Although 22q11.2DS is the most frequent microdeletion in humans, its diagnosis and management are still universally challenging (3, 4, 20, 21). Considering the continental dimensions of Brazil and that the key access to health of the population is through SUS (22), it is essential to seek strategies that facilitate suspicion, investigation and management of this clinical condition. In this context, the BCFP has brought information to subsidize health actions for this population group (8, 15). The perspective of this study is to characterize the clinical trajectories of individuals registered in BDCA until their 22q11.2DS diagnosis. The difference in the percentage of cases between Brazilian regions herein presented only reflects the demand registered by the BCFP participating centers and has no epidemiological value.
The Comprehensive Care Policy for People with Rare Diseases (PAIPDR) establishes as a role of primary care the identification of clinical characteristics that may suggest the need for referral to specialized or reference services in rare diseases (10). However, individuals with important characteristics of 22q11.2DS are arriving late to the reference services, which may compromise therapeutic interventions and genetic counseling of parents.
Individuals with psychiatric disorder (49/83) had a higher median age of 22q11.2DS diagnosis (10 years with psychiatric disorder versus 7.5 years, without a psychiatric disorder). Up to 40% of individuals with intellectual disability have a psychiatric disorder (23), which can contribute to the deficient association between this phenotype and 22q11.2DS. In 22q11.2DS, these alterations manifest more frequently in adolescence (4, 5, 24), which would make the early diagnosis impossible if this was the most evident characteristic of this syndrome in an individual. Instead, in this study, over 53.1% of individuals with a psychiatric disorder also presented other important characteristics of 22q11.2DS, such as NPMDD, lip and/or palate defects, cardiac malformation and/or hematological/immunological alteration.
Similarly, individuals with lip and/or palate defects alone had a higher median age of diagnosis (10 years with lip and/or palate versus 1.1 years without lip and/or palate defects). These defects occur more frequently in isolation (25) but are present in at least 600 other Mendelian syndromes (26). Among these, 22q11.2DS is the most frequent microdeletion (27, 28). In this study, at least 50.6% of the individuals who presented lip and/or palate defects (87/101) also presented other clinical manifestations indicative of 22q11.2DS, such as NPMDD, cardiac malformation and/or hematological/immunological alteration.
The presence of a cardiac malformation was a significant variable of reduction of the diagnostic age (median of 6.5 years with a cardiac malformation versus 11 years without cardiac malformation). Other studies had similar results (20, 29). In total 70.8% (68/96) of the individuals had a cardiac malformation, which is one of the most recognized characteristics of 22q11.2DS.
These results suggest that there is difficulty of 22q11.2DS clinical suspicion or obstacles in referral and access to the genetic service. In any case, the need for improvement in the flow of primary care-specialized/reference service is a reality. Added to this is the absence of geneticists as a requirement for the registration of hospitals that perform integrated procedures for aesthetic-functional rehabilitation of patients with lip-palate malformation by SUS (Brazilian Ordinance SAS/MS No. 62) (30).
In this study, at least 72.06% of individuals present 2 or more recurrent clinical manifestations indicative of 22q11.2DS concomitantly. They are also common abnormalities in this disorder (3). Therefore, an increase of health professional’s awareness about 22q11.2DS phenotype would enable its clinical suspicion even under its phenotypic variability. In this sense, Monteiro and collaborators proposed clinical characteristics for the suspicion of 22q11.2DS and indication of laboratory investigation (15), which were later validated (8).
Using this data to produce information resources aimed at training health professionals is essential for better effectiveness and efficiency of the flow of primary care-reference service. The set of this information can also contribute to the establishment of the national protocol for clinical management of 22q11.2DS and the national standardization of care. Finally, the training of health professionals besides the establishment of the national management protocol are important tools to achieve early diagnosis of 22q11.2DS (8).
Still, within PAIDR, individuals referred to the reference services in rare diseases should return to primary and secondary care to receive multi-professional care according to the therapeutic plan established by the reference team (10). Counter-reference enables individuals to perform evaluations in health units in their region, increasing treatment adherence. In this study, individuals accessed 68.75% of the evaluations available in the BDCA and recommended at the time of 22q11.2DS diagnosis (9). These evaluations happened before the diagnosis, reinforcing the unfamiliarity with this syndrome by health professionals and (or) the difficulty to access genetic evaluation and test.
Individuals that accessed psychiatric and nasopharyngeal assessments had a higher median age of diagnosis, of 10 versus 4 years of age and 9 versus 0 years, respectively. These results add to those got in the presence of psychiatric and lip and/or palate defects versus age of diagnosis and corroborate with the perception that there is an obstacle(s) in the access to the genetics service.
Endocrinology was the least accessed specialty, mentioned by 31.5% (35/111) of the sample group. In 22q11.2DS, the most recurrent endocrinological alteration is idiopathic hypocalcemia, which may be present in up to 60% of individuals since neonatal period (5). This is a 22q11.2DS characteristic manifestation and therefore important for its clinical suspicion and referral to the medical genetics service. We should note that the number of endocrinologists working in SUS is 6990 (31), which makes universal access to this professional very restrictive.
Only 12.6% of the sample group accessed psychopedagogists. Psychopedagogical follow-up is a key aspect for recognition of individual potentials and difficulties, favoring school performance and psychosocial insertion. Psychopedagogy is among the support therapies advocated in reference centers for rare diseases and is mainly indicated in the presence of NPMDD (10). In this study, NPMDD was the recurrent clinical alteration. The number of psychopedagogists working in SUS is 1479 (32), which makes universal access to this professional difficult.
Given the diversity and quantity of rare diseases, raising the suspicion of a specific condition is challenging, but there are possible paths to tread when faced with a complex clinical disease without a defined cause.
It is up to primary health care the recording of the medical history, which includes a meticulous clinical evaluation, active listening, recording of family history and anamnesis. The referral to specialized care allows the performance of a complete check-up, facilitating the detection of cardiac, immunological, endocrinological, neurological, genitourinary and gastrointestinal tract alterations. (10). The set of this information can narrow the range of possible rare diseases and contain possible health aggravations in individuals who have not yet accessed the reference service for rare diseases.
Before the establishment of the PAIPDR (2008–2014), of which some BCFP services are part, mean age of 22q11.2 DS diagnosis obtained was 10.6 years while after PAIPDR (2015–2020), the mean age of diagnosis was 8.3 years. Although the trend was a reduction, both averages are far from ideal.
The consequences of delayed diagnosis associated with incomplete management are many. We highlight the worsening of untreated clinical manifestations and in the prognosis of this individual, the delay in the family’s preparation to deal with the evolution of the clinical condition and the increase in the costs associated with health for both the patient and the state.
In Canada, the mean age of diagnosis of 22q11.2DS is 4.7 years (20) and adult individuals with 22q11.2DS, with continuous interdisciplinary follow-up, have a life expectancy of 46.4 years (33).
Data on post-diagnosis management and life expectancy of Brazilian individuals with 22q11.2DS are not available. The absence of these data makes it impossible to optimize the PAIPDR to ensure that increased life expectancy comes with early diagnosis and increased quality of life.
The lack of 22q11.2DS data from the North and Midwest and the few cases from the Northeast prevented the comparison of the therapeutic itinerary until the moment of diagnosis between the different regions of Brazil. It is noteworthy that BCFP does not has partner centers in the North and Midwest. However, considering that socioeconomic and demographic differences between the five regions of the country correlate directly with the availability and quality of health services (34, 35), the number of evaluations accessed by individuals with 22q11.2DS from different regions may vary.
From this perspective, the small proportion of genetic services in the North (11, 36) added to the reduced number of geneticists in Brazil, allocated mostly in the Southeast (37,38), makes fair access to early diagnosis less probable.
Following the international recommendations for diagnosis, clinical management of 22q11.2DS and the characteristics of the Brazilian Unified Health System (4, 9) we suggest a flowchart with general lines of health care (Fig. 5):
Whereas clinical management should be based on recommendations for each age group, but the establishment of the therapeutic plan should be individualized, the proposed flowchart may guide the multidisciplinary team to define the longitudinal therapeutic plan.
This was a retrospective, cross-sectional study and as one, it has restrictions of working with available data collected through the years. Furthermore, some information is collected from the report of individuals with 22q11.2 DS and/or their responsible, therefore it may contain comprehension and memory bias. Considering Brazil’s inequalities regarding socioeconomic aspects and access to health care it also may contain biases associated with availability and ease of access to health services.