First Report of Concurrent Homozygous LEPR and PKHD1 Pathogenic Variants in a Child with Early-Onset Obesity and Renal Microlithiasis

Articles in Press

Document Type : Case Report

Authors

1 Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

2 Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

3 Children and Adolescents Health Research Center, Research Institute of Cellular and Molecular Science in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran

Abstract

Background: Severe early-onset hyperphagia obesity may be a presentation of a monogenic basic disease, in this instance, of the leptin–melanocortin pathway. Deficiency in leptin receptor (LEPR) is one known etiology of congenital obesity, whereas PKHD1 mutations more broadly underlie autosomal recessive polycystic kidney disease (ARPKD).
Case Presentation: We report a 20-month-old boy born to consanguineous parents with rapid weight gain since birth (current body weight 25 kg), extreme hyperphagia, truncal obesity, acanthosis nigricans, dyslipidemia, and renal microlithiasis/nephrocalcinosis. Endocrine function and thyroid function tests were routine. Renal ultrasonography revealed multiple echogenic foci without cystic dilatation or renal impairment. Whole-exome sequencing identified homozygous pathogenic variants in both LEPR and PKHD1, both inherited in an autosomal recessive manner.
Interpretation: The LEPR variant explains the patient's early severe obesity, hyperphagia, and metabolic abnormalities, as in congenital leptin receptor deficiency. The PKHD1 variant likely explains the unusual renal phenotype of nephrocalcinosis in the absence of overt cystic disease and points toward a hypomorphic or reduced severity allele effect. To our knowledge, this is the first report of simultaneous pathogenic LEPR and PKHD1 variants in an individual.
Conclusion: The case underscores the clinical and diagnostic value of whole-genome analysis in early-onset obesity, particularly in consanguineous families where two or more recessive conditions may be coincidental. More comprehensive genetic evaluation should be encouraged in atypical or multisystem obesity in children to uncover composite molecular etiologies.

Keywords

References

1. Farooqi, I. S., & O'Rahilly, S. (2005). Monogenic obesity in humans. Annu. Rev. Med., 56(1), 443-458.
2. Huvenne, H., Dubern, B., Clément, K., & Poitou, C. (2016). Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obesity facts, 9(3), 158-173.
3. ElSaeed, G., Mousa, N., El‐Mougy, F., Hafez, M., Khodeera, S., Alhelbawy, M., ... & Elsharkawy, M. (2020). Monogenic leptin deficiency in early childhood obesity. Pediatric obesity, 15(1), e12574.
4. Kleinendorst, L., Abawi, O., van Der Kamp, H. J., Alders, M., Meijers-Heijboer, H. E., van Rossum, E. F., ... & van Haelst, M. M. (2020). Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics. European Journal of Endocrinology, 182(1), 47-56.
5. Kleinendorst, L., Abawi, O., van Der Kamp, H. J., Alders, M., Meijers-Heijboer, H. E., van Rossum, E. F., ... & van Haelst, M. M. (2020). Leptin receptor deficiency: a systematic literature review and prevalence estimation based on population genetics. European Journal of Endocrinology, 182(1), 47-56.
6. Nunziata, A., Funcke, J. B., Borck, G., Von Schnurbein, J., Brandt, S., Lennerz, B., ... & Wabitsch, M. (2019). Functional and phenotypic characteristics of human leptin receptor mutations. Journal of the Endocrine Society, 3(1), 27-41.
7. Ruggiero-Ruff, R. E., & Coss, D. (2025). Neuroendocrinology and the Genetics of Obesity. Endocrinology, 166(9), bqaf121.
8. Dias, N. F., Lanzarini, V., Onuchic, L. F., & Koch, V. H. K. (2010). Clinical aspects of autosomal recessive polycystic kidney disease. Brazilian Journal of Nephrology, 32, 263-267.
9. Molinari, E., Srivastava, S., Dewhurst, R. M., & Sayer, J. A. (2020). Use of patient derived urine renal epithelial cells to confirm pathogenicity of PKHD1 alleles. BMC nephrology, 21(1), 435.
10. Liebau, M. C. (2021). Early clinical management of autosomal recessive polycystic kidney disease. Pediatric Nephrology, 36(11), 3561-3570.
11. Letavernier, E., Schwoehrer, M., Livrozet, M., Saint-Jacques, C., Raymond, L., Saraeva, R., ... & Mesnard, L. (2022). Atypical clinical presentation of autosomal recessive polycystic kidney mimicking medullary sponge kidney disease. Kidney International Reports, 7(4), 916-919.
12. Nunziata, A., Funcke, J. B., Borck, G., Von Schnurbein, J., Brandt, S., Lennerz, B., ... & Wabitsch, M. (2019). Functional and phenotypic characteristics of human leptin receptor mutations. Journal of the Endocrine Society, 3(1), 27-41.
13. Liu, D., Liu, Y., yu Lu, C., Wang, Q., Bao, Y., Yu, Y., ... & Peng, W. (2024). Investigating genetic variants in early-onset obesity through exome sequencing: A retrospective cohort study. Obesity Research & Clinical Practice, 18(6), 417-425.
14. Prodan, A. (2024). Predicting the probability of developing obesity depending on leptin and leptin receptor polymorphisms. Med Clin Chem, 2024, 46-53.
15. Mainieri, F., La Bella, S., Rinaldi, M., & Chiarelli, F. (2024). Rare genetic forms of obesity in childhood and adolescence: a narrative review of the main treatment options with a focus on innovative pharmacological therapies. European Journal of Pediatrics, 183(4), 1499-1508.
16. Burgmaier, K., Gimpel, C., Schaefer, F., & Liebau, M. (2024). Autosomal Recessive Polycystic Kidney Disease–PKHD1. GeneReviews®[Internet].
17. Cordido, A., Vizoso-Gonzalez, M., & Garcia-Gonzalez, M. A. (2021). Molecular pathophysiology of autosomal recessive polycystic kidney disease. International Journal of Molecular Sciences, 22(12), 6523.
18. Zeraati, T., Abbaszadegan, M. R., Azarfar, A., Ghayoor Karimiani, E., Lotfi, M., & Zeraati, A. A. (2024). Autosomal recessive polycystic kidney disease: late-onset renal enlargement and proteinuria with rare PKHD1 mutation—a case report. Egyptian Journal of Medical Human Genetics, 25(1), 135.
19. Adeb M, et al. A complex case of congenital cystic renal disease. Journal of Surgical Case Reports. 2012;2012(4):rjs011. doi: 10.1093/jscr/2012.4.0.011. (PMC: PMC3369466)
20. Chen, J., Strodl, E., Huang, L. H., Chen, J. Y., Liu, X. C., Yang, J. H., & Chen, W. Q. (2021). Associations between prenatal education, breastfeeding and autistic-like behaviors in pre-schoolers. Children, 8(2), 124.
21. aylor EN, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA. 2005;293(4):455-462. doi: 10.1001/jama.293.4.455. (PubMed: 15671430)
22. Carbone A, et al. Obesity and kidney stone disease: A systematic review. Minerva Urologica e Nefrologica. 2018;70(4):393-400. doi: 10.23736/S0393-2249.18.03113-2. (PubMed: 29761690)
23. Huvenne, H., Dubern, B., Clément, K., & Poitou, C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obes Facts. 2016; 9 (3): 158–73.
24. Gill, R., Cheung, Y. H., Shen, Y., Lanzano, P., Mirza, N. M., Ten, S., ... & Chung, W. K. (2014). Whole‐exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity. Obesity, 22(2), 576-584.
25. Cordido, A., Vizoso-Gonzalez, M., & Garcia-Gonzalez, M. A. (2021). Molecular pathophysiology of autosomal recessive polycystic kidney disease. International Journal of Molecular Sciences, 22(12), 6523.
26. Bergmann C. Genetics of autosomal recessive polycystic kidney disease and its differential diagnoses. Frontiers in Pediatrics. 2017;5:221. doi: 10.3389/fped.2017.00221. (PMC: PMC5702332)
27. Burgmaier, K., Gimpel, C., Schaefer, F., & Liebau, M. (2024). Autosomal Recessive Polycystic Kidney Disease–PKHD1. GeneReviews®[Internet].
28. Sohn, Y. B. (2022). Genetic obesity: an update with emerging therapeutic approaches. Annals of pediatric endocrinology & metabolism, 27(3), 169-175.
29. Nunziata, A., Funcke, J. B., Borck, G., Von Schnurbein, J., Brandt, S., Lennerz, B., ... & Wabitsch, M. (2019). Functional and phenotypic characteristics of human leptin receptor mutations. Journal of the Endocrine Society, 3(1), 27-41.
30. Gambaro, G., Tzelves, L., Skolarikos, A., Kanbay, M., Ortiz, A., & Cozzolino, M. (2023). The new guidelines of the European Association of Urology on Urolithiasis: the urology–nephrology intersection. Nephrology Dialysis Transplantation, 38(2), 258-260.
31. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney International. 2021;99(3S):S1-S87. doi: 10.1016/j.kint.2020.11.003.
32. Kostyrka J, et al. Autosomal Recessive Polycystic Kidney Disease—The Clinical Aspects and Diagnostic Challenges. Children (Basel). 2021;8(2):124. doi: 10.3390/children8020124. (PMC: PMC7853919)
33. Modarresi, S. Z., Tajik, S., Badalzadeh, M., Fazlollahi, M. R., Houshmand, M., Maddah, M., ... & Pourpak, Z. (2023). The Risk of the Next Child Getting Affected by Chronic Granulomatous Disease in Families with at Least One Autosomal Recessive CGD Child. Iranian Journal of Allergy, Asthma and Immunology.
World Journal of Peri & Neonatology

Articles in Press, Accepted Manuscript
Available Online from 11 November 2025

Files

History

  • Receive Date: 11 November 2025
  • Accept Date: 11 November 2025

Share

How to cite

Statistics