AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 al^{2, 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Child abuse (based on skeletal radiographic findings)
Argininosuccinic aciduria
Björnstad syndrome
Crandall syndrome
Salti-Salem syndrome
Tay syndrome
Conradi-Hünermann chondrodysplasia punctata
Bazex syndrome
Citrullinemia
Hypohidrotic ectodermal dysplasia
Ankyloblepharon-ectodermal defects - Cleft lip and/or palate
Salamon syndrome
Arthrogryposis and ectodermal dysplasia
Ectodermal dysplasia with syndactyly
Tricho-odontonychial dysplasia with pili torti
Pili torti and enamel hypoplasia

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The serum copper level is low.
• The serum ceruloplasmin level is low.
• Copper accumulation may be observed in cultured cells (useful mainly for prenatal diagnosis).
• Copper levels in the intestines, kidney, and skin fibroblasts are within the reference range or high.
• Copper levels in the liver, brain, and endothelial cells are low.
• Urine homovanillic/vanillylmandelic acid ratio of greater than 4 is strongly suggestive of Menkes disease and can be used as a screening method, especially in early infancy. Impaired activity of dopamine beta-hydroxylase, a copper-dependent enzyme, leads to increased homovanillic acid levels.⁸

Imaging Studies

• Radiography of the long bones and skull may be performed.
• Angiography or magnetic resonance angiography may be performed.
• Findings include metaphyseal widening of the femur and ribs, tibial and femoral spurs, and wormian bones of the skull.

Histologic Findings

Light microscopy shows hairs with pili torti that twist along the longitudinal axis. The twisting of the hair fiber creates the illusion of wide and narrow areas along the hair shaft similar to the nodes of monilethrix. Trichorrhexis nodosa also is commonly seen.

Electron microscopy of the skin shows that the diameter of dermal collagen fibrils is decreased and that sparse, amorphous elastin fibers are present.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical care is mainly supportive.

• The administration of parenteral copper is ineffective at influencing the clinical course and fatal outcome. However, early parenteral administration has been demonstrated to prevent some neurological disturbances.
• • Some patients who receive copper-histidinate supplementation have serum copper and ceruloplasmin levels in the reference range.
  • Despite these levels, their clinical features are unaltered.
• Intracerebroventricular copper histidine injection in a rat model of Menkes disease restored the brain copper concentration, suggesting the possibility of this method as a novel treatment approach in Menkes disease infants with severe mutations.⁹
• The use of antiseizure medications may be indicated.

Consultations

• Consult a neurologist for seizure management.
• Consult a geneticist for counseling and prenatal testing.
• • Prenatal diagnosis by means of DNA mutational analysis (preferred method) may be performed.
  • Copper-64 incorporation by chorionic villus cells or amniotic fluid cells may be observed.
• Carrier status can be determined by observing copper-64 uptake in cultured fibroblasts or by means of DNA mutational analysis, which is the preferred method. Denaturing high-performance liquid chromatography has been used effectively for mutation screening in patients with Menkes disease.¹⁰

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Antiseizure medications can be helpful for supportive care. No other therapy is available.

Drug Category: Anticonvulsants

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Seizure management is the most important aspect of outpatient care.

Complications

• Seizures can occur.
• Pneumonia can develop.

Prognosis

• The prognosis is poor.
• Patients experience rapid, progressive neurologic deterioration.
• Death typically occurs by the time the patient is aged 3 years.

Patient Education

• Genetic counseling is indicated.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Genetic counseling is important in the management of future pregnancies.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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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].
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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].
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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].
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16. Hurwitz S. Clinical Pediatric Dermatology: A Textbook of Skin Disorders of Childhood and Adolescence. 2^nd ed. Philadelphia, Pa: WB Saunders; 1993:498-9.
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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].
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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].
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Article Last Updated: Dec 3, 2007