American Journal of Medical Genetics 130A:22 – 25 (2004)

Research Review
Superficial Siderosis: A Potentially Important Cause
of Genetic as Well as Non-Genetic Deafness
Kelley M. Dodson,1* Aristides Sismanis,1 and Walter E. Nance1,2
1

Department of Otolaryngology/Head and Neck Surgery, Virginia Commonwealth University School of Medicine and Health Sciences,
Medical College of Virginia Campus, Richmond, Virginia
2
Department of Human Genetics, Virginia Commonwealth University School of Medicine and Health Sciences,
Medical College of Virginia Campus, Richmond, Virginia

Superficial siderosis is an important disease that
is increasingly being recognized as a cause of
sensorineural hearing loss. Hemosiderin, resulting from repeated episodes of subarachnoid
bleeding, is deposited preferentially on the surface of the eighth nerve, cerebellum, and brain
stem as a consequence of glial catabolism of
ferritin within those structures. This deposition
eventually results in destruction and demyelination within the central nervous system, leading to
the cardinal clinical findings of superficial siderosis: hearing loss, ataxia, and myelopathy. This
mechanism may contribute to the pathogenesis of
several forms of genetic deafness, and should be
considered as a diagnostic possibility in cases of
late onset deafness even in the absence of an overt
history of subarachnoid bleeding.
ß 2004 Wiley-Liss, Inc.

KEY WORDS: deafness; superficial siderosis;
genetics; Alport syndrome; macrothrombocytopenia; cerebral cavernous malformation; MYH9

INTRODUCTION
Our awareness of the importance of superficial siderosis as a
cause for deafness was prompted by the observation of a 35year-old man who presented for evaluation of a progressive,
high frequency sensorineural, non-syndromic hearing loss. At
the age of 21 years, he first became aware of left-sided hearing
loss, which had progressed to involve both ears. He had tried
digital hearing aids with variable success and denied symptoms of imbalance, ataxia, dementia, anosmia, or bladder
dysfunction.
His past medical history revealed that he had a posterior
craniotomy at age 4, for a cystic lesion of the cerebellum. He
suffered residual diplopia, which was reportedly corrected by
ophthalmologic surgery on the left eye at age 6. His medical

*Correspondence to: Kelley M. Dodson, Box 980146, Department of Otolaryngology–Head and Neck Surgery, Virginia
Commonwealth University, Richmond, VA 23298-0146.
E-mail: kelleydodson@comcast.net
Received 10 October 2003; Accepted 10 November 2003
DOI 10.1002/ajmg.a.30050

ß 2004 Wiley-Liss, Inc.

history was otherwise unremarkable. The family history
showed that his mother had a mild to moderate high frequency
sensorineural hearing loss; his only sister was reported to have
normal hearing. Physical examination revealed no abnormalities apart from his hearing loss, except for some unsteadiness
on Romberg testing. However, tandem walking was well
executed and he had a normal gait. A previous MRI examination demonstrated a rim of hypointensity surrounding the
brain stem, consistent with superficial siderosis (Fig. 1). The
pure tone audiogram showed a mild to severe sloping
sensorineural hearing loss (Fig. 2).

DISCUSSION
Until recently, superficial siderosis has been considered to be
a rare pathologic entity characterized by hemosiderin deposition in the leptomeninges, which was originally described as a
postmortem finding [Hamill, 1908]. Noetzel first linked superficial siderosis to subarachnoid hemorrhage in 1940, but it was
not until 1964 that its syndromic association with sensorineural deafness, ataxia, dementia, and myelopathy was first
recognized [Noetzel, 1940; Tomlinson and Walton, 1964].
Superficial siderosis typically results from recurrent subarachnoid bleeding. The bleeding can be clinically silent but
delivers repeated doses of iron breakdown products into the
cerebrospinal fluid. For many years, the prevailing view was
that a defect in iron metabolism, analogous to hemochromatosis, might be required for expression of the disease; however,
the syndrome was subsequently reproduced in several animal
models by repeated injections of blood into the subarachnoid
space [Iwanowski and Olszewski, 1960; Koeppen and Borke,
1991]. Glial cells, which actively take up and metabolize
ferritin, are the most severely affected. Once their capacity to
metabolize the heme degradation products is exceeded, free
iron accumulates and causes lipid peroxidation and cell damage
[Koeppen and Dentinger, 1988; Koeppen et al., 1993]. Prior to
the advent of modern neuroradiology, superficial siderosis was
seldom diagnosed in living patients. However, the paramagnetic
properties of ferritin ions, which shorten the relaxation time of
T2 weighted MRI, produces a characteristic a rim of hypointensity surrounding the brain stem and cerebellum [Bracchi et al.,
1993; Pribitkin et al., 1994].
An astonishing feature of this syndrome is that the
sensorineural hearing loss, which is present in as many as
95% of all affected patients, may not be noted until 4 months to
30 years after the first recognized episode of intracranial
bleeding [Fearnley et al., 1995]. The 8th cranial nerve is
especially vulnerable to hemosiderin deposition, because only
a short segment of the nerve is sheathed with Schwann cells.
This leaves a long residual glial segment, extending from the
exit of the nerve at the cerebellopontine angle to the porus

Superficial Siderosis

23

Fig. 1. T-2 weighted MR image demonstrating a rim of hypointensity
outlining the brainstem and cerebellum, typical of superficial siderosis.

Fig. 2. Audiogram demonstrating an asymmetric, sloping sensorineural
hearing loss.

acousticus, which is bathed by a high flow of cerebrospinal fluid
in the pontine cistern [Koeppen and Dentinger, 1988]. The
audiogram generally reveals a sloping bilateral sensorineural
loss, with corresponding losses in speech discrimination and
word recognition scores [Parnes and Weaver, 1992; Fearnley
et al., 1995; Kale et al., 2003]. Eventually, hearing loss almost
always occurs, and typically progresses to severe or profound
deafness [Parnes and Weaver, 1992; Fearnley et al., 1995;
Dhooge et al., 2002; Kale et al., 2003]. The high frequencies are
most severely affected, and at times a small island of low tones
is preserved. These patterns may well reflect the tonotopic
localization of axons transmitting the high frequency sound at
the surface of the auditory nerve. However, the hearing loss
may initially be asymmetric and/or unilateral [Parnes and
Weaver, 1992; Fearnley et al., 1995; Longridge et al., 1996;
Castelli and Husband, 1997; Li et al., 2001; Kale et al., 2003].
Neurotologic testing shows a retrocochlear pattern of impairment, ranging from increased wave latencies to an undetectable Auditory Brainstem Response (ABR) [Yamana et al.,
2001; Dhooge et al., 2002]. However, electrocochleography
frequently reveals a lack of compound action potentials, as well
as evidence for recruitment on audiometric testing [Yamana
et al., 2001]. These findings suggest that some cochlear
impairment may also be present [Yamana et al., 2001].
The olfactory nerves are coated by glial cells throughout
their course, and are also damaged by hemosiderin deposition.
However, overt anosmia is less often documented clinically
[Fearnley et al., 1995]. Ataxia is the second most common
presenting symptom of superficial siderosis, and generally
occurs after the onset of hearing loss. Pyramidal signs,
dementia, and other neurologic findings occur in order of
decreasing frequency [Fearnley et al., 1995]. Depending on the
cause for the recurrent hemorrhage, focal neurologic signs
such as seizures or paresis may be seen.
The source of the recurrent bleeding is usually a CNS lesion
such as neoplasms, most notably ependymomas, aneurysms,
AV malformations, prior operations, especially of the posterior
fossa and cerebellum, or neonatal intraventricular hemor-

rhage [Kumar et al., 1993; Fearnley et al., 1995; Anderson
et al., 1999]. In about half of cases, no bleeding source is
identified [Fearnley et al., 1995]. The precise diagnosis in our
patient at the time of his craniotomy 31 years ago is unclear. It
is conceivable that he had a vascular anomaly such as the
hereditary cerebral cavernous malformation syndrome (CCM).
Familial cerebral cavernous angiomas are abnormally large
and weak vascular lesions, which are inherited as an
autosomal dominant trait [Rigamonti et al., 1988; Bicknell,
1989]. Depending on the location and number of lesions, this
syndrome frequently presents with focal seizures [Gil-Nagel
et al., 1995]. However, recurrent hemorrhage almost always
occurs, and may lead to the characteristic MRI findings of
superficial siderosis [Gunel et al., 1996; Hsu et al., 1999]. In a
large family reported by Gil-Nagel et al. [1995], 7 of 17 patients
(41%) classified as affected or possibly affected had hearing
loss, which was the second only to seizures as the most frequent
clinical finding. However, the authors did not consider
bilateral hearing loss to be an integral part of the syndrome,
presumably because of the lack of a plausible pathogenic
mechanism. Other familial and isolated cases of hearing loss
have been reported with this syndrome [Bicknell et al., 1978;
Hsu et al., 1999]. However, in most large surveys [Gunel et al.,
1996; Labauge et al., 1998], no mention is made of hearing loss,
possibly because it was considered to be an unrelated
neurologic finding. Familial CCM is now known to be caused
by at least three autosomal dominant genes, one of which
(CCM1) has been shown to be the locus on 7q21-q22, which
codes for KRIT-1, a 529 amino acid protein with an N-terminal
ankyrin repeat domain that is thought to help determine the
cytocellular structure of endothelial cells [Serebriiskii et al.,
1997]. The CCM2 gene has not yet been identified but maps to
7p15-p13, a region that includes DFNA5, a gene coding for a
496 amino acid protein of unknown physiologic function.
Mutations involving this gene cause a dominant, progressive
high frequency hearing loss in humans but not the mouse
[Van Laer et al., 1998]. Similarly, CCM3 maps to 3q25.2-q27, a
region that includes the locus for DFNB15 [Van Camp et al.,

24

Dodson et al.

1997]. MRI and autopsy studies suggest that the prevalence of
CCA may be a high as 0.5%, and the trait appears to be
especially common among Mexican Americans where a founder effect has been documented [Gunel et al., 1996]. In family
members who have had recognized or unrecognized subarachnoid hemorrhage without seizures, hearing loss could be an
early sign of the disease.
Hereditary transthyretin amyloidosis is another genetic
condition in which familial superficial siderosis has been
documented. Recurrent subarachnoid bleeding in the syndrome is though to be related to meningovascular amyloid
deposition [Mascalchi et al., 1999]. Progressive sensorineural
hearing loss is an integral part of the Muckle–Wells syndrome,
another form of dominantly inherited amyloidosis that could
share a common pathogenic mechanism [Gerbig et al., 1998].
Isolated examples of superficial siderosis have also been
reported in patients with coexisting neurofibromatosis Type
I, and Marfan syndrome (Manfredi et al., 2000; Lin and
Westesson, 2001].
Several other genetically determined vascular disorders,
including the Klippel–Trenaunay syndrome and hereditary
hemorrhagic telangiectasia, can be associated with either
sensorineural hearing loss or subarachnoid hemorrhage, and
may represent additional examples of this pathogenic mechanism [Roman et al., 1978; Ishimoto et al., 2002]. In Alport
syndrome, progressive nephritis and late onset hearing loss
result from mutations involving one of three subunits of Type
IV collagen. The resulting weakness in the basement membranes of the renal glomerular capillaries leads to chronic
hematuria and ultimately renal failure. A similar involvement
of the cerebral arteries has been invoked to explain the
association of cerebral aneurysm with Alport syndrome
[Vaicys et al., 2000]. It seems possible that the involvement of
small vessels on the surface of the brain could lead to the
chronic extravasation of red cells into the subarachnoid space.
Alternatively, localized hemorrhage involving the capillaries
of the stria vascularis could lead to hearing loss. Epstein
syndrome (ES), Fechtner syndrome (FS), Sebastian syndrome
(SS), the May–Hegglin anomaly (MH), and DFNA17 are all
caused by allelic mutations of MHY9, a non-muscle myosin, on
22q11.2 [Lalwani et al., 2000; Seri et al., 2003]. In ES and FS,
features of Alport syndrome, including progressive hearing
loss, hematuria, and nephritis occur in association with
macrothrombocytopenia, a prolonged bleeding time, epistaxis
and ecchymoses. Leukocyte inclusions are also seen in FS but
not ES. In SS and MH, only the hematologic features are seen,
but the leukocyte inclusions differ in their morphology [Brodie
et al., 1992]. Similar to the proposed pathogenesis of Alport
syndrome, a different cause for either localized or subarachnoid hemorrhage could account for the hearing loss in these
syndromes. Thrombocytopenia is also one of the best predictors
of hearing loss in children with congenital cytomegalovirus
infection, suggesting that prenatal subarachnoid hemorrhage
might well be considered as a possible explanation for a delayed
onset of hearing loss in these infants [Rivera et al., 2002].
Finally, several distinct forms of non-syndromic, late onset
high frequency hearing loss have been identified, including
DFN 6, DFNA 5, DFNA 17, and DFNA 20, in which nothing is
known about the pathogenesis.
In our case, audiologic studies revealed a mild high frequency loss in the mother of the proband. In a similar case seen
at Baylor, a family history of hearing loss was also noted
[Reddy, 1995]. Clinical geneticists should consider superficial
siderosis as a possible cause for late onset progressive hearing
loss even in the absence of recognized intracranial bleeding.
The diagnosis can readily be confirmed or excluded with a T2
weighted MRI.
Current treatment for superficial siderosis involves identification and correction of the source of subarachnoid bleeding.

When a specific bleeding site can be found, surgical intervention may be indicated. Avoidance of anticoagulants and antiplatelet medications, including aspirin, may also be indicated.
Therapy with metal chelating agents, such as trientene, has
been described but its efficacy remains to be established [River
et al., 1994; Fearnley et al., 1995; Kale et al., 2003]. Cochlear
implantation has also been reported to be beneficial in select
cases [Irving and Graham, 1996; Dhooge et al., 2002].
CONCLUSION
Superficial siderosis is an increasingly recognized entity,
which may be responsible for many cases of genetic as well as
non-genetic deafness. It should be considered in any patient
with risk factors for chronic subarachnoid bleeding, including
but not limited to a personal or family history of vascular
malformations, thrombocytopenia, or prior CNS surgery. We
recognize the possibility that intracranial hemorrhage may
contribute to the hearing loss seen in Alport syndrome, ES, FS,
DFNA17, and the Muckle–Wells syndrome is highly speculative. However, speculation is always justified if it leads to
new knowledge. Our reading of the literature suggests that
the lack of a plausible explanation for bilateral hearing loss
resulting from focal intracranial hemorrhage has contributed
to the failure to recognize hearing loss as an integral part of the
CCM syndrome, and possibly the etiologic role of intracranial
hemorrhage in other genetic deafness syndromes that can
plausibly linked to a bleeding diathesis. If our hypothesis is
correct, it seems clear that some forms of progressive, bilateral
hearing loss could be caused by genes that are not even
expressed in the cochlea! If the positional candidate genes
selected for mutation screening were limited to those that are
specifically expressed in the cochlea, the identification of genes
causing deafness of this type might well be delayed.
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