A further contribution to the delineation of the 17q21.31 microdeletion syndrome: Central nervous involvement in two Italian patients

Abstract

The 17q21.31 microdeletion syndrome is a genetic disorder characterized by intellectual disability, facial dysmorphisms and a typical behavioral phenotype. Patients are usually described as friendly and cooperative but they can also show behavioral problems such as hyperactivity, bad humor, temper tantrums and poor interaction. Central nervous system involvement includes callosal dysgenesis/absence, enlargement of lateral ventricles and abnormalities of cyngulate gyrus. We report on two Italian patients with the 17q21.31 microdeletion syndrome better emphasizing neuroimaging and neuropsychological characteristics. In particular, we carried out an assessment of intellectual efficiency and behavior that turned out to be within the mild-moderate range of mental retardation, as already reported in the literature. To the best of our knowledge this is the first report of a patient with the 17q21.31 microdeletion and a Chiari malformation type 1 coexisting with a mild anomaly of medulla oblongata. This malformation should be considered in patients with the 17q21.31 microdeletion syndrome, presenting suggestive symptoms (headache, neck pain, cerebellar signs or muscle weakness).

Introduction

During the last few years, using high resolution genome analyses, several new microdeletion syndromes have been identified in patients with intellectual disability of unknown etiology and mild dysmorphisms, including, for example, the recurrent deletion involving chromosome region 17q21.31 [1], [2].Array-CGH analysis also allowed to reveal microduplication of the 17q21.31 region, associated with a clinical phenotype milder than those seen in the microdeletion counterpart [1]. The prevalence of the 17q21.31 microdeletion syndrome is 1 in 16,000, while, to the best of our knowledge, only six cases of the 17q21.31 microduplication have been described in literature up till now [1], [2]. Although a specific pattern of phenotypic anomalies has been described, the 17q21.31 microdeletion syndrome is still underdiagnosed.

The critical region deleted in this syndrome spans about 424 kb, encompassing at least six genes, C17orf69, CRHR1, SPPL2C, MAPT, STH, and KANSL1 [2]. Haploinsufficiency of one or more of these genes may underlie the phenotype seen in individuals with the 17q21.31 deletion syndrome. Recently, a smaller deleted interval (205 kb), encompassing only the MAPT, STH and KANSL1 genes has been identified in a patient showing the classical 17q21.31 phenotype [3]. It is known that the deleted region, containing microtubule associated protein tau (MAPT) gene, coincides with an inversion polymorphism of about 900 kb [4]. Two highly divergent MAPT haplotypes, H1 and H2, with distinct linkage disequilibrium patterns across the region have been described [4], [5]. The MAPT haplotype H2, relatively common in European populations, is linked to the recurrent deletion events associated with the 17q21.31 microdeletion syndrome [5]. The MAPT gene is also of particular interest, as it is highly expressed in brain and involved in several neurodegenerative diseases.

Clinical features of the syndrome include: developmental delay, intellectual disability, hypotonia, seizures, heart anomalies, renal/urologic anomalies, hypermetropia, deformities of the feet and/or spine, facial dysmorphisms (abnormal hair color/texture, high/broad forehead, ptosis, blepharophimosis, upward slanting palpebral fissures, epicanthal folds, large/prominent ears, tubular or pear-shaped nose, bulbous nasal tip, everted lower lip). Behavioral style is described as friendly, amiable and cooperative with or without frequent laughing, reminding of the phenotypic features of Angelman syndrome. However, behavioral problems including hyperactivity, bad humor, temper tantrums, poor interaction with other children and speech delay are also reported.

In the present paper, we report on neuroimaging and neuropsychological features of two Italian patients with the 17q21.31 microdeletion syndrome with a focus on their evolution in time.