Interstitial 11q deletion: genomic characterization and neuropsychiatric follow up from early infancy to adolescence and literature review
© Nacinovich et al.; licensee BioMed Central Ltd. 2014
Received: 11 July 2013
Accepted: 28 March 2014
Published: 17 April 2014
Interstitial deletions of chromosome 11 long arm are rarely observed and the associated phenotype ranges from normal to severe, depending on the position and size of the deletion and on the presence of unmasked recessive genes on the normal homologous. To our knowledge 32 cases are reported in literature with three family cases. Phenotype-genotype correlation is not very clear and the most common features are characteristic facial dysmorphisms, palate anomalies and developmental delay. Growth retardation is not typical and other major malformations are reported in some cases.
We described a child with 11q interstitial deletion diagnosed at birth with hypotonia and minor dysmorphisms using standard cytogenetic techniques; array CGH was subsequently performed to define the deletion at a molecular level.
This case gave us the opportunity to attempt a genotype-phenotype correlation reviewing the literature and to describe a rehabilitative program that improved the development perspectives of this child.
KeywordsChromosome 11q deletion Array CGH Genotype-phenotype correlation Follow up Rehabilitation programme
Terminal 11q deletions are reported in literature to be associated with the well-described Jacobsen Syndrome. On the contrary interstitial deletions are very uncommon and heterogeneous in size and location of breakpoints, spanning from bands 11q13 to 11q23. From the first description by Taillemite et al. , 31 more cases were described [2–21], case ID 4366 in the European Cytogenetists Association Register of Unbalanced Chromosome Aberration, ECARUCA (http://www.ecaruca.net), case ID 3945 ECARUCA. Only in seven reports the deletion was characterized by cytogenetic molecular techniques [2–8]. The majority of deletions are de novo, but three family cases are described with normal or borderline phenotype [2, 4, 7]. Position and size of deletions are heterogeneous. The definition of the breakpoints of an interstitial 11q deletion by conventional techniques is difficult because the banding pattern could be confusing, but new molecular methods such as array CGH and SNPs allow an optimal definition of the breakpoint regions. Clinical phenotype includes several dysmorphic features, palate anomalies and developmental delay. Growth retardation, hypotonia, seizures, congenital heart malformation, kidney and skeletal anomalies are associated features in some cases.
Here we describe a case of de novo interstitial deletion of chromosome 11 long arm identified at birth while investigating mild dysmorphisms and hypotonia. The long term rehabilitative program is described and the good results obtained allow us to be positive in the prognosis of similar cases of 11q interstitial deletions. Finally we attempt a genotype/phenotype correlation reviewing the literature to search candidate genes with a role in the phenotype.
The proband is a boy and he is the only child born from a 36 year old father and a 27 year old mother. The parents were healthy and unrelated; paternal family history was negative for genetic diseases, while in the maternal family, eight members were affected by retinitis pigmentosa with an autosomal dominant pattern of transmission. Prenatal ultrasonographic evaluation gave normal results in fetal growth and morphology. No prenatal invasive genetic test was performed.
The child was born by natural delivery after a 40 week gestation plus 5 days. Birth weight was 3420 g (25°- 50° centile for gestational age), length at birth was 52 cm, (between 50°- 75° centile), occipito-frontal circumference (OCF) was 35.5 cm (50°- 75° centile), APGAR score was 9/10. In neonatal period, the child presented hyperpyrexia (blood, urine and cerebrospinal fluid microbiological analyses were all negative) and greater than 10% weight loss, which regressed with adequate nutrition. Episodes of bronchospasm and tirage, repeated episodes of cyanosis and desaturation resolved spontaneously shortly before discharge (at one month of age). During childhood his height growth was at the lower limit. He did not show any major malformation, besides submucous cleft palate. Brain MRI scan did not show any structural anomalies.
He had mild myopia and his hearing was normal. He did not show any significant medical complications.
At the age of 12 years and 1 month his weight was 41.6 kg (25°-50° percentile), his height was 134.2 cm (<3° percentile) and his OFC was 53 cm (50° percentile). His Body Mass Index (BMI) was 23 (75°-90° percentile). Facial dysmorphic features included long face, high nasal bridge, short and smooth philtrum, micrognathia. He had small hands and nasal speech.
Endocrinological analysis (IGF-1 dosage and growth hormone stimulation test with arginine) showed results consistent with isolated growth hormone (GH) deficiency. A further brain MRI scan, carried out when he was twelve, revealed a small pituitary gland. GH treatment has been advised and the patient has just started this therapy.
Written informed consent was obtained from the parents for publication of this case report and any accompanying images.
At birth, karyotype on peripheral blood lymphocytes was requested because of mild hypotonia and minor dysmorphic features.
At 1 month of age, the proband’s neurological examination showed no major dysfunctions; clinical observation according to Prechtl´s Method on the Qualitative Assessment of General Movements  showed a pattern characterized by Poor Repertoire. His motor milestones were not significantly delayed: control of the head at 4 months, sitting without support at 8 months, hands and knees crawling at 11 months, standing with assistance at 13 months, walking alone at 24 months.
Parents reported vocalization, babbling and the first word “mamma” being uttered at one year of age. “Mamma” remained the only word used to name everything word until 19 months of age. After a period of hospitalization following an accidental fall which caused clavicle fracture and a second spell in hospital due to gastroenteritis, the child presented an arrest in speech and psychomotor competencies. These aspects were inscribed in a global regression of communicational and relational capacities.
Speech development between 20 and 36 months was characterized by: aphonia, amimia, pseudo- articulatory movements, reduced opening of the labial rima. Moreover, the child showed a poor communicative intent even at a non verbal level.
At 3 years he was a clumsy, passive and withdrawn child, not interested in playing. Therefore, at 3 years of age a psychomotor treatment with attention to relational aspects was introduced twice a week.
During the first year of rehabilitation, the proband reduced his more passive traits becoming more and more purposeful, actively responsive and assertive. Communicative intention emerged together with the increasing awareness of his speech difficulties.
There was a large discrepancy between the verbal comprehension (discrete) and expressive skills: he used gestures associated with vocalization to indicate, to formulate questions, to express disappointment or excitement. Then, speech therapy sessions began twice a week at the age of 4.
The proband showed a deficit of phonetic and non-phonetic phonation. Later, rhinolalia and rhinophonia, and a deficit in coordination and in phonological memory were observed. Consequently, a double diagnosis of specific expressive language disorder and of childhood apraxia of speech was formulated.
At 5 years, after one year of speech therapy, he achieved a quite complete phonetic repertoire, vocabulary increase with risk threshold for semantic errors, and emerging narrative skills. While he showed an adequate lexical comprehension, morphosyntactic comprehension was delayed of one year and communication was supported by mimics and gestures. At the same time, he developed social skills, showing more relational and playing capacities with peers and adults.
At age 6, verbal speech was sufficiently intelligible despite the persistence of hypotonic and uncoordinated glosso-velo-pharyngeal muscles.
His cognitive development, as measured by WIPPSI Scale, was in the lower limits of the normal range, with a discrepancy between verbal (VIQ) and performance (PIQ) scores (VIQ =85; PIQ =96; Full Scale IQ = 89) .
At the age of 8, the proband presented an impairment in the ability of naming objects and in lexical retrieval with the help of phonemic cues. On using the Italian version of the Peabody Picture Vocabulary Test , comprehension was almost adequate (Language quotient = 82).
Morphosyntactic comprehension using the Rustioni Metz test  showed a delay of about 2 years. The verbal short term memory span was 3 (inadequate).
Moreover, learning difficulties in the presence of a cognitive development at the lower limit of the normal range emerged. In particular, reading comprehension, measured using the MT battery of tests , was inadequate (correct answers: 6/10), in the absence of dyslexia and dysorthography, as measured with the Dyslexia and Orthographic coding test . Therefore, the logopedic rehabilitation continued until the child was 9 years old, with the aim to improve oral and written language comprehension. In the meantime, his writing and reading abilities supported him in planning the phonological string in speech.
Afterwards, counselling to parents and teachers, together with neuropsychiatric follow up continued until today with longitudinal controls (twelve years). We considered highly important to support parents and teachers in finding a harmonious global development which could take into account not only the educational aspects, but also the emotional and relational sides.
Currently the child shows good skills at school in the application of the learned mechanisms, but he has more difficulties when logic skills and problem solving abilities are required. However, he is able to evaluate his work and adopt compensatory strategies in order to overcome his difficulties. He is competitive with his schoolmates, comparing their tests results and scores. He shows a good personal and social independence and participates in curricular and extracurricular activities with peers.
Summary of clinical features from the literature review of 32 cases and present case
Deleted region (range)
Deletion size range (Mb)
Uni/bilateral eyelids Ptosis
Up-slanted palpebral Fissures
Submucous cleft palate
Uni/bilateral club foot
Iris and chorioretinal coloboma
Retinal dysgenesis/bilateral exudative vitreoretinopathy
High arched palate
Minor skeletal anomalies
In the deleted region of our patient, about 94 genes are mapped [http://genome.ucsc.edu/]: 53 of them have known functions, some of them being associated with autosomal recessive disease, others have no OMIM phenotype. A biological role is still unkwnown for the other 41 genes.
Eight OMIM genes are expressed in the brain (FAT 3, MED17, PANX1, GPR83, CNTN5, KIAA1377,GRIA4 and GUCY1A2). The CNTN5 gene, coding for contactins which mediate cell surface interactions in the development of the nervous system, is described as been involved in autism spectrum disorders . The GRIA4 gene belongs to the glutammate receptor family that plays an important role in excitatory synaptic transmission. Patients with mental retardation and multiple congenital abnormalities showed a significant copy number change in the glutammate receptor family . Even if it is very difficult to correlate particular clinical features to a specific gene, we may hypothesize the role of haploinsufficiency of these two genes in the patient phenotype.
In literature [8, 10, 12, 16, 20] a psychomotor delay and a language disorder were described, in a few cases, as an expressive disorder. Our patient also showed the particular trait of a childhood apraxia of speech.
The phenotype we observed in our case has only been described in one other report  in which the proband shows poor eye contact and low interest in his surrounding. The rehabilitation process proposed and the neuropsychiatric follow up and counselling have allowed the recovery of adequate relational competences, improved speech and language abilities and a positive evolution of his global cognitive and adaptive capacities and social and school skills.
After considering all the collected clinical information, we drew the conclusion that it is not possible to define a distinctive phenotype of the 11q partial monosomy due to the heterogeneity in size and position of the deletions and to the absence of a minimal common deleted region. About family cases showing normal phenotype [2, 4] we could hypothesize the effect of modifier genes or a compensatory gene expression of the allele on the normal chromosome 11. More literature data and a better molecular characterization are needed to confirm this hypothesis. Moreover, the phenotype is not only due to haploinsufficient genes but it is the result of complex gene – gene and gene-environment interactions.
We found this case particularly interesting because it gave us the opportunity to describe a rehabilitation program that we believe has improved the development perspectives of this child and therefore his quality of life.
Written informed consent was obtained from the patient’s parents for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We wish to thank the speech therapists S. Artesani and A. Milishy for their valuable help.
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