by a genetic disease. The average life expectancy is up to about 30 years (in Russia, the maximum life expectancy is 25 years), with severe heart defects, kidneys can be no more than one year. In 80% of newborns suffering from it, the cytological basis of this syndrome is a deletion of the short arm of the 4th chromosome. Deletion sizes range from small terminal to occupying about half of the distal part of the short arm.
It is noted that most deletions occur “de novo” - 90%, about 10% occur as a result of translocations in parents (1: 2 - male: female). Less often in the genome of patients, in addition to translocation, there are also ring chromosomes. Along with deletion of chromosomes, the pathology in newborns can be characterized by inversions, duplications, isochromosomes. The disease is characterized by a delay in physiological, mental and psychomotor development. Severe heart and kidney defects can also occur in most cases. With a normal duration of pregnancy, newborns are lightweight (up to 2 kg). Among the external signs can be noted: microcephaly, coracoid nose, epicanthus, antimongoloid section of the eyes (omission of the external corners of the palpebral fissures), abnormal auricles, cleft of the upper lip and palate, small mouth, deformation of the feet, etc.
Cat scream syndrome
The frequency of the syndrome is 1: 20,000 newborns. Feline scream syndrome (born cri du chat syndrome, French: maladie du cri du chat; also feline cry disease, Lejeune syndrome).
Sex ratio M1: G1.3. Chromosomal feline scream syndrome is explained by partial monosomy; it develops with a deletion (with loss from a third to half, less often complete loss) of the short arm of the fifth chromosome. For the development of the clinical picture of the syndrome, it is not the size of the lost site that matters, but the specific minor fragment of the chromosome. Mosaicism by deletion or ring chromosome formation is rarely observed.
With this syndrome, there is observed: a general developmental delay, low birth weight and muscle hypotension, a moon-shaped face with wide eyes, a characteristic cry of a child resembling cat meow, which is caused by a change in the larynx (narrowing, softness of the cartilage, reduction of the epiglottis, unusual mucosal folding shell) or underdevelopment of the larynx. The sign disappears at the end of the first year of life.
In addition, there are congenital defects of the heart, musculoskeletal system and internal organs, microcephaly, ptosis, low location and deformation of the auricles, skin folds in front of the ear, hypertelorism, epicanthus (transverse skin fold near the inner corner of the eye, usually bilateral; most pronounced with Down's disease), antimongoloid eye incision.
The clinical picture of the syndrome and the life expectancy of people with this syndrome vary quite a lot in combination of congenital malformations of organs.
Frequency 1: 15,000 - 20,000 newborns. Sotos syndrome (cerebral gigantism syndrome) is a congenital, in most cases sporadic (there are families with an autosomal dominant type of inheritance) disease. Among the patients, boys predominate. The occurrence of Sotos syndrome is due to a deletion of the 5q35 region. Dysfunction of hypothalamic structures appears; in some cases, the pituitary microadenoma was found. Against the backdrop of progressive gigantism, normal levels of GH are noted, as well as elevated levels of valine, isoleucine and leucine in the blood. The clinical picture of Sotos syndrome is combined with a mutation in the NSD1 gene. The main signs: tall, acromegaloid features, mental retardation. Children are born with a large mass and body length. Growth is accelerated from the first years of life, especially rapid growth is observed in the period of 4-5 years of age, however, over the years, growth rates are reduced, as a result, patients' growth reaches the upper limit of normal or slightly exceeds it, body weight with a slight excess, deposition of subcutaneous fatty tissue is observed in the distal extremities. Facial features are rough, acromegaloid, the skull is microcephalic with an increase in the frontal tubercles and lower jaw, hypertelorism, antimongoloid eye incision, strabismus, "Gothic" palate, large tongue, prognathism, an increase in the size of the hands and feet with a thickening of the subcutaneous fat layer.
Bone maturation is ahead of passport age. Sexual development is normal or early. In most patients, mental development is delayed, mental insufficiency, often mildly expressed, the psyche with elements of aggressiveness is noted. An EEG study reveals various deviations. Often coordination of movements is disturbed, ataxia, tremors are found, convulsive attacks are possible. This pathology is sometimes combined with the development of malignant neoplasms (Wilms tumor, liver, ovarian cancer).
Setr Hotzen Syndrome
Frequency 1: 25,000 - 50,000 babies born. Setr-Hotzen's syndrome (type III acrocephalosindactyly) is a congenital disease characterized by ossification of the bones of the skull, premature obliteration of the sutures of the skull, as well as abnormalities of the lower extremities. The disease is inherited in an autosomal dominant manner. This disease is associated with the TWIST1 gene, which is located on the 7p21.2 chromosome. The regulation of mesenchymal cells is associated with this gene. Some patients have a crossroads genetic syndrome and they find a mutation of the fibroblast growth gene receptor (Muenke syndrome).
The most characteristic signs of the clinical picture are synostosis, brachycephaly, low location of the hairline on the forehead, facial asymmetry, hypertelorism, valgus and deformation of the fingers and toes. With unexpressed manifestations of the disease, the diagnosis is often made in the later stages of the disease.
Frequency 1: 7,500 - 20,000 newborns. Williams-Boyren syndrome (“elf face” syndrome) is a syndrome that arises as a result of hereditary chromosomal rearrangement, suffering from which have a specific appearance and are characterized by a general delay in mental development with the development of certain areas of intelligence. A rare genetic disorder caused by a deletion of the site on which there are about 26 genes located on the long arm of the 7th chromosome (7q11.23). Patients have a special face structure, referred to in the literature as the “face of an elf,” because it resembles the face of elves in their traditional, folklore version.
They are characterized by a wide forehead, a scattering of eyebrows in the midline, full cheeks down, a large mouth with full lips (especially the lower one), a flat nose, a peculiar shape of the nose with a flat blunt end, a small, slightly pointed chin. The eyes are often bright blue, with a stellate iris pattern and bluish sclera. The section of the eyes is peculiar, with swelling around the eyelids. Converging strabismus. Older children have long, rare teeth. With age, the patient’s face changes somewhat: massiveness of the superciliary arches appears, pasty face is less pronounced, there is no flat nose and epicant. The increased distance from the base of the nose to the upper lip is noteworthy. The similarity of faces is enhanced by a smile, which further emphasizes the swelling of the eyelids and the peculiar structure of the mouth. None of these traits is mandatory, but a common combination is always present.
Frequency 1: 12,000 newborns. CHARGE syndrome is a genetic disorder leading to a complex disorder in human systems and organs. CHARGE syndrome usually occurs sporadically. It has an autosomal dominant type of inheritance. The reason for the development of CHARGE syndrome is a mutation of the CHD7 gene, which encodes chromodomein helicase, a family of proteins. Foreign experts working with children with multiple congenital malformations are increasingly talking about this syndrome. This name came from a combination of the first Latin letters of six words denoting lesions of various organs in a child.
C - means damage to the organ of vision in the form of a coloboma (congenital absence of part of the organ’s tissue). This may be a defect in the tissues of the eyelid, and then this does not affect the state of vision. It can be an iris coloboma, and then the child’s eye does not respond well to changes in lighting. But this can also mean a defect in the optic nerve or retina, and then a serious visual impairment is possible.
Н - means a violation of cardiac activity, which can be expressed differently in each individual case. This can be a mild violation of cardiac activity, and severe congenital heart disease.
A - means atresia (narrowing or partial infection) of the choan (nasal openings through which air enters from the nose into the nasopharynx), due to which the child experiences difficulty in swallowing, sucking and breathing. This congenital pathology can cause the death of a newborn or pneumonia at an early age.
It is this congenital disorder that affects the unusual appearance of a child with this syndrome and is its most obvious sign.
R - means a lag in the growth and body weight of the child.
G - genital maldevelopment, usually easily found in boys during external examination and not obvious in girls.
E - ear defects and / or hearing impairment, which can also be expressed differently in children with this syndrome.
For example, these can be altered auricles, either too protruding and large, or too small and undeveloped. These can be congenital changes in the auditory canal (narrowing, etc.), and in other cases, disorders in the middle or inner ear. In some cases, these multiple disorders are joined: imbalance, facial paralysis, difficulty in behavior, and others.
The population frequency of the syndrome is 1: 25,000 newborns. Langer-Gidion syndrome (synonym for trichorinophalangeal syndrome, type II) is a hereditary disease. The frequency of birth of children with this syndrome depends on the age of the mother and increases dramatically after 35 years. In cytogenetic studies, microdeletion of locus q24.1 of chromosome 8 is found. Mosaic forms were also noted. The type of inheritance is not set; almost all cases described are sporadic. The main clinical signs of the disease are thin and sparse hair, a bulbous (pear-shaped) nose, conical epiphyses of the phalanges of the fingers, multiple cartilaginous exostoses, leading to uneven growth of the limbs and their asymmetries, curvature of the spine, conical epiphyses, short-sticking, muscle hypotension, delayed psychoresis mental retardation of varying degrees. In addition to these signs, patients have a number of microanomalies: wide rare eyebrows, deep-set eyes, macrostomy, violation of teething and tooth positioning, micrognathia, large protruding and low located auricles. Multiple cartilaginous exostoses occur until 4 years of age and are located wherever there is cartilage, and their growth is enhanced during periods of active growth of the body and stops at the age of 18-20 years. Newborns have excess skin. There is mental retardation of varying degrees, a delay in speech development.
Di Joey Syndrome II
The frequency of the syndrome is 1: 200,000 births. The symptomatology of the disease is similar to Dee Georges type I syndrome. This form is characterized by hypoparathyroidism, sensorineural deafness, and congenital malformations of the kidneys. Deafness is represented by bilateral, symmetric, sensorineural deficit, affecting the perception of all frequencies, but with the most noticeable defect at the high end of the range.
Similarity deficits in adults and children indicate a lack of progression with age. Intravenous urography showed changes corresponding to the presence of bilateral renal dysplasia. With this form of pathology, the kidneys in patients are small, irregular in shape, with an abnormally compressed renal collection system. The proximal region of DGCR2 is responsible for defects in the heart and thymus hypoplasia / aplasia. The main gene, the mutation of which leads to the indicated consequences, is called BRUNOL3 (the last name is CELF2). In the study of early embryos and fetal material, as well as other body tissues, high expression of the BRUNOL3 gene in the thymus was established at different stages of the development of the body.
Therefore, BRUNOL3 is an important factor for the development of the thymus and, therefore, it is a candidate gene for thymus hypoplasia / aplasia observed in patients with partial 10p monosomy.
The frequency of the syndrome is 1: 10,000 live births. Angelman's syndrome is a genetic anomaly in which some genes from the 15th chromosome are missing (in most cases, a partial deletion or other mutation of the 15th chromosome).
With Angelman syndrome, the maternal chromosome suffers; in case of damage to the paternal chromosome, Prader-Willi syndrome occurs.
In 75% of problems with nutrition, especially with breastfeeding, such babies gain weight poorly; delay in the development of general motor skills (sitting, walking); delayed speech development, undeveloped speech (in all children); children understand more than they can say or express; attention deficit hyperactivity disorder; learning difficulties; epilepsy (80% of cases), violations are also detected during electroencephalography; it is believed that in children with Angelman syndrome, secondary (symptomatic) epilepsy is observed; unusual movements (small tremor, chaotic movements of limbs); frequent laughter for no reason; walking on stubborn legs - because of this feature, children with this syndrome are sometimes compared with puppets; head size smaller than average, often with flattening of the nape; sometimes characteristic features - a wide mouth, rarely spaced teeth, a prominent chin, a tongue protruding outward; sleep disturbances; strabismus (strabismus) in 40% of cases; scoliosis (curvature of the spine) in 10% of cases; hypersensitivity to high temperature; Feel more comfortable in the water.
Prader's Syndrome - Willy
The frequency of pathology in a population of 1: 12,000 live births. Prader's Syndrome - Willy is a rare genetic anomaly. With the syndrome, approximately 7 genes from the 15th chromosome inherited from the father are absent or not expressed. For Prader-Willy syndrome, low fetal mobility is characteristic before birth; often - the wrong position of the fetus; hip dysplasia, obesity; tendency to overeat (more often manifested by 2 years); decreased muscle tone (hypotension). There is also reduced coordination of movements; small hands and feet, short stature; increased drowsiness; strabismus (squint); scoliosis (curvature of the spine); reduced bone density; thick saliva; bad teeth; decreased gonadal function (hypogonadism); as a result, as a rule, infertility. Often characterized by speech delay, mental retardation; lag in mastering the skills of general and fine motor skills, later puberty. But all this is rarely found in one child, more than five of the above signs are more common.
In adults, the nose is pronounced, the forehead is high and narrow; eyes are usually almond-shaped; lips are narrow. For a more effective detection of pathology, genetic diagnosis is recommended for newborns with reduced muscle tone (hypotonus). Sometimes, instead of the Prader-Willi syndrome, doctors mistakenly diagnose Down syndrome (since Down syndrome is much more common). Myopathy is also often diagnosed. Children with Prader-Willi syndrome are very similar to each other.
Rubinstein's syndrome - Tabee
The population frequency is 1: 25,000 - 30,000 newborns. Rubinstein-Teibi syndrome (a synonym is the syndrome of the wide I finger of the hands and feet, a specific person and mental retardation). Autosomal dominant inheritance. The sex ratio is M1: G1. The main signs of the syndrome are lag of psychophysical development, face dysplasia, abnormalities of the fingers. In 94% of patients, growth is below average. Bone age is significantly behind the passport age (94%). Mental retardation (100%) is noted (in most cases, deep oligophrenia, delayed motor and speech development).
The complex of craniofacial dysmorphies includes brachycephaly, microcephaly, a large and late closing fontanel, a protruding forehead with low hair growth, raised arched eyebrows, antimongoloid eye section (93%), wide nose bridge, epicant (62%), long eyelashes, ptosis, wide the back of the nose (71%), the tip of the nose bent downward (the coracoid nose) (90%), hypoplasia of the wings of the nose (72%), moderate retrognathia, a grimace that resembles a smile, and a high arched sky (93%).
Strabismus (79%) and anomalies of refraction (58%) are noted on the part of the eyes. Auricles are deformed, reduced or enlarged (74%). Anomalies of the fingers consist in the expansion, shortening and flattening of the nail phalanges of the first fingers and toes (100%), sometimes the terminal phalanges of the other fingers (60%), hallux valgus deformation of the interphalangeal joints, doubling of the nail phalanx of the first toes (30%), less often proximal phalanx, in some cases - polydactyly of the feet, partial syndactyly of the hands and feet. Also noted are lordosis, kyphosis, scoliosis, anomalies of the sternum and ribs, flattening of the wings of the pelvic bones. In half the cases, hirsutism, a bright red nevus on the skin of the forehead, occiput, and lateral surface of the neck are found. Frequent changes in dermatoglyphic indicators. Malformations of internal organs include obstruction of the ductus arteriosus and defects of the septum of the heart, unilateral aplasia of the kidneys, doubling of the kidneys, hydronephrosis, expansion of the ureters or their stenosis, diverticulum of the bladder, cryptorchidism (in 79% of cases), impaired lung lobulation, agenesis or aplasia of the corpus callosum ( detected by pneumoencephalography or autopsy).
Smith Syndrome - Magenis
Frequency of the disease 1: 25,000 newborns. Smith - Magenis syndrome is an autosomal dominant disease caused by a deletion of 3.7 million nucleotide pairs on chromosome 17 at the 17p11.2 locus (from 75% to 90% of cases) or mutations in the RAI1 gene that lies at this locus. These are mainly sporadic cases, however, inheritance from a mother who had mosaicism in this deletion is described. The disease is manifested by craniofacial anomalies, the characteristic structure of the body, and features of development and behavior. Among craniofacial anomalies, brachycephaly, a flat, wide face, hypoplasia of the middle part of the face, a wide nose bridge, a convex forehead, fused eyebrows, an open mouth with a hipped upper lip, lower micrognathia, eventually turning into prognosis, are distinguished; low-set ears and other ear abnormalities. The structural features of the body include: wide short hands, brachidactyly, stiffness of the elbow joints, flat feet. Also, with this disease, congenital heart defects, malformations of the kidneys, brain abnormalities, eye abnormalities, strabismus, mixed hearing loss, scoliosis, low hoarse voice, low pain sensitivity are found.
In infancy, muscle hypotension is detected. In children, there is a delay in speech development (motor speech suffers more than sensory), IQ ranges from 20 to 78 (in the majority between 40 and 54).
Behavioral features include self-destructive behavior: a child bangs its head, bites its hands, bites or pulls out nails, etc. Also, sleep disorders are characteristic of this disease: early falling asleep (about 8 o’clock in the evening), intermittent sleep (1-3 awakenings per night), very early morning awakening (at 4-6 hours) and drowsiness during the day.
This pathological rhythm of sleep and wakefulness causes irritability and outbursts of anger. Duplication of a plot of 3.7 m.s. The 17th chromosome is associated with Potocki-Lupsky syndrome, which has some similarities with Smith-Magenis syndrome, but a milder course.
Frequency 1: 50,000 newborns. Miller-Dicker Syndrome (Miller-Dicker Lysencephaly Syndrome) is an autosomal dominant disease caused by a deletion of the 17p13.3 locus genes. The loss of this site leads to disruption of neuron migration and, mainly, occurs de novo, however, it can be inherited from the parent with balanced reciprocal translocation. The sex ratio is M: W = 1: 1.
Clinical signs of Miller-Dicker syndrome are: classic lissencephaly (pachygiria or agiria), agenesis or hypoplasia of the corpus callosum, expansion of the ventricles of the brain, expansion of the Virchow – Robin spaces, microcephaly.
Outwardly, wrinkled skin is observed in the area of the interbrow and frontal suture, protruding nape, high forehead, narrowed in the temporal areas, low-set ears, Mongoloid section of the eyes, hypertelorism, “carp mouth” - a long thin upper lip with lowered corners, a short upturned nose, small chin. Congenital heart and kidney defects, Chiari I malformation, cryptorchidism, growth retardation, muscle hypotension, followed by spasticity and opistotonus, severe mental retardation with epileptic seizures are also characteristic.
Life expectancy is sharply reduced, patients die in early childhood. A histological examination of the cerebral cortex reveals a heterotopy of neurons. The cortex is thickened and contains not 6, but 4 layers of neurons; its development corresponds to 3-4 months of fetal development.
Type I neurofibromatosis
The frequency of pathology in a population of 1: 2500-3000 newborns. Neurofibromatosis type I (first) (neurofibromatosis with pheochromocytoma, von Recklinghausen disease, Recklinghausen syndrome, NF-1) is the most common hereditary disease predisposing to the occurrence of tumors in humans.
Type I neurofibromatosis is an autosomal dominant disease with high penetrance and a high incidence of new mutations. The risk of giving birth to a child with neurofibromatosis from a sick person is either 50% (in the case of heterozygotes) or 100% (in the case of homozygotes). About 50% of cases are lat mutations. de novo. The incidence rate of type I neurofibromatosis does not differ in different geographical regions and among ethnic groups. A locus of genes whose breakdown leads to the development of neurofibromatosis is located on the long arm of chromosome 17 (17q11.2).
Type I neurofibromatosis is manifested by a number of pathognomonic symptoms. These include the presence of pigmented spots on the skin the color of "coffee with milk", neurofibroma, most of which are located superficially on the skin, Lisha nodules - hamartomas of the iris. Manifestations of neurofibromatosis of type I often begin with scoliosis (curvature of the spine), then there are difficulties in learning, vision problems and epilepsy.
Neurofibromas are more often localized along the peripheral nerves. However, the spinal cord and brain can be affected, neurofibromas are found on the eyelids, conjunctiva, mediastinum, and abdominal cavity. Depending on the location, neurofibromas can cause various clinical symptoms: convulsions, dysfunction of the cranial nerves and segments of the spinal cord, paralysis of the eye muscles, ptosis, and compression of the mediastinal organs. The following clinical manifestations of type I neurofibromatosis are also characteristic: cognitive impairment - difficulties in mastering writing, reading, and mathematics. Often combined with a moderate decrease in intelligence (IQ <70). Patients often experience depression due to shame caused by disfigurement of the body and face by neurofibromas, fear of society. There are endocrine disorders - pheochromocytoma, impaired growth and puberty; epileptic seizures; decreased muscle tone; behavioral disorders; stenosis of the renal and pulmonary arteries, pulmonary cysts, interstitial pneumonia, clitoral hypertrophy, abnormal formation of the gastrointestinal tract; syringomyelia. Renal artery stenosis, especially in combination with neochromocytoma, causes the development of arterial hypertension. Diseases not directly related to nerve involvement. The prognosis for this disease is usually favorable. Malignant neurofibroma occurs rarely. Disability usually does not suffer, however, with a common lesion, it decreases sharply.
Frequency 1: 7000 newborns. Alagil syndrome (arterihepatic dysplasia, Alagil-Watson syndrome) is a genetic disease inherited in an autosomal dominant manner. The mutation in the 1JAG1 gene is located on the short arm of chromosome 20 at the locus 20p12. Patients with Alagill syndrome have a characteristic appearance: a face with a high, slightly protruding forehead, hypertelorism, deep-lying eyeballs, a long and straight nose, and underdevelopment of the lower jaw.
In addition, they often reveal congenital heart defects (pulmonary stenosis, Fallot tetrad), structural defects of the eyes (posterior embryotoxone), spine (defect of the anterior arch), tubulointerstitial nephropathy. Cholestasis is usually incomplete. The prognosis for life is favorable, but sick children are lagging behind in physical development, they have severe hepatomegaly, splenomegaly, itching, sometimes xanthomas, neurological complications, deficiency of fat-soluble vitamins.
Di George's Syndrome
Frequency 1: 4000 births. Di Georgie's Syndrome (synonyms: Velocardiofacial Syndrome (VCFS), 3-4 gill arch disembryogenesis syndrome, congenital aplasia of the thymus and parathyroid glands, 22q11.2 syndrome, Sprintzen syndrome, CATCH 22) is a type of idiopathic isolated hypoparathyroidism. The syndrome occurs with equal frequency in both boys and girls. The most likely cause of the development of clinical symptoms in this syndrome is an unbalanced translocation, deletion, or microdeletion of the 22 chromosome (22q11.2). As in other microdeletion syndromes, mutations usually occur de novo. However, families with more than one sick member confirm an autosomal dominant type of inheritance. 15 - 20% of patients inherited microdeletion from a conditionally healthy parent. Healthy carriers of deletion often have facial dysmorphisms and mild forms of phenotypic changes associated with 22q11.2 monosomy. Most cases are sporadic due to 22q11 deletions, and 10de14 chromosome microdeletion is also encountered, in which all symptoms similar to 22q11 deletion are preserved. The syndrome is characterized by agenesis or dysgenesis of the parathyroid (parathyroid) glands, aplasia of the thymus (thymus gland), which leads to a sharp decrease in the T-lymphocyte population and immunological deficiency, congenital anomalies of large vessels (aortic defects, Fallot tetrad).
The disease develops as a result of a violation of embryogenesis of 3-4 gill pockets, as a result of which the laying of the parathyroid glands and thymus is disturbed. 70% of newborns with the syndrome have characteristic congenital malformations of the cardiovascular system. In some cases, the child’s state of health requires surgery. However, most children need to undergo regular checkups with a cardiologist. Like all patients with congenital heart defects, children with cyclo-cardiofacial syndrome need a consultation with a cardiologist and prophylactic antibiotics before serious medical interventions and dental procedures.
Patients have a characteristic peculiar appearance. In children with the syndrome, facial features have specific signs: the face is elongated, the chin and mouth are small, the nose is widened. Sometimes external differences from the norm are so slightly pronounced that they are difficult to diagnose during examination. Some children have a deficiency of the immune system and, as a result, a tendency to the development of recurrent infections: tonsillitis, otitis media, pneumonia. In most cases, a tendency to infections is noted in the early stages of a child’s life, over the course of several years the immune system develops and subsequently functions normally.
Phelan-McDermit syndrome or deletions (monosomy) 22q13.3.
Frequency 1: 600,000 newborns.
Phelan-McDermit syndrome (deletion (monosomy) syndrome 22q13.3) is a disease that manifests itself in a severe degree of autism. Deletion occurs in males and females with an equal frequency, and mosaic and regular forms of chromosomal abnormalities are described. Pathology is manifested by deletion of the terminal portion of chromosome 22 at locus 22q13.3, with the larger the deleted portion, the more pronounced autism.
In the 22q13.3 region, the SHANK3 gene is located, mutation or loss of this gene is one of the most common causes associated with autism. Features of 22q13.3 deletion syndrome vary widely and include abnormalities in various organs and systems of the body. Typical signs and symptoms include developmental delay, from moderate to deep mental retardation, decreased muscle tone (hypotension), and lack or delay of speech. Many patients with this syndrome have a diagnosis of autism or autistic behavior that affects communication and social interaction, such as poor eye contact, touch sensitivity, and aggressive behavior. They can also chew inedible items such as clothing. Less commonly, patients with this syndrome have cramps. Persons with 22q13.3 deletion syndrome typically have a reduced sensitivity to pain. Many of them also have a reduced ability to sweat, which can lead to an increased risk of overheating and dehydration. Some patients experience frequent nausea and vomiting (cyclical vomiting) and a backflow of stomach acid into the esophagus (gastroesophageal reflux).
People with 22q13.3 deletion syndrome typically have distinctive facial features: a long, narrow head; protruding ears; pointy chin; hanging eyelids (ptosis); deep set eyes. Other physical features observed with this disease are large and fleshy hands and / or feet, fusion of the second and third fingers (syndactyly), small or abnormal toenails. Some patients have accelerated growth.
Frequency: 1: 8,000 for boys, 1: 40,000 for girls.
The cause of the abnormalities in Kallman's syndrome is a disorder of pulsed secretion of gonadoliberin (GnRH) in the hypothalamus. The lack of gonadotropin releasing hormone is associated with a deletion of the KAL gene located on the short arm of the X chromosome, which encodes the extracellular matrix of glycoprotein (anosmin-1), which belongs to the class of neuromolecules that have adhesive properties that allow GnRH-secreting neurons to enter migrate to the hypothalamus during embryogenesis. Low levels of LH and FSH cause secondary hypogonadism.
Clinical manifestations: delayed sexual development or an isolated delay in menarche, impaired sense of smell (anosmia or hyposmia). Some patients have severe abnormalities of the brain and skull along the midline, for example, cleft palate. Patients often have reduced levels of LH and FSH.
Eunuchoidism is characteristic, cryptorchidism is often observed. Somatic pathology occurs: splitting of the upper lip ("cleft lip") and hard palate ("cleft palate"), polydactyly (six-fingered), high "Gothic" palate, shortening of the frenum of the tongue, asymmetry of the face, gynecomastia, functional disorders of the cardiovascular system. Similar malformations can be detected among family members of the patient.
An X-ray examination of the hands and wrist joints in a direct projection reveals a delay in the period of ossification (age-related differentiation).
In boys, depending on the severity of gonadoliberin deficiency, sexual infantilism of varying severity is detected, up to the complete absence of signs of puberty, the absence of secondary sexual characteristics, small testicles and azoospermia. Signs of secondary hypogonadism may be associated with impaired color vision, optic atrophy, deaf-mute, horseshoe-shaped kidney and cryptorchidism. In girls - primary amenorrhea, genital infantilism (uterine and ovarian hypoplasia with a weakly expressed follicular apparatus), inability to distinguish odors. Other abnormalities may occur (deafness, loss of color vision, cleft palate, anomalies of the kidneys, bones).
Deletion of STS - X locus of the chromosome or X - linked ichthyosis
Frequency 1: 6000 newborns.
Steroid sulfatase is a human sulfatase involved in the metabolism of steroids. Mutations of the STS gene (Steroid Sulphatase Deficiency) leading to steroid sulfatase deficiency cause X-linked ichthyosis, a skin disease. It is assumed that the excessive accumulation of cholesterol sulfate in the skin cells plays an important role in the pathogenesis. Ichthyosis appears only in boys.
Deficiency of the STS enzyme is known to be responsible for the presence of dark, clammy skin with lamellar peeling. It is also suggested that variations or STS deficiency can contribute to the development of attention deficit hyperactivity disorder and affect attention processes. Deletion can increase and involve neighboring genes, resulting in adjacent gene defects.
Thus, STS gene deletions can be associated with a deletion leading to Kallman syndrome. The role of steroid sulfatase in the growth of hormone-dependent tumors is noted. STS inhibitors are planned to be used in antitumor therapy. It is encoded by the pseudo-autosomal STS gene on the X chromosome.
STS is expressed in almost all tissues and organs, at least in a small amount, with a maximum expression in the placenta.
Steroid sulfatase, by hydrolysis of sulfates of a number of steroids, converts them into an active form, but also acts on some steryl sulfates, phenol sulfates, steroid-aryl sulfates, steroid-alkyl sulfates. In particular, the role of the enzyme in the conversion of dehydroepiandrosterone sulfate (DHEAS) to dehydroepiandrosterone (DHEA) is highlighted.
Xist gene deletion of chromosome X
Frequency not established due to spontaneous deletion. Xist (short for X-inactive specifi c transcript) is a gene encoding RNA located on the X chromosome of placental mammals and is the main effector of inactivation of the X chromosome. Most often, microdeletion occurs de novo or in the case of chromosomal rearrangements, especially when X chromosomes are formed.
The transcript of the XIST gene in humans has a length of about 17,000 nucleotides and is expressed on the inactivated X chromosome and is not expressed on the active. An amazing property of the Xist gene is that it does not encode proteins. As a result of gene expression, large RNA is formed, the length of which is 15-17, i.e. After synthesis is complete, RNA remains in the nucleus, and in cells where the X chromosome is already inactivated, this RNA creates a “shell” around the inactive chromosome. In undifferentiated embryonic stem cells, both X chromosomes are active. During cell differentiation, the Xist RNA content zone expands along the future inactive chromosome amid an increase in its number. At the same time, the level of Xist gene expression on the chromosome that remains active decreases sharply.
In early embryos at the preimplantation stage, paternal X chromosomes are coated with Xist RNA, but remain in an active state. This indicates the participation of additional factors in the embryonic inactivation of X chromosomes, which are absent in the cells of early embryos. To inactivate, the X chromosome must be “covered” with transcripts of the Xist gene. X chromosomes with deletions of the Xist gene cannot be inactivated.
Xist gene duplication causes inactivation of both X chromosomes. Often this leads to mild mental retardation, face dysmorphia, and congenital pathologies that are vaguely similar to the characteristics of Sherishevsky-Turner syndrome.