Clinical variability of cardio-facio-cutaneous syndrome: report of two additional cases

Clinical variability of cardio-facio-cutaneous syndrome: repod-of two additional cases Ghezzi M, Parenti G, de Franchis R, Farina V, de Leva F, Guarino A, Berni Canani R, Strisciuglio P. Clinical variability of cardio-facio-cutaneous syndrome: report of two additional cases. Clin Genet 1992: 42: 206-209. We describe two new cases of cardio-facio-cutaneous(CFC) syndrome, and underline the clinical variability of the CFC phenotype in our two patients presenting with border-line psychomotor development. The first patient showed some additional clinical manifestations, such as cryptorchidism and scoliosis, and the second one had atypical skin lesions.

Monica Ghezzl, Glassarlo Parinti', Ratfaella da Franchts, Mncenzo Farina, Fraacasco de Leva*, A b d o Guarino, Roberto Bern1 Canani and

Pietro Strlsclugllo Department of Pediatrics, University of Naples, Italy; 'on leave from Department of Pediatrics, University of Reggio Calabria Catanzaro. Italy; 'Monaldi Hospital, Naples. Italy

Key words: cardio-fadwutaneous (CFC) syndrome clinical variability

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Dr. Petro Strisciuglio. Department of Pediatrics, University of Naples, Via Pansini 5. 1-80131 Naples, Italy Received 30 January, revised 27 May, accepted for publication 9 June 1992

Since the first description of cardio-facio-cutaneous (CFC) syndrome by Reynolds et al. (1986), less than 25 cases have been described. The clinical presentation of the syndrome has not yet been fully defined, and particularly the similarity between CFC syndrome and Noonan syndrome has recently been debated (Freyer et al. 1991, Neri et al. 1991). Here we present two new, unrelated cases which underline the clinical variability of the CFC syndrome. Clinical report Patient 1

L.M., a male, was delivered by cesarean section at term, after an uncomplicated pregnancy, to healthy unrelated parents. From the age of 3 months he had atopic dermatitis. At 18 months a murmur was noticed and echocardiography revealed the presence of pulmonic stenosis and mild mitral insufficiency. He was admitted to our hospital at the age of 34 months. Physical examination revealed a weight of 15.2 kg (75th centile), length of 91 cm (10th centile), and a head circumference (OFC) of 52 cm (90th centile). He had relative macrocephaly with low-set ears, depressed nasal bridge, hypertelorism, bilateral palpebral ptosis, mild micrognathia, highly arched palate, and multiple caries (Fig. 1). His hair was sparse and thin. A loud, ejection type systolic murmur was audible at the upper left 206

sternal border, with a decreased intensity of the second sound, compatible with a pulmonic stenosis. A second echocardiography was performed, confirming the diagnosis of pulmonic stenosis. There was bilateral cryptorchidism. His skin appeared dry and scaly, with areas of atopic dermatitis associated with hyperkeratosis, mainly localized on the face and lower limbs. A skeletal Xray examination showed a right convex thoracic scoliosis. A Brunet-Lezine test was performed and revealed low normal psychomotor development (IQ = 8 1). EEG showed a generalized dysrhythmia. Chromosome analysis and routine laboratory tests were normal. Patient 2

F.M.R., a female, was born at the 36th week of gestation to healthy, unrelated parents. Birth weight was 3050 g. She presented with hypothermia during the neonatal period. At 1 month a systolic murmur was detected and echocardiography showed the presence of atrial septa1 defect and mild pulmonic stenosis. Two elder brothers are physically and mentally normal. When examined in our hospital at 16 months her weight was 9150 g (10th-25th centile), her length 77 cm (25th centile), and her OFC 44 cm ( ~ 5 t hcentile). She

showed microcephaly with bitemporal constriction, epicanthic folds, depressed nasal bridge, and

Clinical variability in CFC syndrome

Fig. I . Patient 1.

Fig. 2. Patient 2.

large prominent ears (Fig. 2). Her hair was thin, curly and sparse; she had a midsystolic murmur with maximum intensity at the second left intercostal space and a wide splitting of the second sound. A second echocardiography was performed, confirming the diagnosis of atrial septa1 defect and pulmonic stenosis. Three capillary hemangiomata were present on her back, left eyelid and nuchal area. Her development was mildly retarded, mainly in the language area.

et al. 1987, Sorge et a]. 1989, Verloes et al. 1988), it became clear that the CFC phenotype showed striking similarities to that of Noonan syndrome. Based on this observation, Fryer et al. (1991) raised some doubts about the existence of CFC syndrome and proposed that Noonan syndrome and CFC syndrome might result from the variable expression of the same genetic defect. Further contributions to the controversy on the existence of CFC syndrome were recently provided by Neri et al. (1991) who reviewed 19 cases in the literature. They concluded that Noonan syndrome and CFC syndrome should be considered as two distinct, specific entities and that a common phenotype referred to as “Noonan phenotype” includes both conditions, even though they are clinically, and probably genetically, different. From analysis of the literature they were able to identify some differential diagnostic criteria discriminating these two diseases. The features recognized as specific to CFC were hyperkeratotic skin lesions, the typical hair texture and a sporadic occurrence. Mental retardation and congenital heart defect were observed

Discussion

During the past few years a number of patients sharing a common phenotype characterized by congenital heart defect, cutaneous involvement and peculiar facial features have been identified as affected by a new disease entity referred to as CFC syndrome (Reynolds et al. 1986). As more patients affected by CFC syndrome were observed (Chrzanowska et al. 1989, Della Monica et al. 1991, Fryer et al. 1991, Gross-Tsur et al. 1990, Matsuda et al. 1991, Mucklow 1989, Neri

207

Ghezzi et al. Table 1 . Clinical findings in our patients and in published cases with CH: syndrome Features Neurological manifestations Mental retardation Hypotonus Abnormd EEG Seizures Strabismus Nystagmus Microcephaly Pale optic disk

Patient 1

Patient 2

+ +

+

+

Skin abnormalities: Hyperkeratosis Eczema Angiomata lchthyosis Folliiular keratosis Cafeau-lait spots Seborrhea Others Heart defects: Atrial septal defect Pulrnonic stenosis Ventricular septal defect Hypertrophic cardiorniopathy Others

+

+

+

+

+

Published cases

21 122' 21/22 7/22 617 5/22 5/22 5/22 4/22 1 13 21122 10122 7/22 6/22 5/22 4/22 2/22 2/22 322a 16/22 8/22 5/22 2/22 2/22 5l22b

~~

Sparse and/or curly hair

+

Miscellaneous: Cryptorchidism Scoliosis

+

+

+

21 122 411 2 2/22

' The patients reviewed are from: Chrzanowska el al. (1989). Della Monica el al.(1991),Fryer el al. (1991). Gross-Tsur et al. (1990), Matsuda el al. (1991).Mucklow (1989), Neri el al. (1987). Reynolds el al. (1986),Sorge el al. (1 989) and Uerloes et al. (1 988). a): naevi (1 122);xeroderma (1 122);cutis marmorata (1122). b): Ebstein anomaly (1 122); pulmonary regurgitation (1 I 22): endocardial cushion defect (1122);thiik aortic and tricuspid valves (11 22); thick pubnonary valve (1122).

with a higher frequency in CFC syndrome, while low posterior hairline, cubitus valgus, neck abnormalities and familial occurrence seemed to be more typically associated with Noonan syndrome. We reviewed 22 cases of CFC syndrome already reported in the literature (Table 1). Some remarkable points arose from the analysis of these cases: 1) cardiac involvement was absent in a considerable number of subjects (6 out of 22); 2) hyperkeratosis has been considered a typical skin lesion of CFC syndrome; however, eczema and hemangiomata are often the only skin manifestations (Matsuda et al. 1991); 3) a careful evaluation of mental development has not always been performed; in some instances, however, near normal values of IQ were reported; EEG abnormalities were in some cases detected; 4) other features, such as palpebral ptosis, 208

squint, nystagmus, joint laxity, nail dystrophy, hypotonus, and scoIiosis were frequently observed, thus suggesting a wide and variable clinical spectrum of the syndrome. In our probands the association of typical heart defect (atrial septal defect, pulmonic stenosis), sparse, curly hair, a peculiar face and a sporadic occurrence may be considered sufficient criteria to classify them as new examples of CFC syndrome. In particular, as pointed out by Neri et al. (1991), the overall impression (gestalt) of the patient's face is of considerable value in defining the diagnosis. The heterogeneity of the skin lesions observed in our two patients seems to confirm that the cutaneous involvement of CFC syndrome is variable; it should be noticed that in case 1 eczema was associated with hyperkeratosis, as already observed in previously reported patients; it is likely that hyperkeratosis is just a consequence of eczema and therefore should not be considered as a major sign of the disease. It is not clear whether mental retardation has to be considered a main diagnostic criterion. According to Neri et al. (1991), mental retardation was constantly present in CFC syndrome, but, as mentioned above, a careful evaluation of IQ has not always been reported in the cases reviewed by these authors. In our first patient low normal mental development was present, while the second patient was only mildly mentally retarded. Other neurological manifestations such as EEG abnormalities, seizures, hypotonia, nystagmus, ataxia and titubation should also be considered as the result of neurological impairment. A cafeful clinical characterization of new patients with CFC syndrome is at present a major task for clinicians in order to define the relationships between Noonan syndrome and CFC syndrome, until data on the molecular background of the two entities become available. The considerable overlap between the two phenotypes might be explained either by different allelic forms at the same gene locus, or by the involvement of different contiguous genes. A contiguous gene syndrome has already been proposed to explain the association of neurofibromatosis type 1 and Noonan syndrome (Listernick & Charrow 1990).

Acknowlidgsmints W e are indebted to Professor G. Andria for critically reviewing the manuscript. W e thank Associazione Italiana per lo Studio delle Malformazioni ( A S M ) for their continued support.

Clinical variability in CFC syndrome

Rafsrsnces Chhanowska K, Fryns JP, Van den Herghe H. Cardio-faciocutaneous (CFC) syndrome: report of a new patient. Am J Med Genet 1989: 33: 471-473. Della Monica M, DAvanzo MG, Romano F, Della Bruna M, Scarano G. Sindrome cardio-facio-cutanea (CFC): un nuovo caso italiano. Riv Ital Pediatr 1991: 17: 220-222. Fryer AE, Holt PJ, Hughes HE. The cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome: are they the same? Am J Med Genet 1991: 38: 548-551. Gross-Tsur V, Gross-Kieselstein E, Arnir N. Cardio-facio cutaneous syndrome: neurological manifestations. Clin Genet 1990: 38: 382-386. Listernick R, Charrow J. Neurofibrornatosis type I in childhood. J Pediatr 1990: 116: 845-853. Matsuda Y, Murano I, Kondoh 0, Mxtsuo K, Kajii T. Cardiofacio-cutaneous (CFC) syndrome: report of two patients without hyperkeratotic skin lesions. Am J Med Genet 1991: 39: 144-147.

Mucklow ES. A case of cardio-facio-cutaneous syndrome. Am J Med Genet 1989: 33: 474-475. Neri G, Sabatino G, Bertini E, Genuardi A. The CFC syndrome. Report of the first two cases outside the United States. Am J Med Genet 1987: 27: 767-771. Neri G, Zollino M. Reynolds JF. The Noonan-CFC controversy. Am J Med Genet 1991: 39: 367-370. Reynolds JF, Neri G, Herrmann JP, Blumberg B, Coldwell JG, Miles PV, Opitz JM. New multiple congenital anomalies/ mental retardation syndrome with cardio-facio-cutaneous involvement. The CFC syndrome. Am J Med Genet 1986: 25: 413427. Sorge G, Di Forti F, Scarano G, Ventruto V, Zelante L, Dallapiccola B. CFC syndrome: report of three additional cases. Am J Med Genet 1989: 33: 476-478. Verloes A, Le Merrer M, Soyeur D, Kaplan J, Pangalos C, Rigo J, Briard ML. CFC syndrome: a syndrome distinct from Noonan syndrome. Ann Genet 1988: 31: 230-234.

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