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Bladder diverticula

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Recurrent urinary infections

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Diarrhea

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Gastrointestinal hemorrhage, polyps (58)

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Retinal degeneration, iris cysts

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+, ++ = finding present with increasing severity; +/- = finding sometimes present; - = finding usually not present.

+, ++ = finding present with increasing severity; +/- = finding sometimes present; - = finding usually not present.

mild hair abnormalities. However, patients are seldom diagnosed as MNK in the neonatal period because these abnormalities also sometimes appear in unaffected premature babies. Physicians usually begin to suspect that a child may have MNK after the age of 3 mo, when the characteristic MNK features, including seizures, delayed development, marked muscular hypotonia, and abnormal hair, become prominent. However, the initiation of treatment at this time is too late to prevent neurological disturbances (see Section 7.). Therefore, early diagnosis of MNK before the appearance of a severe delay in development is extremely important. The most striking finding concerning patients with MNK is the depigmented and friable hair (Fig. 3). A retrospective study examining the cases of 10 patients with MNK revealed that the hair abnormalities began to progress before the appearance of seizures and developmental delay in all cases (37). This seems to be an important clinical clue for early diagnosis. Unfortunately, most pediatricians do not notice these symptoms because this disease is very rare and they seldom have the opportunity to observe a patient with MNK. Thus, pediatricians and neonatologists must be taught to recognize these characteristics to ensure the early diagnosis of patients with MNK.

In patients with MNK, bladder diverticula form and become huge and sometimes rupture (38). Radiographs of the skeleton show a variety of abnormalities, including osteoporosis, metaphyseal spurring, a disphyseal periosteal reaction, and wormian bones in the skull. Fractures often occur in the extremities and vertebrae. Neuroimaging reveals cerebral atrophy, impaired myelination, tortuous and enlarged intracranial vessels, and subdural hemorrhage. Recurrent respiratory and urinary tract infections often occur. Convulsions are usually intractable and the clinical course worsens inexorably. Patients with MNK are bedridden and cannot sit alone, smile, or speak. Most patients die from infection or neurological disturbances by the age of 3 yr, although some survive until the age of 14 (39). The patient in case O.H. in Table 1 is a profoundly handicapped patient who had not received parenteral administration of copper, but survived until the age of 24. One case of macrocephaly and

Fig. 3. A 3-mo-old patient with classical Menkes disease. His hair is depigmented, lusterless, and kinky.

one of congenital skull fractures have been reported (28,40). A few females affected with MNK who have cytogenetically abnormal karyotypes have also been reported (41,42).

Occipital horn syndrome is the mildest type of MNK. The most noticeable difference in clinical features from patients with MNK is that patients with OHS have little or no neurological disturbance and live until adulthood. However, some patients with OHS have recurrent seizures (43). The predominant clinical features of OHS are mild muscle hypotonia and connective tissue abnormalities, including exostosis in the occipital bones, bladder diverticula, and laxity of the skin and joints (Figs. 4 and 5).

Mild MNK is extremely rare and its clinical features are intermediate between those of MNK and OHS. Since the clinical spectrum of MNK and OHS is very wide, patients with neurological retardation, ataxia and connective tissue abnormalities should be evaluated for biochemical evidence of defective copper transport.

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