Dermatologic Manifestations of Menkes Kinky Hair Disease 

Updated: Jun 25, 2018
Author: Suguru Imaeda, MD; Chief Editor: William D James, MD 

Overview

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 al[1] 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.[4] 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).

See the image below.

Classic menkes kinky hair disease in an 8-month-ol Classic menkes kinky hair disease in an 8-month-old male infant.

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.

Etiology

Menkes kinky hair syndrome is a genodermatosis.[5] 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.[6, 7, 8]

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.[9, 10, 11, 12] Differences in ATP7A gene expression underlie intrafamilial clinical and biochemical phenotype variability.[13, 14, 15, 16, 17]

Epidemiology

Frequency

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.

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. Typical initial signs are hypotonia, failure to thrive, and seizures.

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.

Hair changes are usually not present at birth but manifest soon thereafter. Not all hairs are affected. Scalp and eyebrow hairs are most commonly short; sparse; coarse; steel wool–like; and white, silver, or gray.

Prognosis

The prognosis for Menkes kinky hair syndrome is poor. Progressive neurologic deterioration occurs in persons with Menkes kinky hair syndrome. Death, usually due to pneumonia, occurs by the time the patient is aged 2-3 years.

Patient Education

Genetic counseling is indicated in Menkes kinky hair syndrome.

 

Presentation

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 Examination

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 findings are as follows, although changes may not be present at birth:

  • Shorter, thinner on sides and occiput

  • Hypopigmented - White, silver, gray

  • Pili torti (most common but not pathognomonic)

  • Trichoclasis and trichoptilosis

  • Trichorrhexis nodosa

  • Sparse, short, brittle, kinky, steel wool–like

  • Sparse, broken, horizontal eyebrows

  • Sparse eyelashes

Skin findings are as follows:

  • Hypopigmented, pale, mottled (cutis marmorata pattern), doughy, lax

  • Pudgy, sagging cheeks

  • Cupid's bow upper lip

Central nervous system findings include progressive deterioration marked by lethargy, seizures, mental retardation, motor retardation, hypotonia, hypothermia, and microcephaly.

Musculoskeletal findings are as follows:

  • Failure to thrive

  • Metaphyseal widening

  • Spurs of the long bones

  • Wormian bones in the sagittal and lambdoid sutures

  • Pectus excavatum

Cardiovascular findings are as follows:

  • Tortuous arteries

  • Intimal fragmentation of the internal elastic lamina - aneurysm

  • Venous phlebectasia[18]

Genitourinary findings are as follows[19] :

  • Bladder diverticula[20]

  • Nephrocalcinosis[21]

  • Calciuria, aminoaciduria, albuminuria, beta2 microalbuminuria

Other findings may include hypothermia (33-35°C).

Complications

Complications of Menkes kinky hair syndrome include seizures and pneumonia.

 

DDx

Diagnostic Considerations

Also consider the following:

  • 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

Differential Diagnoses

 

Workup

Laboratory Studies

The serum copper level is low in patients with Menkes kinky hair syndrome. 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.

The serum ceruloplasmin level is low.[22]

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.[23, 24]

Urinalysis can be performed to investigate for hypercalciuria, albuminuria, aminoaciduria, and a high rate of beta2 microglobulin excretion.[25]

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.[26] Some patients who receive copper-histidinate supplementation have serum copper and ceruloplasmin levels in the reference range.[27, 28] Despite these levels, their clinical features are unaltered. A copper and disulfiram complex is currently being developed to enhance the delivery of copper via the intestinal route.[29]

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.[30]

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.[31]

Surgical Care

Patients with Menkes kinky hair syndrome frequently have multiple issues that complicate anesthetic management.[32, 33] 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.[34]

Consultations

Consult a neurologist for seizure management.[35]

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 cultured chorionic villus cells or amniocytes 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.[36]

Long-Term Monitoring

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

 

Medication

Medication Summary

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

Anticonvulsants

Class Summary

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

Phenytoin (Dilantin)

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

Carbamazepine (Tegretol)

Carbamazepine may reduce polysynaptic responses and block posttetanic potentiation.