NORD gratefully acknowledges Smriti Singh, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Tooth and nail syndrome (TNS, also known as Witkop syndrome) is a rare genetic condition that belongs to a group of conditions called ectodermal dysplasias. This group has more than 100 separate syndromes and is defined by two or more symptoms in the nails, teeth, hair and/or skin. TNS is characterized by missing and/or incorrect formation of certain baby teeth (primary teeth) and permanent/adult teeth (secondary teeth) and incorrect formation of the nails. The lower lip of individuals with TNS may stick outwards, like a pout. TNS is usually diagnosed at 4-5 years of age when tooth and nail symptoms are found.
Individuals who have TNS may have the following baby/adult teeth features: missing entirely, widely spaced, or shaped like cones (coniform). In addition, the nails in young children, especially the toenails, may be unusually small and underdeveloped (hypoplastic). They can have an obvious, unusual hollow shape, which appear to be spoon-shaped. They are slow-growing, thin and brittle. Nails are often more affected in childhood and can improve with age, so they may appear normal by adulthood. Individuals with TNS can have different numbers of teeth/nails affected, or various types of affected teeth. TNS is an autosomal dominant genetic condition.
TNS involves missing and/or the malformation of certain baby teeth (primary teeth) and permanent/adult teeth (secondary teeth). The number affected can range from 6 to 20 teeth. It also involves incorrect development of the nails. Rarely, affected individuals may also have changes affecting scalp hair, like thinning of the hair. Individuals with this condition usually have typical hair and sweat gland function. Symptoms are most obvious around school-age. TNS symptoms are less severe than other types of ectodermal dysplasia. Because of this, some people with TNS may be undiagnosed.
In some infants with TNS, certain primary teeth may be missing or unusual in shape and look like cones (coniform) or are pointed. In most children with the condition, several secondary (adult) teeth are also absent and/or not properly formed. The most common adult teeth missing include the lower front teeth (mandibular incisors and the teeth next to the incisors). The upper portions (crowns) of certain permanent teeth may be cone-shaped and, and in some people the teeth may be widely spaced. Many infants and children with the disorder appear to have a “pouting” or outwardly turned lower lip (everted). This is due to the missing primary and/or secondary teeth. The jaw can also appear small due to incorrect tooth development. Tooth alignment is also affected, with some teeth growing in incorrectly. There is no standard pattern of missing teeth, and it varies with each individual.
Individuals with TNS also have obvious differences in toenails and/or fingernails. The nails may be absent at birth and may grow very slowly. This typically occurs from infancy to around 2 to 3 years of age. In most individuals with TNS, the toenails are more affected than the fingernails. Sometimes the nails may appear normal in older children and adults, but toenails can continue to appear unusually small and/or spoon shaped. Nails can be rigid and break easily.
Some individuals with TNS have scalp hair that is abnormally thin, fine and brittle. The hair is usually spaced around the head normally.
TNS is a genetic condition caused by a harmful change (mutation) in a gene. This leads to lack of a functional protein which ultimately causes the symptoms of TNS. The gene that causes TNS is called MSX1 and was discovered in 2001. This gene makes a protein that is important in tooth formation. Some mutations lead to a non-functioning protein resulting in TNS. Other rare MSX1 gene variants have been found to be associated with cleft lip and/or palate with or without missing teeth. Research has shown that harmful changes in the MSX1 gene affect the quality of a tooth layer called the mesenchyme. The MSX1 protein is involved in only certain stages of tooth development.
TNS follows an autosomal dominant inheritance pattern. Dominant genetic conditions occur when only a single copy of a non-working gene is necessary to cause a particular condition. The non-working gene can be inherited from either parent or can be the result of a new (de novo) harmful change in the gene in the affected individual. The chance of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
TNS affects males and females in equal numbers. Since the condition was originally described in the medical literature in 1965 by C.J. Witkop, over 30 patients have been reported, with many in several families (kindreds). It has been estimated that 1-2 in every 10,000 individuals may be affected by TNS. The condition appears to be more common in Dutch Mennonites of Canada.
TNS may be suspected at birth if one or more toenails and/or fingernails are absent. More commonly, the condition is diagnosed at around four or five years of age, when certain primary (baby) teeth are missing and underdevelopment of nails may be noted. In some people, a diagnosis of TNS may not be confirmed until seven to fifteen years of age. This can be when the missing and/or unusual shape of several permanent, adult teeth and nail dysplasia has been confirmed. A diagnosis of TNS is confirmed based upon a thorough clinical exam noting the typical physical findings. Molecular genetic testing can also confirm a diagnosis. However, the percentage of patients with a clinical diagnosis of TNS and an identifiable mutation in the MSX1 gene is currently unknown.
The treatment of TNS is directed toward the specific symptoms and findings that are present. The severity may vary from person to person, but the condition of the hair and nails usually gets better when patients get older. Pediatricians, dental surgeons, dental specialists who diagnose and/or
correct wrongly aligned teeth (orthodontists) are involved in the care of people with TNS. Other health care professionals may also be involved to ensure a complete approach to treatment.
Treatment mainly consists of restoring teeth. Artificial teeth and/or other devices (prosthetics) may be used to replace missing teeth. Devices can help with spacing of teeth as well. In addition, braces, dental surgery and/or other corrective procedures may be used to help with these dental differences. Bonding of conical shaped teeth in young individuals improves the look and chewing ability of teeth. It is best to have dental work done at an earlier age, with the first visit during the first year, and visits every 6-12 months. Dental work may be needed every 2-3 years.
Dietary counseling may be helpful for patients who have trouble chewing and swallowing.
Patients may feel self-conscious due to their appearance, so psychological support may be helpful.
Genetic counseling may be recommended for patients and their families.
The National Foundation for Ectodermal Dysplasias (NFED) is involved with programs in dental schools to provide dental implants to individuals affected by ectodermal dysplasia. Such individuals must have ectodermal dysplasia, be missing a majority of teeth in the lower jaw (mandible), and not have any complicating factors. In addition, they must be willing to take part in the related research project, which requires periodic check-ups. For more information, please contact the National Foundation for Ectodermal Dysplasias, which is listed in the Resources section below.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222 TTY: (866) 411-1010 Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Tadini G, Brena M, Gelmetti C and Pezzani L. Witkop Syndrome. In: Atlas of Genodermatoses, United Kingdom: CRC Press, 2015, p.254.
dj-Rabia S, Juhlin L & Baran R. Hereditary and congenital nail disorders. Baran & Dawber’s Diseases of the Nails and their Management, 4th ed. 2012. pp. 485-547.
Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill Companies. New York, NY; 2018.
Gorlin RJ, Cohen MMJr, Hennekam RCM, eds. Syndromes of the Head and Neck, 5th ed. Oxford University Press, New York, NY; 2010.
Najmuddin M, Saheb SAK, Alharbi AN, Alsobil FM, Jhugroo C, Khan AA, Divakar DD, Naik S, Khanagar SB. Autosomal dominant mutation of MSX1 gene causing tooth and nail syndrome. Pan Afr Med J. 2020 Jul 29;36:229. doi: 10.11604/pamj.2020.36.229.23019.
Devasya A, Sarpangala M, Kumara A and Shetty R. Fried’s tooth and nail syndrome with possible mutation – a rare entity. Annals of Medical and Health Sciences Research. 2017;7(5):305-307.
Liang J, Von den Hoff J, Lange J, Ren Y, Bian Z, Carels CE. MSX1 mutations and associated disease phenotypes: genotype-phenotype relations. Eur J Hum Genet. 2016 Dec;24(12):1663-1670. doi: 10.1038/ejhg.2016.78.
Arora V, Agrawal KK, Mishra A, Chandra A. Witkop’s syndrome: A case report. J Oral Biol Craniofac Res. 2016 Jan-Apr;6(1):79-81.
Paradowska-Stolarz A. MSX1 gene in the etiology orofacial deformities. Advances in Hygiene and Experimental Medicine. 2015;69, pp.1499-1504.
Memarpour M, Shafiei F. Witkop tooth and nail syndrome: a report of three cases in a family. Pediatr Dermatol. 2011 May-Jun;28(3):281-5.
Subramaniam P, Neeraja G. Witkop’s tooth and nail syndrome: a multifaceted approach to dental management. J Indian Soc Pedod Prev Dent. 2008 Mar;26(1):22-5.
Devadas S, Varma B, Mungara J, Joseph T, Saraswathi TR. Witkop tooth and nail syndrome: a case report. Int J Paediatr Dent. 2005;15:364-69.
Wicomb GM, Stephen LX, Beighton P. Dental implications of tooth-nail dysplasia (Witkop syndrome): a report of an affected family and an approach to dental management. J Clin Pediatr Dent. 2004;28:107-12.
Jumlongras D, Bei M, Stimson JM, et al. A nonsense mutation in MSX1 causes Witkop syndrome. Am J Hum Genet. 2001;69(1):67-74. doi:10.1086/321271
Hodges SJ, Harley KE. Witkop tooth and nail syndrome: report of two cases in a family. Int J Paediatr Dent. 1999 Sep;9(3):207-11.
Zabawski EJ Jr, Cohen JB. Hereditary hypodontia and onychorrhexis of the fingernails and toenail koilonychia: Witkop’s tooth-and nail syndrome. Dermatol Online J. 1999 May;5(1):3.
Carol Anne Murdoch-Kinch, Dale A. Miles, Chiu-Kwan Poon. Hypodontia and nail dysplasia syndrome: Report of a case. Oral Surgery, Oral Medicine, Oral Pathology, 1993;75(3),403-406.
Wright JT, Grange DK, Fete M. Hypohidrotic Ectodermal Dysplasia. 2003 Apr 28 [Updated 2017 Jun 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1112/ Accessed Dec 1, 2021.
Online Mendelian Inheritance in Man. Entry# 189500 – Witkop Syndrome. Last update 05/12/2016. Available at: https://www.omim.org/entry/189500#:~:text=Witkop%20syndrome%20is%20a%20rare,and%20ability%20to%20tolerate%20heat Accessed Dec 1, 2021.
Wiktop Syndrome National Foundation for Ectodermal Dysplasias. https://www.nfed.org/learn/types/witkop-syndrome/ Accessed Dec 1, 2021.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100