Archives of Disease in Childhood, 1976, 51, 269.

Menkes's steely hair syndromeE. MAY WHEELER and P. F. ROBERTS

From the Departments of Paediatrics and Histopathology, United Norwich Hospitals, Norwich

Wheeler, E. M., and Roberts, P. F. (1976). Archives of Disease in Childhood,51, 269. Menkes's steely hair syndrome. Three unrelated cases of Menkes'ssyndrome are described. In addition to the typical features these cases all showedabnormalities of the urinary tract characterized by hydronephrosis, hydroureter, andbladder diverticula. There was no organic obstruction in the urinary tract and thechanges are presumed to be due to disturbed innervation. The 3 patients showedno overall clinical response to parenteral copper therapy administered for periods of 1to 8 months. Necropsy studies showed structural changes in veins as well as arteriestogether with aneurysm formation in both, and one case showed a polypoid lesion inthe stomach.

Since the first description of the steely-hairsyndrome (Menkes et al., 1962), consisting of maleinfants with characteristic facies, hair resemblingsteel-wool in texture, hypothermia, convulsions,severe mental retardation, and low serum copperand caeruloplasmin levels, many new cases havebeen described. The discovery of the disturbancein copper metabolism (Danks et al., 1972a, b) wasan important step in the understanding of the evolu-tion of the disease and led to the treatment byparenteral copper therapy (Danks et al., 1972b,1973; Walker-Smith et al., 1973; Bucknall, Haslam,and Holtzman, 1973; Dekaban and Steusing, 1974).Unfortunately, in these cases the infants had severeneurological damage before copper therapy wasbegun and no improvement was obtained. Recent-ly an infant has been treated from the age of 28 daysand has so far shown a favourable response (Groverand Scrutton, 1975).Three unrelated cases of Menkes's syndrome seen

at one hospital in Norfolk showing several newclinical and pathological features are reported, andtheir response to parenteral copper therapy isdescribed.

Case reportsCase 1. The first child of unrelated parents.

Birthweight was 2 42 kg at 39 weeks' gestation. Dur-ing the first 2 weeks of life he had a persistently lowtemperature of 36 'C. At 11 days of age he was foundto have a urinary tract infection. In spite of treatment

Received 8 August 1975.

with ampicillin he gained weight very slowly and wasrestless. At 9 weeks he was a thin, wriggling babywho did not smile or pay attention to his mother. Hisweight, length, and head circumference were well be-low the 10th centile. Scalp hair was scanty and crin-kled, resembling his mother's hair. His facies werecharacteristic of Menkes's syndrome and he had apersistent erythematous rash on the head, neck, andtrunk. Hb 11 9 g/dl; white blood count, electrolytes,liver, and thyroid function tests were normal; bloodurea 41-74 mg/100 ml; creatinine clearance 25 ml/minper 1 73 m2 (normal for age). An intravenous urogramshowed that the left kidney was grossly hydronephroticbut with good function. There was obstruction at thepelviureteric junction. The right kidney was normal.A micturating cystogram showed bilateral uretericreflux and a trabeculated bladder.

Over the next few months the child remained in astate of constant activity with athetoid movements oflimbs but there were no major convulsions. Physicallyand mentally he made no progress and at 4 monthsdeveloped intractable diarrhoea. At 5 months the serumcopper level was found to be <5 tg/100 ml; no caerulo-plasmin was detected. Treatment with copper-EDTAby intramuscular injection had no beneficial effect onthe neurological state though serum copper and caerulo-plasmin rose to normal levels. He died at 6 monthsweighing 2 * 92 kg.

Case 2. A boy was born at 38 weeks' gestation bycaesarean section for fetal distress; weight 3 *3 kg. Hewas the only child of unrelated healthy parents. In theneonatal period he had a wrinkled, flabby skin, abnormalfacies, and bilateral talipes. He smiled at 6 weeks butat 8 weeks had prolonged twitching of face and arms.Examination at this stage showed scanty, steely hair onthe scalp and curly eyelashes. Microscopical examina-

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Wheeler and Robertstion of the scalp hair showed pili torti. The hands had asingle palmar crease and the skin was overgrowing thenail folds. There was an umbilical hernia, bilateralundescended testes, and a marked, persistent napkinrash. Neurological examination showed hypotonia,poor head control, and frequent fits. The child hadseveral episodes of hypothermia. Hb 10 g/dl; whiteblood count, platelets, electrolytes, and serum calciumwere normal; blood urea 74 mg/100 ml, serum iron42 jug/100 ml, serum folate 2-3 ng/ml, serum copper4 ,ug/100 ml. No caeruloplasmin was detected. Urinewas sterile. Urinary amino acid chromatography wasnormal. Skull x-rays showed a few wormian bones.The long bones were normal at 2 months of age butlater became osteoporotic.

Treatment with anticonvulsants failed to control thefits. At 11 weeks of age he was given intramuscularcopper-EDTA 1 mg daily for a week. Serum copperthen rose to 47 ,ug/100 ml and caeruloplasmin to 43mg/100 ml. Further courses ofEDTA were necessary tomaintain the serum copper levels at the lower end of thenormal range (Table). In spite of this treatment therewas minimal improvement in the control of fits, feedingability, and temperature regulation. Neurologicalexamination showed no improvement. Tendon re-

flexes disappeared and marked muscle wasting develop-ed. At 7 months of age he had a large palpable bladder,dribbled urine, and had a urinary tract infection. Anintravenous urogram and expression cystogram showednormal kidneys and ureters, but there was massivebladder enlargement with two diverticula. Over thenext few months 2 large cysts grew from his gums causingfeeding difficulties (Fig 1). Soft cystic swellings appear-ed in the neck. He died aged 11 months from broncho-pneumonia.

Necropsy. External examination showed a maleinfant with blonde steely hair and blue eyes. There wasnarrowing of the skull with occipitofrontal elongation.There was a small umbilical hernia and the testes wereundescended. In the cranial cavity the dura and lepto-meninges were markedly thickened by fibrous tissuewith extensive deposits of underlying gelatinous mucoidmaterial. The brain weighed 520 g and showed

FIG. 1.-Case 2. Lobulated epulis of lower jaw. Hairnow blond and straight after 5 months of copper therapy.

atrophy of the white matter and dilatation of theventricular system. There was also atrophy of thecerebellum (Fig. 2). In the mouth there was a pedun-culated epulis on the left upper jaw and generalizedgingival hyperplasia. In the neck there was a 1 cm

aneurysm of the left external jugular vein just belowthe carotid bifurcation. There was a smaller aneurysm

on the right external jugular vein. The right externalcarotid artery showed aneurysmal dilatation above thebifurcation measuring 1 *5 cm in diameter.The lungs showed bilateral bronchopneumonic

consolidation. There was an emphysematous bullaat the apex of the left upper lobe and partial fissuring ofboth lower lobes. The thymus was reduced in size.The heart was normal. There was some thickening ofthe thoracic abdominal aorta. The stomach was

dilated and the pyloric canal was occluded by polypoid,

BLE

Case 2. Response to copper therapy.

Serum copper Serum caeruloplasmin TreatmentAge (~Lg/loo ml) (mg/100 ml) TreDtAn

(normal range 60-12) (normal range 20-44) (copper-EDTA)

8 w 4 nil11 w _ _ 1 mgx713w 47 4 315 w 63 11-7 1 mgx717w 37 5-1 mgx75 m 35 _ 1 mgx l06 m 73 10 2 2 mg weekly7 m 65 10*2 1 mgx7

7i m 107 13-5 2 mg weekly9 m 60 13-7

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Menkes's steely hair syndrome

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FIG. 2.-Case 2. Sagittal section through brain.

mucosal tumour 1 cm in diameter, which had partlyprolapsed into the first part of the duodenum. Theremainder of the intestines was normal. The liver,spleen, and pancreas were normal. Both kidneysweighed 25 g and showed no evidence of scarring.The ureters were normal. The bladder was markedlydistended and completely filled the abdominal cavity.There were several large diverticula in the bladder wallwith areas of petechial haemorrhage in the mucosa.The ureteric orifices appeared normal. The urethrawas removed intact and opened with scissors and noobstruction was found. Apart from a generalizedincrease in subcutaneous fat and associated musclewasting, no other abnormality was found.

Microscopical examination. The changes in the brainwere typical of Menkes's disease and have been describedbefore. The bladder diverticula were covered by a thinattenuated layer of smooth muscle, with areas of mucosalulceration. The antral polyp consisted of hyperplasticpyloric mucosa lying on a thickened muscularis mucosaecontinuous with the normal adjacent muscularis. Theappearances were consistent with repeated prolapse ofredundant antral mucosa to produce a polypoid lesion.The duodenal mucosa appeared normal. Sections ofthe carotid artery aneurysm showed subintimal oedemaand marked widening of the media with extensive lossof elastin (Fig 3). The remaining elastic fibres showedcurling and fragmentation. The jugular vein aneurysmsimilarly showed subintimal oedema and loss of theelastin in the media (Fig 4). There was no inflamma-tory cell infiltration.

Case 3. A male was born at term weighing 2 66 kg.Initially he was hypotonic and required tube feeding for3 weeks. At that time his unusual facies, low set ears,and soft occipital bones were noted. At 7 weeksconvulsions began which were not controlled by pheno-barbitone. He had scanty, steely hair, and eyelashes,

FIG. 3.-Case 2. Normal vessel wall on right andaneurysmal wall on left showing loss of elastin in the media

and subintimal oedema. (Elastin stain x 25.)

with pili torti, dolichocephaly, deeply wrinkled forehead,and loose folds of skin on the dorsum of the hands withthe nail folds overgrowing the nails. Episodes of hypo-thermia occurred, with a temperature of 33 * 9 °C on oneoccasion. Diagnosis of Menkes's syndrome was con-firmed by the following investigations: plasma copper3-8 tg/I100 ml, red cell copper 73 ug/100 ml. Plasmacaeruloplasmin not detectable; plasma zinc 58 tLg/1O0ml. Skull x-rays showed multiple wormian bones in theoccipital region. A skeletal survey at the age of 3months showed metaphyseal spurs at the lower ends ofthe femora. Other investigations: Hb 9 1g/dl; normalfilm and WBC; blood urea 45 mg/100 ml, blood sugar73 mg/100 ml; serum calcium normal; serum folate 3 * 6mg/100 ml, serum iron 15 jtg/100 ml. Initial bacterio-logical examination of urine was normal, and aminoacid chromatogram was also normal. At 4 monthsrecurrent urinary tract infections began and an intra-venous urogram showed that both kidneys were slightlyenlarged. The bladder was markedly sacculated. Acystogram showed a large bladder diverticulum lyingposteriorly with no ureteric reflex.At 4 months of age he was treated with intramuscular

copper-EDTA, which seemed to reduce the number offits and his appetite improved. Episodes of hypother-mia still occurred. He remained on anticonvulsanttherapy. Normal plasma levels of copper, zinc, andcaeruloplasmin were maintained by weekly copperinjections but there was no further neurological develop-ment. At 9 months he was extremely hypotonic, had nohead control, and did not smile or pay attention to hismother. He died aged 10 months after an episode ofprofound hypothermia (29 °C) unresponsive to slow re-warming.

Necropsy. External examination showed the featuresof Menkes's disease. In the cranial cavity the meningeswere thickened and there was associated cerebral atrophy

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Wheeler and Roberts

5 ,v .r,I..f . 14 :'. M.

FIG. 4.-ase 2. Wall ofjugular vein aneurysm. (Elastin stain x 90.)

(brain weight 380 g) with diffuse micropolygyria. Thelungs were acutely haemorrhagic and there were pleuraleffusions. The thymus was normal. The heart showeddilatation of the left ventricle but the coronary vesselswere normal. There was thickening of the aorta andits branches but the endothelial surface appeared to beintact. The stomach was normal. The small bowelwas dilated and in the colon there were punctate hae-morrhagic lesions in the mucosa. Fresh blood waspresent in the rectum. Liver, gallbladder, and spleenwere normal. The kidneys were normal and the ureterswere not dilated. The bladder was markedly dilatedand filled with urine and there was marked trabeculationof the wall with several small diverticula. The otherorgans were normal.

Microscopical examination. The brain showed thechanges previously described in Menkes's disease. Inthe colon there were foci of superficial mucosal necrosiswith focal haemorrhage associated with sludging ofblood in the mesenteric vein tributaries. The appear-ances were probably due to hypothermia. The aortashowed subintimal fibrosis and widening of the mediadue to deposition of basophilic ground substancebetween elastic fibres (Fig. 5).

DiscussionThere have been a number of pubJished reports

of patients with Menkes's syndrome from the USA

and Australia but none from Britain. The 3 casesreported here were seen at one hospital in the courseof one year. The families were not inter-relatedand the parents lived in different parts of Norfolk.

Urological abnormalities have not been reportedbefore. Urinary and blood urea are usually normal.Post-mortem reports in 12 previous cases (Menkeset al., 1962; Aguilar et al., 1966; Walker-Smithet al., 1973; Danks et al., 1972a) recorded no renalchanges except for one child with terminal pyelone-phritis. In our Case 1 there was ureteric reflux andhydronephrosis, in addition to a trabeculatedbladder. In the other 2 cases the trabeculaedbladder contained diverticula suggesting bladderneck or urethral obstruction. No organic obstruc-tion was found at post-mortem examination and aneurogenic bladder appears to be the likely cause,in view of the severe neurological defects.

All these infants received treatment with intra-muscular copper-EDTA and the extremely lowlevels of serum copper and caeruloplasmin rose tonormal or near normal levels. Doses of 170 jig/kgdaily for 7 days obtained a rapid biochemical re-sponse within 2 weeks. Further courses werenecessary, and 250 [ug/kg given weekly proved to besafe and satisfactory in maintaining the serum copperlevels. The use of an intramuscular preparation,

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Menkes's steely hair syndrome

FIG. 5.-Case 3. Intima and part of media of abdominal aorta. (H. and E. X 60.)

which could be given by a nurse at home, greatlyreduced the length of hospital admissions. Groverand Scrutton (1975) when treating a 4-week-oldbaby with intravenous copper sulphate found lowerdoses, such as 10 ,tg/kg per day, ineffective andincreased the dosage to 550-850 ,g/kg weekly individed doses. Dekaban and Steusing (1974) usedintravenous copper sulphate infusions 200-300 jig/kgtwice weekly to raise serum copper level and thenused subcutaneous copper sulphate in salineinfusionsfor maintanance. Whenthe defect in copper absorp-tion by the intestinal mucosa was shown by Dankset al. (1972b) it was hoped that parenteral copperwould benefit these children. Results have beenvery disappointing as assessed by failure of neuro-logical development and post-mortem findings ofgross cerebral degeneration, even in the babytreated from the age of 11 weeks until death at 11months (Case 2).The necropsy findings show several features of

interest. Changes in the brain have been welldescribed in previous reports though micropolygy-ria has not been associated with this syndrome.The marked trabeculation of the bladder and dilata-tion with diverticula has not been reported before inassociation with Menkes's syndrome. Since noorganic obstruction could be found in the lowerurinary tract, it is probable that there is disturbedinnervation ofthe bladder neck. The arterial changesin the second patient were severe with the develop-ment of aneurysm formation. In contrast toprevious reports (Danks et al., 1972a, b) there were

3

extensive changes in the elastic tissue of the media.In addition, the abnormal histological changes inthe veins leading to varix formation has been des-cribed for the first time. The duodenal and jejunalmucosa in Case 2 showed no abnormality of thevillous architecture. Special stains for copperfailed to show evidence of excess copper depositionin the absorptive cells of the duodenum or jejunum.This finding is at variance with the presence ofraised levels of copper in the duodenal mucosa ofother cases using atomic absorption spectrophoto-metry (Danks et al., 1973). In view of the dis-covery of high copper levels in the kidney, spleen,and pancreas of a fetus with Menkes's syndrome(Horn et al., 1975) these tissues were examinedfrom Cases 2 and 3. Using the rubeanic acidmethod, no excess could be shown. It is possiblethat the histological technique is insufficientlysensitive.The underlying defect in Menkes's syndrome

awaits clarification. In addition to the transportdefect in the intestinal mucosa, Danks et al. (1972b)postulated a defect in placental transfer of copper tothe fetus resulting in low levels at birth. Thisagrees with our observation of these 3 babies whohad abnormal facies or hypothermia in the firstweek of life. However, Horn et al., (1975) inDenmark have shown high levels of copper in theplacenta, kidney, spleen, and pancreas of a malefetus with Menkes's syndrome, while the hepaticconcentration was low. There does not appear tobe a defect in the ability of the liver to store copper

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274 Wheeler and Robertsgiven parenterally (Grover and Scrutton, 1975) andcaeruloplasmin is rapidly formed after the admini-stration of parenteral copper. It thus appears thatin utero certain tissues have an abnormal affinityfor maternal copper, causing a deficiency in the fetaland neonatal liver, skin, and brain. After birththe failure of copper transport through the intestinalmucosal cells, leading to an accumulation of copperin those cells and the conservation of normal copperlevels in the erythrocytes, even when serum levelsare very low, support this hypothesis. Moredetailed investigations are required of the bio-chemistry of absorption and transport of copper andthe serum concentrations of caeruloplasmin, caeru-loplasmin-copper, total copper, and noncaerulo-plasmin-copper (Scheinberg and Sternlieb, 1975).

We thank Dr. Delves of the Institute of Child Health,London for measurement of the copper levels and Drs.Quinton, R. D. Jones, and E. H. Back, who wereresponsible for the care of these patients.

REFERENCES

Aguilar, M. J., Chadwick, D. L., Okuyama, K., and Kamoshita, S.(1966). Kinky-hair disease. Journal of Neuropathology andExperimental Neurology, 25, 507.

Bucknall, W. E., Haslam, R. H. A., and Holtzman, B. A. (1973).Kinky-hair syndrome: response to copper therapy. Pediatrics,52, 653.

Danks, D. M., Campbell, P. E., Stevens, B. J. Mayne, V., andCartwright, E. (1972a). Menkes's kinky-hair syndrome.Pediatrics, 50, 188.

Danks, D. M., Stevens, B. J., Campbell, P. E., Gillespie, J. M.,Walker-Smith, J., Blomfield, J., and Turner, B. (1972b).Menkes' kinky-hair syndrome. Lancet. 1, 1100.

Danks, D. M., Cartwright, E., Stevens, B. J., and Townley, R. R. W.(1973). Menkes' kinky-hair disease-further definition of thedefect in copper transport. Science, 179, 1140.

Dekaban, A. S., and Steusing, J. K. (1974). Menkes' kinky-hairdisease treated with subcutaneous copper sulphate. Lancet,2, 1523.

Grover, W. D., and Scrutton, M. C. (1975). Copper infusion ther-apy in trichopoliodystrophy. Journal of Pediatrics, 86, 216.

Horn, N., Mikkelsen, M., Heydorn, K., Damsgaard, E., and Tyg-strup, I. (1975). Copper and steely hair. Lancet, 1, 1236.

Menkes, J. H., Alter, M., Steigleder, G. K., Weakley, D. R., andSung, J. H. (1962). A sex-linked recessive disorder withretardation of growth, peculiar hair, and focal cerebral andcerebellar degeneration. Pediatrics, 29, 764.

Scheinberg, I. H., and Sternlieb, I. (1975). Steely-hair syndromeand copper. New Englandjournal of Medicine, 292, 1192.

Walker-Smith, J. A., Turner, B., Bloomfield, J., and Wise, G. (1973).Therapeutic implications of copper deficiency in Menkes'steely-hair syndrome. Archives of Disease in Childhood, 48, 958.

Correspondence to Dr. P. F. Roberts, Norfolk andNorwich Hospital, Norwich NR1 3SR.

AddendumWe are now treating another baby with Menkes's

syndrome, the sib ofthe first patient, who was diagnosedin the neonatal period.

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Menkes's steely hair syndrome.

E M Wheeler and P F Roberts

doi: 10.1136/adc.51.4.2691976 51: 269-274 Arch Dis Child 

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