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Manuscript_1562f708993120a24cc6083515dc4c1e

Catatonic Syndrome and Baraitser Winter Syndrome: case report and review of the
literature.

DIAB E1, MORIN G2 HERY L3, BARBIER V4, COTTIN G 5, JOBIC F2 and TIR M1

1: Department of Neurology, CHU Amiens Picardie

2 : Department of Clinical Genetic , CHU Amiens Picardie
3 : Department of Pediatric Neurology, CHU Amiens Picardie
4: Department of Physical and Rehabilitation Medicine , CHU Amiens Picardie
5 : Department of Psychiatry , CHU Amiens Picardie
Introduction
Baraitser Winter Cerebrofrontofacial syndrome (BWCFF) is a rare syndrome, with less than
100 cases reported around the world. Its diagnosis is complex due to its clinical variability.
Baraitser-Winter Cerebrofrontofacial syndrome was first reported by Michael Baraitser and
Robin Winter in 1988 (Baraitser and Winter, 1988). This genetic disease is characterised by
facial dysmorphism, non-myopathic ptosis, iris or retinal coloboma, sensorineural deafness,
renal abnormalities such as hydronephrosis, pachygyria and/or heterotopia with
anteroposterior severity gradient, progressive joint stiffness, and intellectual disability of
variable degree, often accompanied by severe epilepsy depending on the degree of gyration
abnormalities. Although the minimum clinical diagnostic criteria are still difficult to define,
the facial phenotype appears to be the most reliable symptom at all ages. Neural migration
defect and ocular coloboma are highly suggestive, but not mandatory.
This relatively recently discovered syndrome is a heterogeneous disorder, caused by a
heterozygous mutation of one of the two genes encoding ubiquitously expressed types of
actin: ACTB and ACTG. All mutations are missense and probably act through a gain-of-
function mechanism, since deletions of these same genes do not lead to the BWCFF (Rivière
et al, 2012). The phenotypic expression of BWCFF syndrome is truly variable, two pathogenic
variants have been found in those with the most severe presentation of the BWCFF
syndrome clinical spectrum :mutation c.359C>T; p.(Thr120Ile) in the ACTB gene
(NM_001101.5) [OMIM 102630 ;243310] and mutation c.608C>T; p.Thr203Met in the
ACTG1 gene ( NM_001614.5) [OMIM 102560; 614583].

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This wide phenotypic spectrum of BWCFF includes : Cerebrofrontofacial syndrome type 1
,Cerebrofrontofacial syndrome type 3 and Fryns-Aftimos syndrome with a later onset (Fryns
and Aftimos, 2000). Among the neurologic symptoms associated, extrapyramidal symptoms
(progressive generalised dystonia without dopamine response) have only been reported in
an allelic disorder called dystonia-deafness syndrome.
Moreover, the biggest series of BWCFF cases included 42 patients (Verloes et al 2015), the
patient we described here is actually Patient B20 of this series.
We present a French case of BWCFF syndrome who presented an acute access of catatonic
syndrome and parkinsonian signs, with a review of the literature.

Clinical report :
This young man is currently 18-year-old and affected by BWCFF syndrome. He is the second
child of healthy unrelated parents, and his old sister is healthy. His story began early during
pregnancy with the discovery at the first trimester of a cystic hygroma at 8mm. Karyotype on
amniotic fluid cells found a 46,XY formula. At 21 weeks of gestation (WG) US examination
found a left pyelic dilatation at 9mm, later increased at 22mm with loss of corticomedullar
differentiation. An intestinal hyperechogenicity was also found, leading to the genetic
testing of both parents for CFTR mutations (negative). Delivery occurred spontaneously at 38
WG. At birth weight was 3620g (+ 1 DS), height 50cm (average growth curve) and head
circumference 35cm (- 1 DS) (french standard growth curve available in appendix). On
physical examination were noted excessive skin on the neck, low set ears with thick lobules,
large and depressed nasal root, marked hypertelorim, down slanting palpebral fissures,
narrow thorax, and bilateral clinodactyly of Vth fingers. A bilateral renal bifidity was
discovered and a left polar superior nephrectomy was performed at 6 years of age. His
mother died from a brain tumour when he was one-year-old. On ophthalmological
examination, iris coloboma was absent, but a bilateral papillary dystrophy was found.
Psychomotor acquisitions were mildly delayed. According to this clinical presentation, the
hypothesis of Noonan syndrome was initially suggested, but molecular analysis of PTPN11
gene was negative. At the age of 4 years, we referred the diagnosis of Baraitser-Winter
Cerebrofrontofacial syndrome. The diagnosis was later demonstrated by the identification of
a de novo heterozygous pathogenic variant :c.224T>C ; p.ILE75THR in the ACTB gene
(NM_001101.5) [OMIM 102630 ;243310].
The patient followed a normal schooling with an auxiliary of school life, although a
specialised education was recommended. He is currently in a horticulture boarding school.
His father works as a farmer and manages his own agricultural exploitation. The patient is
also interested in this area and participates as best as he can to the familial activity.

As the patient and his family did not want regular medical follow-up, he was lost to follow-
up during his late childhood and adolescence. The growth curve was normal (available in
appendix) with at last examination: weight 73 kg, height 185 cm and head circumference
61cm. The recent history begin at the age of 18, the clinical picture began with episodes of
disorientation, apathy , drooling, progressively during 6 months and then he suffered from
an acute abdominal pain, nausea, that led him to the emergency room. Viral gastroenteritis
was suspected but not proven, the patient received oral metoclopramide as a symptomatic
treatment. Few days after he presented an acute catatonic syndrome with marked stiffness
of all four limbs, he wasn’t immobile but had difficulties for walking. He also presented with
akinesia and dysarthria, leading to a hospitalisation in pediatric neurology

Brain MRI, PET scan and DAT scan were performed and returned normal (MRI only showed
dilated Virchow Robin spaces which are frequent in this syndrome). The patient received an
administration of tropatepine chlorhydrate which improved the catatonic syndrome and
allowed the patient to regain autonomy and walk on his own. In front of the persistence of
bradykinesia, and rigidity of the upper limbs a dopatherapy based on levodopa carbidopa in
progressive doses was introduced. The patient improved gradually but akinesia and
apragmatism persisted. These symptoms raised questions because the patient also
presented marked apathy. He was assessed by the child psychiatry team and a characterized
depressive episode was diagnosed. This clinical picture made us question about the
extrapyramidal symptoms related with ACTB mutation, we will discuss this further in the
discussion. The patient, however, is now currently jointly supported by neurologists, PRMs
and child psychiatrists. After regular follow-up by the child psychiatrists, he currently
presents a regression of the major depressive syndrome. The neurological examination has
almost normalised leading to the discontinuation of the dopatherapy. Only a discreet
hypertonia of the upper right limb persists.
Discussion:
First of all, in the series of 42 cases collected around the world, including this patient B20
(Verloes et al, 2015), two identical twins presented with deafness from the age of 4, and
dystonia onset at the age of 12 (Patients B26 and B27). This dystonia was dopa-resistant and
followed by progressive cognitive decline. These two children died in their early 20 s from a
lung infection. Neuropathologic investigations mainly showed extensive aggregation of actin
and/or the actin-associated protein actin depolymerizing factor in eosinophilic rod-like
structures in neurons of the neocortex and basal ganglia. These two children carried the
c.547C>T; p.Arg183Trp mutation in ACTB gene (NM_001101.5) [OMIM 102630 ;607371]
(Gearing et al, 2002; Procacciio et al, 2006). This dystonia- deafness syndrome is actually not
part of BWCFF syndrome spectrum but is an allelic disorder (Verloes et al, 2022).

To date, all the extrapyramidal symptoms reported afterwards were only in patients
carrying this allelic disorder. This hypothesis was reinforced by two other patients, a girl and
her mother reported in 2017 (Eggink et al, 2017). The girl had remarkably high-arched
eyebrows, sensorineural deafness, and at the age of 19 years she presented a writer’s cramp
that progressed to severe diffuse dystonia within 8 months. Pallidal deep brain stimulation
(GPi DBS) was performed allowing major clinical and social improvement. Her mother, first
examined at the age of 49, presented sensorineural deafness from the age of 6, tremors
from the age of 16, writer’s cramp at the age of 21 that slowly progressed to generalized
dystonia and wheelchair dependence at the age 42. As for her daughter, only GPi DBS
allowed clinical improvement. Genetic analysis also revealed the same mutation in the ACTB
gene (c.547C>T;p.Arg183Trp; NM_001101.5) (Eggink et al, 2017). A similar presentation was
reported in 2018 in a 18-year-old girl with minimally dysmorphic features, parkinsonian
syndrome started at the age of 12-13 years with bradykinesia, rigidity and dystonia. From
age 16 she needed wheelchair, and from the age of 17 she was mainly confined to bed in a
prone position. She only improved after bilateral pallidal stimulation. The patient also
carried the same mutation in the ACTB gene (c.547C>T;p.Arg183Trp; NM_001101.5)
(Skogseid et al, 2018). Finally the same mutation of ACTB gene was found in a 13-year-old
male patient with sensorineural hearing loss noticed from the age of 8 months, motor and
language delay requiring physical therapy, mild intellectual disability, dystonia started at the
age of 11, but no relevant dysmorphic features. At the age of 15, the dystonia worsened and
became refractory, requiring deep brain stimulator placement. Unfortunately, this was of
limited benefit and the patient died from the complication of the dystonia (Conboy et al,
2017).
This review of literature highlights a very specific link between the c547C>T;pArg183Trp
mutation in ACTB gene (NM_001101.5) and levodopa unresponsive dystonia.
The patient we described here, is the first patient illustrating extrapyramidal symptoms in
BWCFF syndrome patient and not only in the dystonia-deafness syndrome. Moreover these
two clinical pictures differ from each other in many ways: age of onset, installation mode,
symptoms, response to dopa or evolution (Table 1).

Dystonia Deafness Syndrome with BWCFF syndrome patient with ACTB

ACTB mutation c.547C>T;p.Arg183Trp mutation c.224T>C;p.ILE75THR
(NM_001101.5) (NM_001101.5)
Onset - From 12 to 20 years - 18 years
MRI - Normal - Normal
Installation - Progressive - Acute
Mode
Symptoms - Writer’s cramp - Initial catatonic syndrome
- Upper limbs dystonia,then - Rigidity
truncal dystonia and finally - Akinesia
lower limbs dystonia
- Cognitive decline
- Death
Depression - Described for one case (Egging et - Yes
al,2017)
Response - No - Yes
to Dopa
Severity - Improvement after pallidal - Major improvement after
stimulation or death Dopamine administration
Trigger - No trigger described - Viral infection
- Metoclopramide administration
Treatment - Pallidal stimulation - Dopamine
- Tropatepine for acute phase
Table 1: Comparative table of clinical presentation between dystonia-deafness syndrome
and BWCFF syndrome with ACTB mutation c.224T>C/p.ILE75THR

Even if the factors leading to the acute episode in the case we present remain unclear, this
report might expand the clinical spectrum of BWCFF, it raises the awareness of possible
acute neurological/psychiatric symptoms and subtle persistent extrapyramidal symptoms in
adult patients with BWCFF syndrome.

Conclusion:
Baraitser Winter syndrome is associated with a wide clinical variability. We report here for
the first time a patient with BWCFF syndrome , having extrapyramidal dopa-sensitive
symptoms. This raise awareness of a broader spectrum of neurological symptoms in BWCFF
patient , with extrapyramidal presentation (installation mode, dopamine-response,
evolution) different in many ways from the one observed in the allelic related disorder:
dystonia-deafness syndrome.

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Syndrome de Baraitser Winter ORPHANET