American Journal of Medical Genetics 39:144-147 (1991)
Cardio-Facio-Cutaneous(CFC) Syndrome: Report of Two Patients Without Hyperkeratotic Skin Lesions Yukihisa Matsuda, Ichiro Murano, Osamu Kondoh, Kiyosato Matsuo, and Tadashi Kajii Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Japan
We report on two boys with the cardio-faciocutaneous (CFC) syndrome, but without hyperkeratotic skin involvement. They showed most of the manifestations of the CFC syndrome: growth and developmental retardation, relative macrocephaly, distinct facial appearance, sparse hair, and heart defects. Their skin was not hyperkeratotic, but patient 1 had mild atopic dermatitis and keloid-like depigmented spots.
KEY WORDS mental retardation, multiple congenital anomalies syndrome, ectodermal dysplasia, cardiac defects, sporadic occurrence, CFC syndrome INTRODUCTION Reynolds et al. [1986] described a new syndrome called the cardio-facio-cutaneous (CFC) syndrome, characterized by mental and growth retardation, relative macrocephaly, unusual face, webbed neck, sparse hair, hyperkeratosis, and congenital heart defect. At least 15 patients with the syndrome have been reported [Reynolds et al., 1986; Neri e t al., 1987; Chrzanowska et al., 1989; Mucklow 1989; Sorge et al., 19891. The CFC syndrome resembles the Noonan syndrome. Baraitser and Patton 119861 described four patients whose phenotype was similar to that of the CFC syndrome, but these patients lacked skin involvement. This paper deals with two Japanese boys with the CFC syndrome but without hyperkeratosis of the skin. CLINICAL REPORT Patient 1 Patient T.M. (0522955), a boy, was delivered by vacuum extraction after a 37 week gestation to a 34 year old father and 33 year old mother, both healthy and unrelated. Birth weight was 3,440 g, and length, 47.8 cm. An elder brother is mentally and physically normal. The Received for publication February 12, 1990. Address reprint requests to Dr. Yukihisa Matsuda, Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan 755.
0 1991 Wiley-Liss, Inc.
patient was hospitalized for acute pneumonia a t age 4 weeks, when heart murmurs were audible. He lifted his head at 7 months and walked a t 3 years. His scalp hair was sparse (Fig. 1). He never had his hair cut during infancy, and thereafter, only once a year or two. He has suffered since infancy from atopic dermatitis and later from allergic rhinitis and chronic sinusitis. Bilateral cryptorchidism was corrected surgically. At age 7 years, he weighed 14.4 k g ( - 2 . 4 SD), was 97.5 cm ( - 4.7 SD) tall, and had head circumference (OFC) 50 cm ( - 1 . 3 SD). He showed relative macrocephaly with bitemporal constriction and a high cranial vault, sparse hair, and prominent scalp veins. He had a n unusual facial appearance with absent supraorbital ridges, sparse eyebrows, hypertelorism, downslanting palpebral fissures; bilateral ptosis; a slightly beaked nasal bridge continuous from the forehead and a roundtipped nose and with a prominent columella; posteriorly rotated and apparently low-set ears with a prominent helix; and a “bow-shaped’’ mouth. He had a webbed neck, a shield chest, and pectus excavatum. A Levine 2/6 systolic murmur was audible over the precordium. His limbs were slender. His skin was dark with several keloid-like depigmented spots over the chest and back, left after a chickenpox infection at age 4 years. He had mild eczema in the antecubital and popliteal fossae with several papules, but without thickening of the skin. Upon reexamination a t age 92/12 years (Fig. 21, he weighed 16.6 kg ( - 2.3 SD), measured 104.2 cm ( - 4.8 SD), and head circumference was 51.1 cm ( - 1.0 SD). Radiographs showed a right convex thoracic scoliosis. His bone age was estimated a t 5% years. Computed tomography of the brain did not show any abnormalities. His school performance was poor, but his I& was estimated a t 95. Cardioangiography documented hypertrophic cardiomyopathy. Dermal patterns were (right) t, abed, W,Lu,Lu,Lu,Lu; (left) t, abed, W,Lu,Lr,Lu,W; and total finger ridge count was 166. Chromosomes were normal. The response of his serum growth hormone to insulin loading was normal, a s was its secretion during sleep, whereas the plasma somatomedin-C level was low a t 0.28 Uiml. The response of TSH to TRH (7 ygikg body weight given i.v. in one bolus) was normal, as was the response of serum FSH to LH-RH (100 yg/m2 given i.v. in one bolus), whereas that of LH to LH-RH was weak with a peak value of 5.2 mUlml 30 min after loading.
CFC Syndrome
Fig. 1. Patient 1 a t age 4 years. Note relative macrocephaly and sparse hair.
Patient 2 Patient H.I. (0271226),a boy, was born after a 39 week gestation to a 30 year old father and 23 year old mother, both healthy and unrelated. Birth weight was 2,574 g,
Fig. 2. Patient 1 at
92/12
145
and length, 46 cm. There is a healthy and normal elder brother. When first seen by us a t age 2 months because of feeding difficulties, he weighed 3,430 g (-3.7 SD) and his length was 52.2 cm ( - 3.1 SD). He showed the following anomalies: relative macrocephaly with bitemporal constriction, a high cranial vault, hypertelorism, downslanting palpebral fissures with bilateral ptosis, a short nose with a rounded tip and upturned nostrils, posteriorly angulated and low-set ears, a webbed neck, and sparse and thin hair. His fingernails were hypoplastic. An ophthalmological examination showed bilateral congenital partial cataracts and alternate internal strabismus. He lifted his head at 6 months, sat at 16 months, and walked at 2 years. He was frequently admitted to our ward in the ensuing 4 years because of repeated bronchopneumonia and acute otitis media and sinusitis. Cardioangiography at age 1 year showed valvular pulmonary stenosis and atrial septa1 defect. Computed tomography of the brain revealed no abnormalities. At age 4 years, he weighed 11.2kg ( - 2.5 SD) and had height of 88.2 cm ( - 4.0 SD) and head circumference of 51.8 cm ( + 0.7 SD). His facial appearance was characteristic: relative macrocephaly, dilated scalp veins, a high cranial vault, and sparse hair (Fig. 3). He had
years. Sparse eyebrows with lateral duplication
146
Matsuda et al.
Fig. 3. Patient 2 at 4 years.
slender limbs. His I& was 71. Dermatoglyphics was (R) t, abcd, W,W,W,W,Lu; (L) t, abcd, W,W,W,W,W.His total finger ridge count was 162. Chromosomes were normal.
DISCUSSION The two patients we described had clinical manifestations consistent with the CFC syndrome, but were without hyperkeratotic lesions. Both showed growth and developmental delay with relative macrocephaly, a characteristic facial appearance, webbed neck, congenital heart defect, and sparse hair and eyebrows (Table I). They had a shield-like chest and pectus excavatum. Their facial characteristics included a high boxy appearance of the cranial vault with bitemporal constriction, posteriorly angulated auricles with thick helix, hypertelorism, downslanting palpebral fissures, bilateral ptosis, a short, round-tipped nose, thin upper lip, and high arched palate (Table 11).The columella was promi-
nent in patient 1.In both patients, the nasal bridge was more or less continuous from the forehead partly because of hypoplasia of the supraorbital ridges and slightly beaked in patient 1to continue to a rounded tip. The latter trait is noted also in many of the photographs of the previously reported patients with the syndrome. Both patients showed sparse, thin hair that rarely required cutting and sparse eyebrows. The lateral half of the eyebrows in patient 1was dispersed to a n extent that could be called partial duplication. Patient 1 had several keloid-like, depigmented spots over the body, left after a chickenpox infection, and papulae in the antecubital and popliteal fossae due to mild atopic dermatitis. However, both patients lacked hyperkeratotic skin manifestations, as noted in most of the previously reported patients with the CFC syndrome (Table 111). This lack of skin involvement is noted in one ofthe 15patients in the literature: patient 2, a n 11-month-old girl described by
CFC Syndrome
147
TABLE I. Clinical Manifestations CFC syndrome M:F = 8:7
-
Sex Developmental disability or MR Growth retardation Relative macrocephaly Distinctive face Abnormal hair Hyperkeratotic skin lesions Eye abnormality Webbed neck Cardiac defect Splenomegaly Hemangioma Herniae
Baraitser and Patton [19861 M:F = 1:3 414 414 414 414 414 014 014 314 214 014 014 014
15115 13115 13115 15115 15115 14115 13/15 6115 12114 6115 6115 5115
Patient
Patient
1 -
2
M
M
-
-
+ + + + + + + +
+ + + + + + + +
TABLE 11. Craniofacial Abnormalities -
-~
CFC syndrome ~~
High crainial vault Bitemporal constriction Hypoplasia of supraorbital ridges Downslanting palpebral fissures F’tosis Epicanthic folds Depressed bridge of nose Anteverted nostrils Posteriorly angulated auricles with hypertrophy of helices High-arched palate
Baraitser and Patient Patton [19861 - 1 414 314 114 014 014 014 014 014 3I 4
10115 12/15 11/15 12115 9/15 11115 12/15 7/15 11/15
3
7/15
Patient 2
+ + + + +
+
+
+
+ + + + + +
+
+
Patient 2
TABLE 111. Ectodermal Involvement CFC syndrome
Baraitser and Patton [19861
Patient
14115 2115 12115 1/15
414 014 114 014
+
5/15 8115 5/15
014 014 014
-
~ ~ _ _ _ _ _ ~ ~
Hair Sparse Friable Curly Patchy alopecia Skin Ichthyosis Hyperkeratosis Chronic eczema a
1
-
f a
Mild atopic dermatitis
Reynolds et al. [1986]. It is of interest to note in this connection that Baraitser and Patton [ 1986J described four patients age to years with a ‘Ombinat ion Of clinical manifestations apparently identical with the ‘parse hair and eyebrows, but CFC without skin involvement. We would like to suggest that these 4 patients and the two patients we described represent a part of the clinical spectrum of the CFC syndrome. REFERENCES Baraitser M, Patton MA (1986):A Noonan-like short stature syndrome with sparse hair. J Med Genet 23:161-164.
Chrzanowska K, Fryns JP, Van den Berghe H (1989): Cardio-faciocutaneous (CFC) syndrome: %Port of a new Patient. Am J Med Genet 33:471-473. Mucklow ES (1989):A case of the cardio-facio-cutaneoussyndrome. Am J Med Genet 33:474-475, Neri G, Sabatino G, Bertini E, Genuardi M (1987):The CFC syndrome: Report of the first two cases outside the United States. Am J Med Genet 27:767-771. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz J M (1986): New multiple congenital anomaliesimental retardation syndrome with cardio-facio-cutaneous involvement. The CFC syndrome. Am J Med Genet 25:413-427. Sorge G , Di Forti F, Scarano G, Ventruto V, Zelante L, Dallapiccola B (1989): CFC syndrome: Report of three additional cases. Am J Med Genet 33:476-478.
Cardio-Facio-Cutaneous(CFC) Syndrome: Report of Two Patients Without Hyperkeratotic Skin Lesions Yukihisa Matsuda, Ichiro Murano, Osamu Kondoh, Kiyosato Matsuo, and Tadashi Kajii Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Japan
We report on two boys with the cardio-faciocutaneous (CFC) syndrome, but without hyperkeratotic skin involvement. They showed most of the manifestations of the CFC syndrome: growth and developmental retardation, relative macrocephaly, distinct facial appearance, sparse hair, and heart defects. Their skin was not hyperkeratotic, but patient 1 had mild atopic dermatitis and keloid-like depigmented spots.
KEY WORDS mental retardation, multiple congenital anomalies syndrome, ectodermal dysplasia, cardiac defects, sporadic occurrence, CFC syndrome INTRODUCTION Reynolds et al. [1986] described a new syndrome called the cardio-facio-cutaneous (CFC) syndrome, characterized by mental and growth retardation, relative macrocephaly, unusual face, webbed neck, sparse hair, hyperkeratosis, and congenital heart defect. At least 15 patients with the syndrome have been reported [Reynolds et al., 1986; Neri e t al., 1987; Chrzanowska et al., 1989; Mucklow 1989; Sorge et al., 19891. The CFC syndrome resembles the Noonan syndrome. Baraitser and Patton 119861 described four patients whose phenotype was similar to that of the CFC syndrome, but these patients lacked skin involvement. This paper deals with two Japanese boys with the CFC syndrome but without hyperkeratosis of the skin. CLINICAL REPORT Patient 1 Patient T.M. (0522955), a boy, was delivered by vacuum extraction after a 37 week gestation to a 34 year old father and 33 year old mother, both healthy and unrelated. Birth weight was 3,440 g, and length, 47.8 cm. An elder brother is mentally and physically normal. The Received for publication February 12, 1990. Address reprint requests to Dr. Yukihisa Matsuda, Department of Pediatrics, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan 755.
0 1991 Wiley-Liss, Inc.
patient was hospitalized for acute pneumonia a t age 4 weeks, when heart murmurs were audible. He lifted his head at 7 months and walked a t 3 years. His scalp hair was sparse (Fig. 1). He never had his hair cut during infancy, and thereafter, only once a year or two. He has suffered since infancy from atopic dermatitis and later from allergic rhinitis and chronic sinusitis. Bilateral cryptorchidism was corrected surgically. At age 7 years, he weighed 14.4 k g ( - 2 . 4 SD), was 97.5 cm ( - 4.7 SD) tall, and had head circumference (OFC) 50 cm ( - 1 . 3 SD). He showed relative macrocephaly with bitemporal constriction and a high cranial vault, sparse hair, and prominent scalp veins. He had a n unusual facial appearance with absent supraorbital ridges, sparse eyebrows, hypertelorism, downslanting palpebral fissures; bilateral ptosis; a slightly beaked nasal bridge continuous from the forehead and a roundtipped nose and with a prominent columella; posteriorly rotated and apparently low-set ears with a prominent helix; and a “bow-shaped’’ mouth. He had a webbed neck, a shield chest, and pectus excavatum. A Levine 2/6 systolic murmur was audible over the precordium. His limbs were slender. His skin was dark with several keloid-like depigmented spots over the chest and back, left after a chickenpox infection at age 4 years. He had mild eczema in the antecubital and popliteal fossae with several papules, but without thickening of the skin. Upon reexamination a t age 92/12 years (Fig. 21, he weighed 16.6 kg ( - 2.3 SD), measured 104.2 cm ( - 4.8 SD), and head circumference was 51.1 cm ( - 1.0 SD). Radiographs showed a right convex thoracic scoliosis. His bone age was estimated a t 5% years. Computed tomography of the brain did not show any abnormalities. His school performance was poor, but his I& was estimated a t 95. Cardioangiography documented hypertrophic cardiomyopathy. Dermal patterns were (right) t, abed, W,Lu,Lu,Lu,Lu; (left) t, abed, W,Lu,Lr,Lu,W; and total finger ridge count was 166. Chromosomes were normal. The response of his serum growth hormone to insulin loading was normal, a s was its secretion during sleep, whereas the plasma somatomedin-C level was low a t 0.28 Uiml. The response of TSH to TRH (7 ygikg body weight given i.v. in one bolus) was normal, as was the response of serum FSH to LH-RH (100 yg/m2 given i.v. in one bolus), whereas that of LH to LH-RH was weak with a peak value of 5.2 mUlml 30 min after loading.
CFC Syndrome
Fig. 1. Patient 1 a t age 4 years. Note relative macrocephaly and sparse hair.
Patient 2 Patient H.I. (0271226),a boy, was born after a 39 week gestation to a 30 year old father and 23 year old mother, both healthy and unrelated. Birth weight was 2,574 g,
Fig. 2. Patient 1 at
92/12
145
and length, 46 cm. There is a healthy and normal elder brother. When first seen by us a t age 2 months because of feeding difficulties, he weighed 3,430 g (-3.7 SD) and his length was 52.2 cm ( - 3.1 SD). He showed the following anomalies: relative macrocephaly with bitemporal constriction, a high cranial vault, hypertelorism, downslanting palpebral fissures with bilateral ptosis, a short nose with a rounded tip and upturned nostrils, posteriorly angulated and low-set ears, a webbed neck, and sparse and thin hair. His fingernails were hypoplastic. An ophthalmological examination showed bilateral congenital partial cataracts and alternate internal strabismus. He lifted his head at 6 months, sat at 16 months, and walked at 2 years. He was frequently admitted to our ward in the ensuing 4 years because of repeated bronchopneumonia and acute otitis media and sinusitis. Cardioangiography at age 1 year showed valvular pulmonary stenosis and atrial septa1 defect. Computed tomography of the brain revealed no abnormalities. At age 4 years, he weighed 11.2kg ( - 2.5 SD) and had height of 88.2 cm ( - 4.0 SD) and head circumference of 51.8 cm ( + 0.7 SD). His facial appearance was characteristic: relative macrocephaly, dilated scalp veins, a high cranial vault, and sparse hair (Fig. 3). He had
years. Sparse eyebrows with lateral duplication
146
Matsuda et al.
Fig. 3. Patient 2 at 4 years.
slender limbs. His I& was 71. Dermatoglyphics was (R) t, abcd, W,W,W,W,Lu; (L) t, abcd, W,W,W,W,W.His total finger ridge count was 162. Chromosomes were normal.
DISCUSSION The two patients we described had clinical manifestations consistent with the CFC syndrome, but were without hyperkeratotic lesions. Both showed growth and developmental delay with relative macrocephaly, a characteristic facial appearance, webbed neck, congenital heart defect, and sparse hair and eyebrows (Table I). They had a shield-like chest and pectus excavatum. Their facial characteristics included a high boxy appearance of the cranial vault with bitemporal constriction, posteriorly angulated auricles with thick helix, hypertelorism, downslanting palpebral fissures, bilateral ptosis, a short, round-tipped nose, thin upper lip, and high arched palate (Table 11).The columella was promi-
nent in patient 1.In both patients, the nasal bridge was more or less continuous from the forehead partly because of hypoplasia of the supraorbital ridges and slightly beaked in patient 1to continue to a rounded tip. The latter trait is noted also in many of the photographs of the previously reported patients with the syndrome. Both patients showed sparse, thin hair that rarely required cutting and sparse eyebrows. The lateral half of the eyebrows in patient 1was dispersed to a n extent that could be called partial duplication. Patient 1 had several keloid-like, depigmented spots over the body, left after a chickenpox infection, and papulae in the antecubital and popliteal fossae due to mild atopic dermatitis. However, both patients lacked hyperkeratotic skin manifestations, as noted in most of the previously reported patients with the CFC syndrome (Table 111). This lack of skin involvement is noted in one ofthe 15patients in the literature: patient 2, a n 11-month-old girl described by
CFC Syndrome
147
TABLE I. Clinical Manifestations CFC syndrome M:F = 8:7
-
Sex Developmental disability or MR Growth retardation Relative macrocephaly Distinctive face Abnormal hair Hyperkeratotic skin lesions Eye abnormality Webbed neck Cardiac defect Splenomegaly Hemangioma Herniae
Baraitser and Patton [19861 M:F = 1:3 414 414 414 414 414 014 014 314 214 014 014 014
15115 13115 13115 15115 15115 14115 13/15 6115 12114 6115 6115 5115
Patient
Patient
1 -
2
M
M
-
-
+ + + + + + + +
+ + + + + + + +
TABLE 11. Craniofacial Abnormalities -
-~
CFC syndrome ~~
High crainial vault Bitemporal constriction Hypoplasia of supraorbital ridges Downslanting palpebral fissures F’tosis Epicanthic folds Depressed bridge of nose Anteverted nostrils Posteriorly angulated auricles with hypertrophy of helices High-arched palate
Baraitser and Patient Patton [19861 - 1 414 314 114 014 014 014 014 014 3I 4
10115 12/15 11/15 12115 9/15 11115 12/15 7/15 11/15
3
7/15
Patient 2
+ + + + +
+
+
+
+ + + + + +
+
+
Patient 2
TABLE 111. Ectodermal Involvement CFC syndrome
Baraitser and Patton [19861
Patient
14115 2115 12115 1/15
414 014 114 014
+
5/15 8115 5/15
014 014 014
-
~ ~ _ _ _ _ _ ~ ~
Hair Sparse Friable Curly Patchy alopecia Skin Ichthyosis Hyperkeratosis Chronic eczema a
1
-
f a
Mild atopic dermatitis
Reynolds et al. [1986]. It is of interest to note in this connection that Baraitser and Patton [ 1986J described four patients age to years with a ‘Ombinat ion Of clinical manifestations apparently identical with the ‘parse hair and eyebrows, but CFC without skin involvement. We would like to suggest that these 4 patients and the two patients we described represent a part of the clinical spectrum of the CFC syndrome. REFERENCES Baraitser M, Patton MA (1986):A Noonan-like short stature syndrome with sparse hair. J Med Genet 23:161-164.
Chrzanowska K, Fryns JP, Van den Berghe H (1989): Cardio-faciocutaneous (CFC) syndrome: %Port of a new Patient. Am J Med Genet 33:471-473. Mucklow ES (1989):A case of the cardio-facio-cutaneoussyndrome. Am J Med Genet 33:474-475, Neri G, Sabatino G, Bertini E, Genuardi M (1987):The CFC syndrome: Report of the first two cases outside the United States. Am J Med Genet 27:767-771. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz J M (1986): New multiple congenital anomaliesimental retardation syndrome with cardio-facio-cutaneous involvement. The CFC syndrome. Am J Med Genet 25:413-427. Sorge G , Di Forti F, Scarano G, Ventruto V, Zelante L, Dallapiccola B (1989): CFC syndrome: Report of three additional cases. Am J Med Genet 33:476-478.
