Costello syndrome with decreased glucose tolerance

ARTICLE

Since Costello reported two cases in 1971, the syndrome has become an entity. These patients had coarse faces, redundant skin on the hands and feet, curly hair, growth- and psychomotor retardation. Common but not invariable features are nasal polyps and typical facies associated with feeding problems in infancy and a distinctive friendly personality. Cardiomyopathy may occur, other visceral involvement is rare. The natural history evolves in two phases, a severe failure to thrive during the first months, contrasting with normal weight gain in later life. Accumulation of case reports revealed an additional characteristic phenotype [1].

Materials and methods

Case history

The proband is a twenty-year old girl, who has no brothers or sisters, and has negative family history. The parents are not consanguineous. She was born at the 34th gestational week. The birth-weight was 2,100 g. Cyanosis, irregular conduction defects and arrhythmia developed at birth. Sucking problems with postnatal feeding difficulties were encountered.

At the first examination, characteristic facial changes, the coarse, progeroid face, the depressed nasal bridge, and the large tongue were observed (Figs. 1 and 2). Acanthosis nigricans has developed in the neck region; the palms and soles were hyperkeratotic, with deep palmar and plantar creases (Figs. 3 and 4). The skin was darkly pigmented, loose and thickened. At the age of 19, warty perinasal papules, papillomata developed around the nose. Heat intolerance, increased sweating, and late pubertal development were noted. She had hyperextensible fingers with broad distal phalanges. Joint contractures were observed, and peroneal hypertonicity required treatment by Achilles tendon lengthening (i). Skeletal X-rays showed spina bifida occulta. Growth had decelerated to less than the third percentile for weight and length. On neurological evaluation there was considerable developmental delay, IQ was estimated at 56. Computer tomography scan of the brain was normal. Development of motor milestones was especially delayed. The speech was fluent and ample with a distinctive hoarse character. Walking development was delayed too; running was carried out with difficulty. The personality was outgoing, and friendly. She attended special educational classes in school.

Results

Laboratory studies showed decreased glucose tolerance, other parameters were normal. Analysis of a muscle biopsy specimen was normal. Histology obtained from the plantar area showed mild hyperkeratosis and papillomatosis. By electron microscopy studies, homogenous elektrolucens material was observed in the stratum corneum (Figs. 6 and 7). The karyotype was normal.

Discussion

The pathogenesis and molecular basis of the syndrome are unknown. Prenatal polyhydramnion, postnatal feeding difficulty, short stature, mental retardation, excessive skin on the palms (washer woman's hand), soft skin wrinkling over the dorsum of the hands, soles, fingers, and the nape of the neck, deep palmar and plantar creases, hyperextensibility of digits, generalized hyperpigmentation and silent or clinically significant hypertrophic cardiomyopathy presented in all the reported patients [2].

Other skin findings that occur with less frequency are hirsutism, dark pigmentation, thin deepset nails, acanthosis nigricans, vascular birthmarks and palmar nevi. Many of the older children have papillomata around the nares and scattered on other areas of the body. Papillomata represent the most characteristic manifestation, arising later in life. Although papillomata were not reported in all patients, they appear to be age related, accounting for their absence in younger children. Some authors found the histology suggestive of verrucae although in other patients vacuolated cells were absent. Some of the previous reports listed curly or sparse hair as a feature. In our case curly, but sparse hair was found.

A recognizable face has been described. In one case microcephaly, with digital impression of the X-ray film of the cranium was observed, but most of the authors describe macrocranium, coarse facies and low set posterior angulated ears that may be large. Epicanthic folds, downslanting palpebral fissures, depressed nasal bridge, bulbous nose, flat philtrum, and thick lips may occur. In addition, strabismus is common. Progeroid senile-like appearance, increased fat deposition in the cheeks, a hoarse voice and irregular teeth with gingival proliferation can be observed.

The course of the disease is divided into two distinct phases, with the early manifestations characterized by severe failure to thrive associated with a poor sucking reflex and marasmic appearance. Disproportionate weight gain compared with linear growth follows the resolution of the feeding problems. One of the major problems in infants with Costello syndrome is the inability to suck, although when tested, esophageal motility was normal. This leads to severe failure to thrive, which invariably corrects itself in early childhood. Growth parameters at birth are usually normal, but short stature is a constant feature in later life. A short neck is reported in all cases, occasional1y accompanied by thoracic kyphosis. Other common features include a decreased range of elbow motion, hyperextensible fingers with broad distal phalanges. Ulnar deviation of the hands, positional foot deformities, tight Achilles tendon and increased anteroposterior diameter of the chest are characteristic. Osteoporotic long tubular bones and spina bifida occulta may occur.

All the reported children have mild to moderate mental retardation. A sociable, warm personality is documented in many reports.

A high incidence of cardiac involvement, such as arrhythmia, hypertrophic cardiomyopathy, or congenital anomalies may occur. Heart disease was present in the patients originally described by Costello, and has been reported by other authors. This may include structural defects (ventral and atrial septal defects, pulmonary stenosis) more frequently cardiomyopathies including tachyarrhythmia [3]. Histology of the palms showed hyperkeratosis, papillomatosis, and elastolysis in one case [4].

The cause of Costello syndrome is unknown. Concerning two patients with parental consanguinity and association in sibs, an autosomal recessive inheritance was suggested. Chromosomal studies in one, but not in the other reported cases showed a balanced translocation: 46,XX t (1,22) (q25,q11) [5]. Metabolic studies were negative, with the exception of one report, where high levels of sialic acid was found in the urine. An association with advanced parental age was observed in the reported cases, but not in our case.

The initial description was in 1971, similarly affected patients were reported in 1981, 1989, and 1990. Full reports of patients with Costello syndrome were made in 1991. The patients with the so called "facio-cutaneous-skeletal" syndrome have the same condition [6, 7]. After rediscovering this syndrome, numerous reports have been published in the genetic literature. There are several syndromes to consider in the diagnosis of Costello syndrome. These include progeria, Noonan syndrome, cardio-facial-cutaneous (CFC) syndrome, neurofibromatosis-, Noonan, Weaver, syndrome, Aarskog syndrome, Donohue syndrome (leprechaunism), the SCARF syndrome (skeletal abnormalities, cutis laxa, craniostenosis, psychomotor retardation, and facial abnormalities) and storage disorders. The facial appearance and part of the clinical features of these syndromes are very similar [8, 9]. The characteristic skin symptoms in Costello syndrome provide the diagnosis.

The inheritance is still unknown. Most cases have been sporadic, but the described association with advanced paternal age suggests autosomal dominant inheritance, nevertheless cases with consanguinity and the association in sibs suggest autosomal recessive inheritance [10-12].

It is now clear that Costello syndrome is a distinct clinical entity. Many manifestations involve ectodermal structures, so Torrelo et al. [13] suggested including this entity in the ectodermal dysplasia group. The clinical findings in the present case are consistent with those noted in the first reported cases (Costello, 1977). The decreased glucose tolerance in Costello syndrome is a further clinical sign, which can be independent, but in the view of the presence of acanthosis nigricans may be of interest.

REFERENCES

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13. Torrelo A, Avila AL, Mediero IG, et al. Costello syndrome. J Am Acad Dermatol 1995; 32: 904-7.