**4. Conclusions**

Although HS has been described as a hypersensitivity disease due to CM, there are still pros and cons about its real existence (Table 3), and a certainty of diagnosis is lacking. A challenge test was performed in a few cases and always in an open manner. Again, signs and symptoms develop in the hours or days after milk consumption, and they disappear after the elimination diet. Precipitating IgG antibodies are an old-fashioned laboratory test reported in some patients during the disease; precipitins diminish or disappear during the elimination diet. However, they are not pathognomonic nor specific for the disease diagnosis and their pathogenetic role is still unclear. The prognosis is generally good, even if the extent of the exclusion diet necessary to reach a complete recovery is unclear. HS is a very intriguing disease, in some ways still controversial, but it is important to know and suspect this rare syndrome in any infant or young child with unexplained chronic pulmonary clinical manifestations. The diagnosis should be proved by clinical and radiologic improvements after strict CM avoidance with the recurrence of signs of symptoms and imaging features after a controlled CM reintroduction.


**Table 3.** The real existence of Heiner syndrome: pros and cons.

Considering the high clinical impact of the disease and the associated morbidity, more attention should be devoted to it, both in terms of clinical suspicion and research on the underlining patho-mechanisms with the detection of reliable biomarkers. We highlight the need for more stringent diagnostic criteria that combine both clinical manifestations and imaging features. Moreover, a follow-up evaluation with a well-designed CM OFC/regular reintroduction is of paramount importance to better understand this disease in terms of prognosis and duration. In summary, the future establishment of validated diagnostic criteria, the awareness of specific clinical manifestations and specific imaging features and the results of CM OFC will help health professionals in clinical practice to suspect the disease and to refer patients to the appropriate specialists.

**Author Contributions:** E.N. conceived the study, coordinated it, helped in drafting the manuscript and critically reviewed it. S.A. and C.M. participated in the study's design, carried out the literature research and wrote the first draft of the manuscript. L.P., F.M., M.G. and S.B. reviewed and provided feedback. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
