Pediatric Neurology 52 (2015) 352e355

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Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu

Clinical Observations

Moyamoya Syndrome in a Patient With Noonan-like Syndrome
With Loose Anagen Hair
Jin-Ho Choi MD a,1, Moon-Yeon Oh MD a,1, Mi-Sun Yum MD a, Beom Hee Lee MD a,
Gu-Hwan Kim PhD b, Han-Wook Yoo MD, PhD a, b, *
a
b

Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
Medical Genetics Center, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea

abstract
BACKGROUND: Noonan-like syndrome with loose anagen hair is one of the RASopathies characterized by Noonan
syndrome-like features with unique ectodermal abnormalities. This syndrome is caused by mutations in the
SHOC2 gene. We encountered a patient with moyamoya syndrome associated with Noonan-like syndrome with
loose anagen hair presenting with transient ischemic attacks. PATIENT DESCRIPTION: A 6-year-old girl was diagnosed with Noonan-like syndrome with loose anagen hair because of profound short stature and ectodermal
anomalies such as sparse and easily pluckable hair. A heterozygous mutation of c.4A>G (p.S2G) in the SHOC2 gene
was identified, and recombinant human growth hormone therapy was initiated at 8 years of age. At age 10, she
manifested recurrent left hemiplegia. Moreover, cerebrovascular imaging revealed occlusion or narrowing of both
internal carotid arteries and both middle cerebral arteries with distal moyamoya-like vessels. She is treated with
aspirin and calcium channel blocker. CONCLUSIONS: We describe the first case of Noonan-like syndrome with loose
anagen hair associated with moyamoya syndrome, although it has been reported to be associated with a few cases
of other RASopathies, including Noonan, cardiofaciocutaneous, and Costello syndromes. This report emphasizes
the associations between cerebrovascular anomalies and Noonan-like syndrome with loose anagen hair.
Keywords: Noonan-like syndrome with loose anagen hair, Moyamoya syndrome, Noonan syndrome, SHOC2

Pediatr Neurol 2015; 52: 352-355
Ó 2015 Elsevier Inc. All rights reserved.

Introduction

Since Noonan syndrome was first described by Noonan
in 1968,1 great advances in molecular technology have
enabled the identification of the genetic etiologies of
Noonan syndrome and its related disorders.2 These pathologies are caused by germline mutations in genes
involved in the RAS/mitogen-activated protein kinase
(MAPK) signaling cascade. Thus, these disorders are
referred to as “RASopathies.” 3 In 2003, Mazzanti et al.4

Article History:
Received August 26, 2014; Accepted in final form November 28, 2014
* Communications should be addressed to: Yoo; Department of Pediatrics; Asan Medical Center Children’s Hospital; University of Ulsan
College of Medicine; 88; Olympic-Ro 43-Gil; Songpa-Gu; Seoul 138-736;
Korea.
E-mail address: hwyoo@amc.seoul.kr
1

Jin-Ho Choi and Moon-Yeon Oh contributed equally to this work.

0887-8994/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pediatrneurol.2014.11.017

reported Noonan-like syndrome with loose anagen hair
(NS/LAH) (Online Mendelian Inheritance in Man 60772)
characterized by Noonan-like features, including retarded
growth, neurocognitive deficit, and cardiac defects as well
as a unique pattern of ectodermal abnormalities, such as
easily pluckable, slow-growing, thin, and sparse hair. The
LAH syndrome (Online Mendelian Inheritance in Man
600628) is a distinctive hair disorder that usually occurs as
an isolated disorder or rarely in association with other genetic conditions.5 Patients with NS/LAH have short, blond,
fine-textured, sparse, easily pluckable, and slow-growing
hair in the anagen phase that lacks inner and outer root
sheaths.4 LAH is characterized by the complete absence of
telogen hair and a high prevalence of anagen hair, the
strands of which are mostly in the anagen phase, the active
growth phase, when the hair follicles are in a resting state
because the hair shafts are lost during the anagen phase.4,5
All affected individuals with NS/LAH share the same
missense mutation [c.4A>G (p.S2G)] in SHOC2.6

J.-H. Choi et al. / Pediatric Neurology 52 (2015) 352e355

353

FIGURE.
Findings of brain magnetic resonance (MR) angiography (A) and MR imaging (B). (A) Brain MR angiography showed short segmental nonvisualization of
bilateral terminal internal carotid arteries, bilateral proximal middle cerebral arteries, and anterior cerebral arteries, suggesting the narrowing or occlusion of
proximal cerebral arteries. Moyamoya-like vessels were evident in the area of the basal perforators and leptomeningeal collateral vessels. (B) Brain MR imaging
findings revealed diffuse ventriculomegaly involving both lateral, third, and fourth ventricles. (C) Encephalographic findings of the patient at the time of
diagnosis showed several sharp waves from the right parietal area during waking (arrow). (The color version of this figure is available in the online edition.)

Moyamoya syndrome is a progressive occlusive cerebrovascular disease characterized by the bilateral stenosis
of the distal internal carotid arteries or their proximal
branches, with the eventual development of compensatory
collateral vessels.7 The idiopathic form of moyamoya vasculopathy is classified as moyamoya disease.7 These

features can lead to ischemic stroke, intracranial hemorrhage, headache, seizures, and transient ischemic attacks.
Although some cases have been associated with genetic
factors in autosomal dominant moyamoya disease, the
pathogenesis of moyamoya syndrome remains poorly
understood.8

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J.-H. Choi et al. / Pediatric Neurology 52 (2015) 352e355

TABLE.
Previously Reported Patients With RASopathies and Moyamoya Syndrome
References

Diagnosis

Gene

Age

Sex

Symptoms

Other Features

Medical Treatment

Surgical
Treatment

Outcome

This report

NS/LAH

SHOC2 p.S2G

10

F

ASD, VSD, macrocephaly

Low-dose aspirin

Not yet

Ganesan and
Kirkham, 199711

Noonan syndrome

Unknown

9

M

Transient ischemic
attacks
Transient limb
weakness, dysarthria

Low-dose aspirin /
warfarin

Bilateral EDAS

Schuster and
Roberts, 199912
Tang et al., 199913

Noonan syndrome

Unknown

7

F

Hydrocephalus, factor
V Leiden deficiency,
supravalvular aortic
stenosis, pulmonary
valvular stenosis
Aortic coarctation

Recurrent transient
ischemic attacks
Resolution of symptoms
after warfarin

None

Bilateral EDAS

Noonan syndrome

Unknown

5

F

Flunarizine

Not done

Yamashita et al., 2004

Noonan syndrome

Unknown

12

F

ASD, VSD, pulmonary
stenosis
Antiphospholipid
syndrome

Pimozide, aspirin

Not done

Resolution of symptoms
(2 years’ follow-up)

Hung et al., 20119

Noonan syndrome

PTPN11 p.G503 R

9

F

ASD

Not done

Ishiguro et al., 200210

CFC syndrome

Unknown

6.5

M

ASD

Low-dose aspirin,
flunarizine
Low-dose aspirin,

Not done

Resolution of symptoms
(6 months’ follow-up)
Resolution of symptoms

Shiihara et al., 200515

Costello syndrome

Unknown

2

M

Patent ductus arteriosus

Not mentioned

Not mentioned

Not mentioned

14

Transient right-sided
weakness, dysarthria
Repeated transient
ischemic attack
Headache, right-sided
chorea and hypotonia,
dysarthria
Recurrent headache
with nausea
Transient left
hemiplegia, right-sided
eye deviation
No symptoms

Resolution of symptoms
(2 years’ follow-up)
Resolution of symptoms

Abbreviations:
ASD
¼ Atrial septal defect
CFC syndrome ¼ Cardio-facio-cutaneous syndrome
EDAS
¼ Encephalo-duro-arterio synangiosis
F
¼ Female
M
¼ Male
NS/LAH
¼ Noonan-like syndrome with loose anagen hair
VSD
¼ Ventricular septal defect

We recently encountered a child with moyamoya syndrome associated with NS/LAH who presented with transient ischemic attacks. Here, we describe the clinical
features, radiological findings, molecular characteristics,
and clinical course of this girl and review the previously
reported cases.

ventriculoperitoneal shunt was not required to relieve the hydrocephalus. Electroencephalograph revealed several sharp wave discharges from
the right parietal areas (Figure C). The patient was diagnosed with
moyamoya syndrome and has since been treated with aspirin and calcium channel blockers. However, encephalo-duro-arterio-synangiosis
surgery is planned because of recurrent transient ischemic attacks.
Other vascular anomalies such as renal stenosis were not investigated
because she did not have hypertension or arterial bruits.

Patient Description
A 10-year-old girl presented with a transient ischemic attack. She was
born at term with a birth weight of 4.0 kg and with no perinatal problems to healthy nonconsanguineous parents. In the neonatal period,
small atrial and ventricular septal defects, which later closed spontaneously, were detected by echocardiography. When she reached
1.4 years of age, she presented to an outpatient clinic because of facial
dysmorphism, including macrocephaly, hypertelorism, shallow orbital
ridge, bitemporal narrowing, and exotropia. Her height, weight, and
head circumference were 78.5 cm (e0.72 standard deviation score
[SDS]), 12 kg (0.99 SDS), and 52.8 cm (3.74 SDS), respectively. She could
sit alone, walk with support, and speak some words. Chromosome
analysis and brain magnetic resonance (MR) imaging were normal. She
was not followed after age 1.8 years.
At 6.4 years of age, she presented to our institute again because of
profoundly short stature (104.9 cm; e2.62 SDS) and macrocephaly
(56 cm; 3.44 SDS). Several ectodermal abnormalities, such as sparse, fine
textured, blond hair and erythematous papular skin, became evident. By
direct sequencing of the SHOC2 gene, we identified a heterozygous
mutation, c.4A>G (p.S2G).
At age 10.2 years, our patient experienced recurrent transient left
hemiplegia. Laboratory findings, including complete blood count,
chemical battery, and coagulation battery, as well as protein C, protein S,
and autoimmune antibodies were all normal. Brain MR angiography
demonstrated short, segmental nonvisualization of the bilateral terminal
internal carotid arteries and both proximal middle cerebral arteries and
anterior cerebral arteries at the circle of Willis. Moreover, moyamoyalike vessels in the area of the basal perforators and leptomeningeal
collateral vessels were evident (Figure A). Diffuse ventriculomegaly was
also noted by brain MR imaging (Figure B). However, a

Discussion

Only a few examples of RASopathies associated with
moyamoya syndrome have been reported to date,
including five individuals with Noonan syndrome and one
with Costello and cardio-facio-cutaneous syndromes
(Table).9-15 Here we describe the first patient with NS/LAH
associated with moyamoya syndrome. NS/LAH was first
described by Mazzanti et al.4 It is characterized by NS-like
clinical features and LAH; this condition is also known as
Mazzanti syndrome. Our patient had clinical features
similar to those of the previously reported NS/LAH cases,
such as growth retardation, a cardiac defect, macrocephaly, and LAH.2,4,6 In 2009, Cordeddu et al.6 sequenced
the SHOC2 gene in 410 subjects with Noonan syndrome or
Noonan-related disorders who did not have mutations in
the genes that encode the known components of the RASMAPK pathway. They identified 21 patients (5.1%) who
harbored the p.S2G mutation in the SHOC2 gene. These
patients showed clinical features similar to those of the
Mazzanti syndrome, such as growth retardation, cardiac
anomalies, cognitive deficits, hyperactive behavior, dark
pigmented skin with eczema, and LAH.
In previous studies, cerebrovascular anomalies, such as
cavernous malformations, aneurysms, arteriovenous malformations, and intracerebral occlusive artery diseases,

J.-H. Choi et al. / Pediatric Neurology 52 (2015) 352e355

have been reported in patients with Noonan syndrome.9
The pathophysiology of cerebrovascular anomalies in
RASopathies is unclear. However, previous reports have
suggested that alternations in the RAS-MAPK pathway may
lead to abnormal cerebrovascular formations, such as
moyamoya vessels caused by the disruption of RAF1.
Because RAF1 can be activated by the gene product of
SHOC2, it is a regulatory factor that can play an important
role in vascular endothelial cell proliferation and migration,
which are the first steps in angiogenesis.16 During
embryogenesis, the origin of the internal carotid arteries
and the aortic outlet are closely related. Disrupted vascular
development in this region during the prenatal period accounts for both aortic and carotid abnormalities.9
Our patient exhibited hydrocephalus without periventricular edema from foramen magnum stenosis. She also
had moyamoya syndrome, which has been rarely reported
among RASopathies. In a previous report of hydrocephalus
with moyamoya syndrome, hydrocephalus with Chiari
malformation type I was present before the moyamoya
syndrome developed.16 This finding suggests no direct
relationship between moyamoya syndrome and hydrocephalus. The limitations of this report are that the causal
relationship between hydrocephalus and moyamoya syndrome was not distinct and that the long-term course was
not described.
In conclusion, moyamoya syndrome can be associated
with RASopathies such as NS/LAH. Although the relationship between NS/LAH and moyamoya syndrome remains to
be elucidated, this syndrome should be considered in patients with RASopathies that present with neurological
symptoms such as stroke or transient ischemic attacks.
This study was supported by a grant from the Ministry for Health, Welfare and
Family Affairs, Republic of Korea (2011-0019674). None of the authors has conflict of
interest to disclose. The authors confirm that they have read the journal’s position
on issues relating to ethical publication and affirm that this report is consistent with
those guidelines.

355

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