The RAPADILINO syndrome is a malformation syndrome with the main symptoms of short stature and skeletal malformation. The syndrome is based on a hereditary mutation. The treatment of the incurable disease takes place symptomatically.
What is RAPADILINO Syndrome?
Some congenital malformation syndromes are predominantly associated with short stature. One of these syndromes is the RAOADILINO syndrome, whose name is an acronym of the typical symptoms. These include underdeveloped or absent forearm bones, underdeveloped kneecaps, malformations of the mouth and gums, diarrhea, displaced joints and short stature with deformed limbs. See sportingology for Meaning of Hypochondrogenesis in English.
The complex of symptoms was first described in 1989. The employees of a Finnish research group led by Helena Kääriänen are considered to be the first to describe it. The syndrome was described in more detail by researchers from the University of Helsinki and the University of Turku. In Finland, a prevalence of one affected person is reported in 75,000. The syndrome is not limited to Finland but is associated with documented cases in other countries.
The RAPADILINO syndrome is a hereditary disease that appears to be due to a genetic mutation. More specifically, the syndrome is caused by mutations in the RECQL4 gene. The gene takes over the coding for the so-called ATP-dependent DNA helicase Q4 in the DNA. This is an enzyme that breaks down coiled strands of DNA. Familial accumulation has been observed in the cases documented so far. The syndrome seems to be most likely to be passed on in an autosomal recessive inheritance.
The RECQL4 gene is involved in the replication and repair of DNA components. Various mutations of the gene can trigger REPEDILINO syndrome. For example, nonsense mutations of exons 5, 18 and 19 have been described. These mutations generate an incorrect stop codon and thus shorten the resulting protein, which results in a loss of function of the same.
A frame deletion, which completely removes exon 7 from the protein structure during splicing, appears to be an even more widespread cause of the disease. As a result, approximately 50 amino acids are missing. This frame mutation leaves the structure of the helicase coding intact. The fact that the helikinase still malfunctions is probably due to incorrect protein folding due to the missing exon 7.
The cause of the incorrect folding is probably a shift in the isoelectric point or an increase in polarity of the enzyme. The causal involvement of the helikinase in the symptom complex has now been established, but the exact connection with the individual symptoms remains the subject of speculation. Speculatively, the genetic cell stability sometimes depends on the mutated enzyme, so that there is a susceptibility to cancer, for example.
In addition, since the enzyme was discovered in enterocytes, malabsorption can be explained and diarrhea can be understood. The mutations of the gene described not only restrict helikinase activity, but also have a negative effect on the ability to split ATP.
Symptoms, Ailments & Signs
Newborns with RAPADIILINO syndrome suffer from a complex of different symptoms. The most characteristic of these are already indicated in the name of the syndrome. RA stands for radial hypoplasia, which can go as far as an aplasia of the radius. PA stands for hypoplasia of the patella, which can also correspond to non-attachment.
The patient’s palate is also strongly arched. The missing or underdeveloped kneecaps impair motor development. In addition, there is often a cleft lip and palate. DI stands for diarrhea and dislocated joints in the RAPADILINO syndrome. The joint displacement can manifest itself as a dislocation.
The LI abbreviates “little size” and “limb malformation”. The patients are thus of small size and possess malformed extremities. NO stands for “slender nose” and “normal intelligence”. The mental development of the patients is therefore normal. They are also equipped with an unusually slender nose. Aside from the eponymous symptoms, patients often suffer from malabsorption.
They do not absorb enough nutrients from food. In addition to the characteristic diarrhea, vomiting can also promote malnutrition and exacerbate short stature. In some cases, those affected also showed dermal symptoms such as café-au-lait spots. In addition, the patient’s cancer risk is increased by more than a third, especially the risk of osteosarcoma and lymphoma.
Diagnosis & course of disease
To diagnose the RAPADILINO syndrome, the doctor focuses on the characteristic symptoms. A molecular genetic analysis is possible, but usually not necessary and often imprecise. In terms of differential diagnosis, the doctor must differentiate RAPADILINO syndrome from other mutations in the RECQL4 gene. These include the clinically similar Rothmund-Thomson syndrome and Baller-Gerold syndrome.
The demarcation is often simple, since the first-mentioned syndrome impresses above all with dermal changes. In the second syndrome, there are changes in the bony skull. In the case of the RAPADILINO syndrome, the differential diagnosis and confirmation of the diagnosis can usually be provided by means of imaging. The prognosis of the patient depends on the severity of the syndrome in the individual case.
As a very rare, hereditary disease, the RAPADILINO syndrome mainly shows malformations in the area of the forearm bones, the kneecaps as well as in the mouth and palate. Malabsorption, observed particularly in children, often causes complications. Malabsorption is characterized by persistent diarrhea and frequent vomiting due to decreased utilization of nutrients.
This often leads to malnutrition in the affected children, which leads to stunted growth and thriving. The short stature that occurs in RAPADILINO syndrome can be caused to a large extent not only by disorders in the skeletal system but also by malnutrition. Other problems can be caused by the displaced and constantly dislocated joints. The malformations in the joint system can be corrected surgically.
Sometimes prostheses have to be used. Malabsorption can also be treated well with medication. In severe cases, however, artificial nutrition is sometimes necessary in order to supply the body with sufficient nutrients again. The greatest danger, however, comes from the approximately 40 percent higher cancer risk compared to the general population. An increased occurrence of lymphomas and osteosarcomas is observed.
Therefore, special attention should be paid to changes in symptoms in patients with RAPADILINO syndrome. Increasing bone pain, frequent fractures and worsening gait disorders are warning signs of a possible osteosarcoma. Furthermore, regular examinations for the possible development of lymphomas should be carried out.
When should you go to the doctor?
RAPADILINO syndrome must always be treated by a doctor. Since this is a genetic disease, it cannot be treated causally, but only purely symptomatically. However, the affected person can also undergo genetic counseling so that the RAPADILINO syndrome is not passed on to the descendants. In most cases, the RAPADILINO syndrome is diagnosed by the doctor before birth or shortly after birth.
Therefore, no visit to the doctor is necessary to diagnose the syndrome. However, further treatment involves various surgical interventions that can alleviate the individual symptoms. A doctor should be consulted if the child cannot be fed properly and this leads to malnutrition. Since the risk of cancer is also significantly increased by the RAPADILINO syndrome, regular check-ups should be carried out in order to detect and treat tumors at an early stage. In some cases, the patient’s life expectancy is therefore also reduced by the disease. The treatment itself takes place at various specialists.
Treatment & Therapy
Since the RAPADILINO syndrome is based on a genetic mutation, the complex of symptoms has so far been incurable. Only a gene therapy approach could eliminate the cause of the disease and thus cure the syndrome. Although gene therapy approaches are a subject of research, they have not yet reached the clinical phase. Therefore, the syndrome can currently only be treated symptomatically.
The therapy depends on the symptoms in the individual case. The multiple malformations of the skeleton can be treated with reconstructive surgery. The non-formation of the individual bones can also be compensated for by the use of prostheses. The treatment of disorders in the digestive tract is of particular relevance. This symptom urgently needs to be counteracted with medication to prevent a more severe nutrient deficiency.
If such a problem has already set in, a direct administration of appropriate medication and substitutions is indicated. Physiotherapeutic measures can be useful to support the motor development of the patient . Since patients with the syndrome do not have to expect any mental limitations, early promotion of intelligence is not a necessary therapeutic step.
The RAPADILINO syndrome can at best be prevented by genetic counseling during family planning. Since the fine ultrasound also detects deformities during pregnancy, parents can decide against the child if necessary.
In RAPADILINO syndrome, follow-up care depends on the symptoms and the type of therapy. Following reconstructive surgery or the use of a prosthesis, taking medication correctly is essential. Doctors often recommend physiotherapy to improve the patient’s motor skills.
The parents of the sick children are responsible for their support and should be well prepared. On the one hand, this involves practical assistance in everyday life and, on the other hand, psychological support. The child needs some stimulation for physical activities. Such aftercare serves to gradually build muscle.
If the child is still bedridden, it must not lie sore. Depending on the individual situation, the young patients need occupational therapy, and an outpatient nursing service may also be necessary. With comprehensive education about the disease, the children deal better with the syndrome. It is also helpful for the other family members to be open about it.
Since it is a hereditary disease, the specialists recommend genetic counseling as part of the preventive and follow-up care. This is for family planning. Contact with other affected families also protects the parents and other relatives from frustrating experiences.
You can do that yourself
Children suffering from the RAPADILINO syndrome must be treated with medication, surgery and physiotherapy. Parents of affected children can do a number of things to support treatment.
In everyday life, aids such as walking aids or a wheelchair can be used, which often only need to be used for a few weeks or months if the course is positive. In general, care should be taken to ensure that the child moves sufficiently. Special attention should be paid to sore spots in bedridden children. The child needs sufficient activity and should ideally be cared for by an outpatient care service. In addition, the affected person must be informed about their illness at an early stage. An open approach makes it easier to deal with the serious hereditary disease.
Regular contact with other sufferers is just as important. The doctor can give tips for further measures with which the medical therapy of the RAPADILINO syndrome can be supported. Mothers who wish to become pregnant again after having a child with RAPADILINO syndrome should seek genetic counseling. In addition, there are a number of measures to be taken before and during pregnancy, which are discussed in detail with a specialist in hereditary diseases.