Combination of Netherton Syndrome and Hypopituitarism with Isolated Somatotropin Deficiency: Case Study

Background. Netherton syndrome is a genetic disease characterized by combination of ichthyosiform erythroderma, hair growth abnormalities, and severe atopic dermatitis with a high total IgE levels in the blood serum. However, beside the described “triad", patients with Netherton syndrome can have growth and physical development delays. In most cases, it is associated with severe course of the underlying condition, but in some cases, the cause of short stature is hypopituitarism with somatotropin deficiency. Case description. The patient with confirmed Netherton syndrome was hospitalized with physical development delay and short stature, as well as a severe course of the underlying disease with ichthyosiform erythroderma development. Patient was administered with IL-4/13 inhibitor, dupilumab, according to the off-label indication due to severe Netherton’s syndrome course. Additional examination has revealed comorbid hypopituitarism with isolated somatotropin deficiency. Growth hormone therapy was prescribed. As a result of such combined treatment, we have achieved significant improvement in the patient’s condition. No clinically significant adverse events have been reported during therapy. Conclusion. Physical development delay in patients with Netherton syndrome is the reason for conducting research on the short stature causes. The combination of growth hormone therapy with genetically engineered biologic drug dupilumab is effective and safe, however, it requires multidisciplinary approach to the management of such patients.

1. Sun JD, Linden KG. Netherton syndrome: a case report and review of the literature. Int J Dermatol. 2006;45(6):693-697. doi: https://doi.org/10.1111/j.1365-4632.2005.02637.x

2. Choi DI, Park JH, Choi JY, et al. Keratinocytes-Derived Reactive Oxygen Species Play an Active Role to Induce Type 2 Inflammation of the Skin: A Pathogenic Role of Reactive Oxygen Species at the Early Phase of Atopic Dermatitis. Ann Dermatol. 2021;33(1):26-36. doi: https://doi.org/10.5021/ad.2021.33.1.26.

3. Herz-Ruelas ME, Chavez-Alvarez S, Garza-Chapa JI, et al. Netherton Syndrome: Case Report and Review of the Literature. Skin Appendage Disord. 2021;7(5):346-350. doi: https://doi.org/10.1159/000514699

4. Sarri CA, Roussaki-Schulze A, Vasilopoulos Y, et al. Netherton Syndrome: A Genotype-Phenotype Review. Mol Diagn Ther. 2017;21(2): 137-152. doi: https://doi.org/10.1007/s40291-016-0243-y

5. Komatsu N, Saijoh K, Otsuki N, et al. Proteolytic processing of human growth hormone by multiple tissue kallikreins and regulation by the serine protease inhibitor Kazal-Type5 (SPINK5) protein. Clin Chim Acta. 2007;377(1-2):228-236. doi: https://doi.org/10.1016/j.cca.2006.10.009

6. Aydin BK, Ba§ F, Tamay Z, et al. Netherton syndrome associated with growth hormone deficiency. Pediatr Dermatol. 2014;31(1):90-94. doi: https://doi.org/10.1111/pde.12220

7. Mazereeuw-Hautier J, Hernandez-Martín A, O'Toole EA, et al. Management of congenital ichthyoses: European guidelines of care, part two. Br J Dermatol. 2019;180(3):484-495. doi: https://doi.org/10.1111/bjd.16882

8. Yalcin AD. A case of Netherton syndrome: Successful treatment with omalizumab and pulse prednisolone and its effects on cytokines and immunoglobulin levels. Immunopharmacol Immunotoxicol. 2015;37(6):550-554. doi: https://doi.org/10.3109/08923973.2015.1115518

9. Barbieux C, Bonnet des Claustres M, de la Brassinne M, et al. Duality of Netherton syndrome manifestations and response to ixekizumab. J Am Acad Dermatol. 2021;84(5):1476-1480. doi: https://doi.org/10.1016/j.jaad.2020.07.054

10. Ragamin A, Nouwen AEM, Dalm VASH, et al. Treatment Experiences with Intravenous Immunoglobulins, Ixekizumab, Dupilumab, and Anakinra in Netherton Syndrome: A Case Series. Dermatology (Basel). 2023;239(1):72-80. doi: https://doi.org/10.1159/000525987

11. Luchsinger I, Knopfel N, Theiler M, et al. Secukinumab Therapy for Netherton Syndrome. JAMA Dermatol. 2020;156(8):907-911. doi: https://doi.org/10.1001/jamadermatol.2020.1019

12. Mahajan R, Bakshi S, Kumar A, et al. Case report: Interleukin-17 targeted biological therapy in Netherton syndrome. Front Pediatr. 2023;11:1297658. doi: https://doi.org/10.3389/fped.2023.1297658

13. Vollmuth Y, Alelq NA, Sattler F, et al. Dupilumab in a 9-week-old with Netherton Syndrome Leads to Deep Symptom Control. J Clin Immunol. 2024;45(1):42. doi: https://doi.org/10.1007/s10875-024-01837-z

14. Yan S, Wu X, Jiang J, et al. Dupilumab improves clinical symptoms in children with Netherton syndrome by suppressing Th2-mediated inflammation. Front Immunol. 2022;13:1054422. doi: https://doi org/10.3389/fimmu.2022.1054422

15. Martin-García C, Godoy E, Cabrera A, et al. I. Report of two sisters with Netherton syndrome successfully treated with dupilumab and review of the literature. Int J Immunopathol Pharmacol. 2023;37:3946320231172881. doi: https://doi.org/10.1177/03946320231172881

16. Murashkin NN, Opryatin LA, Bridan-Rostovskaya AS, et al. Results of Combined Pathogenetic Therapy in Netherton Syndrome: Clinical Case. Voprosy sovremennoi pediatrii — Current Pediatrics. 2023;22(5):433-442. (In Russ). doi: https://doi.org/10.15690/vsp.v22i5.2621

17. Barbati F, Giovannini M, Oranges T, et al. Netherton Syndrome in Children: Management and Future Perspectives. Front Pediatr. 2021;9:645259 doi: https://doi.org/10.3389/fped.2021.645259