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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, (), -.
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, , , 2025, -.
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, (), pp. -.
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; (): -.

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

World Journal of Peri & Neonatology
Articles in Press, Accepted Manuscript, Available Online from 11 November 2025
Document Type: Case Report
Authors
Somayeh Talaeipour1; Seyedeh Zalfa Modarresi* 2; elham shafighii* 3
1Mother and Newborn Health Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
2Children Growth Disorder Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
3Children 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
obesity; LEPR deficiency; PKHD1; dual molecular diagnosis; nephrocalcinosis; consanguinity; whole-exome sequencing
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