Disproportionate Short Stature in Nail Patella Syndrome: Clinical, Radiological, and Genetic Insights

Abstract

This case report discusses a rare manifestation of Nail Patella Syndrome (NPS) in an 11-year-old male patient who presented with disproportionate short stature. NPS, an autosomal dominant disorder resulting from mutations in the LIM homeobox transcription factor 1-beta (LMX1B) gene, is typically characterized by nail dysplasia, patellar anomalies, and renal complications. The patient's clinical features included dysmorphic traits, nail abnormalities, and specific radiological findings, confirming the diagnosis through genetic analysis. The identified pathogenic variant (c.661C > T; p.Arg221Ter) emphasized the importance of genetic testing in NPS diagnosis. While NPS is commonly associated with renal and ophthalmological complications, this case highlights the significance of recognizing short stature as a potential feature. The report emphasizes comprehensive clinical evaluations, genetic testing, and vigilant monitoring for managing potential complications in individuals with NPS, contributing to a deeper understanding of this complex genetic disorder.

Keywords

• Childhood anomalies
• Short Stature
• Nail-Patella Syndrome

References

1. 1. BRIXEY AM, BURKE RM. Arthro-onychodysplasia; hereditary syndrome involving deformity of head of radius, absence of patellas, posterior iliac spurs, dystrophy of finger nails. Am J Med 1950;8:738–44. https://doi.org/10.1016/0002-9343(50)90098-2.
2. 2. Schulz-Butulis BA, Welch MD, Norton SA. Nail-patella syndrome. J Am Acad Dermatol 2003;49:1086–7. https://doi.org/10.1016/j.jaad.2002.01.001.
3. 3. Finsterer J, Stöllberger C, Steger C, Cozzarini W. Complete heart block associated with noncompaction, nail-patella syndrome, and mitochondrial myopathy. J Electrocardiol 2007;40:352–4. https://doi.org/10.1016/j.jelectrocard.2006.11.008.
4. 4. Lucas GL, Opitz JM, Wiffler C. The nail-patella syndrome: Clinical and genetic aspects of 5 kindreds with 38 affected family members. J Pediatr 1966;68:273–88. https://doi.org/https://doi.org/10.1016/S0022-3476(66)80159-2.
5. 5. Milla E, Gamundi MJ. Novel LMX1B mutation in familial Nail patella syndrome with variable expression of open angle glaucoma. 2007.
6. 6. Bongers EMHF, Huysmans FT, Levtchenko E, de Rooy JW, Blickman JG, Admiraal RJC, et al. Genotype-phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy. Eur J Hum Genet 2005;13:935–46. https://doi.org/10.1038/sj.ejhg.5201446.
7. 7. Ding YQ, Yin J, Kania A, Zhao ZQ, Johnson RL, Chen ZF. Lmx1b controls the differentiation and migration of the superficial dorsal horn neurons of the spinal cord. Development 2004;131:3693–703. https://doi.org/10.1242/dev.01250.
8. 8. Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 1994;78:335–42. https://doi.org/10.1016/0092-8674(94)90302-6.

9. 9. Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, et al. Achondroplasia is defined by recurrent G380R mutations of FGFR3. Am J Hum Genet 1995;56:368–73.
10. 10. Guidera KJ, Satterwhite Y, Ogden JA, Pugh L, Ganey T. Nail patella syndrome: a review of 44 orthopaedic patients. J Pediatr Orthop 1991;11:737–42.
11. 11. Bongers EMHF, Gubler M-C, Knoers NVAM. Nail-patella syndrome. Overview on clinical and molecular findings. Pediatr Nephrol 2002;17:703–12. https://doi.org/10.1007/s00467-002-0911-5.
12. 12. Goecke C, Mellado C, García C, García H. Short stature and hypothyroidism in a child with Nail-Patella Syndrome. A case report. Rev Chil Pediatr 2018;89:107–12. https://doi.org/10.4067/S0370-41062018000100107.
13. 13. McIntosh I, Dunston JA, Liu L, Hoover-Fong JE, Sweeney E. Nail patella syndrome revisited: 50 years after linkage. Ann Hum Genet 2005;69:349–63. https://doi.org/10.1111/j.1529-8817.2005.00191.x.
14. 14. Lemley K V. Kidney disease in nail-patella syndrome. Pediatric Nephrology 2009;24:2345–54. https://doi.org/10.1007/s00467-008-0836-8.
15. 15. Haddad S, Ghedira-Besbes L, Bouafsoun C, Hammami S, Chouchene S, Ben Meriem C, et al. Nail-patella syndrome associated with short stature: a case series. Case Rep Med 2010;2010. https://doi.org/10.1155/2010/869470.
16. 16. Álvarez-Martín N, Gamundi MJ, Hernan I, Carballo M, Isabel Luis-Yanes M, García-Nieto V. Nail-patella syndrome. A case with a de novomutation in the LMX1B gene not previously described. Nefrologia 2013;33:585–6. https://doi.org/10.3265/Nefrologia.pre2013.Apr.12006.
17. 17. Lindelöf H, Horemuzova E, Voss U, Nordgren A, Grigelioniene G, Hammarsjö A. Case Report: Inversion of LMX1B - A Novel Cause of Nail-Patella Syndrome in a Swedish Family and a Longtime Follow-Up. Front Endocrinol (Lausanne) 2022;13. https://doi.org/10.3389/fendo.2022.862908.
18. 18. Jang J, Im H, Lee H, Sung H, Cho SI, Lee J-S, et al. A Family With Nail-Patella Syndrome Caused by a Germline Mosaic Deletion of LMX1B. Ann Lab Med 2024;44:625–7. https://doi.org/10.3343/alm.2024.0140.
19. 19. Levy M, Feingold J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int 2000;58:925–43. https://doi.org/10.1046/j.1523-1755.2000.00250.x.
20. 20. Letts M. Hereditary onycho-osteodysplasia (nail-patella syndrome). A three-generation familial study. Orthop Rev 1991;20:267–72.
21. 21. THOMPSON EA, WALKER ET, WEENS HS. Iliac horns; an osseous manifestation of hereditary arthrodysplasia associated with dystrophy of the fingernails. Radiology 1949;53:88–92. https://doi.org/10.1148/53.1.88.
22. 22. Fong EE. “Iliac Horns” (Symmetrical Bilateral Central Posterior Iliac Processes). Radiology 1946;47:517–8. https://doi.org/10.1148/47.5.517.
23. 23. Álvarez-Martín N, Gamundi MJ, Hernan I, Carballo M, Luis-Yanes MI, García-Nieto V. Nail-patella syndrome. A case with a de novo mutation in the LMX1B gene not previously described. Nefrologia 2013;33:585–6. https://doi.org/10.3265/Nefrologia.pre2013.Apr.12006.
24. 24. Mimiwati Z, Mackey DA, Craig JE, Mackinnon JR, Rait JL, Liebelt JE, et al. Nail-patella syndrome and its association with glaucoma: a review of eight families. Br J Ophthalmol 2006;90:1505–9. https://doi.org/10.1136/bjo.2006.092619.
25. 25. Sweeney E, Fryer A, Mountford R, Green A, McIntosh I. Nail patella syndrome: a review of the phenotype aided by developmental biology. J Med Genet 2003;40:153–62. https://doi.org/10.1136/jmg.40.3.153.
26. 26. Pinette MG, Ukleja M, Blackstone J. Early prenatal diagnosis of nail-patella syndrome by ultrasonography. J Ultrasound Med 1999;18:387–9. https://doi.org/10.7863/jum.1999.18.5.387.
27. 27. Figueroa-Silva O, Vicente A, Agudo A, Baliu-Piqué C, Gómez-Armayones S, Aldunce-Soto MJ, et al. Nail-patella syndrome: report of 11 pediatric cases. J Eur Acad Dermatol Venereol 2016;30:1614–7. https://doi.org/10.1111/jdv.13683.
28. 28. Dreyer SD, Zhou G, Baldini A, Winterpacht A, Zabel B, Cole W, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet 1998;19:47–50. https://doi.org/10.1038/ng0598-47.
29. 29. Beals RK, Eckhardt AL. Hereditary onycho-osteodysplasia (Nail-Patella syndrome). A report of nine kindreds. J Bone Joint Surg Am 1969;51:505–16.