Holoprosencephaly is a severe disorder of brain formation, in which a complete or partial absence of separation into hemispheres is recorded in combination with other malformations of the head and face. Symptoms of this condition are abnormal facial formation with the development of cyclopia, proboscis-like nose (or lack of nose), cleft lip and cleft hard palate. Generalized seizures and other disorders are observed. Diagnosis of holoprosencephaly is not particularly difficult due to the severity of the disorders, in some cases, prenatal detection of the disease using ultrasound or molecular genetic techniques is possible. Treatment is only symptomatic. Depending on the severity of the pathology, patients die in utero or in the first hours after birth, rarely live for several years or live to adulthood.
ICD 10
Q04.2 Holoprosencephaly
General information
Holoprosencephaly is a developmental defect characterized by various severe disorders of the division of the brain into two hemispheres up to the formation of a single “brain bubble”. This anomaly is one of the most common disorders of the formation of the terminal brain. The first complete description of pathology was prepared in 1963 by V. De Maeyr. The researcher identified three varieties of this condition: alobar, semilobar and lobar. In 1993, after additional study, experts identified the fourth subtype of holoprosencephaly – the middle interhemispheric fusion, which is the mildest variant of this disease. The occurrence of all forms of pathology according to various data is 1 case per 8,000-16,000 births, especially often such defects are detected in people from Pakistan, Hawaii and Southeast Asia. In girls, holoprosencephaly is diagnosed about 2 times more often than in boys.
Causes
Holoprosencephaly is a polyetiological condition that occurs under the influence of a variety of genetic and chromosomal defects. So far, no clear indications have been found on the existence of a relationship between certain clinical forms of the disease and the type of disorders of the genome of patients. One of the most studied genes, mutations of which lead to holoprosencephaly, is SHH, located on the 7th chromosome. The gene expression product is a signaling protein that is directly involved in embryogenesis, in particular in the formation of the central nervous system. Depending on the nature of the SHH mutation, the protein has defects in its structure or is not isolated at all. This genetic disorder is detected in 30-40% of patients, the mechanism of inheritance is autosomal dominant with incomplete penetrance. In some cases, instead of brain formation disorders, there are such microsymptoms as the absence of one incisor, the absence of a tongue frenulum and convulsive syndrome.
Among other genetic defects that can lead to the appearance of holoprosencephaly, mutations of ZIC2, TGIF, SIX3 and some other genes are distinguished. Almost half of all cases of the disease are associated not with genetic, but with chromosomal abnormalities – for example, Patau syndrome, Edwards syndrome and triploidy. In addition, holoprosencephaly is detected with deletions of individual sections of the 2nd, 7th, 13th, 21st chromosomes, which indicates the possibility of damage to genes localized there. Such malformations of the brain and face can also act as part of the symptom complex of Meckel-Gruber syndrome and a number of other conditions. Sometimes the specific mechanism of holoprosencephaly development in these conditions and other chromosomal pathologies remains unknown. It was found that the onset of the development of defects of the central nervous system and elements of the skull falls on the period between the 1st and 4th month of gestation. The earlier violations occur, the more severe the manifestations of the disease will be.
Various acquired factors and peculiarities of the course of pregnancy can have a certain influence on the development of brain formation abnormalities. So, if a mother has severe insulin-dependent diabetes mellitus, the probability of giving birth to a child with holoprosencephaly is 1%, which is about 200 times higher than in a healthy woman. The use of certain medications during pregnancy can also lead to such a congenital disorder – for example, the relationship between the disease and taking anticholesterol drugs (statins) has been established. Common teratogens play a certain role: toxins, ethyl alcohol, elements of tobacco smoke, retinoic acid. Determining the causes of holoprosencephaly is important for making a decision about planning the next pregnancies – depending on the nature and etiology of this condition, the probability of re-birth of a child with this anomaly varies greatly.
Classification
Currently, there are several clinical forms of holoprosencephaly, which differ in severity of manifestations, severity of malformations and prevalence in the population. Geneticists have not been able to identify a clear relationship between individual types of the disease and genetic mutations or chromosomal abnormalities, therefore, the causes of the development of one, and not another form of pathology remain unknown. It is assumed that this may depend on the penetrance of the defective gene, which part of the chromosome was damaged, the conditions of pregnancy and a number of other factors. To date, there are four main forms of holoprosencephaly:
- Alobar form is the most severe form, characterized by the grossest malformations of the brain, face and other organs. It is diagnosed in 15-25% of cases of the disease.
- Semilobar form is a classic variant of holoprosencephaly, manifested by severe but less pronounced developmental anomalies. It is also the most common type of disease, accounting for 40 to 60% of all episodes of pathology.
- Lobar form is a more smoothed version of holoprosencephaly, in which, through surgical correction and symptomatic therapy, it is possible to improve the quality of life of the patient and extend it to adulthood. This variety accounts for about 15-20% of all cases of the disease.
- Middle hemispheric fusion is the rarest form of holoprosencephaly, which is characterized by blurred symptoms and often differs greatly from the classical types of pathology. It has been considered as a mild form of this malformation since 1993.
Some experts single out the so-called abortive forms of holoprosencephaly in phenotypically healthy individuals as a separate option. There are no characteristic symptoms of the disease, however, patients may experience the absence of one incisor or frenulum of the tongue, anomalies in the structure of the nasal cavity. Occasionally there are convulsive seizures. All of these microsymptoms indicate the presumed presence of genetic defects that can be transmitted to offspring and cause the development of a full-fledged form of holoprosencephaly. Persons with such symptoms should be particularly careful about prenatal diagnosis during pregnancy planning and fetal development.
Symptoms
The manifestations of holoprosencephaly vary greatly depending on the form of pathology. Nevertheless, there are common symptoms characteristic of almost all varieties of the disease. The list of such symptoms includes cleavage of the hard palate and upper lip, which are detected in almost all patients (with the exception of the variant of the middle interhemispheric fusion). In addition, all patients with holoprosencephaly have seizures, severe mental retardation, impaired reflexes, corneal and retinal pathology. With the most severe alobar form of the disease, cyclopism, the absence of a nose, a sharp decrease in the size of the head and numerous defects of other organs are detected. With this type of holoprosencephaly, spontaneous abortion or stillbirth occurs in 70% of cases, surviving infants rarely live up to 6 months.
The semilobar form of the disease is characterized by milder symptoms. The eyes of patients are closely located (hypotelorism), the head is somewhat reduced in size, there are often defects in the nose (underdevelopment of one nasal passage). Holoprosencephaly of this type, however, is a rather serious condition, patients die in the first two years of life. The lobar form is characterized by even milder manifestations. With timely surgical correction of defects of the palate and upper lip, it is possible for patients to reach adolescence and even adulthood. Lethality in this type of holoprosencephaly largely depends on the presence or absence of concomitant diseases and malformations. The variant of the middle interhemispheric fusion is characterized by the absence of facial development abnormalities, but mental retardation, seizures and other neurological manifestations persist.
Almost all the symptoms of holoprosencephaly are detected immediately at the birth of a child or even at the stage of intrauterine development. Patients may have endocrine disorders, dysplasia of the kidneys, ovaries, lungs and other organs. According to medical statistics, it is these disorders that in most cases cause death in patients with holoprosencephaly. Sometimes patients are also diagnosed with immunological disorders, congenital heart defects, areflexia and other pathologies. Due to muscle weakness and the presence of oral cavity defects, feeding of such children is often difficult, which is why they slowly gain weight and lag behind in physical development.
Diagnostics
In pediatrics and neonatology, the diagnosis of holoprosencephaly is not particularly difficult, since even the erased version of the middle hemispheric fusion is quite easy to identify using modern medical imaging methods. Often, this disease is diagnosed even at the prenatal stage during preventive ultrasound examinations (sometimes as early as the 12th week of pregnancy). On ultrasound, you can clearly see the abnormal structure of the skull and brain of the fetus. With the alobar form, the brain looks like a liquid-filled bubble without any signs of separation into hemispheres. The semilobar type of holoprosencephaly is characterized by the presence of a furrow in the posterior part of the brain corresponding to an incomplete or initial division into hemispheres. The lobar form of the disease is somewhat more difficult to detect using ultrasound, since signs of a violation of the division of the brain are recorded only in its deep layers – the corpus callosum, thalamus and ventricles.
It is possible to determine the presence of holoprosencephaly at the prenatal stage of development using molecular genetics methods. The material for the study in suspicious cases (ambiguous ultrasound results, the presence of similar disorders in relatives or in past pregnancies, microsymptomas in parents, diabetes mellitus in the mother) is taken by amniocentesis or biopsy of chorionic villi. Genetic diagnosis of holoprosencephaly may include direct sequencing of the SHH gene to detect mutations, as well as examination of the karyotype of the fetus or child to identify chromosomal pathologies. In about 60% of cases of the disease, changes in the karyotype are not detected, so the technique is considered low-specific.
Treatment
There is no specific treatment for holoprosencephaly. Surgical correction of facial development abnormalities is carried out, symptomatic therapy is carried out. With alobar and semilobar forms of the disease, neurosurgeons rarely resort to the help of neurosurgeons because of the severity of the patient’s condition – the child simply cannot endure such an operation. In the lobar form of holoprosencephaly, in the first 6 months, they try to perform surgical intervention to eliminate cleavage of the palate and lip and the formation of a normal nose. Anticonvulsant therapy is used for all types of pathology. Correction of other violations is carried out in the presence of indications. Patients who have survived to childhood or adulthood need to be treated by a psychiatrist, a defectologist and other specialists due to pronounced mental retardation.
Prognosis and prevention
The prognosis for most forms of holoprosencephaly is unfavorable – patients either die in the first hours, days, months or years of life (alobar and semilobar forms), or remain mentally retarded for life, suffer from seizures and other neurological disorders. Prevention of this condition is reduced to early prenatal diagnosis by ultrasound or genetic techniques. If the disease is detected in the fetus, the question of termination of pregnancy for medical reasons is raised. Prenatal diagnosis is especially relevant if one of the parents has microsymptoms of holoprosencephaly, if the disease was observed in close relatives, if the pregnant woman suffers from diabetes mellitus or is exposed to teratogens.
