History

See the list below:

Family history: Collect a full 3 generation pedigree to detect family history of autosomal dominant nail-patella syndrome (NPS). Currently, 88% of affected individuals have a positive family history of nail-patella syndrome. Nail-patella syndrome is fully penetrant, but significant interfamilial and intrafamilial variability is noted.
Nail/digit anomalies: Nail anomalies are present at birth.
Knees: Recurrent patellar dislocations, deformity of knee joint, and knee pain are noted.
Elbows: Elbow pain, decreased flexion, pronation, and supination are reported.
Back pain: This is common in nail-patella syndrome; underlying spinal problems such as spondylolisthesis may be observed.
Renal disease: Proteinuria, hypertension, and/or decreased renal function may be observed in patients with nail-patella syndrome. End-stage renal disease is relatively rare and is reported in approximately 5% of patients.
Preeclampsia: This condition is more common in patients with nail-patella syndrome than in the general population.
Ophthalmology: Ocular hypertension or open-angle glaucoma may be observed.
Neurology: Attention deficit disorder with and without hyperactivity (ADHD) may be more common in adults with nail-patella syndrome and does not exhibit the same increased male prevalence as in the general population.^[14]Major depressive symptoms may also be part of the syndrome. A significant proportion of patients exhibit decreased sensitivity to pain and temperature in the extremities. Signs and symptoms of chronic fatigue may be present due to maldevelopment of the serotonergic system.
GI problems: Constipation and irritable bowel syndrome are more common in patients with nail-patella syndrome than in the general population.

A study by Bech et al found a Danish family in which early onset paroxysmal cranial dyskinesia was part of the nail-patella spectrum. The family had a novel variant in LMX1B, and the investigators suggested that the dyskinesia might be associated with aberrant dopaminergic circuits.^[10]

Physical

Pes planus is seen in majority of patients with nail-patella syndrome. These patients also tend to have an overall typically thin body habitus, and they have difficulty gaining weight. Other findings on physical examination may include the following:

Nail/digit anomalies: Nails may be absent, hypoplastic, or dystrophic; triangular lunulae may be the sole nail anomaly. Typically, the thumb is most severely affected, with possible decreasing severity progressing to the fifth digit. Decreased creases over the distal interphalangeal (DIP) joints are noted.
Patellar anomalies: Patellae may be absent or hypoplastic. Dislocation in the superior and lateral direction is common. Pain is also common, and osteoarthritis may be present.
Iliac horns: These bony prominences are typically asymptomatic and may be palpable on the posterolateral iliac bones. If not palpable, they are often detected using radiography. They are present in about 70% of patients and are pathognomonic of nail-patella syndrome.
Elbow anomalies: Decreased flexion, supination, and pronation are noted. The radius may be hypoplastic and posteriorly placed. Skin webbing (pterygia) may be present.
Renal disease: Proteinuria with or without hematuria may be present in 30-50% of patients. This progresses to end-stage renal disease in approximately 5%. No evidence suggests that renal transplantation has different outcome in patients with nail-patella syndrome than in the general population.
Open-angle glaucoma: Optic nerve and visual field damage can be prevented with early detection of elevated intraocular pressure and appropriate treatment.
Lester sign: A hyperpigmented, irregular ring in the iris may be noted.

Causes

See the list below:

The LMX1B gene is a transcription factor involved in the dorsoventral patterning of vertebrate limbs (including patterning of the nails, digits, elbows and patellae), the differentiation and function of kidney podocytes, development of the anterior eye structures, and the CNS.
The loss of function of one allele of LMX1B is the only known cause of nail-patella syndrome.^{[8, 9, 10]}

Differential Diagnoses

Lovelace PD, May LA. Nail Patella Syndrome. StatPearls. 2021 Jan. [QxMD MEDLINE Link]. [Full Text].
West JA, Louis TH. Radiographic findings in the nail-patella syndrome. Proc (Bayl Univ Med Cent). 2015 Jul. 28 (3):334-6. [QxMD MEDLINE Link]. [Full Text].
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 Mar. 40(3):153-62. [QxMD MEDLINE Link].
Romero P, Sanhueza F, Lopez P, Reyes L, Herrera L. c.194 A>C (Q65P) mutation in the LMX1B gene in patients with nail-patella syndrome associated with glaucoma. Mol Vis. 2011. 17:1929-39. [QxMD MEDLINE Link]. [Full Text].
Chatterjee M, Chatterjee C. Nail-patella syndrome--a preliminary study for genetic linkage with ABO blood group. J Indian Med Assoc. 2010 Nov. 108(11):747-9. [QxMD MEDLINE Link].
Bongers EM, van Kampen A, van Bokhoven H, Knoers NV. Human syndromes with congenital patellar anomalies and the underlying gene defects. Clin Genet. 2005 Oct. 68(4):302-19. [QxMD MEDLINE Link].
McIntosh I, Dunston JA, Liu L, Hoover-Fong JE, Sweeney E. Nail patella syndrome revisited: 50 years after linkage. Ann Hum Genet. 2005 Jul. 69(Pt 4):349-63. [QxMD MEDLINE Link].
Jones MC, Topol SE, Rueda M, et al. Mutation of WIF1: a potential novel cause of a Nail-Patella-like disorder. Genet Med. 2017 Oct. 19 (10):1179-1183. [QxMD MEDLINE Link]. [Full Text].
Hall G, Lane B, Chryst-Ladd M, et al. Dysregulation of WTI (-KTS) is Associated with the Kidney-Specific Effects of the LMX1B R246Q Mutation. Sci Rep. 2017 Jan 6. 7:39933. [QxMD MEDLINE Link]. [Full Text].
Bech S, Lokkegaard A, Nielsen TT, et al. Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene. Mov Disord. 2020 Dec. 35 (12):2343-7. [QxMD MEDLINE Link]. [Full Text].
Dunston JA, Hamlington JD, Zaveri J, et al. The human LMX1B gene: transcription unit, promoter, and pathogenic mutations. Genomics. 2004 Sep. 84(3):565-76. [QxMD MEDLINE Link].
Marini M, Bocciardi R, Gimelli S, et al. A spectrum of LMX1B mutations in Nail-Patella syndrome: new point mutations, deletion, and evidence of mosaicism in unaffected parents. Genet Med. 2010 Jul. 12(7):431-9. [QxMD MEDLINE Link].
Clough MV, Hamlington JD, McIntosh I. Restricted distribution of loss-of-function mutations within the LMX1B genes of nail-patella syndrome patients. Hum Mutat. 1999. 14(6):459-65. [QxMD MEDLINE Link].
López-Arvizu C, Sparrow EP, Strube MJ, Slavin C, DeOleo C, James J, et al. Increased symptoms of attention deficit hyperactivity disorder and major depressive disorder symptoms in Nail-patella syndrome: potential association with LMX1B loss-of-function. Am J Med Genet B Neuropsychiatr Genet. 2011 Jan. 156B(1):59-66. [QxMD MEDLINE Link].
Tigchelaar S, Lenting A, Bongers EM, van Kampen A. Nail patella syndrome: knee symptoms and surgical outcomes. A questionnaire-based survey. Orthop Traumatol Surg Res. 2015 Dec. 101 (8):959-62. [QxMD MEDLINE Link].
[Guideline] Papnicolaou N, Francis IR, Casalino DD, et al. ACR Appropriateness Criteria renal failure. [online publication]. Reston (VA): American College of Radiology (ACR); 2008. [Full Text].
Bongers EM, Huysmans FT, Levtchenko E, 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 Aug. 13(8):935-46. [QxMD MEDLINE Link].
Chen H, Lun Y, Ovchinnikov D, et al. Limb and kidney defects in Lmx1b mutant mice suggest an involvement of LMX1B in human nail patella syndrome. Nat Genet. 1998 May. 19(1):51-5. [QxMD MEDLINE Link].
Cormier-Daire V, Chauvet ML, Lyonnet S, et al. Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation. J Med Genet. 2000 Jul. 37(7):520-4. [QxMD MEDLINE Link].
Dai JX, Johnson RL, Ding YQ. Manifold functions of the Nail-Patella Syndrome gene Lmx1b in vertebrate development. Dev Growth Differ. 2009 Apr. 51(3):241-50. [QxMD MEDLINE Link].
Dreyer SD, Zhou G, Baldini A, et al. Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet. 1998 May. 19(1):47-50. [QxMD MEDLINE Link].
Dunston JA, Reimschisel T, Ding YQ, et al. A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression. Eur J Hum Genet. 2005 Mar. 13(3):330-5. [QxMD MEDLINE Link].
Fong EE. Iliac horns' (symmetrical bilateral central posterior iliac processes):a case report. Radiology. 1946. 47:517-518.
Galloway G, Vivian A. An ophthalmic screening protocol for nail-patella syndrome. J Pediatr Ophthalmol Strabismus. 2003 Jan-Feb. 40(1):51-3. [QxMD MEDLINE Link].
Krawchuk D, Kania A. Identification of genes controlled by LMX1B in the developing mouse limb bud. Dev Dyn. 2008 Apr. 237(4):1183-92. [QxMD MEDLINE Link].
Lemley KV. Kidney disease in nail-patella syndrome. Pediatr Nephrol. 2008 Jun 6. [QxMD MEDLINE Link]. [Full Text].
Mimiwati Z, Mackey DA, Craig JE, Mackinnon JR, Rait JL, Liebelt JE. Nail-patella syndrome and its association with glaucoma: a review of eight families. Br J Ophthalmol. 2006 Dec. 90(12):1505-9. [QxMD MEDLINE Link].

Media Gallery

Nail of a patient the nail-patella syndrome.
Decreased severity of nail dystrophy towards the fifth finger and loss of skin creases over the distal interphalangeal joints. Courtesy of Journal of Medical Genetics, BMJ Publishing Group Ltd.
Triangular lunules. Courtesy of Journal of Medical Genetics, BMJ Publishing Group Ltd.
X-ray of pelvis showing iliac horns. Courtesy of Journal of Medical Genetics, BMJ Publishing Group Ltd.
X-ray of pelvis showing iliac horns in early childhood. Courtesy of Journal of Medical Genetics, BMJ Publishing Group Ltd.
Lester's sign of the iris. Courtesy of Journal of Medical Genetics, BMJ Publishing Group Ltd.

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Author

Julie Hoover-Fong, MD, PhD, FACMG Professor, Department of Genetic Medicine, Director, Greenberg Center for Skeletal Dysplasias, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Julie Hoover-Fong, MD, PhD, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, American Society of Human Genetics, International Skeletal Dysplasia Society

Disclosure: Nothing to disclose.

Coauthor(s)

Iain McIntosh, PhD President, Bendel Camus Medical Education, Inc

Iain McIntosh, PhD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

Elizabeth Sweeney, MBChB, MD Consultant Clinical Geneticist, Royal Liverpool Children’s Hospital, UK

Elizabeth Sweeney, MBChB, MD is a member of the following medical societies: British Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Christian J Renner, MD Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Suzanne M Carter, MS, and Susan J Gross, MD, FRCS(C), FACOG, FACMG, to the original writing and development of this article.