Pictorial Essay 33

Intrapartum Acquired Skull Fracture as First Sign of Menkes Disease Intrapartal erworbene Schädelfraktur als erstes Zeichen eines MenkesSyndroms

Authors

P. Freidl1, L. Rauter2, R. Moser2, R. Kerbl2

Affiliations

1



2

Key words ▶ Menkes disease ● ▶ copper transport disorder ● ▶ skull fracture ● ▶ neurodegeneration ● ▶ pili torti ●

Case report

Bibliography DOI  http://dx.doi.org/ 10.1055/s-0033-1363246 Published online: January 21, 2014 Klin Padiatr 2015; 227: 33–34 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0300-8630 Correspondence Dr. Patrick Freidl Internal Medicine LKH Voitsberg C. v. Hötzendorfstrasse 31 8570 Voitsberg Austria Tel.:  + 43/314/22012 878 Fax:  + 43/314/22012 523 [email protected]



Intrapartum acquired skull fracture as first sign of Menkes disease

The patient is a white, male firstborn of a 29-yearold woman. He was born in the 39th week of gestation (38 + 4) after an unremarkable pregnancy, birth weight was 2 790 g. Due to prolonged labour and the presence of meconium-stained amniotic fluid, Caesarean section was performed. The operative delivery proved to be difficult because the child’s head was already deep down in the birth canal. The first examination of the newborn showed hypotonia and compromised spontaneous breathing. The Apgar score was 6, 9 and 9 after 1, 5 and 10 min, respectively. Immediately after birth crepitation of the cranium was noticed in the right occipital region. On palpation a contour disruption in this area accompanied by hematoma was noticed, pointing towards skull fracture. Internal and neurological status were both normal inconspicuous. The patient was admitted to the neonatal intensive care unit (NICU). Computed tomography as well as ultrasound imaging of the skull and brain showed an open skull fracture in the right parietooccipital region with intracerebral bleeding of ▶  Fig. 1). Fol15 mm in its maximum diameter ( ● lowing neurosurgical consultation it was decided to refrain from surgical treatment, and antibiotic as well as analgesic therapy were administered. During next days, the patient developed jaundice with bilirubin values up to 19.7 mg/dl, requiring intermittent phototherapy. The patient recovered from his injury quickly, and by the end of the third postnatal week could be discharged with normal internal and neurological status. Also EEG was normal at this time. During next weeks, several developmental assessments were performed. The patient showed a development delay, reduced head control and general muscular hypotonia especially of

the trunk. As a consequence, physiotherapy was initiated. At the age of 5 months, the patient developed seizures and was again admitted to the hospital. Now EEG investigation revealed a hypsarrhythmia-like pattern, most pronounced over the right parietooccipital region, however also anomalies over the left cerebral side. Magnetic resonance tomography of the head showed loss of parenchyma in the region of the previous skull fracture. In addition, confluent finger-shaped signal alterations were seen in the left white matter, as well as focal alterations of the basal ganglia on both sides. These results were interpreted as posttraumatic lesions. Antiepileptic therapy with levetiracetam and topiramate was established and periodic clinical and EEG controls were carried out, both pointing towards severely compromised neurological sequelae. At the age of 7 months, the patient developed symptoms of an urinary tract infection. Ultrasound imaging of the urinary tract showed a trabecular urinary bladder and multiple diverticula. To protect the infant from further UTIs, antibiotic prophylaxis with cefaclor was initiated. Nevertheless, the patient suffered from recurrent urinary tract infections during next weeks. At the age of 8 months, circumcision was performed and a suprapupic catheter was implanted to release the urinary tract. By 10 months of life, the boy’s scalp hair attracted attention. Due to the progress of hair growth, the lustreless, wiry and hard to comb hair became ▶  Fig. 2). Microscopic striking at this time ( ● examination was carried out, and depigmented and twisted hair corresponding to “pili torti” became apparent (Fig. 3 – online). Based on this new insight, the tentative diagnosis of a Menkes kinky hair syndrome was made and pursuing laboratory tests were prompted. The results showed a significantly reduced copper level of 11 µg/dl

Freidl P et al. Intrapartum Acquired Skull Fracture …  Klin Padiatr 2015; 227: 33–34

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Schlüsselwörter ▶ Menkes-Syndrom ● ▶ Kupfertransportstörung ● ▶ Schädelfraktur ● ▶ Neurodegeneration ● ▶ Pili torti ●

 Internal Medicine, LKH Voitsberg, Voitsberg, Austria  Department of Pediatrics and Adolescent Medicine, LKH Leoben, Austria

Fig. 1  3D reconstruction of the skull fracture parietooccipital right.

Fig. 2  Depigmented and lustreless kinky hair of the patient.

(normal values between 50 and 100 µg/dl), as well as a very low caeruloplasmin of 0.047 g/l (normal values between 0.220 and 0.605 g/l). As a consequence of the diagnosis Menkes Disease, the pathological findings in cerebral magnetic resonance tomography were at least in part now interpreted as degenerative changes in the course of Menkes disease rather than as trauma-induced alterations. Finally, also genetic testing confirmed the suspected diagnosis. Parenteral copper-histidine administration was initiated as therapeutic measure, but unfortunately the symptoms are progressive and the patient’s prognosis appears to be very bad.

Discussion



John Menkes first described the Menkes kinky hair syndrome as an X-linked disorder with progressive neurodegeneration and connective tissue dysfunction [6]. In Europe, the incidence of this extremely rare disease is about 1 in 250 000 births [7]. The disease is caused by a disorder of copper transport which is due to different mutations in the ATP7A gene encoding for a coppertransporting ATPase. The result of this mutation is an accumulation of copper in the cytosol of affected cells. In intestinal cells it results in an absorption failure leading to copper deficiency of the body. Furthermore, the blood-brain barrier and the chorioid plexus are affected, and copper is not transported to the neurons [2]. As a consequence, there is decreased activity of several copper-dependent enzymes leading to different clinical features. In the neonatal period some patients present with prolonged jaundice, hypothermia and hypoglycaemia. Up to an age of 3–4 months, psychomotor development seems to be normal. After this period patients expose development delay, hypotonia and most of them develop therapy-resistant seizures. There is a predisposition to urinary tract infections caused by diverticula of the bladder, usually not requiring release by a suprapubic catheter. Furthermore, arterial abnormalities and bone changes (such as osteoporosis) are quite common. The skin is lax and lacking of pigmentation. The most striking feature however is the abnormal depigmented and lustreless hair that feels like

Freidl P et al. Intrapartum Acquired Skull Fracture …  Klin Padiatr 2015; 227: 33–34

steel wool and shows a twisted hair shaft in microscopy (pili torti) [5, 8]. Spontaneous fractures often occur due to osteoporosis, but to date there is only one published report of a congenital skull fracture in Menkes disease [9]. The diagnosis of classical Menkes disease is based on the clinical features and the low serum levels of copper and caeruloplasmin [5]. However, since these levels are also low in healthy newborns, the markers are unreliable predictors in the neonatal period. Other neurochemical investigations may be helpful in the neonatal period. For example, the ratio of dihydroxyphenylacetic acid and dihydroxyphenolglycol is significantly elevated in patients with Menkes disease [3]. Beside laboratory findings, there are several radiological changes, and magnetic resonance imaging commonly shows severe brain atrophy with subdural effusion and hematomas together with aneurysmal dilatation and stenosis of arteries [5]. Finally, the molecular defect in ATP7A confirms the diagnosis [8]. At present, the only treatment option for patients with Menkes disease is parenteral copper-histidine administration [4]. Other therapeutic trials like in utero copper treatment or gene therapy are still experimental and require further research [1, 2]. The prognosis of Menkes disease is poor, leading to death in early childhood in its severe form. It is very important to start copperhistidine supplementation as soon as possible, since only early intervention may modify disease progression substantially. However, even in case of early onset the treatment is unable to cure the disease itself or to improve already acquired sequelae [5, 8].

Conclusions



The present case demonstrates that clinicians should also consider Menkes disease in newborns with bone fractures, especially if lacking an adequate trauma. Such an early diagnosis, followed by immediate onset of copper-histidine therapy, may improve the outcome in individual patients.

Conflict of interest: The authors have no conflict of interest to disclose. References

1 Donsante A, Yi L, Zerfas PM. ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model. Mol Ther 2011; 19: 2114–2123 2 Haddad MR, Macri CJ, Holmes CS et al. In utero copper treatment for Menkes disease associated with a severe ATP7A mutation. Mol Genet Metab 2012; 107: 222–228 3 Kaler SG, Holmes CS, Goldstein DS et al. Neonatal diagnosis and treatment of Menkes disease. N Engl J Med 2008; 358: 605–614 4 Kodama H, Fujisawa C, Bhadhprasti W. Inherited copper transport disorders: biochemical mechanisms, diagnosis and treatment. Curr Drug Metab 2012; 13: 237–250 5 Kodama H, Murata Y, Kobayashi M. Clinical manifestations and treatment of Menkes disease and its variants. Pediatr Int 1999; 41: 423–429 6 Menkes JH, Alte M, Steigleder GK et al. A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 1962; 29: 764–769 7 Tønnesen T, Kleijer WJ, Horn N. Incidence of Menkes disease. Hum Genet 1991; 86: 408–410 8 Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet 2010; 18: 511–518 9 Ubhi T, Reece A, Craig A. Congenital skull fracture as a presentation of Menkes disease. Dev Med Child Neurol 2000; 42: 347–348

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Intrapartum acquired skull fracture as first sign of Menkes disease.

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