LEOPARD syndrome is closely related to Noonan syndrome and is characterized by dermal and cardiac malformations that may be associated with symptoms such as deafness and retardation. The cause of the syndrome is a mutation in the PTPN11 gene. Treatment of affected individuals is symptomatic and focuses primarily on the cardiac defect.
What is LEOPARD syndrome?
Malformation syndromes are recurrent combinations of different malformations that are congenital and affect multiple tissues or organ systems. One of the most common malformation syndromes with a genetic basis is Noonan syndrome, which is considered the second most common cause of congenital heart defects. For every 1000 births, the syndrome affects an average of one newborn within Germany. Closely related to the common Noonan syndrome is LEOPARD syndrome. Like Noonan syndrome, LEOPARD syndrome is associated with cardiac malformation, which is usually associated with cutaneous malformations as part of the disease. The term LEOPARD is an acronym for the typical clinical features of the malformation complex. Lentiginosis, ECG changes, ocular abnormalities, pulmonary stenosis, genital abnormalities, retarded growth, and deafness are grouped together as symptoms in the acronym. Synonymous terms for the condition include progressive cardiomyopathic lentiginosis and Capute-Rimoin-Konigsmark-Esterly-Richardson syndrome, in addition to the terms cardiocutaneous syndrome, cardiomyopathic lentiginosis, and lentiginosis syndrome.
Causes
As with Noonan syndrome, the cause of LEOPARD syndrome is genetic. The disease trigger is a genetic mutation. Also common to both syndromes is the categorization as a hereditary disease with sometimes sporadic cases. Familial clustering has therefore been observed for LEOPARD syndrome and can be explained in this case by autosomal dominant inheritance. However, new mutations also occur, as they account for cases without a family history or inherited disposition. In most cases, LEOPARD syndrome is preceded by a mutation in the PTPN11 gene. This gene codes for a so-called non-receptor protein, tyrosine phosphatase SHP-2. The protein loses part of its function due to the mutation of the gene. Due to the mutation-related defects, the non-receptor protein tyrosine phosphatase SHP-2 has its catalytically intended activity. Thus, it exerts insufficient influence on certain growth or differentiation factors, which may account for the symptoms of LEOPARD syndrome.
Symptoms, complaints, and signs
Like any other malformation syndrome, LEOPARD syndrome is characterized by different symptoms. The main symptoms include lentiginosis, which means a multiply lenticular dermal macula. ECG changes present in patients are conduction disturbances such as bundle branch blocks. Ocularly, there is hypertelorism in the sense of increased interocular distance. Pulmonary artery stenosis with possible obstructive cardiomyopathy may also be symptomatic of the syndrome. In addition, genital anomalies are common, particularly cryptorchidism or monoorchidism. Musculo-skeletal development in patients is usually delayed in onset. Deafness is another leading symptom. In addition to the leading symptoms, there may be accompanying symptoms, especially neurological symptoms such as seizures or nystagmus. In isolated cases, mental retardation has been observed in patients. The lentigines of the syndrome usually develop in childhood and often cover the entire body surface. With age, the changes fade in the face but persist in the oral cavity.
Diagnosis and course of the disease
The initial suspected diagnosis of LEOPARD syndrome is made on the basis of the clinical picture and history. Extensive and organ-specific investigations may be required to detect abnormalities such as a cardiac defect. To confirm the suspected diagnosis, similar malformation syndromes must be ruled out in a differential diagnostic manner during the diagnostic process. Molecular genetic testing can conclusively confirm the tentative diagnosis. The prognosis for patients with LEOPARD syndrome depends on the symptoms, their severity and treatability in each individual case. The life expectancy of patients is usually not affected.
Complications
Due to LEOPARD syndrome, affected individuals suffer from various complaints and symptoms. However, these complaints are very severe and can significantly reduce the quality of life of the affected person. Usually, there is numbness and possibly also discomfort in the eyes. Especially in children, these limitations can lead to severe delays in the development of the affected person. Furthermore, various malformations of the entire body also occur, so that in most cases the patients are dependent on the help of other people in their daily lives. Mental retardation also occurs as a result of LEOPARD syndrome. Not infrequently, the relatives or parents of the affected children also suffer from psychological complaints and depression. Likewise, the syndrome can lead to a heart defect and thereby significantly reduce the life expectancy of the patient. Seizures may also occur and be associated with pain. Various changes occur in the face, which can lead to bullying or teasing of the patient. There is no causal treatment for LEOPARD syndrome. Affected individuals rely on various therapies to alleviate the symptoms. Although no further complications occur, this does not result in a completely positive course of the disease.
When should one go to the doctor?
LEOPARD syndrome is often diagnosed immediately after birth. Whether further medical treatment is necessary depends on the severity of the malformations and accompanying symptoms. Basically, anomalies in the genital area as well as muscular disorders must be treated. Parents should confer with the responsible physician on this and then arrange for appropriate measures to be taken. If complications arise in the course of the disease, such as seizures or serious skin changes, the doctor must be informed. If an accident occurs as a result of a seizure, the emergency medical service is the appropriate point of contact for parents. In addition to the general practitioner, an orthopedist, urologist, gynecologist, neurologist, and/or dermatologist must be involved, depending on the complex of symptoms. Malpositions and incorrect postures are treated by a physiotherapist. Often, LEOPARD syndrome is associated with psychological complaints that require therapeutic treatment. Therapy for physical complaints lasts several months to years, and individual symptoms must be treated throughout life, even with early treatment.
Treatment and therapy
Causal therapy to resolve LEOPARD syndrome has not been available to date. However, because the symptoms of the malformation syndrome are due to a genetic defect, advances in gene therapy may provide causal treatment options within the next few decades. To date, gene therapy approaches have not reached the clinical stage. For this reason, patients with the malformation syndrome have so far been treated symptomatically and supportively. Depending on the symptoms present in the individual case, the treating physician prioritizes, for example, the treatment of vital organs. If a heart defect is present, invasive treatment is usually performed. After corrective surgery, conservative drug therapy steps may be required. Except for cardiac defects, most malformations in LEOPARD syndrome do not require therapeutic intervention. Monitoring and regular check-ups of lentiginosis are usually not required. Studies have shown that there is no increased tendency for degeneration for the dermal changes. Therefore, patients do not have to expect a higher risk of cancer. In individual cases, measures such as physiotherapy or early intervention can be used to counteract the mental and sometimes motor developmental delays that are sometimes present. The widespread deafness of patients can also be treated in moderation. Provision of hearing aids may be considered under certain conditions. For inappropriate patients, prompt introduction to sign language is helpful in providing them with unrestricted expression.
Outlook and prognosis
Although Leopard syndrome does not necessarily limit the patient’s life expectancy, the patient may experience symptoms during the course of the disease that can severely limit quality of life. Deafness is possible, and discomfort in the eyes may also occur.In young patients, these limitations can also lead to delayed development of the affected person. Malformations of the patient’s body are also possible, which in the further course can make the affected person dependent on constant help in everyday life. Mental impairments have also been observed, but these do not occur regularly. It is recommended, especially in juvenile patients, to offer psychological support to the parents of the affected persons, because not infrequently the relatives of the children suffer very much from the course of the disease, so that under certain circumstances depression or psychological complaints may occur. Heart defects can also occur during the course of the disease. Seizures associated with pain are possible and should be treated separately. Another problem may be changes in the patient’s face. A psychological aspect is the possible teasing or mobbing by the social environment. A causal treatment of Leopard syndrome is not yet possible. Various forms of therapy provide relief and partial improvement for those affected, but a cure is not possible according to the current state of medicine. Even if further complications can be ruled out in the course of therapy, it is not generally possible to speak of a positive course of the disease.
Prevention
Because LEOPARD syndrome is a genetically determined malformation syndrome, prevention of the condition has been limited to date. In the broadest sense, genetic counseling during the family planning phase, for example, can be considered a preventive step. However, because of the possibility of a new mutation, the condition cannot be completely ruled out for a planned child despite genetic counseling.
Follow-up
The affected person usually has very few, if any, special measures and options for aftercare available in LEOPARD syndrome. First and foremost, early detection is very important to prevent further worsening of symptoms. The earlier a doctor is contacted, the better the further course of the disease. Since LEOPARD syndrome is a hereditary disease, genetic testing and counseling should always be performed in the event that the patient wishes to have children, in order to prevent the recurrence of the disease in the descendants. As a rule, patients with LEOPARD syndrome rely on various surgical procedures to relieve symptoms and remove tumors. After such a procedure, the affected person should rest and take care of his body in any case. They should refrain from exertion or physical activities. Furthermore, many patients are also dependent on the help of other people in their daily lives. Thereby, especially the help and care by one’s own family has a very positive effect on the course of the LEOPARD syndrome and can thereby possibly also prevent depression or other psychological upsets.
What you can do yourself
Self-help and symptom relief measures are very limited for patients. However, alleviation of symptoms that do occur is possible in some cases. Because it is a hereditary condition, genetic counseling is highly advisable for affected individuals and their parents. This can prevent the syndrome from occurring in further generations. The motor and mental delays in this syndrome are treated by physiotherapy measures and intensive support. The exercises from physiotherapy can often be performed in the patient’s own home, which also accelerates the therapy. Furthermore, parents and relatives should always encourage the child in order to compensate for the intellectual complaints. Especially early support has a very positive effect on the further course of these complaints. In the case of deafness, the affected person should always wear a hearing aid, because without a hearing aid further damage to the ears can occur due to too loud noises. This usually also promotes the development of the child, as he or she can participate in conversations. Furthermore, contact with other LEOPARD syndrome sufferers is often worthwhile, as this can lead to an exchange of information.