Syndrome of the month

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23823 Med Genet 1998;35:238-240

Syndrome of the month Costello syndrome Nicole Philip, Sabine Sigaudy

Abstract Costello syndrome is characterised by postnatal growth deficiency, coarse facies, redundant skin on the neck, palms, soles, and fingers, dark skin, acanthosis nigricans, and papillomata. The natural history evolves in two phases, a severe failure to thrive during the first months contrasting with a normal weight gain in later life. Cardiomyopathy is frequent but other visceral involvement is rare. Mild to moderate mental retardation is usual and most patients exhibit a characteristic sociable and friendly personality. The pathogenesis and molecular basis of the syndrome are unknown and the diagnosis is reliant on clinical expertise. Papillomata represent the most characteristic manifestation but may arise late in life. The peculiar course of the disease, the typical facies, and the ectodermal involvement with loose and hyperpigmented skin are characteristic enough to allow an early diagnosis. Most cases have been sporadic, suggesting de novo dominant mutations. (7Med Genet 1998;35:238-240) Keywords: Costello syndrome; papillomata

In 1971, Costello' 2 described a new syndrome consisting of postnatal growth deficiency, mental retardation, coarse facies, and nasal papillomata. No further cases were reported until 1991 when Der Kaloustian et ar and Martin and Jones4 reported children with the same manifestations. Since then, other cases have been reported.5"'4 The pattern of anomalies is characteristic and the diagnosis is usually easy, even when the pathognomonic papillomata are not present.

Departement de Genetique Medicale, Hopital d'Enfants de la Timone, 13385 Marseille Cedex 5, France N Philip S Sigaudy Correspondence to: Professor Philip.

Natural history Polyhydramnios is noted in approximately one third of the pregnancies. Birth weight and length are usually normal or at the upper limit, contrasting with the final height. The course of the disease is marked by two successive phases. The first one, so-called marasmic, is characterised by severe postnatal failure to thrive. It remains unclear whether swallowing difficulties and poor sucking ability are responsible for the poor growth, since high calorie intake and tube feeding do not seem to improve weight gain in the first months of life. In later childhood, the

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. . . . . ...Figure I Facial appearance of an infant with Costello syndrome. The facies is coarse with a large mouth, full lips, anteverted nares, and thickened and anteverted ear lobes. Note excessive skin over the neck and forearm. (Photographs reproduced with permission.)

linear growth deficiency persists but weight gain improves slowly. In two cases with a long term follow up, the final height was very short.'5

Dysmorphic features Relative macrocephaly is usual. The face is coarse, with downward slanting palpebral fissures, epicanthic folds, low nasal bridge, and a large mouth with thick lips (fig 1). The forehead is sometimes hairy. The neck is short and the ears are low set with typically large, fleshy, and prominent lobes. The thorax is large with an increased anteroposterior diameter. The hands and feet appear large with marked creases over the palms and soles (figs 2 and 3). The small joints, particularly those of the fingers, are hyperextensible, whereas limitation of larger ones, such as the elbow, has been reported in several cases. Positional foot defects are frequent and have been related to a tightness of the Achilles tendon (fig 4). Cardiac involvement is frequent and a cardiac murmur is present in most cases. Ventricular septal defect, atrial septal defect, and pulmonary stenosis have been reported occasionally. Hypertrophic cardiomyopathy was documented in several instances and appears to be an important diagnostic and prognostic element. A systematic screening for cardiac anomalies is recommended. Other visceral involvment is rare. Umbilical hernias can occur. Benign tumours, such as epithelioma,4 or malignant ones, such as ganglioneuroblastoma,9 have been reported in some cases.

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Costello syndrome

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Figure 2 The hands are large with redundant skin and deep palmar creases.

papillomata is highly characteristic and this cutaneous manifestation has been considered mandatory for the diagnosis since Costello's first description.' 2 However, the age of onset of the papillomata is variable, between 2 years of age and late adolescence. This is probably the reason why the syndrome has been underdiagnosed for many years. These cutaneous growths resemble warts and are preferentially located in the perioral, nasal, and anal regions, but papillomata can be found on the trunk, limbs, and larynx. Histological findings are indistinguishable from those seen in verruca vulgaris.

CNS involvement The occipitofrontal circumference is large at birth and relative macrocephaly is present in older patients. Hydrocephalus requiring ventriculoperitoneal shunt has been reported twice.6 9 Mild to moderate mental retardation is always present. The majority of patients are said to have a happy, outgoing personality. This behaviour seems consistent enough to be proposed as a diagnostic criterion.

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Figure 3 Deep plantar creases.

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Genetics Most cases have been sporadic. Case reports have documented recurrence among sibs in one family9 and consanguinity in two others.'7 This has led some authors to propose a recessive mode of inheritance. However, the consanguineous children were ofArabic-Druze ancestry in which consanguineous matings are frequent. Lurie" carried out a segregation analysis from the 28 published cases. The results were consistent with a sporadic autosomal dominant mutation. A significant increase in the mean paternal age was also found and reinforced this hypothesis. Recurrences among sibs could be the result of germline mosaicism or genetic heterogeneity with a small proportion of recessively inherited cases. A single case presented with a balanced (1;22) translocation,"3 suggesting that the two chromosomal breakpoints represent good candidate loci for the disease gene.

Differential diagnosis It is now thought that the facio-cutaneousskeletal syndrome described by Borochowitz et al'7 18 represents the same condition as Costello syndrome rather than a separate entity.'9-2' There is some degree of overlap between Costello and Noonan and cardiofaciocutaneous syndromes since short stature, developmental delay, macrocephaly, curly hair, low set ears, and cardiac involvement are common to all three of them. Some cases of Figure 4 Severe positionalfoot defect. Costello syndrome are likely to have been misEctodermal features diagnosed as having one of these conditions in The skin is loose and the redundancy is more the past. However, the particular redundancy marked around the neck and over the hands of the skin over the hands and feet, the deep and feet. A dark, olive colouration is frequently palmar and plantar creases, the olive skin colreported. In several instances, this hyperpig- ouration, the papillomata, the foot position mentation disappeared later in life. Acanthosis defects, and subtle dysmorphic features, such nigricans is present in one third of the cases. as thick and prominent ear lobes and a large Patchy hyperkeratosis of the palms and soles as mouth with thick lips, are characteristic well as pigmented palmar naevi have been enough of Costello syndrome to differentiate it reported several times. The hair is curly and the from these clinically related conditions. In nails are small and deep set. The presence of infancy, Costello syndrome can be mistaken


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for leprechaunism and two cases had been diagnosed as having "congenital cutis laxa with retarded growth and development".5 " However, these two different recessive syndromes are characterised by prenatal growth retardation, whereas birth weight is usually normal in Costello syndrome. Pathogenesis The pathogenesis of the disease is unknown. Similarities to leprechaunism have prompted authors to investigate the insulin receptor, but all results were normal. The apparent coarseness of the facies associated with hypertrophic cardiomyopathy suggests a storage disorder. However, there is no visceromegaly and the coarseness of the facial features is present from birth. Electron microscopy of the skin or liver has failed to show any storage material. Mucopolysaccharide and oligosaccharide screening were negative in all patients. Two single cases presented with sialuria, but these patients could have a similar but different condition.'0 Mori et al'4 examined several tissues from two different patients under EM and found abnormalities consisting of fine, disrupted, and loosely constructed elastic fibres with hyperplasia of collagen fibres in the skin. The same authors observed calcifications and ballooning of the skeletal muscle fibres with infiltration of macrophages. These findings are in contradiction to repeated reports of normal EM findings. However, they represent an interesting clue to the pathogenesis of the disorder since they suggest a connective tissue disorder rather than a storage disorder. 1 Costello JM. A new syndrome.

NZMed_ 1971;74:397.

2 Costello JM. A new syndrome: mental subnormality and nasal papillomata. Aust Paediatrj7 1977;13: 114-18. 3 Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S. Costello syndrome. Amz 7 Med Genet 199 1;41:69-73. 4 Martin RA, Jones KL. Delineation of the Costello syndrome. Am JMed Genet 1991;41:346-9. 5 Patton MA, Baraitser M. Cutis laxa and the Costello syndrome. J Med Genet 1993;30:622. 6 Say B, GuSsavas M, Morgan H, York C. The Costello syndrome. AmJ Med Genet 1993;47:163-5. 7 Teebi AS, Shaabani IS. Further delineation of Costello syndrome. Am .7 Med Genet 1993;47: 166-8. 8 Philip N, Mancini J. Costello syndrome and faciocutaneous-skeletal syndrome. Am .7 Med Genet 1993;47: 174-5. 9 Zampino G, Pastroiacovo P, Ricci R, et al. Costello syndrome: further clinical delineation, natural history, genetic definition, and nosology. Am _7 Med Genet 1993;47: 176-83. 10 Di Rocco M, Gatti R, Gandullia P, Barabino A, Picco P, Borrone C. Report on two patients with Costello syndrome and sialuria. Am J7 Med Genet 1993;47:1135-40. 11 Davies SJ, Hughes HE. Costello syndrome: natural history and differential diagnosis of cutis laxa. .7 Med Genet 1994;31:486-9. 12 Umans S, Decock P, Fryns JP. Costello syndrome: the natural history of a true postnatal growth retardation syndrome. Genet Couns 1995;6:121-5. 13 Czeizel AE, Timar L. Hungarian case with Costello syndrome and translocation t(1,22). Am .7 Med Genet 1995;57:501-3. 14 Mori M, Yamagata T, Mori Y, et al. Elastic fiber denegeration in Costello syndrome. Am .7 Med Genet 1996; 61:304-9. 15 Costello JM. Costello syndrome: update on the original cases and commentary. AmJ7Med Genet 1996;62:199-201. 16 Lurie IW. Genetics of the Costello syndrome. Am _7 Med Genet 1994;52:358-9. 17 Borochowitz Z, Pavone L, Mazor G, Rizzo R, Dai- H. New multiple congenital anomalies-mental retardation syndrome (MCA/MR) with facio-cutaneous-skeletal involvement. Am JMed Genet 1992;43:678-85. 18 Borochowitz Z, Pavone L, Mazor G, Rizzo R, Dar H. Faciocutaneous-skeletal syndrome: new nosological entity or Costello syndrome. Am J Med Genet 1993;47:173. 19 Der Kaloustian VM. Not a new MCA/MR syndrome but probably Costello syndrome? Am .7 Med Genet 1993;47: 170-1. 20 Teebi AS. Costello or facio-cutaneous-skeletal syndrome? AmJMed Genet 1993;47:172. 21 Martin RA, Jones KL. Facio-cutaneous-skeletal syndrome is the Costello syndrome. Am JMed Genet 1993;47:169.


Costello syndrome. N Philip and S Sigaudy J Med Genet 1998 35: 238-240

doi: 10.1136/jmg.35.3.238

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