eMedicine Specialties > Dermatology > Pediatric Diseases

Menkes Kinky Hair Disease

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

Updated: Nov 13, 2009

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 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

In Menkes kinky hair syndrome, 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, Menkes kinky hair syndrome occurs in 1 case per 35,000 population. Worldwide, Menkes kinky hair syndrome occurs in 1 case per 300,000 population.

Mortality/Morbidity

• Progressive neurologic deterioration occurs in persons with Menkes kinky hair syndrome.
• Death, usually due to pneumonia, occurs by the time the patient is aged 2 or 3 years.

Race

No racial predilection exists for Menkes kinky hair syndrome.

Sex

• The phenotype of Menkes kinky hair 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 of Menkes kinky hair syndrome 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

• Individuals with Menkes kinky hair syndrome 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 in individuals with Menkes kinky hair syndrome.

Physical

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

Physical findings of Menkes kinky hair syndrome 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
• Genitourinary⁵
  • Bladder diverticula
  • Nephrocalcinosis⁶
  • Calciuria, aminoaciduria, albuminuria, beta2 microalbuminuria
• Other - Hypothermia (33-35°C)

Causes

Menkes kinky hair syndrome is a genodermatosis.⁷

• The gene locus for Menkes kinky hair syndrome 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.^8,9
• 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.^10,11,12
• Differences in ATP7A gene expression underlie intrafamilial clinical and biochemical phenotype variability.^13,14

Differential Diagnoses

Ectodermal Dysplasia

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

Laboratory Studies

• The serum copper level is low in patients with Menkes kinky hair syndrome.
• 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.¹⁵
• Urinalysis can be performed to investigate for hypercalciuria, albuminuria, aminoaciduria, and a high rate of beta2 microglobulin excretion.¹⁶

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

Medical Care

Medical care is mainly supportive for Menkes kinky hair syndrome patients.

• 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.¹⁷
  • Some patients who receive copper-histidinate supplementation have serum copper and ceruloplasmin levels in the reference range.^18,19
  • 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.²⁰
• The use of antiseizure medications may be indicated.
• One clinical trial measured plasma dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol levels in 81 infants at risk. In 12 newborns who met the eligibility criteria, copper-replacement therapy was begun within 22 days after birth. Survival and neurodevelopment was tracked longitudinally for 1.5-8 years; survival at a median follow-up of 4.6 years was 92%, compared with 13% at a median follow-up of 1.8 years for a historical control group of 15 late-diagnosis and late-treatment patients. Two of the 12 patients had normal neurodevelopment and brain myelination.²¹

Surgical Care

Please see Special Concerns for problems associated with airway management.

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.²²

Medication

Antiseizure medications can be helpful for supportive care in Menkes kinky hair syndrome. No other therapy is available.

Anticonvulsants

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

Phenytoin (Dilantin)

May act in motor cortex where may inhibit spread of seizure activity. Activity of brainstem centers responsible for tonic phase of grand mal seizures also may be inhibited. Individualize dosing; if dose cannot be divided equally, larger dose should be taken before retiring for the evening.

Dosing

Adult

If rapid achievement of steady-state serum levels needed (eg, in status epilepticus), administer loading dose of 15-20 mg/kg PO/IV once or divided, followed by 100 mg q6-8h
Initial dose: 100 mg (125-mg susp) PO/IV tid
Maintenance dose: 300-400 mg/d PO/IV divided tid or qd/bid if using extended release; gradual increase by 100 mg q2-4wk to 600 mg/d (625 mg/d susp) may be necessary; infusion rate not to exceed 50 mg/min (25 mg/min in geriatric patients with heart disease) to avoid hypotension and arrhythmias; total dose not to exceed 1500 mg/24h

Pediatric

<6 years: 15-20 mg/kg PO/IV loading dose once or in divided doses; rate not to exceed 1-3 mg/kg/min; dose not to exceed 20 mg/kg/d; follow with initial 5 mg/kg/d maintenance dose (range, 4-8 mg/kg/d) PO/IV divided bid/tid
>6 years: May require minimum adult dose (300 mg/d); not to exceed 300 mg/d

Interactions

Amiodarone, benzodiazepines, chloramphenicol, cimetidine, fluconazole, isoniazid, metronidazole, miconazole, phenylbutazone, succinimide, sulfonamides, omeprazole, phenacemide, disulfiram, ethanol (acute ingestion), trimethoprim, and valproic acid may increase toxicity; effects may decrease when taken concurrently with barbiturates, diazoxide, ethanol (chronic ingestion), rifampin, antacids, charcoal, carbamazepine, theophylline, and sucralfate
May decrease effects of acetaminophen, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, amiodarone, carbamazepine, cardiac glycosides, quinidine, theophylline, methadone, metyrapone, mexiletine, oral contraceptives, and valproic acid; coadministration of acetazolamide and phenytoin may produce osteomalacia if these medications are used on a long-term basis; TCAs may lower seizure threshold in epileptic patients stabilized on anticonvulsants; concurrent use of phenytoin and clofazimine may result in reduced phenytoin efficacy; diltiazem is documented to result in clinically significant elevations in phenytoin serum levels associated with signs and symptoms of phenytoin toxicity; concurrent use of folic acid and phenytoin has resulted in increased seizure frequency and decreased phenytoin levels in some patients; significantly increased phenytoin levels reported with concurrent use of phenytoin and nafimidone in epileptic patients; concurrent administration of phenytoin and viloxazine may produce elevated phenytoin serum concentrations

Contraindications

Documented hypersensitivity to drug or related agents, sinoatrial block, second- and third-degree AV block, sinus bradycardia, or Adams-Stokes syndrome

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Perform CBC counts and urinalyses when therapy is begun and at monthly intervals for several months thereafter to monitor for blood dyscrasias; discontinue if rash appears, and do not resume if rash is exfoliative, bullous, or purpuric; rapid IV infusion may result in death from cardiac arrest marked by QRS widening; caution in acute intermittent porphyria and diabetes (may elevate blood glucose level); discontinue if hepatic dysfunction occurs; abrupt withdrawal may precipitate status epilepticus; nephrotoxicity that includes interstitial nephritis, nephrotic syndrome and renal failure reported with therapeutic phenytoin use; coarsening of facial features, enlargement of lips, and hypertrichosis has occurred with phenytoin therapy; phenytoin interferes with vitamin D metabolism and may cause osteomalacia; long-term phenytoin therapy is associated with symptomatic and asymptomatic peripheral neuropathy and neuromuscular disorders

Carbamazepine (Tegretol)

May reduce polysynaptic responses and block posttetanic potentiation.

Dosing

Adult

200 mg PO bid (or 100 mg susp PO qid); increase by no more than 200 mg/d tid/qid (bid with extended release) at weekly intervals until best response obtained; not to exceed 1200 mg/d, or in rare instances, 1600 mg/d

Pediatric

<6 years: 10-20 mg/kg/d PO bid/tid (qid with susp); increase weekly to tid/qid achieve optimal clinical response; not to exceed 35 mg/kg/d
6-12 years: 100 mg PO bid (50 mg susp qid); increase by 100 mg/d PO divided tid/qid (bid with extended release) weekly until best response; not to exceed 1000 mg/d
>12 years: Administer as in adults; not to exceed 1000 mg/d in children 12-15 y or 1200 mg/d if >15 y

Interactions

Serum levels may increase significantly within 30 d of danazol coadministration (avoid whenever possible); do not coadminister with MAOIs; cimetidine may increase toxicity, especially if taken in first 4 wk of therapy; may decrease primidone and phenobarbital levels (coadministration may increase carbamazepine levels); coadministration with erythromycin may increase serum levels; doses of carbamazepine may need to be increased in patients receiving antineoplastic therapy with doxorubicin or cisplatin

Contraindications

Documented hypersensitivity to drug or related products; history of bone marrow depression, MAOIs within last 14 d

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Not for use to relieve minor aches or pains; caution with increased intraocular pressure; obtain CBC counts and serum iron baseline prior to treatment, during first 2 mo, and yearly or every other year thereafter; can cause drowsiness, dizziness, and blurred vision; caution while driving or performing other tasks requiring alertness; adverse effects include acute intermittent porphyria, acute renal failure, agranulocytosis, aplastic anemia, AV block, bone marrow depression, cardiac dysrhythmia, congestive heart failure, drug-induced eosinophilia, hepatitis, leukocytosis, leukopenia, nephrotoxicity, systemic lupus erythematosus, thrombocytopenia, and toxic epidermal necrolysis
Caution in breastfeeding, elderly patients, history of adverse hematological reaction to any drug, history of cardiac damage, increased intraocular pressure, kidney dysfunction, liver dysfunction, and history of atypical absence seizures; MAOIs must be discontinued for a minimum of 14 d before starting carbamazepine; patients with underlying mental illness may experience activation of latent psychosis or agitation; do not discontinue abruptly; patients receiving carbamazepine therapy should avoid grapefruit juice consumption

Follow-up

Further Outpatient Care

• Seizure management is the most important aspect of outpatient care in Menkes kinky hair syndrome.

Complications

• Complications of Menkes kinky hair syndrome include seizures and pneumonia.

Prognosis

• The prognosis for Menkes kinky hair syndrome 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 in Menkes kinky hair syndrome.

Miscellaneous

Medicolegal Pitfalls

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

Special Concerns

• Patients with Menkes kinky hair syndrome frequently have multiple issues that complicate anesthetic management.^23,24 Physical characteristics (eg, small chin, prominent upper incisors) alter airway anatomy, and marked dental fragility make airway management potentially difficult. Alternatives to traditional direct laryngoscopy may be more suitable for these patients. The propensity for tooth fracture during laryngoscopic manipulation may be related to the defective collagen and connective tissue formation that are characteristic of Menkes kinky hair syndrome.²⁵

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, 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. 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].

6. Balestracci A, Caletti MG, Missoni M. A case of Menkes' disease with nephrocalcinosis and chronic renal failure. Pediatr Nephrol. Jun 2009;24(6):1255-6. [Medline].

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

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

9. 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].

10. 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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13. Donsante A, Tang J, Godwin SC, 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].

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

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31. Martins C, Goncalves C, Moreno A, Goncalves 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].

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Keywords

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

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

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

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