Leprechaunism

Leprechaunism

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Leprechaunism is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Donohue syndrome

Disorder Subdivisions

  • None

General Discussion

Leprechaunism is an extremely rare disorder characterized by abnormal resistance to insulin that results in a variety of distinguishing characteristics, including growth delays and abnormalities affecting the endocrine system (i.e., the system of glands that secrete hormones into the blood system). Affected infants may also have distinctive characteristics of the head and face (craniofacial region), low birth weight, skin abnormalities, and enlargement of the breast and clitoris in females and the penis in males. Leprechaunism is inherited as an autosomal recessive genetic trait.

Symptoms

Leprechaunism is characterized by growth delays, as well as abnormalities of the head and face (craniofacial region) and of the endocrine system. Many of the symptoms associated with leprechaunism are present at birth (congenital). The range and severity of symptoms and physical characteristics may vary from case to case.



In most instances, infants with leprechaunism exhibit delayed growth before and after birth (pre- and postnatal growth deficiency), delayed bone age or maturation. Affected infants tend to have a low birth weight, may fail to gain weight or grow at the expected rate (failure to thrive), and may become abnormally thin (emaciated). They often lack muscle mass.



Infants with leprechaunism have distinctive facial features, including abnormally large, low-set and poorly developed ears; an unusually flat bridge of the nose; large, thick lips; an abnormally large mouth (macrostomia); and widely spaced eyes (hyptertelorism). Affected infants may also have an abnormally small head (microcephaly).



In most cases, leprechaunism is associated with abnormal darkening and thickening of patches of skin in certain areas of the body (acanthosis nigricans), unusual thickening of the skin (pachyderma), excessive hair growth (hirsutism), and malformation (dysplasia) of the nails. In addition, infants with leprechaunism exhibit absence of most of the body fat under the skin (subcutaneous adipose tissue).



Leprechaunism is also characterized by abnormalities of the endocrine system (i.e., the system of glands that secrete hormones into the blood system). Such abnormalities include excessive secretion of the hormone insulin (hyperinsulinemia). Insulin regulates blood sugar (glucose) levels by promoting the movement of glucose into bodily cells. Infants with leprechaunism fail to use insulin effectively (insulin resistant). Because of this, they may experience abnormally high blood sugar levels (hyperglycemia) after eating a meal (postprandial) and abnormally low blood sugar levels (hypoglycemia) when not eating.



Additional abnormalities resulting from improper function of the endocrine system include abnormal enlargement of the breast and clitoris in females and the penis in males. In some cases, cysts have formed in the ovaries. Hypertrophic cadiomyopathy may be seen in these patients as in diabetic mother babies.



Infants with leprechaunism may experience additional abnormalities, including intellectual disability, abnormally large hands and feet, an unusually widened (dilated) or enlarged (distended) stomach, abnormal amounts of iron in the liver, and/or stoppage of the flow of bile (cholestasis) from the liver. In addition, affected infants may experience protrusion of portions of the large intestine through an abnormal opening in musculature lining the abdominal cavity in the area of the groin (inguinal hernia) or protrusion of part of the intestine through the abdominal wall near the navel (umbilical hernia). Affected infants are also more susceptible to repeated infections.

Causes

Leprechaunism is inherited as an autosomal recessive genetic trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.



Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.



All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.



Investigators have determined that leprechaunism may be caused by disruption or changes (mutations) of the insulin receptor gene located on the short arm (p) of chromosome 19 (19p13.2). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. For example, "chromosome 19p13.2" refers to band 13.2 on the short arm of chromosome 19.



Due to the mutation in the insulin receptor gene, individuals with leprechaunism are unable to use insulin effectively. Insulin is a hormone produced by the pancreas that plays an important role in the absorption of sugar (glucose) into muscle cells. Glucose is the body's main source of energy. Some symptoms associated with leprechaunism, including growth deficiencies and hyperglycemia, develop as a result of severe insulin resistance of affected individuals.

Affected Populations

In reported cases, leprechaunism has occurred twice as often in females as in males (F2:M1). More than 50 cases have been reported in the medical literature. Leprechaunism was first identified in the 1948 by Dr. W.L. Donohue.

Standard Therapies

Diagnosis

The diagnosis of leprechaunism may be confirmed by a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and physical findings. The diagnosis requires measurement of insulin levels, with a blood test, and confirmation of defective insulin binding on the cells known as fibroblasts.



Prenatal diagnosis is possible through analysis of DNA obtain through a procedure known as amniocentesis. During amniocentesis, a sample of fluid that surrounds the developing fetus (amniotic fluid) is removed and studied. DNA obtained from amniotic cells is analyzed through a test known as polymerase chain reaction (PCR). PCR, a laboratory technique that many have described as a form of "photocopying," enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes (mutations). In leprechaunism, polymerase chain reaction is used to identify mutations to the insulin receptor gene.



Treatment

The treatment of leprechaunism is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat endocrine abnormalities (endocrinologists), and specialists who assess and treat skin abnormalities (dermatologists) and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.



Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

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: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co; 1997:599.



Magalini SI, et al, eds. Dictionary of Medical Syndromes. 4th ed.New York, NY: Lippincott-Raven Publishers; 1997:233.



Gorlin RJ, et al, eds. Syndromes of the Head and Neck, 3rd ed. New York, NY: Oxford University Press; 1990:822.



Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1044-45.



JOURNAL ARTICLES

Baykan A, et al. Hypertrophic cardiomyopathy with leprechaunism. J Pediatr Endocrinol Metab. 2008;21(4):317-8.



Nakae J, et al. Long-term effect of recombinant human insulin-like growth factor I on metabolic growth control in a patient with leprechaunism. J Clin Endocrinol Metab. 1998;83:542-9.



Kosztolanyi G. Leprechaunism/Donohue syndrome/insulin gene mutations: a syndrome delineation story from clinicopathological description to molecular understanding. Eur J Pediatr. 1997;156:253-5.



Gurgey A, et al. Leprechaunism is two Turkish patients. Turk J Pediatr. 1997;39:387-93.



Longo N, et al. Prenatal diagnosis of the insulin receptor gene in a family with leprechaunism. Prenat Diagn. 1995;15:1070-4.



Longo N, et al. Two mutations in the insulin receptor gene of a patient with leprechaunism: application to prenatal diagnosis. J Clin Endocrinol Metab. 1995;80:1496-501.



Imamura T, et al. Donohue's syndrome. Nippon Rinsho. 1994;52:2643-7.



Ioan D, et al. Leprechaunism: report of two cases and review. Endocrinologie. 1988;26:205-9.



INTERNET

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Donohue Syndrome. Entry No: 246200. Last Edited February 14, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 19, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Williams-Beuren Syndrome; WBS. Entry No: 194050. Last Edited August 17, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 19, 2012.



Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Patterson Pseudoleprechaunism Syndrome. Entry No: 169170. Last Edited September 9, 2010. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 19, 2012.

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



Human Growth Foundation

997 Glen Cove Avenue

Suite 5

Glen Head, NY 11545

Tel: (516)671-4041

Fax: (516)671-4055

Tel: (800)451-6434

Email: hgf1@hgfound.org

Internet: http://www.hgfound.org/



Children's Craniofacial Association

13140 Coit Road

Suite 517

Dallas, TX 75240

USA

Tel: (214)570-9099

Fax: (214)570-8811

Tel: (800)535-3643

Email: contactCCA@ccakids.com

Internet: http://www.ccakids.com



March of Dimes Birth Defects Foundation

1275 Mamaroneck Avenue

White Plains, NY 10605

Tel: (914)997-4488

Fax: (914)997-4763

Tel: (888)663-4637

Email: Askus@marchofdimes.com

Internet: http://www.marchofdimes.com



The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



NIH/National Institute of Child Health and Human Development

31 Center Dr

Building 31, Room 2A32

MSC2425

Bethesda, MD 20892

Fax: (866)760-5947

Tel: (800)370-2943

TDD: (888)320-6942

Email: NICHDInformationResourceCenter@mail.nih.gov

Internet: http://www.nichd.nih.gov/



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



For a Complete Report

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