RAPADILINO syndrome is a malformation syndrome with the leading symptoms of short stature and skeletal malformation. The syndrome is based on a hereditary mutation. Therapy of the incurable disease is symptomatic.
What is RAPADILINO syndrome?
Some congenital malformation syndromes are predominantly associated with short stature. One of these syndromes is RAOADILINO syndrome, whose name is acronymic of the typical symptoms. These include underdeveloped or missing forearm bones, underdeveloped kneecaps, malformations of the mouth and palate, diarrhea, displaced joints, and short stature with malformed limbs. The complex of symptoms was first described in 1989 by a Finnish research group led by Helena Kääriänen. The syndrome was described in more detail by researchers at the University of Helsinki and the University of Turku. In Finland, the prevalence is reported to be one affected person in 75000. The syndrome is not limited to Finland, but is associated with documented cases in other countries. RAPADILINO syndrome is a hereditary disease that appears to be caused by a genetic mutation. More precisely, the syndrome is caused by mutations in the RECQL4 gene. The gene codes in the DNA for the so-called ATP-dependent DNA helicase Q4. This is an enzyme for the splitting of coiled DNA strands. Familial clustering has been observed in the cases documented so far. The syndrome seems most likely to be passed on in autosomal recessive inheritance.
Causes
The RECQL4 gene is involved in the replication and repair of DNA components. Several mutations of the gene can cause REPEDILINO syndrome. For example, nonsense mutations of exons 5, 18 as well as 19 have been described. These mutations create an incorrect stop codon and thus shorten the nascent protein, resulting in a loss of function of the same. An even more common cause of the disease appears to be a frame deletion, which completely removes exon 7 from the protein structure during splicing. As a consequence, nearly 50 amino acids are missing. This frame mutation leaves the structure of the helicase coding intact. The fact that the helicinase nevertheless malfunctions is probably due to incorrect protein folding caused by the missing exon 7. The cause of the incorrect folding is probably a shift in the isoelectric point or an increase in the polarity of the enzyme. Although the causal involvement of helicinase in the symptom complex is now established, the exact relationship to the individual symptoms remains a matter of speculation. Speculatively, genetic cell stability is sometimes dependent on the mutated enzyme, resulting, for example, in susceptibility to cancer. Furthermore, since the enzyme was discovered in enterocytes, malabsorption can be explained and diarrhea can be traced. The mutations of the described gene not only restrict helicinase activity but also have a negative effect on ATP cleavage ability.
Symptoms, complaints, and signs
Newborns with RAPADIILINO syndrome suffer from a complex of symptoms. The most characteristic of these are already implied in the syndrome’s name. RA stands for radial hypoplasia, which may progress to aplasia of the radius. PA stands for hypoplasia of the patella, which may also correspond to nonunion. The palate of the patients is also strongly arched. The absent or underdeveloped patellas impair motor development. In addition, cleft lip and palate is often present. DI stands for diarrhea and displaced joints in the term RAPADILINO syndrome. The joint displacement may manifest as dislocation. LI abbreviates “little size” and “limb malformation.” So patients are small in size and have malformed extremities. NO stands for “slender nose” and “normal intelligence.” Thus, the mental development of the patients is normal. They are also endowed with an unusually slender nose. Apart from the eponymous symptoms, the patients often suffer from malabsorption. Thus, they do not adequately absorb nutrients from food. In addition to the characteristic diarrhea, vomiting can also promote malnutrition and exacerbate short stature. In some cases, affected individuals also showed dermal symptoms such as café-au-lait stains.In addition, patients’ risk of cancer is increased by more than one-third, such as the risk of osteosarcoma and lymphoma in particular.
Diagnosis and disease progression
To diagnose RAPADILINO syndrome, physicians focus on the characteristic symptoms. Although molecular genetic analysis is possible, it is usually unnecessary and often inaccurate. Differentially, the physician must distinguish RAPADILINO syndrome from other mutations in the RECQL4 gene. These include the clinically similar Rothmund-Thomson syndrome and Baller-Gerold syndrome. The differentiation is often easy, because the first syndrome is mainly characterized by dermal changes. The second syndrome is characterized by changes of the bony skull. In the case of RAPADILINO syndrome, differential diagnosis and confirmation of diagnosis can usually be achieved by imaging. The prognosis of patients depends on the severity of the syndrome in each individual case.
Complications
As a very rare, hereditary disorder, RAPADILINO syndrome predominantly presents with malformations of the forearm bones, patellae, and mouth and palate. Malabsorption, especially observed in children, often causes complications. Malabsorption is characterized by constant diarrhea and frequent vomiting due to decreased utilization of nutrients. This often results in malnutrition of the affected children, leading to failure to thrive and grow. The short stature that occurs in RAPADILINO syndrome may be largely due to malnutrition, in addition to the skeletal system disorders. Other problems may be caused by the displaced and constantly dislocated joints. The deformities in the joint system can be corrected surgically. Sometimes prostheses must then be used. Malabsorption can also be treated well with the administration of medication. In severe cases, however, artificial nutrition is sometimes necessary to supply the body with sufficient nutrients again. The greatest danger, however, comes from the approximately 40 percent increased risk of cancer compared to the normal population. An increased incidence of lymphomas and osteosarcomas has been observed. Therefore, special attention should be paid to changes in symptoms in patients with RAPADILINO syndrome. Increasing bone pain, frequent bone fractures, and worsening gait disturbances are considered warning signs of possible osteosarcoma. Furthermore, regular examinations should be performed for the possible development of lymphoma.
When should you see a doctor?
RAPADILINO syndrome must always be treated by a physician. Because it is a genetic disorder, it cannot be treated causally, but only purely symptomatically. However, the affected person can undergo genetic counseling to ensure that RAPADILINO syndrome is not inherited by the descendants. In most cases, RAPADILINO syndrome is diagnosed by the doctor before birth or shortly after birth. Therefore, no visit to the doctor is necessary for the diagnosis of the syndrome. However, further treatment is provided by various surgical procedures that can alleviate the individual symptoms. A doctor should be consulted if the child cannot be fed properly, resulting in malnutrition. Since the risk of cancer is also significantly increased by RAPADILINO syndrome, regular screening examinations should be performed to detect and treat tumors at an early stage. In some cases, therefore, the life expectancy of the patient is also reduced by the disease. The treatment itself takes place at different specialists.
Treatment and therapy
Because RAPADILINO syndrome is based on a genetic mutation, the complex of symptoms is incurable to date. Only a gene therapy approach could eliminate the cause of the disease and cure the syndrome in this way. Gene therapy approaches are the subject of research, but have not yet reached the clinical phase. Therefore, the syndrome can currently only be treated symptomatically. Therapy thus depends on the symptoms in each individual case. The multiple malformations of the skeleton can be treated reconstructively by surgery. The nonunion of the individual bones can also be compensated by the use of prostheses. The treatment of disorders of the digestive tract is of particular relevance. This symptom must be urgently counteracted with medication to prevent more severe nutrient deficiencies.If this has already occurred, direct administration of appropriate medications and substitutions is indicated. In order to support the motor development of the patients, physiotherapeutic measures can be useful. Because patients with the syndrome are not expected to have intellectual limitations, early promotion of intelligence is not a required therapeutic step.
Prevention
At best, RAPADILINO syndrome can be prevented by genetic counseling during family planning. In addition, because fine ultrasound detects malformations during pregnancy, parents may decide against having the child if necessary.
Follow-up
In RAPADILINO syndrome, follow-up depends on the symptoms and the type of therapy. Following reconstructive surgery or the use of a prosthesis, proper medication is essential. Doctors often recommend physiotherapy to improve the patients’ motor skills. The parents of the ill children are responsible for their support and should be well prepared. This involves practical assistance in everyday life on the one hand, and psychological support on the other. The child needs some stimulation for physical activities. Such aftercare serves to gradually build up the child’s muscles. If the child is still bedridden, he or she should not be sore. Depending on the individual situation, young patients may need occupational therapy, and outpatient nursing services may also be necessary. With comprehensive education about the disease, children cope better with the syndrome. It is also helpful for other family members to be open about it. Since it is a hereditary disease, specialists recommend genetic counseling as part of the pre- and post-treatment care. This helps with family planning. Contact with other affected families also protects parents as well as other relatives from frustrating experiences.
What you can do yourself
Children who suffer from RAPADILINO syndrome require medication, surgery, and physical therapy. Parents of affected children can do a few things to help with treatment. In everyday life, aids such as walking aids or a wheelchair can be used, which often only have to be used for a few weeks or months if the course of treatment is positive. In general, care should be taken to ensure that the child gets enough exercise. In the case of bedridden children, particular attention should be paid to sore spots. The child needs sufficient activity and should ideally be cared for by an outpatient nursing service. In addition, the affected person must be informed about his or her illness at an early stage. An open approach makes it easier to deal with the severe hereditary disease. Regular contact with other affected persons is equally important. The doctor can give tips for further measures to support the medical therapy of RAPADILINO syndrome. Mothers who wish to become pregnant again after having a child with RAPADILINO syndrome should seek genetic counseling. In addition, some measures should be taken before and during pregnancy, which will be discussed in detail with a specialist in hereditary diseases.
