eMedicine Specialties > Dermatology > Pediatric Diseases

Menkes Kinky Hair Disease

Author: Suguru Imaeda, MD, Chief of Dermatology, Yale University Health Services; Chief of Dermatology, West Haven Veterans Affairs Medical Center; Assistant Professor, Department of Dermatology, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Dec 3, 2007

Introduction

Background

Menkes kinky hair syndrome is an X-linked recessive multisystemic lethal disorder of copper metabolism. The clinical phenotype is marked by fine silvery wiry hair, doughy skin, connective tissue disturbances, and progressive neurologic deterioration. In 1962, Menkes et al1 first described the syndrome, and, 10 years later, Danks et al2,3  noted the association with copper metabolism. The affected copper-transporting p-type ATPase (ATP7A) gene was cloned in 1993.

In Menkes kinky hair syndrome, intestinal copper uptake by brush border cells is normal, but copper transport to other tissues is affected. This change alters the activities of various copper-dependent metalloenzymes. Male infants who are affected typically die by the time they are aged 2-3 years. Carrier female patients may have only a hair-shaft abnormality (ie, pili torti).

Pathophysiology

A defect in intestinal copper transport with associated low serum copper and ceruloplasmin levels results in a deficiency in copper-dependent enzyme activity. Copper-dependent metalloenzymes relevant to the clinical phenotype include tyrosinase (pigmentation of skin and hair), lysyl oxidase (elastin and collagen cross-linking), ascorbate oxidase (skeletal development), monoamine oxidase (possibly responsible for pili torti), superoxide dismutase (free-radical detoxification), dopamine beta-hydroxylase (catecholamine production), peptidyl-glycine alpha-amidating mono-oxygenase (bioactivation of peptide hormones), and cytochrome c oxidase (electron transport and possibly responsible for hypothermia). The resulting defects are reflected in the clinical phenotype.

Frequency

United States

Menkes kinky hair syndrome occurs in 1 case per 300,000 population.

International

In Australia, this condition occurs in 1 case per 35,000 population. Worldwide, it occurs in 1 case per 300,000 population.

Mortality/Morbidity

  • Progressive neurologic deterioration occurs.
  • Death, usually due to pneumonia, occurs by the time the patient is aged 2 or 3 years.

Race

No racial predilection exists.

Sex

  • The phenotype of the syndrome is manifest in male patients.
  • Female carriers may have pili torti and uneven skin pigmentation, which appears unilaterally or along the lines of Blaschko.

Age

Symptoms are noted within the patient's first few months of life.

  • Hair changes may not be present in newborns, and not all hairs are affected.
  • Seizures usually begin within the patient's first few days or months of life.
  • Hypotonia and developmental delays are typically noted during the patient's first year of life.

Clinical

History

  • Affected individuals typically have hypotonia and seizures when they are infants.
  • Although development initially appears normal, marked developmental delays are noted within the patient's first year of life.
  • Feeding difficulties are common.

Physical

Common early physical features are microcephaly; distinct facial features; and silvery, wiry scalp hair.

Physical findings are as follows:

  • Hair (Changes may not be present at birth.)
    • Pili torti (most common but not pathognomonic)
    • Trichorrhexis nodosa
    • Hypopigmented, sparse, short, brittle, kinky, steel wool–like
    • Sparse, broken, horizontal eyebrows
    • Sparse eyelashes
  • Skin
    • Hypopigmented, pale, mottled (cutis marmorata pattern), doughy, lax
    • Pudgy cheeks
    • Cupid's bow upper lip
  • Central nervous system - Progressive deterioration marked by lethargy, seizures, mental retardation, motor retardation, hypotonia, hypothermia, and microcephaly
  • Musculoskeletal
    • Failure to thrive
    • Metaphyseal widening
    • Spurs of the long bones
    • Wormian bones in the sagittal and lambdoid sutures
  • Cardiovascular
    • Tortuous arteries
    • Intimal fragmentation of the internal elastic lamina - aneurysm
    • Venous phlebectasia4
  • Genitourinary - Bladder diverticula
  • Other - Hypothermia (33-35°C)

Causes

Menkes kinky hair syndrome is a genodermatosis.5

  • The gene locus is in band Xq13.3.
  • Mutations at band Xq13.3 result in increased copper uptake in the small intestine, but an inability to transport copper from the brush border intestinal cells into the plasma results in a total-body copper deficiency.
  • The defective protein is a copper-binding ATPase, ATP7A, localized to the trans-Golgi apparatus. The defective protein is present in all tissues, although it is barely detectable in hepatocytes.6
  • Differences in ATP7A gene expression underlie intrafamilial clinical and biochemical phenotype variability.7

More on Menkes Kinky Hair Disease

Overview: Menkes Kinky Hair Disease
Differential Diagnoses & Workup: Menkes Kinky Hair Disease
Treatment & Medication: Menkes Kinky Hair Disease
Follow-up: Menkes Kinky Hair Disease
References
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References

  1. Menkes JH, Alter M, Steigleder GK, Weakley DR, Sung JH. A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics. May 1962;29:764-79. [Medline].

  2. Danks DM, Campbell PE, Stevens BJ, Mayne V, Cartwright E. Menkes's kinky hair syndrome. An inherited defect in copper absorption with widespread effects. Pediatrics. Aug 1972;50(2):188-201. [Medline].

  3. Danks DM, Campbell PE, Walker-Smith J, Stevens BJ, Gillespie JM, Blomfield J, et al. Menkes' kinky-hair syndrome. Lancet. May 20 1972;1(7760):1100-2. [Medline].

  4. Price DJ, Ravindranath T, Kaler SG. Internal jugular phlebectasia in Menkes disease. Int J Pediatr Otorhinolaryngol. Jul 2007;71(7):1145-8. [Medline].

  5. Spitz JL. Genodermatoses. Vol 1. Baltimore, Md: Williams & Wilkins; 1996:230-1.

  6. La Fontaine S, Mercer JF. Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Arch Biochem Biophys. Jul 15 2007;463(2):149-67. [Medline].

  7. Donsante A, Tang J, Godwin SC, Holmes CS, Goldstein DS, Bassuk A, et al. Differences in ATP7A gene expression underlie intrafamilial variability in Menkes disease/occipital horn syndrome. J Med Genet. Aug 2007;44(8):492-7. [Medline].

  8. Matsuo M, Tasaki R, Kodama H, Hamasaki Y. Screening for Menkes disease using the urine HVA/VMA ratio. J Inherit Metab Dis. 2005;28(1):89-93. [Medline].

  9. Lem KE, Brinster LR, Tjurmina O, Lizak M, Lal S, Centeno JA, et al. Safety of intracerebroventricular copper histidine in adult rats. Mol Genet Metab. May 2007;91(1):30-6. [Medline].

  10. Watanabe A, Shimizu N. Identification of three novel mutations in Japanese patients with Menkes disease and mutation screening by denaturing high performance liquid chromatography. Pediatr Int. Feb 2005;47(1):1-6. [Medline].

  11. Brownstein JN, Primosch RE. Oral manifestations of Menkes' kinky hair syndrome. J Clin Pediatr Dent. 2001;25(4):317-21. [Medline].

  12. Freedberg IM, Eisen AZ, Wolff K. Fitzpatrick's Dermatology in General Medicine. New York, NY: McGraw-Hill; 1999:732, 2141.

  13. Harris ED, Qian Y, Reddy MC. Genes regulating copper metabolism. Mol Cell Biochem. Nov 1998;188(1-2):57-62. [Medline].

  14. Hart DB. Menkes' syndrome: an updated review. J Am Acad Dermatol. Jul 1983;9(1):145-52. [Medline].

  15. Hoppe-Tichy T, Nguyen TH, Hentze BW, Lorke M. [Manufacturing and stability of copper-histidine solution for treatment of Menkes' Kinky Hair Syndrome]. Pharmazie. Mar 2005;60(3):205-7. [Medline].

  16. Hurwitz S. Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 2nd ed. Philadelphia, Pa: WB Saunders; 1993:498-9.

  17. Jayawant S, Halpin S, Wallace S. Menkes kinky hair disease: an unusual case. Eur J Paediatr Neurol. 2000;4(3):131-4. [Medline].

  18. Liu PC, Chen YW, Centeno JA, Quezado M, Lem K, Kaler SG. Downregulation of myelination, energy, and translational genes in Menkes disease brain. Mol Genet Metab. Aug 2005;85(4):291-300. [Medline].

  19. Madsen E, Gitlin JD. Copper and iron disorders of the brain. Annu Rev Neurosci. 2007;30:317-37. [Medline].

  20. Madsen E, Gitlin JD. Copper deficiency. Curr Opin Gastroenterol. Mar 2007;23(2):187-92. [Medline].

  21. Martins C, Gonçalves C, Moreno A, Gonçalves O, Baptista AP, Bairos V. Menkes' kinky hair syndrome: ultrastructural cutaneous alterations of the elastic fibers. Pediatr Dermatol. Sep-Oct 1997;14(5):347-50. [Medline].

  22. Munakata M, Sakamoto O, Kitamura T, Ishitobi M, Yokoyama H, Haginoya K, et al. The effects of copper-histidine therapy on brain metabolism in a patient with Menkes disease: a proton magnetic resonance spectroscopic study. Brain Dev. Jun 2005;27(4):297-300. [Medline].

  23. Oshio T, Hino M, Kirino A, Matsumura C, Fukuda K. Urologic abnormalities in Menkes' kinky hair disease: report of three cases. J Pediatr Surg. May 1997;32(5):782-4. [Medline].

  24. Sheela SR, Latha M, Liu P, Lem K, Kaler SG. Copper-replacement treatment for symptomatic Menkes disease: ethical considerations. Clin Genet. Sep 2005;68(3):278-83. [Medline].

  25. Sybert VP. Genetic Skin Disorders. ed. New York, NY: Oxford University Press; 1997:195-8.

  26. Tümer Z, Horn N. Menkes disease: underlying genetic defect and new diagnostic possibilities. J Inherit Metab Dis. Aug 1998;21(5):604-12. [Medline].

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Further Reading

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Keywords

steely hair syndrome, trichopoliodystrophy, copper metabolism, copper deficiency, pili torti, hair-shaft abnormality

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Contributor Information and Disclosures

Author

Suguru Imaeda, MD, Chief of Dermatology, Yale University Health Services; Chief of Dermatology, West Haven Veterans Affairs Medical Center; Assistant Professor, Department of Dermatology, Yale University School of Medicine
Suguru Imaeda, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Connecticut State Medical Society, Sigma Xi, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

Medical Editor

Mark A Crowe, MD, Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine
Mark A Crowe, MD is a member of the following medical societies: American Academy of Dermatology and North American Clinical Dermatologic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology
Disclosure: elsevier Royalty Other

 
 
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