Mowat-Wilson syndrome is a rare, genetic developmental disorder with multiple symptoms. As part of the genetic defect, heart defects and brain developmental abnormalities present themselves in addition to facial, intestinal, and genital abnormalities. The disease, which is as yet incurable, can only be treated symptomatically.
What is Mowat-Wilson syndrome?
Mowat-Wilson syndrome is a rather recent clinical entity. The clinically diverse phenomenon was first described by Mowat and Wilson in 1998. In addition to developmental abnormalities, microcephalies and the symptom complex of Hirschsprung disease characterize the clinical picture. A genetic defect is considered to be the cause of the disease. Overall, the symptoms are extremely diverse. The rare disease has been little researched so far. Therefore, few therapeutic options are available so far. There is no definite prevalence, as the disorder was rarely or never diagnosed until the 21st century. Currently, a total of about 200 patients with the syndrome have been documented.
Causes
A gene mutation causes Mowat-Wilson syndrome. According to current research, the ZFHX1B gene is the disease-causing gene. The causative gene defect is thought to be located in chromosomal region 2q22. The affected gene is about 70 kb in size and is composed of a total of ten exons of 1214 amino acids. This gene codes for the protein SIP1, which is active as a transcriptional modulator and participates in embryogenesis. The embryogenesis of affected individuals is therefore disturbed. The disease-causing abnormalities of the gene may correspond to a complete deletion, a repositioning or a sequential abnormality. The genetic defect is passed on in autosomal dominant inheritance. Thus, one defective allele on the two homologous chromosomes is already sufficient to pass on the hereditary disease.
Symptoms, complaints, and signs
The symptoms of Mowat-Wilson syndrome correspond to a complex developmental disorder and are clinically diverse. Leading symptoms include cerebrally triggered seizures and microcephaly. Such microcephaly presents as a result of premature hardening of all cranial sutures and constricts the brain during the growth phase. For this reason, patients are affected by mental retardation. In addition, facial anomalies are often present, often giving the patient an eagle-like profile. These abnormalities may correspond, for example, to large, deep-set eyes, horizontally directed eyebrows, auricular anomalies, attached earlobes and a prominently protruding chin. In 90 percent of cases, affected individuals suffer from epilepsy. Mental development is severely delayed and language development is often completely absent. The motor development of the patients is also slowed down. In addition, secondary short stature often occurs with normal birth measurements. Malformations of the urethra may be present. Congenital heart defects or malformations of the genitalia are also conceivable. In addition, neuronal abnormalities of the intestinal wall plexus occur, as is characteristic of Hirschsprung’s disease.
Diagnosis and course of the disease
The diagnosis of Mowat-Wilson syndrome cannot be made on the basis of mere examination but requires analysis of genetic material. From the patient’s genomic DNA, the laboratory amplifies exons two through ten of the ZFHX1B gene. This amplification takes place with the help of PCR. This material and the intron-exon splice sites are analyzed by DNA sequencing. Using multiplex ligation-dependent probe amplification, each exon of the ZFHX1B gene is analyzed for deletion and duplication. This complex procedure takes about three weeks and, unlike simply examining the patient, can provide an undoubted diagnosis. In most cases, not only the DNA of the affected person but also that of his or her parents is sequenced and analyzed. The course of the disease strongly depends on the form of the genetic anomaly and the extent of deletion or repositioning of chromosomal parts. Definitive prognoses can hardly be made, if only because of the few documented cases of the disease to date. However, early diagnosis and subsequent therapy probably influence the prognosis favorably.
Complications
Mowat-Wilson syndrome causes severe symptoms and complications in the patient that significantly reduce life expectancy and quality of life.As a rule, the patient’s everyday life is also significantly restricted and the affected persons are dependent on the help of other people in their daily lives. Furthermore, mental retardation occurs, in which it is not uncommon for relatives and parents to also suffer from psychological complaints or depression. In most cases, the affected persons also suffer from cramps and reduced resilience. Furthermore, various deformities of the face also occur and epilepsy develops. Linguistic development is also significantly delayed, resulting in significant difficulties in the patient’s communication in adulthood. A heart defect and short stature also occur. The heart defect can lead to spontaneous cardiac death, so that the life expectancy of the affected person is limited by Mowat-Wilson syndrome. It is not possible to cure Mowat-Wilson syndrome. However, the various symptoms can be limited and treated so that the affected person has a tolerable everyday life. No complications occur, but positive treatment is not possible in every case.
When should one go to the doctor?
Although Mowat-Wilson syndrome cannot be cured with current legal and medical options, significant relief is achieved via treatment of the symptoms that occur. Normally, the earlier a diagnosis can be made, the better the patient’s treatment options. Consultation with a physician is necessary when there is a developmental disorder in the growing child. If individual abnormalities occur in direct comparison to peers, a doctor is needed. The observations should be discussed with him, so that an assessment of the state of health is possible. A learning disability, disturbances in memory, a speech delay or peculiarities in movement patterns should be presented to a doctor. If cramps, pain or abnormality of posture occurs, a doctor should be consulted. Malformations or abnormalities of the face indicate a condition for which treatment is needed. A visual blemish or abnormality of facial features should be clarified by a physician. Slowed thought processes or movements are signs of a disorder and should be investigated. If disturbances of the heart rhythm occur, if there are problems with the excretions or if there are irregularities of the reaction or perception ability, a visit to the doctor should be made. Behavioral abnormalities, vegetative disorders or peculiarities of the skin appearance should be examined by a physician.
Treatment and therapy
Mowat-Wilson syndrome is incurable to date. Symptomatic treatment options are also limited. Drug therapies are mostly used against the seizures. Antiepileptic drugs show the greatest efficacy in this context. Some of the symptomatic malformations can be corrected surgically. Especially the manifestations of Hirschsprung’s disease should be corrected as early as possible, otherwise sepsis or transmigratory peritonitis could develop. Symptomatic therapy of Mowat-Wilson syndrome is primarily intended to improve the quality of life of those affected. With this goal, mental and motor retardation can also be counteracted. Speech therapy may help with language development, which is often absent in Mowat-Wilson syndrome without supportive therapeutic measures. Physiotherapeutic and occupational therapy treatments can also counteract the delayed development of motor skills. Mowat-Wilson syndrome is often an almost unimaginable psychological burden for the parents of an affected person. For this reason, the parents of the patients are often supported by psychotherapists. Currently, medical research is concerned with gene therapy approaches, which should cure gene defects in the future. For example, the defective ZFHX1B gene of affected individuals may soon be replaced, which may make the disease curable.
Prospects and prognosis
Mowat-Wilson syndrome is nowadays well treatable. Life expectancy and quality of life are based on the type and severity of the congenital malformations. In the case of mild abnormalities that do not affect the heart, affected individuals can live into adulthood. Severely affected patients usually die during childhood or adolescence as a result of the disease.Typical causes of death are myocardial infarction or the characteristic HSCR diseases. Due to the cerebral seizures, death often occurs during the first years of the child’s life. The rare syndrome can be treated symptomatically, allowing patients to live symptom-free lives, at least temporarily. In the long term, however, Mowat-Wilson syndrome does not offer a positive prognosis, as the various malformations and anomalies result in progressive deterioration of health and eventually lead to death. The prognosis regarding life expectancy and the course of the disease is usually made by the specialist in charge. This is usually a neurologist or a specialist in genetic diseases. Depending on the symptom picture, the diagnosis of the disease already turns out to be difficult, which is why Mowat-Wilson syndrome is often not detected before the condition is already far advanced.
Prevention
Because Mowat-Wilson syndrome is a complex developmental disorder with a genetic cause, it is difficult to prevent. However, couples in the family planning process may be able to have their DNA sequenced to assess their personal risk for passing on genetic defects.
Follow-up
In most cases, affected individuals have little or no follow-up care available for Mowat-Wilson syndrome because it is a genetic disease. Therefore, affected individuals should ideally see a doctor at an early stage to avoid further symptoms or complications, which can have a negative impact on the life expectancy and quality of life of the affected individual. Self-cure is usually not possible, so a doctor should be consulted at the first signs and symptoms of the disease. In case of a desire to have children, genetic testing and counseling may be useful to prevent the recurrence of the syndrome in the descendants. As a rule, those affected with Mowat-Wilson syndrome are dependent on taking various medications. These should always be taken in time and also in the correct dosage to alleviate the symptoms. In the case of children, it is above all the parents who should control the intake. Likewise, measures of physiotherapy are necessary in many cases, although some of the exercises can also be performed at home. Whether there is a reduced life expectancy of the affected person due to Mowat-Wilson syndrome cannot be universally predicted in this case.
Here’s what you can do yourself
Since there are unfortunately no cures for Mowat-Wilson syndrome as yet, the current priority is to improve the child’s quality of life. In many cases, early logopedic therapy can counteract delayed language development and ensure significant success in language development. In addition, intensive physiotherapeutic and occupational therapy measures ensure better motor and mental development. Beyond the measures prescribed by the doctor, it is definitely advisable to deal with the issue oneself and to continue the therapy in the home environment. Caring for a disabled child is an enormous burden, especially for the parents, but also for any siblings who may be present, and family life and ultimately the quality of care can suffer as a result. It is therefore enormously important that parents in such cases seek psychotherapy in good time, which will give them more strength again in the long term by learning methods of relaxation and conflict management. It is also important to remember that those affected are entitled to annual preventive care of up to six weeks’ duration, for which the nursing care insurance fund covers the costs. There are already facilities where intensive care is provided during the day, while relatives can relax during outings. This can be a great help, especially for siblings.