Williams–Beuren syndrome and West “syndrome:” Causal association or contiguous gene deletion syndrome?

The Williams–Beuren syndrome (WBS, MIM 194050) is a genetic disorder caused by a microdeletion at 7q11.23 that involves the ELN (Elastin) and LIMK1 amongst other genes [Meng et al., 1998]. Its frequency varies from 1:13,700 to 1: 25,000 [Udwin, 1990] with an equal proportion amongst both sexes. The main phenotypic features are: distinctive face, cardiovascular malformations, fundamentally supravalvular aortic stenosis with or without supravalvular pulmonary stenosis, and a typical growth pattern with a precocious puberty in a subgroup of affected women. They can also present with anomalies in the kidneys, as well as radio-ulnar synostosis. Generally they have mild to moderate mental retardation with an outgoing personality, hyperacousia, and attention deficit hyperactivity disorder (ADHD) [Osborne, 1999]. The causative hemizygotic deletion in 7q11.23 was described first by Ewart et al. [1993] in 1993. The West ‘‘syndrome’’ (WS), although not a syndrome in the true genetic sense, is an age-dependent epileptic encephalopathy that is characterized by a clinical triad of epileptic spasms, psychomotor delay, and hypsarrhythmia. It is a symptom complex of multiple etiology due to the inadequate response of an immature brain to a variety of causes [Watanabe, 1998]. Its frequency is estimated to be 2–5:10,000, with equal proportions between both sexes [Wong and Trevathan, 2001]. Although the WS has been considered inside the refractory epilepsy, its prognosis varies extensively according to its etiology. It can be classified in prenatal, perinatal, and postnatal, depending on the period in which the cerebral damage is produced. According to the ‘‘International Classification of Epilepsies and Epileptic Syndromes,’’ the WS can be also classified as symptomatic and cryptogenic. The symptomatic group are those in which it is possible to recognize or to suspect an underlying pathogenesis of the central nervous system, while in the cryptogenic group, the underlying cause is not known [Commission on Classification and Terminology of the International League against Epilepsy, 1989]. Our propositus is a 3-year-old Arabian male of Egyptian origin born of a third pregnancy with a premature delivery at the 7th month. There was no family history of developmental or psychomotor delay. His parents were healthy and nonconsanguineous, and they have previously had two healthy children. He was born at 42 weeks of gestational age by a delivery complicated with dystocia, a stained amniotic fluid and a weight of 3,350 g. His Apgar score was 9 at the min, and 10 at 5 min of life, respectively. At 3 weeks a heart murmur was observed and diagnosed as an interventricular communication that had been followed by the Cardiology Service. The psychomotor development was retarded: he smiled at 2.5 months, laughed spontaneously at 3 months, kept his head upright at 6 months, sat with tripod at 10 months, stood up at 13 months, and began to walk at 2 years. He emitted his first vocalizations at 2 months and monosyllabic words at 1 year. At 5 months he was referred to the pediatrician because of generalized spasms, and he was evaluated subsequently in Egypt by a neurologist who performed him a cranial CAT that was normal and began treatment with piracetam and vincamyn. We evaluated him at 7.5 months because of a psychomotor delay. He had an OFC of 45.5 cm (50 centile), and had the anterior fontanel opened. His weight was 9,200 g (50– 75 centile). He was alert but irritable, with a lack of visual responsiveness. He had a lively and hoarse cry, could not grip objects, and could not sit unsupported. We observed hypotonia of the extremities and also axial hypotonia with a light retraction of the aquileus and isquiotibial muscles, although he did not present parachuting. No anomalies were found in the strength, sensation, and reflexes. A distinctive facial phenotype was observed including large ears, thick lips, and upturned nose, all suggestive of WBS (Fig. 1). Genomic DNA was obtained from the patient and his parents by standard methods [Miller et al., 1988]. Polymerase chain reaction (PCR) for the amplification of the markers D7S672, D7S613, ELN-i-1, ELN-i-18, D7S1870, D7S2490, D7S2518, D7S2421, and D7S634 were performed as described in the Genome data bank (http://www.gdb.org). The PCR products were analyzed on nondenaturant 8% and 10% polyacrylamyde gel slabs (19:1). This molecular genetic study comprising the WBS critical region at 7q11.23 with polymorphic markers intra and extradeletion, showed a de novo deletion of paternal origin (Fig. 2). The following studies showed as normal: abdominal echography, cranial MRI, biochemistry (muscular enzymes included), and standard karyotype. Nevertheless the trunk evoked auditory potentials showed a cochlear bilateral hypoacusia of 50 db. In the visual potentials the only finding of interest was their low amplitude, and in the EEG a pattern of hypsarrhythmia was appreciated. The patient was re-evaluated subsequently at 11 and 19 months and at 2 years we verified slow progression of his motor and cognitive capacities. He was derived to the Hypoacusia Unit where they prescribed him audiphones. He still does not pronounce any word albeit he has received physiotherapy and early stimulation. The EEGs of control became normal, and the antiepileptic treatment was withdrawn. We present here a new case of WS associated with WBS. The WBS has been confirmed by the presence of the hemizygotic deletion of the critical region of WBS, analyzed with microsatellites intra and extradeletion (Fig. 2). The pattern of interictal hypsarrhythmia in the EEG and the presence of spasms were pathognomonic of WS. The patient did not have SVAS, but did have an interventricular communication. He did not present episodes of hypercalcemia. *Correspondence to: Miguel Fernández-Burriel Tercero, Laboratorio de Genética Molecular, Hospital Universitario MaternoInfantil de Canarias, Avda, Marı́tima del Sur s/n, 35016-Las Palmas de Gran Canaria, Canary Islands, Spain. E-mail: mferter@gobiernodecanarias.org