Communicating the diagnosis
Communicating a r(14) syndrome diagnosis to parents requires specific skills and abilities. If not performed appropriately, the effect can be shocking, leaving the caregivers with a sense of abandonment and despair. Specialized multidisciplinary clinics (tertiary centers) can provide optimized diagnostic and management services for children with r(14) and their families.
Recommendation 1.1)
The diagnosis should be pursued as soon as possible: children with neurodevelopmental disorders are usually addressed to conventional or molecular cytogenetic tests. Karyotype analysis is essential for the detection of the ring chromosome and the definite diagnosis of r(14) syndrome:
Grade A
Recommendation 1.2)
Karyotype: The analysis of at least 30 metaphases is necessary for a >95% chance of detecting a r(14) chromosome that occurs in at least 80% of cells:
Grade A
Recommendation 1.3)
Patients with r(14) syndrome should consult with an experienced geneticist with the highest priority:
Grade A
Recommendation 1.4)
The diagnosis should be communicated in person by a geneticist, ensuring enough time for discussion with the parents ensuring to provide sufficient and clinically detailed information and avoiding unwanted information:
Grade C
Recommendation 1.5)
Provide printed materials about the r(14) syndrome, R14I, health care services and useful websites. A copy of the clinical report can be helpful for any caregivers and must be authorized by parents. Assure parents that they will be supported by a professional social-clinical team, with regular follow -up visits, ideally within the next 6 months:
Grade C
General management and follow-up
The management of children with disabilities is one of the important challenges that pediatricians are currently facing. These patients often require a multi-disciplinary approach which takes into account all the medical issues of the child. Patients and families should be supported by a healthcare services and a professional care team with regular follow-up visits (Recommendation 2.4).
Recommendation 2.1)
Multidisciplinary care at a major clinical facility should be available for patients and their relatives to reduce medical complications and improve quality of life. The general practitioner could have consultation from the following specialists: child neurologist, respiratory physician & therapist, gastroenterologist/nutritionist, dietitian, pediatrician, cardiologist, rehabilitation medicine physician, social counsellor, occupational therapist, speech therapist, specialized nurse, physical therapist, ophthalmologist, immunologist, and psychologist:
Grade C
Recommendation 2.2)
The initial clinical evaluation should comprehend: cerebral MR, EEG, heart and abdomen US, oculistic and audiologic evaluation, neuropsychological assessment:
Grade C
Recommendation 2.3)
Other common examinations usually performed in the r(14) syndrome are: celiac disease and autoimmunity screening, first tier immunological analysis, auxological evaluation:
Grade C
Recommendation 2.4)
Affected children should generally be reviewed with the following scheme: Immunologist, once per year; child Neurologist/Neurologist, as needed; Ophthalmologist, as needed; Gastroenterologist/Nutritionist, as needed and in case of malnutrition; Rehabilitation therapists (physical, psychomotor, speech and language therapist), every week if needed:
Grade C
Recommendation 2.5)
The patient’s support team should keep regular contacts with the family between visits. A referent of the support team should be in charge of keeping contacts:
Grade C
Recommendation 2.6)
Ideally, an effective coordination is essential between the multidisciplinary clinical team, the general practitioner and primary community services:
Grade C
Recommendation 2.7)
Parents and caregivers should preserve as much autonomy as possible for their child:
Grade C
Recommendation 2.8)
Good relationship between patients and others caregivers is vital; they also may have health needs: psychological support should be considered and offered to all caregivers when necessary:
Grade C
Symptomatic and specific treatment of the major symptoms
Recommendation 3.1)
Conduct regular clinical follow-up examinations to evaluate epileptic seizures:
Grade A
Recommendation 3.2)
Do not interrupt effective antiepileptic therapies even if the symptomatology appears less severe:
Grade C
Recommendation 3.3)
Start physical therapy early to reduce hypotonic complications (such as scoliosis) due to the reduced muscle tone:
Grade B
Recommendation 3.4)
Conduct regular physiatric assessments to identify possible hypotonic complications:
Grade C
Recommendation 3.5)
Carry out periodic eye examinations with evaluation of the fundus oculi:
Grade B
Recommendation 3.6)
In case of recurrent ear infections, perform audiometric evaluation:
Grade A
Respiratory issues
Respiratory complications are frequent in patients with r(14) syndrome, primarily because of diaphragmatic weakness combined with aspiration and recurrent infections. Therefore, it is important to provide a program of respiratory physiotherapy individualized for each patient. Furthermore, when facing with recurrent infections, individuals with r(14) syndrome should be promptly addressed to a clinical immunologist at the first sign of infection to identify possible immunological defect (Table
2) and to optimize therapeutic strategies in compliance with the best standards of care [
46] is of the utmost importance. Prompt antibiotic treatment is recommended in all cases to control acute episodes of infection. Antibiotic prophylaxis can also be considered in case of recurrent infection and its duration must be determined in individual cases by the attending physician. To prevent infections, the administration of vaccines is recommended, in particular anti-pneumococcus, anti-H. influenzae, and anti-meningococcal.
Table 2
Immunological tests
Serum Immunoglobulins (IgG, IgA, IgM, IgE) |
Lymphocyte sub-populations (CD3, CD4, CD8, CD19, DR, and CD16) |
Adaptive immune system to vaccines such as tetanus, hepatitis |
Complement levels |
Recommendation 4.1)
Any respiratory symptoms should be promptly checked; screening tests for the monitoring of respiratory function are strongly recommended. Signs of respiratory failure should be discussed with the parents to allow advanced planning:
Grade A
Recommendation 4.2)
In case of recurrent pulmonary infections, consider respiratory physiotherapy antibiotic prophylaxis; an immunological evaluation is also strongly recommended:
Grade A
Recommendation 4.3)
Recommended (inactivated) vaccines include anti-haemophilus, anti-pneumococcal, anti-meningococcal and flu vaccine:
Grade C
Recommendation 4.4)
In severe conditions, oxygen therapy at home could be necessary:
Grade C
Nutritional support
In most of cases, children with r(14) syndrome are extremely underweight and are frequently affected by anorexia that leads to malnutrition, therefore all children should undergo repeated measures of anthropometric variables and nutritional evaluation. Each clinical visit should include weight measurement and nutrition assessment with proper scales for children with motor impairments. A teamwork with a skilled dietician or nutritionist would then lead to a prescription or oral nutritional supplements when needed. In presence of dysphagia restricted to liquid foods, a speech therapist should be involved to investigate the extent of swallowing disturbance and the possible oral rehabilitation strategy. When oral feeding not possible is only temporarily or in case of severe dysphagia, the use of a naso-gastric tube is the best option. If dysphagia becomes permanent or long lasting, a gastrostomy (PEG) should be considered, either by surgical or endoscopy procedures. PEG is very important to ensure drug delivery, not only for epilepsy, but also for the very frequent gastro-intestinal (GI) symptoms, such dyspepsia and constipation that are respectively treated with anti-acid and osmotic laxative drugs (Table
3).
Table 3
Nutritional challenges and suggested standards
Screening for malnutrition | Anthropometric measures as part of routine clinical assessment |
Nutrition support | Managed by a Pediatric nutritional team |
Treating malnutrition | Enteral nutrition, oral nutrition supplements and tube feeding as needed, oral rehabilitation |
Physicians should note that although quite safe and useful, feeding tubes often intimidate caregivers, that need reassurance and adequate training before starting such treatments. Children with r(14) syndrome have normal digestive and absorptive functions, therefore can be nourished with intact protein formulas and should be allowed to eat all the food they can safely ingest by mouth. Micronutrient and vitamin intake must be monitored; vitamin D daily supplementation must be given at twice the of recommended daily allowance (approximately 800-1.000 IU/day).
Recommendation 5.1)
Nutritional status, especially body weight, should be checked regularly in patients affected by r(14) syndrome:
Grade A
Recommendation 5.2)
Malnourished children should be referred to a pediatric nutrition team:
Grade C
Recommendation 5.3)
Children with dysphagia should be referred to a speech therapist:
Grade A
Recommendation 5.4)
A careful prescription of oral nutritional supplements can help to reduce malnutrition in orally competent children:
Grade B
Recommendation 5.5)
Enteral tube feeding is recommended when anorexia is limiting caloric intake and/or when aspiration occurs during swallowing:
Grade A
Communication and language disorders
As reported above, intellectual disability and language disorders have been found in almost all children with r(14) syndrome [
22], although high individual variability emerged in their communicative skills. In a survey study was showed that only four out of 12 children and young adults with r(14) syndrome can use words to communicate [
23]; in addition, only two of them could speak fluently. It has to be noted that the parents of “non-verbal” children have reported the presence of a higher number of challenging behaviors. Assessment of language development in children with r(14) syndrome has to be conducted by clinicians with sufficient experience not only in language disorders, but also in intellectual disabilities and autism spectrum disorders. Some children seem to use communicative gestures to compensate for their expressive language difficulties [
23], so assessment must evaluate also non-verbal communication skills. To increase children’s linguistic abilities, clinical practice suggests the use of augmentative and alternative communication strategies, although there are not yet specific studies on their effective validity in children with r(14) syndrome. The presence of autistic traits in most of these individuals strongly affects their communicative skills. As in children with autism spectrum disorders, an intensive behavioral treatment, combined with parent training, could be helpful in reducing challenging behaviors. A specific program of speech and language therapy has to be planned for every children considering their age and individual characteristics.
Recommendation 6.1)
Full psychomotor and neuropsychological testing is useful from the first 2 years to detect early communication and language disorders:
Grade A
Recommendation 6.2)
Regular assessment of speech and language function by a trained therapist is recommended:
Grade B
Recommendation 6.3)
Communication support systems (e.g., pointing boards with figures or words) should be used with individuals with severe communicative impairment; individualized training should be guaranteed to affected people and appropriate support provided to their caregivers:
Grade C
Recommendation 6.4)
If autistic traits are shown, an intensive behavioral treatment, combined with parent training, could be helpful in reducing challenging behaviors:
Grade C
Scientific research aspects
In the field of rare diseases, easy access to standardize clinical data [
47] as well as to high-quality samples [
48] are the key prerequisites for promoting research. Thus, both genetic biobanks and registries/clinical databases play an increasingly important role in facilitating diagnoses and in developing translational research, through collecting, storing and distributing biospecimens and related data in a standardized framework. Therefore, R14I signed in 2009 an agreement with the Telethon Network of Genetic Biobanks (TNGB) in order to provide services for storage and distribution of biospecimens from persons affected by r(14) syndrome and their relatives [
49]. The agreement favors a centralized sample collection and ensures visibility via the TNGB online catalogue (
http://biobanknetwork.telethon.it/) as well as an easy samples accessibility for a wide scientific community. Request evaluation is carried out in agreement with the board of management of TNGB and its policy based on predefined criteria shared among the partners to avoid any possible conflict of interests with R14I. Moreover, R14I is directly engaged in collecting and storing clinical data of patients and families all around the world in a dedicated and accessible clinical database (
http://www.ring14.org/eng/460/database/). Data are directly extracted from clinical records and evaluated by clinicians. Presently more than 300 samples and related data have been distributed to accredited researchers to support project on the r(14) syndrome. Newly diagnosed children and their families are recommended to contribute their data and biological samples to our database and biobank resources. Moreover, R14I is actively funding other scientific projects with dedicated funds available through yearly-issued calls for grants [
1]; however, identifying and supporting other areas with further research is urgently needed.
Recommendation 7.1)
Further molecular studies to optimize the treatment of the most relevant symptoms (i.e., epileptic crisis and bronchial secretions) are needed:
Grade A
Recommendation 7.2)
Further improvements to harmonize data collection in the clinical database are needed:
Grade B
Recommendation 7.3)
New diagnosed children or families who have not yet participated in clinical database/biobank should be invited to do:
Grade B
Recommendation 7.4)
Further studies on the psychosocial determinants of quality of life in children and caregivers are urgent:
Grade C
Recommendation 7.5)
Further studies to evaluate communication disorders and their treatment in r(14) syndrome are needed:
Grade B