Costello syndrome: report of a new case with choanal atresia and fatal outcome

ARTICLE

The association of cutis laxa with retardation of growth and motor development has been reported [1-5]. A postnatal growth retardation syndrome with distinct phenotype was described in 1971, and further delineated in 1977 and 1996, by Costello [6-8]. He originally described two young children with the following clinical features: poor sucking and postnatal growth, developmental delay, nasal papillomata, hyperextensible fingers with loose integument of hands and feet, pigmented skin colour, and a distinctive facial appearance: apparently large head, curly hair, short neck, low-set ears with large earlobes, depressed nasal bridge, epicanthic folds and thick, full-lips [6-8].

Costello syndrome has emerged as a distinct disorder that should be considered in the evaluation of patients with cutis laxa and delayed development [8-18]. Recently we have had the opportunity to study a patient with most of the features described under this syndrome who had a fatal outcome at an early age and displayed choanal atresia, a feature not previously described in this syndrome so far, to our knowledge.

Case report

A 3 month-old-girl, the third child of healthy, unrelated parents was born at term by Caesarean section after an uneventful 39 week gestation. Her two siblings are normal. At birth she weighed 4,200 g (+ 1 S.D.), her length was 50 cm, head circumference 38 cm (+ 2.8 S.D.), Apgar score 9-9. Because of respiratory distress and feeding difficulties she was placed in a neonatal unit.

At 2.5 months a hemangioma was resected from her left mammary area.

At three months of age the patient was referred to us in order to further investigate severe failure to thrive, choanal atresia, dysmophic features and developmental delay.

On physical examination we observed a severely malnourished girl with loss of subcutaneous fat and loose skin most prominently over the neck, axilary and inguinal folds (Fig. 1). Clinical evaluation disclosed distinct craniofacial dysmorphic features: relative macrocephaly with frontal bossing, sparse, thin, curly hair, large eyes with epicanthic folds, depressed nasal bridge, wide anteverted nostrils and bulbous tip, full cheeks, large mouth with thick lips, prominent low-set ears with large thick lobes, and a relatively short neck (Figs. 2 and 3). The hair became curlier, thinner and less pigmented with age (Fig. 4) Hands and feet were short and broad with hyperextensible fingers, redundant and deep creases were noticed over the palmar and plantar surface (Fig. 5). A surgical scar from a previously resected hemangioma was present over the left mammary area; a paravertebral superficial hemangioma was present on the dorsum.

Skin biopsy sections showed no abnormality with hematoxylin and eosin stain. The Verhoeffs stain for elastic fibers showed absence of the elastic tissue network at the superficial and deep dermis (Fig. 6). Examination of the scalp hair under polarized light disclosed uniform but reduced diameter with absence of hair canals, pigment was present but markedly reduced.

From birth on, extreme feeding and respiratory difficulties were noted. Breathing was strenuous with expiratory stridor. Endoscopic examination confirmed bilateral hypoplastic choanae; at laryngeal level no anatomic or motility abnormalities were found.

Ecographic survey did not disclose any abdominal or genito-urinary malformations. Cardiovascular evaluation produced a normal ECG and echocardiography.

Neurological evaluation revealed vertical and horizontal central nistagmus, general hypertonicity with tendency to opistotonus, limb flexion attitude with thumb inclusion. There was a bilateral equinovarus position of both feet, superior and inferior limb hypereflexia, with absence of palmar-plantar reflexes. EEG was normal. Brain CT scan did not disclose gross cerebelar or cerebral anormalies but enlargement of supratentorial cistern and cortical furrows. A discretely increased subaracnoidal cortical and supratentorial space was also noted. Ophthalmological examination revealed right exoforia, epicanthic folds were present giving an appearance of hypertelorism. Eye fundus and anterior segment were without alterations. A central nistagmus due to delayed myelinization of the optic nerves was present.

Despite choanal atresia correction, the patient's physical and neurological development progressively deteriorated and she died at 11 months of age.

No papillomata were found at this age.

Discussion

Costello syndrome has become a better-delineated condition and should be included in the differential diagnosis of cutis laxa in association with postnatal growth and mental retardation [10]. As illustrated in the present case, the Costello syndrome is a true postnatal growth retardation syndrome with extreme feeding difficulties and poor sucking from birth on [9, 17-19]. In the first months the severe failure to thrive appears not only to be related to poor feeding as it continues despite improvement in caloric intake and gastric feeding [9, 11, 16, 19-21]. The loose skin together with the virtual absence of subcutaneous tissue leads in our patient, as well as in previously described patients, to a clinical feature closely resembling leprechaunism, Donahue syndrome or Berardinelli-type or Roussel-type lipodystrophy [9, 15, 16, 19, 22, 23]. The occasional abnormalities of glucose metabolism and the presence of acanthosis nigricans bring to mind the possibility of these lipodistrophic syndromes [19, 24]. Neurological examinations in the first year of life show a severe developmental delay. After this time however, psychomotor development presents a relative improvement, and most of the cases finally display a mild to moderate range of mental retardation and exhibit a pleasant sociable, humorous behavior [19, 25, 26]. Ventricular widening and other signs of subcortical atrophy were recorded with CT-scans of the brain in previous cases, and were also observed in this patient [9, 12, 15, 16, 27]. So far, brain CT-scans have not contributed very much in the diagnosis and give no explanation for the altered neurological development, more pronounced in the first year of life [9, 18]. Moreover in the presence of central nistagmus, as it is in our case, the absence of a brain tumour should help in the differential diagnosis with Roussel syndrome. The developmental delay persisted in this girl although the choanal atresia was corrected.

Dermatological manifestations include soft skin with excess of wrinkling over the dorsum of the hands and deep creases on the palms and soles, hyperextensibility of digits, generalized hyperpigmentation, pigmented nevi often on the palms and soles, vascular birthmarks, papillomatas around the nares, mouth, anus, or elsewhere, that developed at later ages, and acanthosis nigricans [9, 18, 19]. The loose and hyperlax skin with deep palmar and plantar creases, hyperextensible fingers, and excessive infraorbital folds have been noted in all patients from the first months of life. Redundant skin is more evident on the skin folds and over the palmar and plantar surface. Deep palmar and plantar creases and thickened dermal ridges with a "velvety" feel, as seen in the present case, distinguished this syndrome from other cases of cutis laxa [9-11, 17-19, 21]. Histological studies of skin biopsies showed no evidence for storage disease except for vacuoles in fibroblasts in one patient [19] and metachromatic granules in lymphocytes in another case [16]. Although the elastic fibers have been normal in some cases Vila-Torres et al. [28] found increased fragmentation and loss of anastomosing points in Costello syndrome and cutis laxa when compared to normal skin, and Mori et al. [29] found fine, disrupted and loosely-constructed elastic fibers. In the present case the Verhoeff's stain for elastic fibers demonstrate absence of the normal elastic tissue network at the papillary as well as at the deep dermis. Further ultrastructural and biochemical studies are required in order to further delineate the elastic defect. Studies of copper and lisiloxidase metabolism need to be added to a detailed clinical description since anomalies in the cross-linking of elastin has been associated with these biochemical abnormalities in cutis laxa [30-33].

The hair, in most reported cases, is sparse, brittle and curly [10, 12, 16, 29]. In this case, the alopecia became more evident as the patient grew, the amount of hair decreased, and it became thinner and lighter in colour; under polarizing light most of the hairs had small diameter, diminished pigment and lack of hair canal.

The distinctive skin papillomatas have a predilection for areas around the mucous membranes (nose, mouth, anus) but seem to appear later in life in the majority of cases. Although they seem to be almost pathognomonic their absence early in life does not rule out the diagnosis [8, 12, 19, 27, 34, 35]. The present case fulfilled most of the other features of the syndrome described by Costello [6-8]; the absence of skin papillomatas in this patient may be due to her early age of death.

Hoarseness of the voice has been related to papillomatas or crumbling of the vocal cords [15, 16, 18, 19]. Choanal atresia was the only airway anomaly documented in our case, a striking expiratory noise persisted after surgery and would probably be related to a disorder related to the laxity of the laryngeal structures or may reflect abnormal central nervous system function [19]. To our knowledge, choanal atresia has not been previously documented in this syndrome so far.

To our knowledge nine deaths have been documented [18, 19] as in the present case, with differences and no steady patterns. The patient describe by Mori et al. [29] who died at the age of 6 months of generalized rhabdomiolysis, and the present case, who died at 11 months, are the youngest reported fatal cases.

Most of the published cases of Costello syndrome have been sporadic except for a sib pair described by Zampino et al. [16], Berberich et al. [26] and case 6 and 7 of the series reported by Johnson et al. [19]. Consanguinity, which favours autosomal recessive inheritance, has rarely been documented [10, 18]. Advanced paternal age has been communicated in this syndrome and is a finding in new mutation dominant conditions [18, 19, 36].

Congenital cardiac abnormalities are common in Costello syndrome [18, 24, 26, 37, 38]. It has been mentioned that Costello, Noonan and cardio-facio-cutaneous (CFC) syndromes share some findings [8, 12, 16, 18, 24, 39]. Because of the overlapping features of facial appearance, heart defects, skin and hair abnormalities, and mental retardation, it can be difficult to separate CFC syndrome, Noonan from Costello syndrome. Because the skin papillomas occur later in life it would be difficult to separate these entities during the first year of life. In our case, the presence of loose skin, an infrequent feature of CFC and Noonan syndromes [39], and the abnormalities in elastic fibers as well as the absence of cardiac abnormalities, facilitate the differential diagnosis. Borochowitz et al. [40] describe a "new" multiple congenital anormalies/mental retardation (MCA/MR) syndrome with facio-cutaneous-skeletal involvement. Whether this condition should be considered a separate entity is currently a matter of debate [8, 16, 41].

Besides the cardio-facio-cutaneous and the Noonan syndromes among the syndromes with cardiac abnormalities, and the postnatal lipoatrophic syndromes (leprechaunism, Donahue, Roussell, Berardinelli) [9, 15, 16, 19, 22] we need to perform the differential diagnosis between syndromes in which cutis laxa is seen together with motor and mental retardation [4, 5, 10, 11, 17, 29]. Among the syndromes with lax skin, severe postnatal growth retardation and developmental delay we considered the differential diagnosis with skeletal abnormalities, cutis laxa, craniostenosis, ambiguous genitalia, retardation, facial abnormalities (SCARF) and the Lenz-Majewski syndromes (Table I). The SCARF syndrome presents peculiar facial features (multiple hairwhorls, epicanthal folds, ptosis, low set posterior rotated ears, high and broad nasal root, small chin) associated to skeletal abnormalities, teeth alterations, craneoestenosis, and ambiguous genitalia [42, 43]; the Lenz-Majewski hyperostotic dwarfism syndrome is a skelatal dysplasia syndrome with progeroid appearance, choanal atresia, characteristic facial (relative macrocephaly, frontal bossing, midfacial. hypoplasia, thin upper lip) and limb anomalies (broad short hands and feet, cutaneous syndactyly), multiple synostosis, a distinctive skeletal change (diffuse sclerotic process) and deafness [44, 45].

In summary, this case as well as those reviewed in the literature, illustrate the importance of the study and follow up of children with cutis laxa, postnatal growth and psychomotor retardation, and dysmorphic features, by a multidisciplinary teem. This approach allows the opportunity to diagnose uncommon disorders and establish the proper prognosis and therapeutic approach. *

Article accepted on 27/11/00

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