Menkes Syndrome

Genetic disorder of copper metabolism beginning before birth. Copper accumulates in excessive amounts in the liver and is deficient in most other tissues of the body. Structural changes occur in the hair, brain, bones, liver, and arteries. Other clinical features include spontaneous hypothermia, severe developmental delay, loss of early development skills, and seizures. Spontaneous subdural hematoma and/or rupture or thrombosis of arteries in the brain may occur. Spastic dementia may eventually arise. Osteoporosis as a result of abnormal copper metabolism can result in pathologic fractures. The combination of subdural hematoma and bone fractures may lead to an incorrect diagnosis of child abuse. Emphysema, bladder abnormalities, degeneration of the retina, and cysts of the iris have been described.

Kinky Hair Disease; Steely Hair Disease; X-Linked Copper Malabsorption; Trichopoliodystrophy.

Neurodegenerative and connective tissue disorder first described by John H. Menkes, an American neuropediatrician, in 1962.

In the early 1970s, an incidence of 1:35,000 male births was suggested. However, in the 1980s, this frequency was reviewed at 1:90,000 live births. Finally, most agree that the incidence is estimated at 1:50,000-100,000 live births.

X-linked recessive. Caused by mutation in the gene encoding the Cu2+-transporting ATPase α-polypeptide. Gene map locus is X-q12-q13.

Defective coding for an intracellular copper-transporting protein called the human Menkes protein (MNK or ATP7A), which travels between the Golgi apparatus and the cell membrane, transporting copper to the exterior of the cell. Defective MNK prevents proper intestinal absorption of copper. Resultant free-copper deficiency affects function of copper-dependent enzymes such as cytochrome oxidase, tyrosinase, and lysyl oxidase, which results in symptoms and signs of disease.

Menkes syndrome should be considered in any male infant with unexplained seizures, hypothermia, and mental retardation. Hair changes (stubby, tangled, sparse, steely, or kinky hair that is easily broken), low serum copper and ceruloplasmin concentrations, and radiologic findings are characteristic. Copper levels are elevated in fibroblasts and the placenta. Carrier status for the abnormal gene can usually be determined by microscopic examination of multiple hairs from scattered scalp sites for pili torti (twisted hair). Prenatal diagnosis is available (DNA probe).

In the classic form, the disease starts before age 3 months by loss of neurologic development (hypotonia progressively evolving to spasticity), severe seizures, and subdural hematoma. Patients manifest hypopigmentation, growth failure, skeletal defects, arterial aneurysms, and progressive cerebral and cerebellar degeneration. Myoclonic seizures and hypothermia are frequent. Fragile steely depigmented (grayish or ivory colored) hair is present in the newborn period; they appear as pili torti at microscopic examination. Typical facies consist of frontal or occipital bossing, abnormal or absent eyebrows, pudgy cheeks with sagging jowls, micrognathia, and pallor. Characteristic radiographic changes include wormian bones in lamboid and sagittal sutures, anterior rib flaring, spur formation on the femoral and humeral metaphysis, and osteoporosis. Arteriography shows elongation, tortuosity, narrowing, and dilatation of cerebral, visceral, and limbs arteries. Gastroesophageal reflux and recurrent aspiration frequently accompany progressive central nervous system deterioration. Joint hyperlaxity and capillary fragility caused by defective lysyl oxidase, a copper-containing enzyme involved in the cross-linking of collagen similar to Ehlers-Danlos syndrome. Diverticular malformations of the bladder and ureters. Treatments have been generally unsuccessful; oral copper helps control the seizures but has no effect on progression of neurologic damage. Death within 3 years as a consequence of intractable seizures or pneumonia.

Anticonvulsant therapy should be assessed and optimized preoperatively and continued through the perioperative period. Consider raised intracranial pressure if previous intracranial hemorrhage. Repeated aspiration pneumonias plus hypotonia may compromise respiratory function. May need evaluation with chest radiograph, arterial blood gases, and other tests. Rule out ongoing pneumonia. Check for anemia secondary to aneurysmal bleeding. Hypovolemia and/or electrolyte disturbances may be present if diarrhea is severe. Postural vital signs to check for orthostatic hypotension.

Risk of pulmonary aspiration because of gastroesophageal reflux. Postoperative upper airway obstruction secondary to hypotonia: the two infants reported in the anesthetic literature eventually needed a tracheostomy. Therefore, overnight admission in the pediatric intensive care unit should be planned, as well as prolonged tracheal intubation or the use of a nasopharyngeal airway. Difficult tracheal intubation caused by redundancy of pharyngeal soft tissue has been described. As a consequence of capillary fragility, patients are at increased risk for hemorrhage during surgery and regional anesthetic techniques, especially the central neuraxial blocks, which are relatively contraindicated. Measures to prevent hypothermia should be instituted vigorously. Thick skin makes insertion of intravenous catheters and other lines more difficult. Osteoporotic bones may be brittle and prone to fracture during positioning.

Anesthetic agents known to trigger the occurrence of seizures must be avoided (enflurane with hypocapnia, methohexital, ketamine, and sustained high concentration of sevoflurane). Anticonvulsant therapy results in induction of hepatic enzymes, so the metabolism of anesthetic agents (e.g., local anesthetics) might be affected.

A forme fruste of Menkes syndrome presents with cerebellar ataxia and mild mental retardation.

Occipital Horns Syndrome: A phenotypic overlap between Menkes syndrome and occipital horns syndrome that is caused by a mutation of the same ATP7A gene. Clinical findings include mild mental retardation, joint hyperlaxity, dysfunction of the autonomous nervous system (chronic diarrhea, orthostatic hypotension), bladder anomalies, and ossified occipital horns on skull radiographs.

Wilson Disease: Copper and ceruloplasmin metabolic disorder characterized by liver disease, brain dysfunction, and a characteristic rusty-brown colored ring around the cornea of the eye (Kayser-Fleischer ring). Individual affected with this disease do not have the characteristic kinky hair of Menkes syndrome.

Amish Hair-Brain Syndrome: Sulfur-deficient brittle hair, short stature, mental deficiency, sexual infantilism, and infertility originally observed in the Amish kindred.

Hereditary Wooly Hair Syndrome (Salamon Syndrome): Autosomal dominant; characterized by the presence of woolly, kinky hair often associated with ocular disorders or atrophic keratosis of the hair (with partial or complete axillary or pubic alopecia).

Brittle Hair and Mental Deficit Syndrome: Autosomal recessive disorder with fragile hair, onychodystrophy, mental retardation, and scalp hypotrichosis.

Tay Syndrome (Ichthyosis-Brittle Hair-Impaired Intelligence-Decreased Fertility-Short Stature [IBIDS] Syndrome): Photosensitivity, ichthyosiform erythroderma, progeria-like facies, failure to thrive, mental retardation, occasional infertility, and trichothiodystrophy (sulfur-deficient brittle hair). First described by Chong H. Tay, a Singapore physician, in 1971.