Arch Pediatr Crit Care Search

CLOSE


Arch Pediatr Crit Care > Volume 2(1); 2024 > Article
Song, Yu, and Jhang: Internal carotid artery aneurysms in a 22-month-old boy with Menkes disease: a case report

Abstract

Menkes disease (MD) is an X-linked recessive multisystem disorder of copper metabolism. Patients with MD present a wide range of manifestations including kinky hair, dysmorphic faces, osteoporosis, hypothermia, hypoglycemia, feeding difficulties, autonomic dysfunctions, seizures, neurological deterioration, and developmental delay. Patients usually exhibit a progressive clinical course with various adverse events and die within 3 years. Although the early diagnosis is quite challenging because of the subtle clinical presentation, prompt management is crucial to reduce morbidity and mortality. Here, we present a rare case of internal carotid artery aneurysms in a 22-month-old boy with MD. It was found incidentally during a trial of sonography-guided central venous catheter insertion.

INTRODUCTION

Menkes disease (MD) is a fatal multisystem disorder associated with genetically impaired copper metabolism. Mutations in the ATP7A gene result in disturbances of ATP7A functions, including control of copper export, intracellular copper trafficking, and delivery to copper-dependent enzymes [1-4]. Consequently, MD leads to characteristic clinical phenotypes such as progressive neurodegeneration and marked connective tissue dysfunction. Furthermore, patients severely affected by MD experience multiple complications and eventually die, usually before the third year of life [5]. In this report, we describe rare vascular complications in a child with MD. The requirements for approval of the Institutional Review Board of Asan Medical Center (No. 2024-0727) and informed consent were waived.

CASE REPORT

A 22-month-old boy was admitted to Asan Medical Center Children’s Hospital for a regular nephrostomy tube change. His growth parameters showed a weight of 10.0 kg (5th to 10th percentile) and length 78.7 cm (<3rd percentile). His medical history was significant for MD. At the age of 60 days, he presented with seizures accompanied by features such as kinky hair, hypotonia, and osteoporosis. Subsequent laboratory findings revealed a serum copper level of 3 µg/dL and ceruloplasmin level of <3.0 dL. Molecular genetic testing included a whole-exome sequencing study, which identified an ATP7A mutation (c.2323G>T [p.Gly775Ter]), leading to the diagnosis of MD. He was transferred to our hospital to receive copper histidine supplementation at age 3 months. Initial brain magnetic resonance imaging and head angiography were compatible with MD, showing symmetric diffuse increased signal intensity of the bilateral basal ganglia (especially globus pallidus), abnormal gyral swelling with increased T2/fluid-attenuated inversion recovery signal intensity of the bilateral frontal-parietal-temporal lobes, and tortuous intracranial arteries. During follow-up, he developed progressively intractable seizures, multiple fractures, and large bladder diverticula, complicated by obstructive uropathy with obstruction of both ureteropelvic junctions. The management of these complications included left percutaneous nephrostomy (PCN) at age 14 months. Tracheostomy was also performed at age 14 months due to combined severe laryngomalacia and recurrent apnea associated with seizures. Subsequently, the left PCN tube was regularly changed every 4 months. Peripheral intravenous line access was attempted after admission for the second change of the PCN tube. However, due to tortuosity of the vessels, it was difficult to place a proper peripheral intravenous line, and multiple trials resulted in several long bone fractures due to severe osteoporosis. Consequently, it was decided to insert a central line. Before insertion of a sonography-guided central venous catheter into the internal jugular vein, ultrasound evaluation of the neck was performed, which incidentally detected a huge saccular hypoechoic lesion (2.4 cm×2.8 cm) in the right neck (Fig. 1). A subsequent neck computed tomography scan with angiography showed that tortuous bilateral carotid arteries and markedly dilated vascular aneurysms in the bilateral neck were communicating with the internal carotid arteries (ICAs) (Fig. 2). Concerned about sudden rupture or thrombosis of the ICAs, we consulted an interventional radiologist and a vascular surgeon. However, due to the patient’s small body and vessel size and limited life expectancy, aggressive intervention or surgical management was refused. We decided to provide supportive care and regular follow-up without any other intervention. His PCN change was performed smoothly on hospital day 6. Due to the recurrent vascular access problems and for the regular PCN change procedures, a permanent central venous Broviac catheter was inserted and he was discharged. Five months later, he presented to the emergency room with a chief complaint of color change and enlargement of both sides of the neck. Point-of-care ultrasound showed that both ICA aneurysms were markedly enlarged and measured up to 10 cm on the right side and 6 cm on the left side with an internal echogenic swirling pattern of fluid movement. Blood testing revealed a hemoglobin level of 5.0 g/dL, which was significantly decreased from 8.9 g/dL at the time of his third regular admission for PCN change 1 month earlier. Since his family understood his desperate situation and that it could not be managed, they agreed to a “do-not-resuscitate” status. He was then transfused with packed red blood cells and discharged. Several days later, his mother reported his death, likely due to upper airway compression by the bilateral enlarged ICA aneurysms.

DISCUSSION

MD is a copper metabolism disorder secondary to a mutation in the ATP7A gene located on Xq13.3. This gene encodes ATP7A, a transmembrane active copper transporter protein [3,6]. A deleterious mutation in this gene results in generalized copper deficiency. Copper is required for the biochemical functions of several enzymes, including those involved in cellular respiration (cytochrome C oxidase), neurotransmitter biosynthesis (dopamine beta-hydroxylase), cross-linking of elastin and collagen (lysyl oxidase [LO]), melanin production (tyrosinase) and free-radical scavenging (superoxide dismutase) [1,2,5,7]. As these enzymes are abundantly expressed, their dysfunction characteristically manifests with multisystemic symptoms. However, until age 2 months, there are often nonspecific symptoms such as cephalohematoma, hypoglycemia, hypothermia, and prolonged jaundice, which frequently delay the diagnosis [5]. Neurologic manifestations such as seizures and developmental delay usually present within 2 to 3 months. These characteristic symptoms progress following different stages [8]. In addition, connective tissue dysfunction, skeletal problems, and urological complications are very common including tortuous blood vessels, osteopenia, multiple fractures, bony deformities, and bladder diverticula with bladder outflow obstruction, renal rupture, cryptorchidism, urinary tract infections, and vesicoureteral reflux [9-12]. This patient presented with a classic course of MD.
In terms of vascular complications in MD, the pathophysiology is mainly explained by decreased LO function. LO oxidizes lysyl and hydroxylysyl residues in collagen and elastin, as the first step for collagen cross-linkage and stabilization of these extracellular matrix proteins, an essential process for connective tissue maturation [5,8,13]. Dysfunction of LO leads to poor integrity of the vessel walls contributing to the tortuosity of vessels, kinking, ectasia, or aneurysms. There are several case reports involving aneurysms in various vessels, including the brachial artery, lumbar artery, iliac artery, splenic and hepatic artery, gastric artery, and internal jugular vein, usually detected incidentally and leading to complications including death [14-19]. Although embolization and surgical control of bleeding with retroperitoneal hematoma evacuation were rarely performed, most cases were not aggressively managed but given supportive care considering the patients’ age, size, underlying disease, and limited life expectancy.
To our best knowledge, our case of ICA aneurysms in a 22-month-old patient with MD, which resulted in death after aggressive intervention was deemed futile, is the first reported in Korea. Due to the rarity of this disease and nonspecific presenting symptoms, early diagnosis is often challenging. However, to avoid irreversible neurodegenerative progress and reduce morbidity, prompt recognition and proper intervention are needed. A multidisciplinary approach and interprofessional consultations that include genetic counseling are also crucial for an optimal management plan and control of complications [13].
We reported the first case of ICA aneurysms in a 22-month-old patient with MD in Korea. The aneurysms were associated with impaired vessel integrity caused by underlying copper metabolism dysfunction. As MD is a multisystem disease, it is important to know the various characteristic manifestations for early diagnosis and proper management. Affected patients can suffer from a wide range of morbidities, requiring a meticulous evaluation and multidisciplinary approach.

ARTICLE INFORMATION

CONFLICT OF INTEREST
Won Kyoung Jhang is an editor-in-chief of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
AUTHOR CONTRIBUTIONS
Conceptualization: WKJ, JY. Visualization: HYS. Project administration: HYS. Writing - original draft: HYS, WKJ. Writing - review & editing: WKJ.

Fig. 1.
Carotid ultrasonography: (A) B-mode and (B) color Doppler images show bilateral saccular hypoechoic lesions in the neck, indicating aneurysmal dilatation of the internal carotid arteries.
apcc-2024-00073f1.jpg
Fig. 2.
Coronal views of the neck: (A) volume rendering and (B) maximum intensity projection computed tomography angiography images show tortuous bilateral internal carotid arteries and markedly dilated vascular structures (arrows) in the bilateral neck (right > left), communicating with the internal carotid arteries. The right-side lesion measures 3.4 cm × 2.8 cm; the left-side lesion measures 2.9 cm × 1.9 cm.
apcc-2024-00073f2.jpg

REFERENCES

1. de Bie P, Muller P, Wijmenga C, Klomp LW. Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes. J Med Genet 2007;44:673-88.
crossref pmid pmc
2. Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY. Function and regulation of human copper-transporting ATPases. Physiol Rev 2007;87:1011-46.
crossref pmid
3. Kodama H, Fujisawa C, Bhadhprasit W. Inherited copper transport disorders: biochemical mechanisms, diagnosis, and treatment. Curr Drug Metab 2012;13:237-50.
crossref pmid pmc
4. Skjørringe T, Amstrup Pedersen P, Salling Thorborg S, Nissen P, Gourdon P, Møller LB. Characterization of ATP7A missense mutants suggests a correlation between intracellular trafficking and severity of Menkes disease. Sci Rep 2017;7:757.
crossref pmid pmc
5. Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet 2010;18:511-8.
crossref pmid pmc pdf
6. Schmidt K, Ralle M, Schaffer T, Jayakanthan S, Bari B, Muchenditsi A, et al. ATP7A and ATP7B copper transporters have distinct functions in the regulation of neuronal dopamine-β-hydroxylase. J Biol Chem 2018;293:20085-98.
crossref pmid pmc
7. Schlief ML, West T, Craig AM, Holtzman DM, Gitlin JD. Role of the Menkes copper-transporting ATPase in NMDA receptor-mediated neuronal toxicity. Proc Natl Acad Sci U S A 2006;103:14919-24.
crossref pmid pmc
8. Więcek S, Paprocka J. Disorders of copper metabolism in children: a problem too rarely recognized. Metabolites 2024;14:38.
crossref pmid pmc
9. Jacobs DS, Smith AS, Finelli DA, Lanzieri CF, Wiznitzer M. Menkes kinky hair disease: characteristic MR angiographic findings. AJNR Am J Neuroradiol 1993;14:1160-3.
pmid pmc
10. Eradi B, Rajimwale A. Excision of massive bladder diverticula in Menkes disease. J Pediatr Urol 2010;6:312-4.
crossref pmid
11. Kim D, Choi J, Han KM, Lee BH, Choi JH, Yoo HW, et al. Impaired osteogenesis in Menkes disease-derived induced pluripotent stem cells. Stem Cell Res Ther 2015;6:160.
crossref pmid pmc pdf
12. Kim MY, Kim JH, Cho MH, Choi YH, Kim SH, Im YJ, et al. Urological problems in patients with Menkes disease. J Korean Med Sci 2018;34:e4.
crossref pmid pmc pdf
13. Ojha R, Prasad AN. Menkes disease: what a multidisciplinary approach can do. J Multidiscip Healthc 2016;9:371-85.
crossref pmid pmc
14. Adaletli I, Omeroglu A, Kurugoglu S, Elicevik M, Cantasdemir M, Numan F. Lumbar and iliac artery aneurysms in Menkes’ disease: endovascular cover stent treatment of the lumbar artery aneurysm. Pediatr Radiol 2005;35:1006-9.
crossref pmid pdf
15. Godwin SC, Shawker T, Chang B, Kaler SG. Brachial artery aneurysms in Menkes disease. J Pediatr 2006;149:412-5.
crossref pmid
16. Olivieri JF, Jeyakumar A, Shivaram GM, Koo KS, Monroe EJ. Emergent embolization of a ruptured splenic artery aneurysm complicating Menkes disease. Radiol Case Rep 2018;13:1267-70.
crossref pmid pmc
17. Peng CH, Hsu CH, Wang NL, Lee HC, Lin SP, Chan WT, et al. Spontaneous retroperitoneal hemorrhage in Menkes disease: a rare case report. Medicine (Baltimore) 2018;97:e9869.
crossref pmid pmc
18. Ng R, Eliezer D, Vilain R, Kamien B, Deshpande AV. Fatal exsanguination following rupture of an iliac artery aneurysm in an infant with Menkes disease. Pediatr Dev Pathol 2019;22:486-91.
crossref pmid pdf
19. Kaplan J, Wagner R, White LE, Pederson WC. Recurrent brachial artery aneurysm repair in a child managed with Gore-Tex conduit reinforcement. J Vasc Surg Cases Innov Tech 2021;7:295-7.
crossref pmid pmc
TOOLS
Share :
Facebook Twitter Linked In Google+ Line it
METRICS Graph View
  • 0 Crossref
  •   Scopus
  • 223 View
  • 2 Download
Related articles in Chronobiology Med


ABOUT
ARTICLE CATEGORY

Browse all articles >

BROWSE ARTICLES
EDITORIAL POLICIES
FOR CONTRIBUTORS
Editorial Office
Room 214, 14, Toegye-ro 49-gil, Jung-gu, Seoul 04559, Korea
Tel: +82-2-744-7888    E-mail: office@apccjournal.org                

Copyright © 2024 by Korean Society of Pediatric Critical Care Medicine.

Developed in M2PI

Close layer
prev next