Cardio-Facio-Cutaneous Syndrome

Transcription

1 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: , 2006) Key words: Cardio-Facio-Cutaneous syndrome, Costello syndrome, Noonan syndrome ( 24: , 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: FAX: hmsheu@mail.ncku.edu.tw 140 Dermatol Sinica, June 2006

2 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 There is some overlap between the clinical manifestations of this syndrome and the syndromes described by Noonan 3 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. 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 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 Dermatol Sinica, June

3 (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 index 6 was calculated to be , 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 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

4 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 CFC syndrome a Our patient Costello syndrome b Noonan syndrome c (%) (%) (%) (%) Number Main feature Growth failure Development delay Heart defects Craniofacial changes Mental retardation Ectodermal abnormalities Hair Sparse Curly Fine/Thin N Sparse eyelashes/eyebrows ND ND Skin Hyperkeratosis Dry 25 + ND ND Eczema ND ND Keratosis pilaris 10.6 ND 14 Loose skin of hands and feet ND Wrinkled palms and soles ND Fetal pads ND Papillomata ND 48 ND Seborrheic dermatitis 8.5 ND ND Acanthosis nigricans ND Cafe-au-lait spots 7.3 ND 3 Pigmented nevi 5.5 ND 25 Nails Dysplastic/thin/deep-set nails ND 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 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 Dermatol Sinica, June

5 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 studies 7, 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 , which falls within the diagnostic range ( ) as suggested by Kavamura et al. 6 Noonan and Costello patients are measured below So far, most CFC syndrome cases, including the case reported here, are sporadic, born to non-consanguineous parents, and have apparently normal chromosomes. At the present time, there is no lab- 7, 15, 16 oratory 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: , Nanda S, Rajpal M, Reddy BS: Cardio-facio-cutaneous syndrome: report of a case with a review of the literature. Int J Dermatol 43: , Noonan JA, Ehmke DA: Associated noncardiac malformations in children with congenital heart disease. J Pediatr 63: , Costello JM: A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J 13: , Ward KA, Moss C, McKeown C: The cardio-faciocutaneous syndrome: a manifestation of the Noonan syndrome? Br J Dermatol 131: , Kavamura MI, Peres CA, Alchorne MM, et al.: CFC index for the diagnosis of cardiofaciocutaneous syndrome. Am J Med Genet 112: 12-16, 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, Tagami H: Japanese dermatological association criteria for the diagnosis of atopic dermatitis. [Japanese] Nippon Hifuka Gakkai Zasshi 104: 1210, Sharland M, Burch M, McKenna WM, et al.: A clinical study of Noonan syndrome. Arch Dis Child 67: , Hennekam RCM: Costello syndrome: an overview. Am J Med Genet C 117: 42-48, 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: , 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: , Tartaglia M, Mehler EL, Goldberg R, et al.: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29: , 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: , Ion A, Tartaglia M, Song X, et al.: Absence of PTPN11 mutations in 28 cases of cardiofaciocutaneous (CFC) syndrome. Hum Genet 111: , 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: , Dermatol Sinica, June 2006