Pitt-Hopkins syndrome is the name given to an extremely rare genetic disorder that has no cure. The genetic defect results in motor and intellectual disabilities, among other symptoms.
What is Pitt-Hopkins syndrome?
Pitt-Hopkins syndrome (PHS) is a genetic disorder associated with mental retardation, inadequate or complete absence of spoken language, epilepsy, and respiratory regulation disorders. In addition, there are typical facial abnormalities. The disease manifests itself only very rarely. So far, only 150 cases are known in the whole world, and they occur equally in males and females. However, physicians suspect a higher number of unreported cases because the disease has only been diagnosed reliably for a few years. The name Pitt-Hopkins syndrome is derived from the two Australian physicians D. Pitt and I. Hopkins, who first described the disease in 1978. The discovery of the causative gene did not take place until 2007. Two research groups in Erlangen and Paris discovered mutations in the TCF4 gene at the same time. As a result, a clear diagnosis of Pitt-Hopkins syndrome is now possible. It is estimated that the hereditary disease manifests in one in 34,000 to 41,000 births.
Causes
Pitt-Hopkins syndrome is inherited in an autosomal dominant manner. The cause of the inherited disease is heterozygous new mutations within the TCF4 gene. This gene codes for a ubiquitous b-HLH transcription factor. The TCF4 gene is located on chromosome 18, and the gene either mutates on one of exons 1 to 20 or is deleted completely. If a person suffers from Pitt-Hopkins syndrome, the risk of passing on the hereditary disease to offspring is about 50 percent. Normally, however, most patients do not have children. In most cases, the disease occurs even though both parents are healthy and have no mutations in the TCF4 gene. The risk of PHS recurrence in additional pregnancies is considered very low, at one percent.
Symptoms, complaints, and signs
Pitt-Hopkins syndrome has a variety of different symptoms. However, these never fully manifest in any one patient. In most affected individuals, the characteristic features of the syndrome only develop over time so that they eventually become clearly recognizable. Immediately after birth and in the first few months of life, there are usually no distinctive symptoms. As time goes on, parents notice an abnormally slow development of their child. For example, he or she rarely reaches for toys, does not turn on his or her own, or squints. There may also be moderate to severe mental retardation, postnatal growth retardation, limited walking abilities, movement coordination disorders and muscle hypotonia. Hyperventilation episodes, sleep disturbances, severe constipation, scoliosis, and genital abnormalities have also been recorded in this clinical picture. In addition, language development is poor or even completely absent. Visible facial abnormalities such as thick heart-shaped lips, a wide flat palate with a large mouth, a macrostomy with large spaces between teeth, and protruding teeth are also considered typical of Pitt-Hopkins syndrome. In addition, flared nostrils, deep-set eyes, the expression of a groove between the lip and nose, the absence of flexion of the thumb or fingers, and narrow hands that have broad fingertips are considered external identifying features. Basically, however, most PHS patients have a cheerful disposition, so they laugh frequently. They also need a lot of love and physical contact.
Diagnosis and course of the disease
Diagnosis of Pitt-Hopkins syndrome is mostly made by clinical examination. Electroencephalography (EEG) is also considered an important examination method, through which changes can be detected. Furthermore, imaging procedures such as magnetic resonance imaging (MRI) can be used. These may indicate changes in the temporal lobes as well as changes in the hippocampus. In some cases, detection of dilated ventricles or a hypoplastic corpus callosum (brain bar) is also possible. If the gene mutation is already known, prenatal diagnostics can be performed. This means that the hereditary disease can be detected before birth.Differential diagnosis also plays an important role, as the symptoms of some disorders are similar to those of Pitt-Hopkins syndrome. These include Goldberg syndrome, Angelman syndrome, Mowat-Wilson syndrome, and Rett syndrome. Because Pitt-Hopkins syndrome is a genetic defect, it has no cure. In most cases, permanent intellectual disabilities are to be expected. In addition, most PHS patients are unable to speak. The life expectancy of those affected depends on the extent of health problems and deformities. They usually require assistance from others throughout their lives.
Complications
Due to Pitt-Hopkins syndrome, most affected individuals usually suffer from various motor and mental limitations and disabilities. As a result, patients are usually dependent on the help of other people in their lives and can no longer cope with everyday life on their own without further ado. Those affected suffer from strabismus and increased retardation. Speech defects and coordination problems can also occur as a result of Pitt-Hopkins syndrome, significantly reducing the patient’s quality of life. Constipation and sleep disturbances also occur. The overall development of the child is significantly negatively affected by Pitt-Hopkins syndrome, resulting in complications even in adulthood. Especially in children, the symptoms of Pitt-Hopkins syndrome can lead to teasing or bullying. Causal treatment of Pitt-Hopkins syndrome is not possible, so sufferers are dependent on various therapies that can make everyday life easier. Sometimes the relatives and parents also need psychological treatment. The life expectancy of the patient is usually not affected by this disease. Furthermore, parents should consider genetic counseling.
When should one go to the doctor?
Since Pitt-Hopkins syndrome is a congenital disorder in which there is no self-healing, the syndrome must always be treated by a physician. However, a complete cure is not possible, so that the affected person is dependent on medical treatment throughout his or her life. A doctor should be consulted in the case of Pitt-Hopkins syndrome if the child shows significantly slowed development. Also, strabismus may occur, and many children also have coordination disorders. A doctor should also always be consulted for deformities or abnormalities of the face. The earlier these are recognized and treated, the higher the probability of a positive course of the disease. Likewise, abnormalities in the child’s hands and feet may indicate Pitt-Hopkins syndrome and must be examined by a physician. The diagnosis of the syndrome itself can be performed by a pediatrician or by a general practitioner. However, further treatment requires a specialist, and the treatment depends on the exact manifestation of the syndrome. It cannot be generally predicted whether the disease will result in a reduced life expectancy for the patient. Because the syndrome often also causes psychological distress in parents and family members, a psychologist may also be consulted.
Treatment and therapy
Since Pitt-Hopkins syndrome cannot be cured, therapy is limited to treating the symptoms, which in turn depends on the individual. In any case, it is important to start treatment of the hereditary disease as early as possible. Suitable forms of therapy are primarily physiotherapeutic measures, speech therapy, occupational therapy, riding therapy (hippotherapy) or music therapy. In the case of strabismus, occlusion therapy is important, in which one eye is masked with a special eye patch to counteract the visual disorder. Medicinal treatment with the carbonic anhydrase inhibitor acetazolamide, which serves to lower blood pressure and intracranial pressure, is also considered useful. Some patients are also given medications for sleep disorders, constipation, and epilepsy. A major problem of Pitt-Hopkins syndrome is a lack or absence of spoken language. For this reason, affected children should learn to communicate through sign language. For parents, genetic counseling is considered advisable.
Outlook and prognosis
The outlook for cure or improvement for hereditary Pitt-Hopkins syndrome is not very good. The genetically caused syndrome occurs very rarely. More than 400 cases have not been documented worldwide. Pitt-Hopkins syndrome results in a whole range of severe to moderate functional disorders, and mental impairments. Among other things, short stature or epilepsies develop. The children cannot speak. It is problematic for the parents of such children that the correct diagnosis is usually only made after several years. It is then important to distinguish Pitt-Hopkins syndrome from other syndromes with similar symptoms. In view of the large number of abnormalities and sequelae, medicine can only intervene symptomatically. Affected individuals are often hospitalized because they may have severe respiratory problems. The interdisciplinary treatment of the affected persons is standard. The prognosis for positive developments for sufferers is not particularly good, given the wide range of disorders. Even surgical measures cannot change the degree of disability. The affected persons need permanent care. For the parents of such children, this prognosis is a relevant factor. It is true that the chances of having another child with this disability are rather small. However, they are given. Therefore, in case of another pregnancy, amniocentesis is recommended. If necessary, abortion must be recommended.
Prevention
There are no measures to prevent Pitt-Hopkins syndrome. Thus, it is a hereditary disease that is already congenital.
Follow-up
In Pitt-Hopkins syndrome, the measures of a follow-up are significantly limited in most cases. It is a genetic disease that cannot be completely cured, so the priority in this disease is early detection and treatment to prevent further complications or other medical conditions from developing. The earlier the syndrome is detected and treated by a doctor, the better is usually the further course. If a child is desired, genetic testing and counseling should be performed to prevent the recurrence of Pitt-Hopkins syndrome. Affected children are dependent on regular check-ups by various physicians throughout their lives. Care and support from their own family is also very important, as this can especially prevent the development of depression or other psychological upsets. Intensive support of the affected children is also very important at school. Some symptoms of Pitt-Hopkins syndrome are treated with the help of medication. Care must always be taken to ensure the correct dosage and also that the medication is taken regularly. Possibly, Pitt-Hopkins syndrome reduces the life expectancy of the affected person.
Here’s what you can do yourself
People who have Pitt-Hopkins syndrome are usually unable to live without help. Relatives must give the sufferer the support he or she needs and watch for health complaints. In addition to regular visits to the doctor, therapeutic measures such as breathing exercises and regular conversations are also part of self-help. The lack of speech can be compensated for by targeted speech training. In the case of external malformations, talk therapy may also be necessary. After an operation, bed rest applies. The doctor can recommend suitable home and natural remedies for the pain and, if necessary, consult an alternative physician. In case of acute respiratory distress, the emergency physician must be alerted. Until medical help arrives, first aid should be given to the sufferer and ensure that he or she remains calm. Pitt-Hopkins syndrome can be treated well with comprehensive care. Patients should be cared for at home by an ambulatory care service and must attend a special kindergarten and school later in life. The stress associated with this puts a strain on the sufferer as well as the parents, who should talk to the doctor about their fears and problems. Accompanying therapy can improve well-being and open up a new perspective on life for those affected.
