UC Irvine
UC Irvine Previously Published Works
Title
A unique case of progressive hemifacial microsomia or Parry-Romberg syndrome
associated with limb and brain anomalies with normal neurological findings: A review of
the literature

Permalink
https://escholarship.org/uc/item/2dx1m6fs

Journal
European Journal of Medical Genetics, 64(9)

ISSN
1769-7212

Authors
Pattnaik, Anandita
Lim, Alexandra
Sabeti, Sara
et al.

Publication Date
2021-09-01

DOI
10.1016/j.ejmg.2021.104234

Copyright Information
This work is made available under the terms of a Creative Commons Attribution License,
availalbe at https://creativecommons.org/licenses/by/4.0/
Peer reviewed

eScholarship.org

Powered by the California Digital Library
University of California

European Journal of Medical Genetics 64 (2021) 104234

Contents lists available at ScienceDirect

European Journal of Medical Genetics
journal homepage: www.elsevier.com/locate/ejmg

A unique case of progressive hemifacial microsomia or Parry-Romberg
syndrome associated with limb and brain anomalies with normal
neurological findings: A review of the literature
Anandita Pattnaik a, Alexandra Lim a, Sara Sabeti a, Ashley Kwon a, Katherine Hall a, Ira Lott b,
Virginia Kimonis a, *
a
b

Division of Genetics and Metabolism, Department of Pediatrics, University of California, Irvine School of Medicine, Orange, CA, USA
Division of Neurology, Department of Pediatrics, University of California, Irvine School of Medicine, Orange, CA, USA

A R T I C L E I N F O

A B S T R A C T

Keywords:
Parry-Romberg syndrome
Hemifacial atrophy
Midline indentation
White matter lesions

In this report, we describe an unusual case of progressive hemifacial atrophy or Parry-Romberg syndrome in a
10-year-old girl with progressive hemifacial microsomia and limb anomalies who had brain magnetic resonance
imaging (MRI) findings of white matter hyper-intensities. Patients typically present with neurological manifes­
tations such as epilepsy, facial pain, and migraines and ophthalmological symptoms in conjunction with white
matter lesions. The patient demonstrated normal cognition and psychomotor development despite the presence
of white matter lesions in her frontal lobe that is commonly associated with neurological symptoms. This report
brings attention to the complicated relationship between facial, limb and brain imaging findings in ParryRomberg syndrome and differentiates it from hemifacial microsomia syndrome.

1. Introduction
Parry-Romberg syndrome (PRS) is a rare neurocutaneous disorder
that was first described by Caleb Parry in 1825 and further studied by
Moritz Romberg in 1846 (Xu et al., 2013). PRS is characterized by
progressive hemifacial atrophy (PHFA) that often coexists with en coup
de sabre, a specific form of linear scleroderma found on the forehead and
frontoparietal scalp (Maletic et al., 2010; El-Kehdy et al., 2012).
Neurological symptoms that PRS patients most often experience are
seizures, trigeminal neuralgia, and migraines (Maletic et al., 2010;
El-Kehdy et al., 2012; Stone, 2003; Mazzeo et al., 1995). Some affected
patients also present with ophthalmological manifestations such as
enophthalmos, uveitis, and heterochromia (Maletic et al., 2010; Stone,
2003). The etiology of PRS is still not fully understood, although some
have postulated that it may have an autoimmune basis (El-Kehdy et al.,
2012; Stone, 2006). Other theories suggest sympathetic cervical gan­
glion dysfunction or abnormal embryogenesis in the etiology of PRS
(Wong et al., 2015). PRS usually manifests between 5 and 15 years of
age and has been shown to affect females more frequently than males
(Xu et al., 2013). Overall, PRS is a self-limiting disease that is not

generally fatal (El-Kehdy et al., 2012; Mazzeo et al., 1995; Stone, 2006).
We describe the severe cutaneous and skeletal muscle manifestations
in a 10-year-old female patient with Parry-Romberg syndrome. The
patient described in this case report had abnormal brain magnetic
resonance imaging (MRI) that showed white matter lesions of the frontal
lobe. Remarkably, she did not exhibit significant PRS neurological
manifestations impairing her cognitive or psychomotor abilities that are
typically associated with this syndrome.
2. Case report
We report a 10-year-old female patient of Mexican descent who was
diagnosed with Parry-Romberg syndrome at 3-years-old. She was born
vaginally to a healthy 23-year-old mother and 30-year-old father. The
pregnancy was complicated by decreased fetal movements and hyper­
glycemia. Her birth head circumference, length and weight was not
available but was reported as normal. There was no family history of
scleroderma or Parry-Romberg syndrome.
At age 3 years, the patient was observed to have regions of sclero­
derma, involving hyperpigmentation and atrophy, on her trunk and

* Corresponding author. Division of Genetics and Metabolism, Department of Pediatrics, University of California, Irvine School of Medicine, 101 The City Drive
ZC4482, Orange, CA, 92868, USA.
E-mail address: vkimonis@uci.edu (V. Kimonis).
https://doi.org/10.1016/j.ejmg.2021.104234
Received 12 November 2020; Received in revised form 25 March 2021; Accepted 26 April 2021
Available online 1 June 2021
1769-7212/© 2021 The Author(s).
Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

A. Pattnaik et al.

European Journal of Medical Genetics 64 (2021) 104234

PRS at an early age. Her most recent measurements at 9 years 8 months
were: head circumference 53.5 cm height 140.2 cm, weight 36.7 kg. (Z
scores 0.15, 0.56 and 0.71 respectively). Recently SNP microarray
testing in a blood sample did not reveal any chromosomal abnormalities.

limbs. She demonstrated facial asymmetry, which progressed until she
developed significant right hemifacial atrophy and a deep indentation
with a bluish-tinged vascular malformation along the midline of her
forehead (Fig. 1) and gradual involvement of a large region on the left
side of her neck (Fig. 2A) and her right ear which was significantly
smaller. She also developed involvement of the skin over her left lower
limb and by age 6 years it was underdeveloped compared to the right
(Fig. 2B).
Additionally, multiple neurological examinations of the patient since
age 3 years were reported as unremarkable with no focal abnormalities.
She was consistently found to be alert, oriented, and to have a full range
of eye movements and well-functioning cranial nerves. She was consis­
tently observed to have a normal gait with normal muscle strength, tone,
range of motion, and reflexes. She had a negative history of seizures, and
at age 8 years an electroencephalogram study reported no areas of focal
slowing or epileptiform abnormalities. She did, however, experience
infrequent, mild facial pain, and recurrent headaches which were
treated symptomatically, the latter being attributed to a family history of
headaches and less likely related to PRS.
A brain MRI scan, performed at 3 years of age, revealed abnormal
white matter signals in the right frontal subcortical region. The findings
showed a mild peritrigonal white matter signal abnormality that was
asymmetrically prominent on the right and a mild asymmetric peri­
ventricular white matter signal abnormality adjacent to the right lateral
ventricle. There was, however, predominant sparing of the subcortical U
fibers. MRI findings also revealed right sphenoid sinus disease and mild
bilateral mastoid fluid which later resolved. Further follow-up brain MRI
scans at age 4 years, 5 years, 6 years, 7 years, and 8 years (Fig. 3)
revealed stable T2 white matter hyper-intensities and no significant
interval changes compared to previous MRI reports.
At age 4 years, the patient had a skin biopsy of sun-exposed nonlesional skin that was evaluated by direct immunofluorescence studies
which showed significant deposits of IgM and C5b-9 along the dermalepidermal junction and vascular deposits of IgM and C5b-9 indicative
of an autoimmune etiology. The patient’s blood studies were negative
for anti-endothelial cell antibodies. She was treated with steroid creams
which were reported to help; however methylprednisolone injections
were reported to be ineffective.
In general, the patient’s physical appearance and neurological status
have been stable upon evaluation over the years, despite a diagnosis of

3. Discussion
The 10-year-old female in the present case report has had a long-term
brain MRI and clinical follow-up starting from the first diagnosis at age 3
years. She had severe facial features including progressive hemifacial
microsomia (PHFM) and en Coup de Sabre with limb involvement. The
patient’s brain MRI findings showed white matter lesions in the right
frontal subcortical region that remained unchanged from the ages of 3–8
years and were not associated with neurological impairment. She had
normal psychomotor development, as evidenced by her normal devel­
opmental milestones, gait, and lack of obvious muscle weakness. She
was able to attend school at her grade level, had normal social in­
teractions, and did well on school evaluations with no special education
services requirements.
We reviewed the literature for similar cases with limb, hemifacial
microsomia, and brain MRI white matter hyperintensities (WMH) as
seen in our patient with normal cognition and neurological findings.
Zulian et al. reported only eight cases with isolated PHFM and six with
both PHFM with head and limb involvement among 113 patients with
juvenile localized scleroderma (Zulian et al., 2006). Detailed informa­
tion on these subjects, however, was not available in this report. We
found a few isolated reports of hemifacial atrophy and limb anomalies
(Table 1), including a case report of a 48-year-old female with hemi­
facial atrophy but normal brain MRI (Aydın et al., 2015) and an
11-year-old boy with severe scleroderma of left side of the body and
intellectual deficit with an abnormal brain MRI (Grosso et al., 2003). In a
report of 19 cases of PHFM, several had morphea or linear scleroderma
of the trunk and/or extremities; however, details were not available and
brain anomalies were not investigated (Blaszczyk et al., 2003).
The literature was also reviewed for patients with PRS, without
associated limb involvement, with brain white matter involvement. A
study of a cohort of 10 patients with PRS revealed that half of the pa­
tients had abnormal MRI findings, most frequently in patients who also
exhibited neurological symptoms (Moko et al., 2003). These abnormal
MRI findings were most frequently WMH and cerebral hemiatrophy,

Fig. 1. Craniofacial Features associated with Parry Romberg syndrome. A. Frontal view of the face reveals midline indentations of the forehead extending into
the nose and right sided hemifacial atrophy.
B. Side view of the face showing the bluish-tinged indentation of the forehead.
2

A. Pattnaik et al.

European Journal of Medical Genetics 64 (2021) 104234

Fig. 2. Areas of subcutaneous and muscular atrophy of the neck and thigh. A. Left side view of the neck shows a patch of subcutaneous atrophy B. An area of
subcutaneous and muscular atrophy of the left thigh.

Fig. 3. Brain magnetic resonance imaging (MRI) findings in the patient at age 4 years: T2 axial (left, middle) and T1 sagittal (right) reveals white matter hyperintensities of the peritrigonal and periventricular region adjacent to the right lateral ventricle.
Table 1
Comparison of Clinical and Neuro-Imaging findings of the present case with patients reported in detail in the literature.
Age
(Y)

Sex

Face

Limbs

Brain MRI changes

Psychomotor
development

Progression

Other findings

R

L

R

L

Present case

10

F

þ

-

-

þ

Normal

þ

-

Normal

-

-

Intellectual deficit

-

-

White matter lesions (Right frontal
subcortex)
Asymmetric fatty loss of scalp and galeal
subcutaneous fatty tissue (Left frontal)
No cortex white matter anomaly
Left cerebral hemisphere atrophy (Sylvian
fissure)
WMH of the right cerebral hemisphere

Aydın et al. (2015)

48

F

-

þ

-

þ

Grosso et al. (2003)

11

M

-

-

-

þ

Normal

-

-

-

WMH left frontal lobe
Right temporal lobe atrophy

Normal
Mild cognitive
Impairment

Recurrent complex
partial seizures
Trigeminal neuralgia
Right-sided deafness

Vix et al. (2015)

55

M

þ

-

-

Vix et al. (2015)
Klimiec and
Klimkowicz-Mrowiec
(2016)
Okumura et al. (2006)

44
23

F
F

þ

þ
-

þ

-

5.4

M

-

þ

-

-

White matter lesions (Left cerebral
hemisphere)

Normal

þ

-

M = male, F = female, R = Right side, L = left side, WMH = white matter hyperintensities.

interestingly most frequently on the ipsilateral side of the HFA (Wong
et al., 2015; Moko et al., 2003).
PRS patients may present with neurological complications including,
but not limited to, seizures, headaches, and neuropsychological symp­
toms (Vix et al., 2015). In one study on 32 patients aged 3–17 years with
PRS, 28% had additional neurologic symptoms, most common being

seizures (Vix et al., 2015\). A detailed report of a 55-year-old male pa­
tient with HFA indicated he had extended areas of T2-FLAIR WMH
involving posterior occipital and part of the corpus callosum, the
caudate nucleus, and the anterior limb of the internal capsule of the right
hemisphere but without significant cognitive impairment (Vix et al.,
2015). Long-term follow-up of a 9-year-old male PRS patient revealed
3

A. Pattnaik et al.

European Journal of Medical Genetics 64 (2021) 104234

stable neurological and MRI findings despite the progression of his facial
atrophy (Klimiec and Klimkowicz-Mrowiec, 2016). Observation of a
male from age 22–65 months revealed normal psychomotor and
neurological development despite white matter lesions involving the
entire left cerebral hemisphere (Okumura et al., 2006).
The differential diagnosis of progressive hemifacial microsomia in­
cludes hemifacial microsomia (HFM) syndrome, a sporadically occur­
ring disorder of unknown etiology. It is associated with congenital
malformations of the first and second branchial arches resulting in facial
asymmetry with unilateral hypoplasia of maxilla, mandibular, zygoma,
temporal bones, and surrounding soft tissue. HFM and Goldenhar syn­
drome are considered variants under the same clinical continuum of
disorders termed the oculo-auriculo-vertebral spectrum. Goldenhar
syndrome encompasses HFM phenotypes along with epibulbar dermoid
and vertebral anomalies. Cranial nerve abnormalities and function
deficits occur in some individuals; however, the marked atrophy of the
limbs and brain white matter changes are not seen in HFM (Strömland
et al., 2007). Berardinelli-Seip congenital generalized lipodystrophy is
suspected in individuals with lipoatrophy affecting the trunk, limbs, and
face. In some individuals, the face may be normal at birth with lipoa­
trophy of the face and body becoming apparent during the first months
of life. Skeletal muscle hypertrophy is also present giving the individual
an athletic appearance. The disorder is associated with elevated serum
concentration of triglycerides and insulin resistance.
Direct immunofluorescence studies of our patient’s sun-exposed nonlesional skin showed significant deposits of IgM and C5b-9 along the
dermal-epidermal junction and vascular deposits of IgM and C5b-9
indicative of an autoimmune etiology. Additionally PRS are typically
sporadic providing evidence against a genetic association of this con­
dition. Only two cases were reported in biological first cousins (Ander­
son et al., 2005). Nevertheless future trio genome sequencing is being
explored for our unique patient. A case of a woman who was mis­
diagnosed as multiple sclerosis indicate that the brain lesions in PRS are
located in the same region as in multiple sclerosis (Long et al., 2020).
The authors thus hypothesized that PRS may be an autoimmune in­
flammatory process. The variability in MRI findings and clinical features
of PRS may be a reflection of the multiple pathogenetic pathways
involved in different patients (Long et al., 2020).
Currently, there is no cure or any proven treatment available for PRS
(Mazzeo et al., 1995; Stone, 2006), although immunosuppressant drugs
have been shown to be beneficial in some cases, thus supporting the
theory that PRS may be an autoimmune disorder (El-Kehdy et al., 2012;
Stone, 2006). In the case of our patient, methylprednisolone injections
were reported as ineffective. In a clinical study, it was found that
collagen-polyvinylpyrrolidone could be a potential new treatment for
PRS since it works well in alleviating hemifacial atrophy and inflam­
mation (Hernández-Vega et al., 2013). Restorative plastic surgery using
fat or silicone implants, flap grafts, or bone implants is often beneficial
for PRS patients (Mazzeo et al., 1995; Stone, 2006). At the age of 9 years,
our patient underwent fat grafting, without issues, and her facial de­
formities were much improved. Although surgeries may prevent further
atrophy of the face, it is usually recommended after the disease has run
its course (El-Kehdy et al., 2012).
In conclusion, our present understanding of the etiology of this rare
disorder is limited. There has been little study of the significance of
white matter lesions, how these lesions arise in the brain, and how they
are related to the other PRS features. The comparison of other cases with

our patient demonstrates that the presentation of neurological mani­
festations and cerebral white matter atrophy in PRS patients is quite
variable. Thus, the findings in our unique patient with PHFM, limb at­
rophy, and brain findings present an important opportunity to further
understand the enigmatic disease that is PRS.
CRediT authorship contribution statement
Anandita Pattnaik: Data curation, Writing – original draft. Alex­
andra Lim: Writing – review & editing. Sara Sabeti: Writing – review &
editing. Ashley Kwon: Writing – review & editing. Ira Lott: Writing –
review & editing, Validation. Virginia Kimonis: Conceptualization,
Methodology, Resources, Writing – review & editing, Supervision,
Validation, and, Supervision.
Acknowledgement
We thank the patient, and her family for permission to publish her
features. We thank Dr. Zadeh for management of the patient.
References
Anderson, P.J., Molony, D., Haan, E., et al., 2005. Familial Parry–Romberg disease. Int. J.
Pediatr. Otorhinolaryngol. 69 (5), 705–708.
Aydın, H., Yologlu, Z., Sargın, H., et al., 2015. Parry-Romberg syndrome. Physical,
clinical, and imaging features. Neurosciences 20 (4), 368–371. https://doi.org/
10.17712/nsj.2015.4.20150142.
Blaszczyk, M., Królicki, L., Krasu, M., et al., 2003. Progressive facial hemiatrophy: central
nervous system involvement and relationship with scleroderma en coup de sabre.
J. Rheumatol. 30 (9), 1997–2004.
El-Kehdy, J., Abbas, O., Rubeiz, N., 2012. A review of Parry-Romberg syndrome. J. Am.
Acad. Dermatol. 67 (4), 769–784.
Grosso, S., Fioravanti, A., Biasi, G., et al., 2003. Linear scleroderma associated with
progressive brain atrophy. Brain Dev. 25 (1), 57–61.
Hernández-Vega, G.A., Ruiz-Eng, R., Montiel-Jarquín, Á., et al., 2013. Use of collagenpolyvinylpirrolidone in the treatment of Parry-Romberg syndrome. Rev. Méd. Inst.
Mex. Seguro Soc. 51 (6), 692–695.
Klimiec, E., Klimkowicz-Mrowiec, A., 2016. Mild cognitive impairment as a single sign of
brain hemiatrophy in patient with localized scleroderma and Parry–Romberg
syndrome. Neurol. Neurochir. Pol. 50 (3), 215–218.
Long, L., Kang, Z., Chen, S., et al., 2020. A case report of Parry–Romberg syndrome
misdiagnosed as multiple sclerosis. Front. Neurol. 11.
Maletic, J., Tsirka, V., Ioannides, P., et al., 2010. Parry-Romberg syndrome associated
with localized scleroderma. Case reports in neurology 2 (2), 57–62.
Mazzeo, N., Fisher, J.G., Mayer, et al., 1995. Progressive hemifacial atrophy (ParryRomberg syndrome) Case report. Oral Surg. Oral Med. Oral Pathol. Oral Radiol.
Endod. 79 (1), 30–35.
Moko, S.B., Mistry, Y., de Chalain, T.M.B., 2003. Parry–Romberg syndrome: intracranial
MRI appearances. J. Cranio-Maxillofacial Surg. 31 (5), 321–324.
Okumura, A., Ikuta, T., Tsuji, T., et al., 2006. Parry-Romberg syndrome with a clinically
silent white matter lesion. Am. J. Neuroradiol. 27 (8), 1729–1731.
Stone, J., 2003. Parry–Romberg syndrome: a global survey of 205 patients using the
Internet. Neurology 61 (5), 674–676.
Stone, J., 2006. Parry-Romberg syndrome. Practical Neurol. 6 (3), 185–188.
Strömland, K., Miller, M., Sjögreen, L., et al., 2007. Oculo-auriculo-vertebral spectrum:
associated anomalies, functional deficits and possible developmental risk factors.
Am. J. Med. Genet. 143 (12), 1317–1325.
Vix, J., Mathis, S., Lacoste, M., et al., 2015. Neurological manifestations in
Parry–Romberg syndrome: 2 case reports. Medicine 94 (28).
Wong, M., Phillips, C.D., Hagiwara, M., et al., 2015. Parry Romberg syndrome: 7 cases
and literature review. Am. J. Neuroradiol. 36 (7), 1355–1361.
Xu, M., Yang, L., Jin, X., et al., 2013. Female predominance and effect of sex on ParryRomberg syndrome. J. Craniofac. Surg. 24 (4), 1195–1200.
Zulian, F., Athreya, B.H., Laxer, R., et al., 2006. Juvenile localized scleroderma: clinical
and epidemiological features in 750 children. An international study. Rheumatology
45 (5), 614–620.

4