Statistics

Number of Journals8
Number of Issues60
Number of Articles447
Article View170,251
PDF Download113,878
Talaeipour, S., Modarresi, S., shafighii, E. (2025). First Report of Concurrent Homozygous LEPR and PKHD1 Pathogenic Variants in a Child with Early-Onset Obesity and Renal Microlithiasis. Shahid Sadoughi University of Medical Sciences- Journal Management System, 7(2), 104-109. doi: 10.18502/wjpn.v7i2.20452
Somayeh Talaeipour; Seyedeh Zalfa Modarresi; elham shafighii. "First Report of Concurrent Homozygous LEPR and PKHD1 Pathogenic Variants in a Child with Early-Onset Obesity and Renal Microlithiasis". Shahid Sadoughi University of Medical Sciences- Journal Management System, 7, 2, 2025, 104-109. doi: 10.18502/wjpn.v7i2.20452
Talaeipour, S., Modarresi, S., shafighii, E. (2025). 'First Report of Concurrent Homozygous LEPR and PKHD1 Pathogenic Variants in a Child with Early-Onset Obesity and Renal Microlithiasis', Shahid Sadoughi University of Medical Sciences- Journal Management System, 7(2), pp. 104-109. doi: 10.18502/wjpn.v7i2.20452
Talaeipour, S., Modarresi, S., shafighii, E. First Report of Concurrent Homozygous LEPR and PKHD1 Pathogenic Variants in a Child with Early-Onset Obesity and Renal Microlithiasis. Shahid Sadoughi University of Medical Sciences- Journal Management System, 2025; 7(2): 104-109. doi: 10.18502/wjpn.v7i2.20452

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

Journal of Integrated Maternal and Pediatric Care
Article 8, Volume 7, Issue 2, October 2025, Pages 104-109    PDF (583.77 K)
Document Type: Case Report
DOI: 10.18502/wjpn.v7i2.20452
Authors
Somayeh Talaeipour1, 2; Seyedeh Zalfa Modarresi* 2, 3; elham shafighii4
1Mother and Newborn Health Research Center, Comprehensive Research Institute for Maternal and Child Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
2Children Growth Disorder Research Center, Comprehensive Research Institute for Maternal and Child Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
3Department of Pediatrics, School of Medicine, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
4Children 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 obesity with hyperphagia may be caused by a monogenic disorder involving the leptin–melanocortin pathway. Leptin (LEP) deficiency is a known cause of congenital obesity, whereas PKHD1 mutations are associated with 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 of 25 kg), extreme hyperphagia, truncal obesity, acanthosis nigricans, dyslipidemia, and renal microlithiasis or nephrocalcinosis Results of endocrine and thyroid function tests were unremarkable. Renal ultrasonography revealed multiple echogenic foci, with no cystic dilatation or sonographic evidence of impaired renal function. Whole exome sequencing identified homozygous pathogenic variants in both LEP and PKHD1, consistent with autosomal recessive inheritance.
Interpretation: The LEP variant explains the early-onset severe obesity, hyperphagia, and metabolic abnormalities observed in this patient, as seen in congenital leptin deficiency. The PKHD1 variant likely accounts for the atypical renal phenotype of nephrocalcinosis without overt cystic disease and may result in a truncating frameshift. To our knowledge, this is the first report of simultaneous pathogenic LEP 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 can co-occur by chance. More comprehensive genetic evaluation should be encouraged in atypical or multisystem obesity in children to uncover composite molecular etiologies.
Keywords
Leptin; Deficiency; PKHD1; Nephrocalcinosis; Consanguinity; Whole-exome sequencing
References
  1. Farooqi IS, O'Rahilly S. Monogenic obesity in humans. Annu Rev Med 2005; 56(1): 443-58.
  2. 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.
  3. Kleinendorst L, Abawi O, van Der Kamp HJ, Alders M, Meijers-Heijboer HE, van Rossum EF, et al. Leptin deficiency: a systematic literature review and prevalence estimation based on population genetics. Eur J Endocrinol 2020; 182(1): 47-56.
  4. Nunziata A, Funcke J-B, Borck G, von Schnurbein J, Brandt S, Lennerz B, et al. Functional and phenotypic characteristics of human leptin mutations. J Endocr Soc 2019; 3(1): 27-41.
  5. Ruggiero-Ruff RE, Coss D. Neuroendocrinology and the Genetics of Obesity. Endocrinology 2025; 166(9): bqaf121.
  6. Dias NF, Lanzarini V, Onuchic LF, Koch VHK. Clinical aspects of autosomal recessive polycystic kidney disease. J Bras Nefrol 2010; 32(3): 263-7.
  7. Molinari E, Srivastava S, Dewhurst RM, Sayer JA. Use of patient derived urine renal epithelial cells to confirm pathogenicity of PKHD1 alleles. BMC Nephrol 2020; 21(1): 435.
  8. Liebau MC. Early clinical management of autosomal recessive polycystic kidney disease. Pediatr Nephrol 2021; 36(11): 3561-70.
  9. Letavernier E, Schwoehrer M, Livrozet M, Saint-Jacques C, Raymond L, Saraeva R, et al. Atypical clinical presentation of autosomal recessive polycystic kidney mimicking medullary sponge kidney disease. Kidney Int Rep 2022; 7(4): 916-9.
  10. Prodan A. Predicting the probability of developing obesity depending on leptin and leptin receptor polymorphisms. Med Clin Chem 2024; 2024: 46-53.
  11. Liu D, Liu Y, yu Lu C, Wang Q, Bao Y, Yu Y, et al. Investigating genetic variants in early-onset obesity through exome sequencing: A retrospective cohort study. Obes Res Clin Pract 2024; 18(6): 417-25.
  12. Burgmaier K, Gimpel C, Schaefer F, Liebau M. Autosomal Recessive Polycystic Kidney Disease–PKHD1. Seattle (WA): University of Washington, Seattle; 2024.
  13. Cordido A, Vizoso-Gonzalez M, Garcia-Gonzalez MA. Molecular pathophysiology of autosomal recessive polycystic kidney disease. Int J Mol Sci 2021; 22(12): 6523.
  14. Zeraati T, Abbaszadegan MR, Azarfar A, Ghayoor Karimiani E, Lotfi M, Zeraati AA. Autosomal recessive polycystic kidney disease: late-onset renal enlargement and proteinuria with rare PKHD1 mutation—a case report. Egyptian Journal of Medical Human Genetics2024; 25(1): 1-9.
  15. Cordiner DS, Evans CA, Brundler M-A, McPhillips M, Murio E, Darling M, et al. A complex case of congenital cystic renal disease. BMJ Case Rep 2012; 2012: bcr1220115463.
  16. Chen J, Strodl E, Huang L-H, Chen J-Y, Liu X-C, Yang J-H, et al. Associations between prenatal education, breastfeeding and autistic-like behaviors in pre-schoolers. Children (Basel) 2021; 8(2): 124.
  17. Taylor EN, Stampfer MJ, Curhan GC. Obesity, weight gain, and the risk of kidney stones. JAMA 2005; 293(4): 455-62.
  18. Modarresi SZ, Tajik S, Badalzadeh M, Fazlollahi MR, Houshmand M, Maddah M, et al. The Risk of the Next Child Getting Affected by Chronic Granulomatous Disease in Families with at Least One Autosomal Recessive CGD Child. Iran J Allergy Asthma Immunol 2023; 22(1): 119-23.
  19. Mainieri F, La Bella S, Rinaldi M, Chiarelli F. Rare genetic forms of obesity in childhood and adolescence: a narrative review of the main treatment options with a focus on innovative pharmacological therapies. Eur J Pediatr 2024; 183(4): 1499-508.
Statistics
Article View: 136
PDF Download: 30


Journal Management System. Powered by Sinaweb