Gorham-Stout disease of the craniovertebral junction causing basilar impression and Chiari malformation type I: illustrative case

Abstract

BACKGROUND

Gorham-Stout disease (GSD) is an extremely rare osteolytic disorder characterized by resorption of skeletal bone due to aggressive, nonneoplastic lymphatic proliferation.

OBSERVATIONS

The authors report the 14th case of GSD of the craniovertebral junction (CVJ), which resulted in cranial settling, basilar impression, and an acquired Chiari malformation type I (CM-I) in a pediatric patient. A 4-year-old girl initially presented with recurrent symptoms of pharyngitis, bacteremia, and neck pain. She continued experiencing waxing and waning symptoms of fever and neck pain that gradually worsened. At 12 years old, imaging revealed progressively worsening osteolytic changes with bone marrow edema involving the CVJ and subaxial cervical spine with progressive cranial settling, basilar impression, and 14 mm of tonsillar herniation, consistent with an acquired CM-I. She underwent a frontal bone biopsy, which confirmed the diagnosis of GSD. Treatment with sirolimus and bisphosphonates stabilized the osteolysis.

LESSONS

GSD represents a rare group of osteolytic bone disorders with a highly variable clinical course. A high index of suspicion is warranted, as diagnosis can be challenging. Early referral to a specialized center is key, as treatment is directed toward symptomatic management and a multidisciplinary team approach. GSD is another syndrome associated with CVJ bony changes and tonsillar herniation.

https://thejns.org/doi/10.3171/CASE24298

Gorham-Stout disease (GSD), also known as “vanishing bone disease,” “idiopathic osteolysis,” or “phantom bone disease,” is a rare osteolytic disorder characterized by a slow and insidious resorption of skeletal bone.^1–3 In GSD, endothelial proliferation of lymphatic vasculature causes resorption of the osseous matrix, which composes the functional unit of both cancellous and compact bone.³ Although this disease was first described in the scientific literature in 1838, its etiology remains unclear.⁴

Typically, GSD affects maxillofacial bones and bones in the upper extremities, shoulder, and pelvis. Involvement of the craniovertebral junction (CVJ) is extremely rare and signifies a poorer prognosis due to cervical instability, basilar impression, and cerebrospinal fluid (CSF) leakage, with patients experiencing neurological impairment due to brainstem compression and/or recurrent meningitis.⁵

Herein, we present the case of a 12-year-old girl with GSD of the CVJ and calvaria who initially presented at 4 years of age with recurrent pharyngitis with bacteremia, neck pain, and headaches. The patient was later diagnosed with GSD after a left frontal bone biopsy was performed, and treatment with bisphosphonate and sirolimus was initiated. This is the 14th published case of pediatric GSD of the CVJ resulting in basilar impression and Chiari malformation type I (CM-I).

Illustrative Case

A 4-year-old girl initially presented with recurrent symptoms of streptococcal pharyngitis with neck pain and headaches. These symptoms were associated with an increase in the prominence of a facial hemangioma over the left periorbital and forehead region. The patient was given intravenous antibiotics over several hospitalizations. The initial hypothesis theorized that the patient’s vascular malformation was serving as a nidus of infection, causing exacerbation of both the facial hemangioma during illness and bacteremia. During one of these hospitalizations, she developed torticollis, which prompted computed tomography (CT) and magnetic resonance imaging (MRI) of the cervical spine. CT revealed rotatory subluxation of C1 over C2 suspected to be from inflammation in the parapharyngeal tissues (Griesel syndrome; Fig. 1A and B). In addition, MRI revealed a CM-I with 14 mm of tonsillar herniation (Fig. 1C and D). The patient was initiated on oral antibiotics and muscle relaxants for Griesel syndrome, and her torticollis improved. As the patient had only mild Valsalva-induced headaches and nonfocal findings on neurological evaluation, she was followed serially in the neurosurgery clinic for the CM-I. By 7 years old, osteolytic changes were observed at the CVJ, specifically in the clivus, occipital condyles, and C1. This led to cranial settling (Fig. 1E–H). Because of these imaging findings and recurrent streptococcus pharyngitis, she was re-evaluated by the infectious disease, immunology, and genetics teams and underwent an extensive workup for congenital/acquired immunodeficiency and other rare genetic syndromes. Her immunology workup was unremarkable, and the genetic workup also revealed no clinically significant chromosomal microdeletions or duplications. Furthermore, the hematological workup was also negative.

FIG. 1.

Initial presentation parasagittal (A) and axial (B) CT demonstrating rotatory subluxation of C1 on C2 from Griesel syndrome when the patient was 4 years old. Sagittal T2-weighted MRI (C and D) demonstrating the CM-I and tonsillar descent of 14 mm. Midsagittal (E) and parasagittal (F and G) CT demonstrating early osteolytic changes in the clivus, occipital condyle (OC), and C1 (arrows) when the patient was 7 years old. Sagittal T2-weighted MRI (H) revealed slight worsening of the tonsillar descent. Dashed lines (D and H) represent the McRae line, which marks the boundary of the foramen magnum from the basion to the opisthion.

The patient’s headaches and neck pain continued to gradually worsen by the age of 10 years. This led to multiple emergency department visits due to complaints of worsening neck pain and fever with elevated inflammatory markers (C-reactive protein and erythrocyte sedimentation rate). Her infectious workup was negative. However, MRI of the cervical spine revealed vertebral body contrast enhancement from C1 to C4, and CT demonstrated worsening osteolytic changes at the clivus and occipital condyles (Fig. 2A–D), resulting in progressive cranial settling, basilar impression, and fusion of the occipital condyles with C1. Radiographs and CT of the head revealed osteolytic changes in the skull, skull base, and facial bones (Fig. 2E–G). With a bacterial infection ruled out after a lack of improvement with antibiotics, these imaging findings became concerning for GSD. Subsequently, she was maintained in a Miami J collar for concerns of cervical instability. A left frontal skull biopsy was performed to confirm the diagnosis of GSD.

FIG. 2.

Follow-up imaging when the patient was 10 years old. Midsagittal (A) and parasagittal (B and C) CT demonstrating progressive osteolytic changes in the clivus, OC, and C1 (arrows) now with fusion of the OC to C1. Sagittal MRI (D) of the cervical spine with gadolinium contrast demonstrating worsening of caudal tonsillar descent and progressive bone marrow changes with contrast enhancement involving the CVJ and C1–C4 vertebral bodies (arrow). Note the McRae line (dashed line). Radiograph (E) and bone-window CT images (F) of the skull and skull base (G) demonstrating extensive osteolytic changes of the calvaria, facial bones, and skull. The overall radiological findings were considered diagnostic for GSD.

A bone biopsy was performed with CT Stealth guidance (Medtronic Inc.), targeting a small area of osteolysis in the left frontal bone. Histopathological analysis of the biopsy specimen revealed areas of abnormal thin-walled vessels, with some sections showing many luminal cross-sections of thin-walled vessels interspersed between bony trabeculae, beyond what would be expected in normal bone. The endothelial cells were cytologically bland and were highlighted with CD34 and CD31 immunohistochemical stains. Similarly, a D2-40 immunohistochemical stain highlighted most of the vessels, supporting the possibility of lymphatic differentiation (Fig.3). While the histological feature of this lesion was not specific, given the clinical and radiographic findings, it was thought to be most consistent with an osteolytic angioproliferative process like GSD.

FIG. 3.

Pathology of the skull bone biopsy. A: Hematoxylin and eosin staining revealed a fragment of bone with proliferation of thin-walled vessels between bony trabeculae with cytologically bland nuclei. B: CD31 immunohistochemical staining highlighted the small, endothelial-lined vessels within the angioproliferative lesions. Original magnification ×200 (A) and ×400 (B).

Subsequently, the patient was initiated on treatment with bisphosphonate and sirolimus. However, due to concerns for pain-related side effects, the bisphosphonate infusions were halted after 1 round of treatment, and the patient was started on vitamin D and calcium supplements. Furthermore, her sirolimus treatment was discontinued after a 7-month course due to frequent infections (sinusitis, pharyngitis, otitis media, and COVID pneumonia) and the family’s preference for conservative management with close observation, given her stable clinical examination and stable radiological findings on initial follow-up.

At 13 years old and the last follow-up to date, cervical spine CT and MRI were concerning for continued osteolysis of the upper cervical spine vertebrae with new disruption of the joints at C1–2, C2–3, and C3–4 bilaterally, causing anterolisthesis, worsening kyphosis, and increased tonsillar descent and brainstem compression at the CVJ (Fig. 4). Clinically, however, the patient continued to do well, with slight interval worsening of her mild Valsalva-induced headaches but an otherwise stable neurological examination. Following multidisciplinary discussions, her parents were advised to resume treatment with sirolimus and bisphosphonates, and treatment was prescribed. Control of the underlying osteolytic disease process was deemed necessary prior to any consideration of surgical intervention for decompression and stabilization of the CVJ and upper cervical spine.

FIG. 4.

Follow-up Imaging when the patient was 13 years old. Midsagittal (A) and parasagittal (B and C) CT demonstrating progressive osteolytic changes in the clivus, OC, and C1–4 (arrows) now with fusion of the OC to C1 and progressive joint disruption at C1–4. Lateral radiograph (D) of the cervical spine demonstrating kyphosis. Sagittal T2-weighted MRI (E) of the cervical spine showing progressive loss of normal cervical lordosis and worsening tonsillar descent, now 22 mm. Dashed line represents the McRae line. There is also an increase in the high T2 signal intensity corresponding to an increase in bone marrow edema now extending to C6. The involvement of the facet joints and emerging anterolisthesis is concerning for cervical instability.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

GSD, also known as vanishing bone disease, idiopathic osteolysis, or phantom bone disease, is a rare condition characterized by intraosseous proliferation of endothelial-lined lymphatic vessels, resulting in progressive osteolysis and destruction of skeletal bone.^1–3 These osteolytic lesions are not associated with new bone formation or periosteal reaction, distinguishing GSD from other forms of osteolytic disorders caused by inflammation or malignancy.^6,7

GSD was first described by Jackson in 1838, and the association of GSD with hemangiomatosis was later well detailed in the seminal paper by Gorham and Stout in 1955.⁸ Despite the disease’s early description, however, its exact etiology remains to be elucidated.⁹ The proposed pathological process leading to osteolytic destruction of bone is an aggressive nonneoplastic proliferation of vascular and lymphatic vessels, which leads to the replacement of the osseous matrix with a hypervascular, fibrous, and angiomatous tissue.¹ The stimulus leading to this irregular lymphatic vessel proliferation and osteolysis remains speculative, and several theories have been hypothesized.⁹ Most prominent theories include alterations in local growth factor levels, changes in structural features with unusually wide thin-walled vessels resulting in stasis of blood flow, and the possible role of osteoclasts and interleukin-6 (IL-6) in the bone resorption process.^10–13 Because of the rarity of this condition, descriptions of its epidemiology, clinical presentation, radiological appearance, and appropriate management are limited to case reports and small case series.

GSD can involve any part of the skeleton in the body, but has a predilection to bones in the pelvis, humerus, femur, and maxillofacial structures.^14,15 Skull base and CVJ involvement is rare, with around 30 cases of GSD involving the CVJ reported so far.¹⁶ Skull base involvement tends to affect multiple cranial bones but is usually centered on the petrous and mastoid temporal bones in most cases.¹⁶ When the lesion extends posterior to the temporal bones and involves the CVJ, cervical instability with platybasia, basilar impression, and acquired Chiari malformation can result (Fig. 2). Involvement of the spine and CVJ is associated with a poor prognosis given the risks of neurological compromise from spinal and CVJ instability and brainstem compression.^16,17

Epidemiologically, most cases of GSD occur in children and adults younger than 40 years of age, with a slight male predilection.^1,16 The disease appears to be nonhereditary, with no attributable genetic mutations identified to date.¹⁶ Clinically, the presentation of GSD can vary significantly based on the bones affected and the degree of bone involvement. Symptoms can range from asymptomatic, until insufficiency fracture occurs, to severely disabling neurological impairment, with up to 16% of GSD cases deemed fatal.⁴ Spinal and CVJ involvement does not usually cause local tenderness but can result in neurological symptoms characterized by bowel/bladder dysfunction, paraparesis, and/or radiculopathy.¹⁵ CVJ GSD can also predispose patients to recurrent meningitis from CSF leakage, especially with involvement of the temporal bone or due to CSF-lymphatic fistulas.^6,18 The association of GSD with CM-I is very rare, and only 13 cases have been reported in the literature to date.¹⁹ Chiari malformation in the setting of GSD is often associated with skull base and temporal bone involvement and ensuing CSF leakage resulting in intracranial hypotension, though a few cases without CSF leakage have been reported. In these cases, acquired Chiari malformation is largely thought to be due to cranial settling and basilar impression due to insufficiency of bones in the CVJ.¹⁹ For patients presenting with Chiari symptoms, the diagnosis of GSD is often delayed.¹⁹

The patient in this case presented at 4 years of age with persistent neck pain and headaches in the setting of recurrent group A streptococcal pharyngitis. Despite receiving broad-spectrum intravenous antibiotics over several hospitalizations, she continued to experience head and neck pain. This is an atypical presentation, as craniofacial and CVJ GSDs are not associated with local tenderness or pain.¹⁵ Furthermore, workup during repeated emergency department visits due to persistent pain often revealed fever and elevated inflammatory markers without any infectious focus. This resulted in extensive infectious and immunological workup and suspicion for Griesel syndrome, the nontraumatic subluxation of the atlantoaxial joint due to soft tissue inflammation. Although GSD can present alongside infectious processes such as osteomyelitis and/or septic arthritis, this has rarely been reported.^20–22 Furthermore, little research has been done to investigate the correlation between immune dysfunction and GSD; it is unknown whether immunological impairment is a risk factor for the development of GSD or whether GSD can induce or precede an impaired immune response. However, a single study by Colucci et al. revealed that monocytes obtained from an adult patient with GSD had immature features and were associated with invasive angiogenesis and osteoclastogenesis both in vitro and in in vivo murine models.²³ This patient highlights the importance of maintaining a low threshold for confirmatory testing when considering GSD of the CVJ. Patients can typically present with an accompanying CM-I and the associated symptoms of headaches, nausea, and vomiting. However, it is possible that the initial presentation can mimic infectious or immunological processes. Failure to recognize GSD of the CVJ can have devastating consequences for the patient, leading to delayed diagnosis and therapeutic intervention.

The diagnosis of GSD is based on clinical, radiological, and histopathological findings. Radiologically, given that osteolytic bone lesions encompass a broad spectrum of differential diagnoses, the diagnosis of GSD is often difficult to establish.²⁴ On CT and/or MRI, an extraosseous stage with cortical erosion, adjacent soft tissue involvement, and fibrovascular replacement of bone without periosteal reaction follows an early intraosseous stage with patchy intramedullary and subcortical radiolucencies that coalesce.¹¹ In advanced stages, radionucleotide bone scans exhibit greater absorption but can also appear cold due to resorbed bone.^10,25,²⁶ Confirmatory diagnosis is often made with histopathological analysis, after inflammatory, infectious, metabolic, and neoplastic etiologies are ruled out.¹⁶ Histopathology specimens demonstrate pathognomonic lymphatic and vascular proliferative changes with the replacement of healthy bone matrix with fibrovascular tissue (Fig. 3).^9,24 To facilitate a standardized diagnosis, Heffez et al. suggested 8 criteria for the diagnosis of GSD.²⁷ In our patient’s case, diagnosis was delayed due to the unique patient presentation, which was initially concerning for an infectious etiology, prompting workup for Griesel syndrome. The patient continued to remain febrile and have elevated inflammatory markers as well, which led to genetic and hematological analyses prior to proceeding with more invasive but confirmatory testing. However, the diagnosis was quickly established with a bone biopsy, leading to prompt initiation of appropriate treatment.

The rarity of GSD precludes the establishment of a standardized treatment algorithm. The mainstay of treatment of multifocal disease involves a multimodal approach to slow angiogenesis and bone resorption with systemic treatments targeting antilymphangiogenic and antiosteoclastic pathways.²⁸ Frequently used medications aimed at slowing lymphoproliferation and osteolysis include sirolimus, beta blockers, bisphosphonates, IL-6 inhibition-targeted therapy, and interferon alpha.²

Bisphosphonates have demonstrated efficacy in the medical treatment of GSD, as they decrease bone resorption by interfering with osteoclast activity.² In addition, there has been accumulating evidence more recently that sirolimus, an mTOR inhibitor, may play a role in stabilizing disease progression in GSD.² Ricci et al. conducted a prospective analysis of a phase 2 clinical trial in which patients with GSD were treated with sirolimus, demonstrating that 60% of the cohort showed at least partial clinical improvement as measured by clinical status and functional impairment assessment.² Additionally, 1 of the 5 GSD patients in that study demonstrated radiographic improvement, and another reported improvement in bone pain when sirolimus treatment was combined with bisphosphonate infusion.

The other treatment modality aimed at slowing angiogenesis is radiation therapy.¹⁰ Radiotherapy (RT) can play a role in treatment-resistant localized lesions and has been demonstrated to halt disease progression, though it carries the risk of delayed adverse effects, especially in pediatric patients.^10,29 There have been several case reports of patients with GSD of the CVJ who responded well to treatment with RT, with a dose ranging from 20 to 45 Gy.³⁰ In a review by Roy et al., of patients with GSD of the CVJ who received RT, 10 of the 13 patients demonstrated no local progression after RT.³⁰

The role of surgery in GSD of the CVJ is mainly to treat complications and assumes an ancillary role.⁵ Serious complications like CSF leakage, spinal instability, or pathological fracture may warrant resection of the affected bone, reconstruction with autologous or allograft bone graft, and instrumentation for stabilization.⁵ However, even with bone graft reconstruction, lysis of grafted bone can result during phases of activity of GSD unless osteolytic disease is controlled.³¹ In rare cases of isolated calvarial disease limited to a single site, excision could be offered first line and cranioplasty might be possible.¹⁶ Similarly, in cases of CVJ instability, surgical stabilization could be indicated to prevent quadriparesis and death; however, surgical stabilization with instrumentation might be impossible due to the poor quality of adjacent bone and can predispose the patient to instrumentation failure. Hence, in some cases of severe GSD of the CVJ, a long-term custom-made orthosis could be indicated.¹⁶ Similarly, suboccipital decompression for CM-I due to GSD of the CVJ is also associated with poor outcomes and continued disease progression.^19,32 In a review by Stephens et al., among 12 patients in the literature with GSD of the CVJ and CM-I, 7 underwent suboccipital decompression, and 5 of these patients had disease recurrence due to continued cranial settling, basilar impression, and CSF flow obstruction.¹⁹

The clinical course of GSD, after initial presentation, is usually prolonged and progressive but may eventually stabilize.⁶ The long-term outcome and prognosis of patients with GSD vary based on disease localization and extent of involvement. Most cases of GSD of the CVJ that have been documented in the literature revealed either continued progression or stabilization of the disease after one or more phases of progression, and only one-third of all cases showed an improvement.¹⁶ Bone formation rarely takes place, even when the disease stabilizes. Given the paucity of data on the natural history of GSD, it is unclear if stabilization of the disease process is the result of treatment or part of the natural course of a self-limited disease.¹⁶ Long-term complications of GSD of the CVJ include CSF leakage, cranial settling, basilar impression, recurrent meningitis, and neurological compromise from compression of the brainstem or upper cervical spinal cord.^33,34 These complications might be disabling or lethal even in the setting of treatment (Table 1).^6,35–41

TABLE 1.

Literature review of all reported cases of CM-I and GSD

Authors & Year	Age (yrs)/Sex	Location of GSD	Sxs	Time From Presentation to GSD Dx	Tx of CM-I	Complication of Op Tx	Tx of GSD	FU Yrs Since Dx/Outcome
Stephens et al., 202019	5/M	Occipital bone, clivus, sphenoid, C1–4, femur, pelvis, sacrum	HA, emesis, neck stiffness	33 mos	Occipital decompression	Craniocervical junction restenosis after decompression	Sirolimus & bisphosphonate	Alive at 13 mos
Coulter et al., 201426	37/F	Occipital bone, clivus, mastoid bilat	HA, hearing loss, facial paresthesia	7 mos	Occipital decompression	Recurrence of compression at craniocervical junction	Bisphosphonate	Alive at 9 yrs
Girn et al., 200632	2/F	Clivus, occiput, cervical, temporal, pelvis, femur, ribs	HA, vomiting, palpable temporal mass	72 mos	Occipital decompression	None	RT, bisphosphonate, halo collar	Died at 6 yrs
Costa et al., 201833	8/M	Occipital bone, lt mastoid, C1–4	Gait disturbance & spastic tetraparesis	24 mos	Occipital decompression	None	Bisphosphonate & interferon	Died of medullary compression secondary to atlanto-occipital dislocation
Jea et al., 200334	4/F	Sphenoid, clivus, medial petrous apex, OC, inner ear, C1–4, C6, mandible	HA, ear pain, posttympanostomy otorrhea	12 mos	Occipital decompression	None	NS	NS
Peragallo & Soares, 201835	14/F	Rt petrous temporal, rt mandible	HA, unilat hearing loss, papilledema	48 mos	Secondary to CSF leak, no surgical decompression performed	None	Bisphosphonate	Alive at 2 yrs
Nagashima et al., 201736	25/F	Petrous apex	Paresthesia after bacterial meningitis, hearing loss	NS	Transsphenoid repair of CSF leak	None	NS	Alive at 1 yr
Yoshimoto et al., 201841	19/F	Femur, pelvis	HAs, grip weakness	132 mos	Secondary to intracranial hypotension treated w/ epidural blood patch	None	Sirolimus, interferon, bisphosphonate	Died at 1 yr
Adler et al., 201138	1/F	Lumbosacral, pelvis	HA	NS	Occipital decompression	Persistent Sxs, later managed w/ several epidural blood patches	Interferon, bisphosphonate, vitamin D	Alive at 1 yr, recurring postural HAs
Suero Molina et al., 201439	30/M	T12, L1, lower ribs, splenic cysts, chylothorax	HA	Diagnosed w/ GSD at 13 yrs	Dural repair of spinal CSF leak, no occipital decompression	None	Interferon, bisphosphonate, spinal fusion, sirolimus	Alive at 12 mos, HAs resolved
Agrawal et al., 200618	25/F	Thoracic spine, ribs	Fever, fatigue, dysphagia	12 mos	Occipital decompression	None	Vitamin D	Fistula repair intact at 6-wk FU
Hughes et al., 201040	4/M	Ribs, T2–12	HA, emesis	None	Decompression	None	Interferon, bisphosphonate	Alive at 1 yr
Xing et al., 20236	20/M	Thoracic, lumbar spine	HA, nausea, vomiting	Diagnosed w/ GSD at 8 yrs	No decompression, increased ICP, hypotension treated w/ epidural blood patch	Rebound intracranial hypertension treated w/ acetazolamide & mannitol	NS	Alive at 1 yr
Present case	4/F	Upper cervical spine, CVJ, facial bones	HA, neck pain, recurrent bacteremia	Diagnosed w/ GSD at 9 yrs	None	None	Bisphosphonate, sirolimus, vitamin D	Alive at 3 yrs

Dx = diagnosis; FU = follow-up; HA = headache; ICP = intracranial pressure; NS = not specified; OC = occipital condyle; Sx = symptom; Tx = treatment.

Our patient was managed in a multipronged approach consisting of medical therapy with bisphosphonates and sirolimus and spinal stabilization with external cervical orthosis. RT was not offered due to the patient’s young age. Surgical intervention was also deferred due to the presence of adjacent bone softening, lack of debilitating symptoms, and presence of active osteolytic disease.

Observations

We report the 14th case of GSD of the CVJ that was later complicated by cranial settling, basilar impression, and acquired CM-I. The patient initially presented at 4 years of age with recurrent symptoms of pharyngitis, bacteremia, and neck pain and was managed with a long course of antibiotics. She continued to experience waxing and waning symptoms of fever, neck pain, and headaches that gradually worsened despite a negative infectious workup. Follow-up imaging subsequently revealed progressively worsening osteolytic changes with bone marrow edema involving the bones of the CVJ, upper cervical spine, and facial bones with progressive cranial settling, basilar impression, and atlas assimilation. She underwent a left frontal bone biopsy, which confirmed the diagnosis of GSD. She was later initiated on medical treatment with sirolimus and bisphosphonates.

Lessons

GSD represents a rare group of osteolytic bone disorders characterized by progressive osteolysis due to aggressive nonneoplastic lymphatic and vascular proliferation. The clinical course of the disease is highly variable, and a high index of suspicion is warranted, as diagnosis can be challenging. Early referral to a specialized center is key following diagnosis, as treatment and care are directed toward specific symptoms and require a multidisciplinary team approach with a long-term follow-up, given that the natural history of the disease remains unclear.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Teferi, Glennon, Sato, Dlouhy. Acquisition of data: Teferi, Syed, Glennon, Chenoweth, Eschbacher, Ferguson, Sato, Dlouhy. Analysis and interpretation of data: Teferi, Glennon, Chenoweth, Ferguson, Sato, Dlouhy. Drafting the article: Teferi, Syed, Glennon, Chenoweth, Dlouhy. Critically revising the article: Teferi, Syed, Chenoweth, Eschbacher, Ferguson, Sato, Hitchon, Dlouhy. Reviewed submitted version of manuscript: Teferi, Chenoweth, Eschbacher, Ferguson, Hitchon, Dlouhy. Approved the final version of the manuscript on behalf of all authors: Teferi.

Correspondence

Nahom Teferi: University of Iowa Hospitals and Clinics, Iowa City, IA. nahom-teferi@uiowa.edu.