ૺ̚Ꮈ
͕᝙.ᓚ.ϩቲᇈ࣏ཏ
ęঽּಡӘę
Ꮵᖳ౰
ధ႔ᅛ
઼ϲјΑ̂ጯϩቲࡊ
Cardio-Facio-Cutaneous Syndrome
- A Case Report Feng-Jie Lai Hamm-Ming Sheu
We report on a 9-year-old boy with typical manifestations of cardio-facio-cutaneous (CFC) syndrome. The patient was affected by congenital heart defects, short stature, mild mental retardation and
cutaneous abnormalities, including dry skin, eczematous skin, sparse, curly eyebrows/eyelashes, mildly
curly hair, a peculiar craniofacial appearance with low-set posteriorly rotated ears. Clinically, CFC syndrome has several features in common with Costello syndrome (CS) and Noonan syndrome (NS)
including craniofacial changes, growth retardation, development delay, and heart defects. CFC syndrome and CS can be distinguished from NS by the presence of ectodermal abnormalities, mental retardation and a lack of familial cases. CFC syndrome can be distinguished from CS by the rare presence of
papillomata, fetal pads, acanthosis nigricans, wrinkled palms and soles, and loose skin of the hands and
feet. This is the first reported case of this disease in Taiwan. We also review the literature concerning
the clinical course and pathogenesis of this uncommon entity. (Dermatol Sinica 24: 140-144, 2006)
Key words: Cardio-Facio-Cutaneous syndrome, Costello syndrome, Noonan syndrome
ԧࣇಡӘ˘Ҝ9໐̂۞շආĂࠎ˘‫͕۞ݭ׏‬᝙-ᓚ-ϩቲᇈ࣏ཏଈ۰Ą΁‫׍‬ѣА͇͕᝙৿
ౝĂ༣̈Ăᅅ‫ޘ‬ംᅪͽ̈́ϩቲ˯۞ள૱ĂΒ߁ϩቲ઀ᒌĂᒅৃّϩቲ‫ۆ‬ĂංழĂଡѡ۞࠺ͨ
Ɲ༘ͨ̈́ᅅ‫ޘ‬ଡѡ۞ᐝጀĂ፾প۞្ࢬγ៍‫׀‬ѣҲҜͷШ‫ޢ‬୊ᖼ۞҅ѧĄᓜԖ˯Ă͕᝙-ᓚϩቲᇈ࣏ཏᄃࡊ೻পࠃᇈ࣏ཏ̈́Ӆշᇈ࣏ཏˬ۰ѣధкপᕇᙷҬĂΒ߁ѣ្ࢬγ៍۞ԼតĂ
Ϡ‫ܜ‬ቤၙĂ൴ֈᏵቤ͕̈́᝙৿ౝĄ͕᝙-ᓚ-ϩቲᇈ࣏ཏ̈́ࡊ೻পࠃᇈ࣏ཏ˟۰Ӯ‫׍‬ѣγࡣᆸ
۞ள૱ĂംᅪĂ̈́৿ͻछ୉९ּĂ఺ֱΞͽ‫׶‬Ӆշᇈ࣏ཏડҾć͕҃᝙-ᓚ-ϩቲᇈ࣏ཏଈ۰
ց֍֯ࡎሳĂࡩ‫׊‬ါĂโഌϩঽĂ͘ೠཙೠሸ৳̈́͘ཙழᗫ۞ϩቲĂ఺ֱΞͽ‫ࡊ׶‬೻পࠃᇈ
࣏ཏડҾĄ఺ߏௐ˘Ѩдέ៉ಡӘѩ჌ঽּĂԧࣇТॡаᜪ͛ౢ੅ኢѩ჌̙૱֍ᇈ࣏ཏ̝ᓜ
Ԗܑன̈́࡭ঽࣧЯĄ (̚රϩᄫ 24: 140-144, 2006)
From the Department of Dermatology, National Cheng Kung University
Accepted for publication: December 01, 2005
Reprint requests: Hamm-Ming Sheu, M.D., Department of Dermatology, National Cheng Kung University, 138, Sheng-Li Road,
Tainan 704, Taiwan, ROC
TEL: 886-6-2004326 FAX: 886-6-2004326 E-mail: [email protected]
140
Dermatol Sinica, June 2006
͕᝙.ᓚ.ϩቲᇈ࣏ཏ ęঽּಡӘę
INTRODUCTION
Cardio-facio-cutaneous (CFC) syndrome
describes the physical findings in children with
multiple congenital anomalies/mental retardation syndrome. Dr. Jim Reynolds and colleagues
first described CFC syndrome in 1986 with very
facial abnormalities, mental retardation, early
failure to thrive, congenital heart defects, short
stature, and ectodermal abnormalities. 1 CFC
syndrome is a rare condition with less than 100
cases having been reported in the literature up
to 2004.2 There is some overlap between the
clinical manifestations of this syndrome and the
syndromes described by Noonan3 and Costello.4
Initially, CFC was considered to be a variant of
Noonan syndrome (NS),5 but now it has been
recognized as a separate entity.6 All the CFC
cases tested, so far, have tested negative for
PTPN11 mutations of the Noonan gene.7
We report a rare instance of CFC occurring
in a 9-year-old boy with a wide range of cutaneous abnormalities, congenital heart defects,
short stature and mild mental retardation.
CASE REPORT
The patient was the second of two children
born to healthy nonconsanguineous parents.
His mother and father were 28 and 36 years old,
respectively, at the time of his birth. His elder
sister was healthy. Neither the parents nor their
firstborn child had a medical history suggestive
Fig. 1
A: When the patient was 3 years and 10 months old, a chest
X-ray showed no active lung lesions. The heart had
enlarged status post sternostomy with ventricular septal
defect patch repair. B: When the patient was 8 years and 4
months old, bone age was 3 years old.
Dermatol Sinica, June 2006
of CFC. They had no facial abnormalities, no
congenital heart defects and were of normal
height. The patient was a full-term baby, delivered smoothly in a tertiary care hospital. His
birth weight was 3650g, and his head circumference was normal. There were feeding problems,
and failure to thrive since the neonatal period
was noted. At 2 months old, ventricular septal
defect (type II), tricuspid regurgitation, and
mild pulmonic stenosis were noted. Surgical
correction was performed at the age of 46
months (Fig. 1A). The patient had delayed
developmental milestones, for example, saying
"Pa Pa" or "Ma Ma" at 30 (normal: 10-12)
months old and walking at 32 (normal: 12-15)
months old. Genetic studies revealed a normal
karyotype of 46XY. He had bilateral orchiopexy
for undescended testicles at the age of 4. When
he was 8 years and 4 months old, his bone age
was about 3 years (Fig. 1B). His performance
in school was below average, with a decreased
"attention" span. Mild mental retardation was
also noted when he was 6 years and 5 months
old (psychological age: 4 years and 11 months
old), with IQ of 70.
When examined at 8 years and 10 months
old (Fig. 2), his body weight was 16.6 kg (< 3th
percentile) and body length 104 cm (< 3th percentile). He was presented to us with complaints of generalized itching since 4 years of
age. He had generalized eczema (Fig. 2, A and
B) with lichenification of the arms and legs,
especially on the cubital and popliteal fossae
(Fig. 2B). These cutaneous features are characteristics of severe atopic dermatitis according to
the Japanese Dermatological Association criteria for the diagnosis of atopic dermatitis.8 Total
serum immunoglobulin E (IgE) levels were
197.4 IU/ml. Multiple-antigen simultaneous test
(MAST) for 35 allergen-specific IgE antibodies
revealed only low sensitization to milk. His
facial anomalies were a broad forehead, hypertelorism, slightly antimongoloid slant of the
eyes, ptosis, depressed nasal bridge, broad nose,
and triangular mouth with a highly arched
palate. Other physical anomalies were low-set
and posteriorly rotated ears with thick helices
141
Ꮵᖳ౰
(Fig. 2, A and C), webbing of the neck (Fig.
2A), sparse and mildly curly eyebrows, long
and unruly eyelashes (Fig. 2D), curly scalp hair
with normal posterior hairline (Fig. 2C), thin
and slowly-growing nails (Fig. 2E), wrinkled
palms and soles (Fig. 2F). A diagnosis of CFC
syndrome was made based on his characteristic
facial, cutaneous and systemic features (Table
1). His CFC index6 was calculated to be 17.824,
which confirms the CFC diagnosis for this
patient.
His dermatitis was treated by moisturizing
creams, antihistamines, and sometimes by narrow band UVB, topical tacrolimus (0.03%),
topical steroids, and systemic antibiotics. His
cutaneous condition improved significantly
after 10 months of treatment (Fig. 2C).
DISCUSSION
Cardio-facio-cutaneous (CFC) syndrome
was first described by Reynolds et al. in 1986.1
Four consistent abnormalities in all eight
patients of the case study of Reynolds et al.
were (1) growth and psychomotor retardation
with various neurological findings; (2) characteristic facial appearance with a relatively disproportionately large head, high forehead,
bitemporal constriction, hypoplasia of supraorbital ridges, antimongoloid slant of palpebral
fissures, depressed bridge of the nose, and posteriorly angulated ears with prominent helices;
(3) congenital heart defects such as pulmonic
stenosis and atrial septal defect; and (4) ectodermal dysplasia with various skin findings such as
sparse, friable, curly hair, patchy alopecia,
ichthyosis, and hyperkeratosis.
CFC, Costello and Noonan syndromes
have some features in common. The main features of NS are (1) short stature; (2) a short neck
with webbing or skin redundancy; (3) congenital heart defects; (4) peculiar chest deformity
with pectus carinatum superiorly and pectus
excavatum inferiorly; (5) wide-spaced nipples;
(6) a peculiar facial appearance, made up of
hypertelorism, low-set posteriorly rotated ears,
downslanting palpebral fissures, deeply grooved
philtrum and a broad nasal tip; and (7) usually
normal intelligence.3, 9 CS is characterized by
(1) prenatally increased growth, postnatal
growth retardation, (2) coarse face, (3) loose
skin resembling cutis laxa, (4) nonprogressive
cardiomyopathy, (5) developmental delay, (6)
nasal papillomata, and (7) an outgoing, friendly
behavior.10 The major characteristics and cutaneous features along with their frequency in
CFC patients in comparison with NS and CS are
listed in Table 1. Craniofacial changes, growth
failure, development delay, and heart defects are
common features of each syndrome. Ectdermal
abnormalities are seemingly a major feature in
CFC syndrome (100%) and CS (100%), but not
in NS (27-35%). Mental retardation is more fre-
Fig. 2
Patient at the age of 8 years and 10 months and at
the age of 9 years and 8 months. A: Facial appearance with high forehead, bitemporal constriction,
bilateral epicanthic folds, ptosis, broad-based
nose, low-set ears and hyperkeratotic skin lesions.
A scar over chest wall was also noted after ventricular septal defect patch repair at 3 years and 10
months old. B: Lichenification of the arms and
legs, especially at the popliteal fossi. C: When the
patient was 9 years and 8 months old, atopic-like
dermatitis over the face improved significantly
after treatment. Note posterior angulation of auricles with hypertrophy of helices. D: Eyebrows
showed a sparse and mild curly appearance with
long and unruly eyelashes. Atopic-like dermatitis
was prominent over the temporal area. E: Brittle
thin broad nails and slow growth since birth. F:
Wrinkled palms were also noted.
142
Dermatol Sinica, June 2006
͕᝙.ᓚ.ϩቲᇈ࣏ཏ ęঽּಡӘę
Table I. Main characteristics and cutaneous features and their frequencies in cardio-facio-cutaneous
(CFC) syndrome, including our one patient, Costello and Noonan syndromes
Characteristics
Number
Main feature
Growth failure
Development delay
Heart defects
Craniofacial changes
Mental retardation
Ectodermal abnormalities
Hair
Sparse
Curly
Fine/Thin
Sparse eyelashes/eyebrows
Skin
Hyperkeratosis
Dry
Eczema
Keratosis pilaris
Loose skin of hands and feet
Wrinkled palms and soles
Fetal pads
Papillomata
Seborrheic dermatitis
Acanthosis nigricans
Cafe-au-lait spots
Pigmented nevi
Nails
Dysplastic/thin/deep-set nails
CFC syndrome a
(%)
59
Our patient
(%)
1
Costello syndrome b
(%)
71
Noonan syndromec
(%)
151
77.8
81.5
80.4
100
94.6
100
+
+
+
+
+
+
96
100
63
100
83.8
100
50
100
87.5
100
24-35
27-35
76.3
59.3
37.3
35.6
+
+
82
14.3
ND
11
29
N
ND
67.6
ND
ND
ND
99
100
87.9
48
ND
24.2
ND
ND
5
ND
ND
14
ND
ND
67
ND
ND
ND
3
25
74.3
ND
54.3
25
18.7
10.6
8.5
9.3
ND
ND
8.5
4.3
7.3
5.5
14.8
+
+
+
+
+
+
ND, not described.
a
Incidence figures are derived from reviews of Kavamura et al.6 and Weiss et al.11
b
Incidence figures are derived from reviews of Hennekam 10 and Weiss et al.11
c
Incidence figures are derived from reviews of Sharland 9 and Weiss et al.11
quent in CFC syndrome (94.6%) and CS
(83.8%) than in NS (24-35%). 11 Pulmonary
stenosis is most common in both CFC and NS,
while cardiomyopathy is most common in CS.
Mental retardation and ectodermal anomalies
are apparently major features in CFC syndrome
and CS, but not in NS.
While CS and CFC syndromes show striking phenotypic similarities, loose skin of the
entire integument, papillomata and acanthosis
Dermatol Sinica, June 2006
nigricans are characteristic cutaneous findings
in CS.11 These findings are rarely documented
in NS and CFC syndrome. The loose skin of the
hands and feet, deep palmar/plantar creases,
coarse face, full cheeks, large mouth, thick lips,
macroglossia, limited extension of the elbows,
hyperextensible fingers, tight Achilles tendons,
generalized hyperpigmentation and excessive
infra-orbital folds are the characteristic dermatological features seen in CS.10
143
Ꮵᖳ౰
NS and CFC have the same spectrum of
congenital heart abnormalities (pulmonic stenosis
and atrial septal defects), although the presence of
ectodermal anomalies (hyperkeratosis, dry skin,
eczematous skin, keratosis pilaris, seborrheic dermatitis) and the typical appearance of the hair
(sparse, curly, fine/thin, sparse eyelashes/eyebrows, poor hair growth), mental retardation and
neurological impairment (muscular hypotonia,
nystagmus, seizures) are the clinical features of
CFC syndrome that allow it to be distinguished
from NS.5 A low posterior hair line, neck abnormalities, cubitus valgus and familial occurrence
are more characteristically linked with NS.
The clinical similarities amongst CFC, NS
and CS might be the result of allelic or locus
heterogeneity, or perhaps of modifying influences of other genetic or nongenetic factors.12
NS is a genetically heterogeneous disorder. The
gene responsible for the disorder (PTPN11)13
was recently identified, explaining nearly one
half of the cases clinically diagnosed as NS.14
However, recent studies7, 15 have shown no abnormalities in the PTPN11 gene of CFC cases.
Our patient had mental retardation and a
wide spectrum of ectodermal abnormalities
including dry, rough skin, eczematous skin,
sparse curly eyelashes/eyebrows, slow growth,
curly hair and slow growth nails. The CFC
index, an objective way of measuring the set of
phenotypic characteristics,6 of our patient was
measured at 17.824, which falls within the diagnostic range (9.5.19.9) as suggested by
Kavamura et al.6 Noonan and Costello patients
are measured below 9.5.6 So far, most CFC
syndrome cases, including the case reported
here, are sporadic, born to non-consanguineous
parents, and have apparently normal chromosomes.7, 15, 16 At the present time, there is no laboratory test for CFC syndrome. The diagnosis
depends on the observations of a clinician.
More reports of this type would help to better
characterize and define this rare syndrome.
REFERENCES
1. Reynolds JF, Neri G, Herrmann JP, et al.: New
multiple congenital anomalies/mental retardation
syndrome with cardio-facio-cutaneous involvement--the CFC syndrome. Am J Med Genet 25:
413-427, 1986.
144
2. Nanda S, Rajpal M, Reddy BS: Cardio-facio-cutaneous syndrome: report of a case with a review of
the literature. Int J Dermatol 43: 447-450, 2004.
3. Noonan JA, Ehmke DA: Associated noncardiac
malformations in children with congenital heart
disease. J Pediatr 63: 468-469, 1963.
4. Costello JM: A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J 13: 114118, 1977.
5. Ward KA, Moss C, McKeown C: The cardio-faciocutaneous syndrome: a manifestation of the Noonan
syndrome? Br J Dermatol 131: 270-274, 1994.
6. Kavamura MI, Peres CA, Alchorne MM, et al.:
CFC index for the diagnosis of cardiofaciocutaneous
syndrome. Am J Med Genet 112: 12-16, 2002.
7. Kavamura MI, Pomponi MG, Zollino M, et al.:
PTPN11 mutations are not responsible for the
Cardiofaciocutaneous (CFC) syndrome. Eur J
Hum Genet 11: 64-68, 2003.
8. Tagami H: Japanese dermatological association
criteria for the diagnosis of atopic dermatitis.
[Japanese] Nippon Hifuka Gakkai Zasshi 104:
1210, 1994.
9. Sharland M, Burch M, McKenna WM, et al.: A
clinical study of Noonan syndrome. Arch Dis
Child 67: 178-183, 1992.
10.Hennekam RCM: Costello syndrome: an overview.
Am J Med Genet C 117: 42-48, 2003.
11. Weiss G, Confino Y, Shemer A, et al.: Cutaneous
manifestations in the cardiofaciocutaneous syndrome, a variant of the classical Noonan syndrome.
Report of a case and review of the literature. J Eur
Acad Dermatol Venereol 18: 324-327, 2004.
12.Manoukian S, Lalatta F, Selicorne A, et al.:
Cardio-facio-cutaneous (CFC) syndrome. Report
of an adult without mental retardation. Am J Med
Genet 27: 382-385, 1987.
13.Tartaglia M, Mehler EL, Goldberg R, et al.:
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.
Nat Genet 29: 465-468, 2001.
14.Jongmans M, Sistermans EA, Rikken A, et al.:
Genotypic and phenotypic characterization of
Noonan syndrome: new data and review of the literature. Am J Med Genet A 134: 165-170, 2005.
15.Ion A, Tartaglia M, Song X, et al.: Absence of
PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. Hum Genet 111: 421-427,
2002.
16.Kavamura MI, Zollino M, Lecce R, et al.:
Absence of 12q21.2q22 deletions and subtelomeric rearrangements in cardiofaciocutaneous (CFC)
syndrome patients. Am J Med Genet A 119: 177179, 2003.
Dermatol Sinica, June 2006