Severe Speech Delay Research Articles

Novel clinical finding in MECP2 duplication syndrome

MECP2 duplication syndrome (MECP2 DS) is a newly described genetic condition, with approximately 120 affected males being reported in so far [1–11]. The clinical features of this syndrome are hypotonia with feeding difficulties in the first month of life followed by spasticity in childhood, delayed motor developmental milestones, severe speech delay, dysmorphic features (brachycephaly, midfacial hypoplasia, large ears, and flat nasal bridge), moderate to severe intellectual disability, autistic features, seizures, recurrent respiratory infections, hypoplasia of the corpus callosum, severe constipation, and less frequent bladder dysfunction (urinary retention, bladder dilatation) [8]. Movement disorders (i.e., choreiform movements, stereotypies, and repetitive behaviors—especially, midline hand movements) were reported in various percentages of patients; rocking, spinning, and self-injurious behavior were also reported [11]. Most females heterozygous for MECP2 duplication are asymptomatic, but can exhibit features of the broad autism phenotype or other symptoms like anxiety, depression, and compulsions [11]. These patients’ management is multidisciplinary, including the treatment of feeding difficulties and of respiratory infection, physical therapy, speech therapy, ergotherapy, and specific behavioral therapy. We report on a 6-year-old boy, the first child of healthy nonconsanguineous parents, born after an uneventful pregnancy with a birth weight 2,500 g, Apgar score 10. No movement disorders or attention disorders in the family history were reported. Shortly after birth, the boy presented hypotonia with delayed psychomotor development; he held his head at 10 months, sat at 15 months, walked alone at 36 months, and spoke first words at 40 months. In the first year of life, the patient had feeding difficulties and recurrent respiratory infections. The clinical examination showed: weight 23 kg (Pc 75), height 115 cm (Pc 50), occipitofrontal circumference 48 cm (\2 DS); facial dysmorphism (hypertelorism; partial palpebral ptosis; open, carp-shaped mouth; micrognathia) (Fig. 1); cryptorchidism; bilateral pyramidal syndrome; severe intellectual disability; severe speech delay; autistic features; drooling. A prominent feature of the clinical picture was severe hyperkinesis, manifested as random non-purposeful movements, occurring throughout the day, in any environment (at home, in kindergarten, and in other public spaces), more prominent during the morning and in the afternoon impairing daily activities (the child was not able to play or to stay at the table to do a task for more than 5 min, thus not being able to participate in different activities together with other children). The patient presented also stereotyped movements (hand-flapping movements) and agitation during sleep. Hyperkinesis was, actually, the main reason for referral to our Department. The patient had not chorea, tremor, or epileptic seizures. To our knowledge, this is the first case with confirmed MECP2 duplication and hyperkinesis and the MECP2 duplication syndrome patients being considered rather hypoactive [12]. Biological tests, EEG and cerebral MRI were normal. M. Budisteanu, S. M. Papuc and A. Arghir equally contributed to this paper.

Hemizygous deletions on chromosome 1p21.3 involving the DPYD gene in individuals with autism spectrum disorder

We describe the identification and clinical presentation of four individuals from three unrelated families with hemizygous deletions involving the DPYD gene at chromosome 1p21.3. DPYD encodes dihydropyrimidine dehydrogenase, which is the initial and rate-limiting enzyme in the catabolism of pyrimidine bases. All four individuals described met diagnostic criteria for autism spectrum disorder with severe speech delay. Patient 1's deletion was originally reported in 2008, and more detailed clinical information is provided. Subsequently, this male individual was found to have a missense mutation in the X-linked PTCHD1 autism susceptibility gene, which may also contribute to the phenotype. Patients 2 and 3 are siblings with a novel deletion encompassing the DPYD gene. In their mother, the genomic region deleted from chromosome 1p21.3 was inserted into chromosome 10. A fourth proband had a novel 10-kb intragenic deletion of exon 6 of the DPYD gene detected on a higher resolution microarray. Our study suggests that hemizygous deletions involving the DPYD locus present with variable phenotypes which can include speech delay and autistic features, and may also be influenced by additional mutations in other genes, issues which need to be considered in genetic counseling.

Language disorder with mild intellectual disability in a child affected by a novel mutation of SLC6A8 gene

We describe the clinical and molecular features of a child harboring a novel mutation in SLC6A8 gene in association with a milder phenotype than other creatine transporter (CT1) deficient patients (OMIM 300352) [1–7]. The mutation c.757 G>C p.G253R in exon 4 of SLC6A8 was hemizygous in the child, aged 6 years and 6 months, who showed mild intellectual disability with severe speech and language delay. His carrier mother had borderline intellectual functioning. Although the neurochemical and biochemical parameters were fully consistent with those reported in the literature for subjects with CT1 deficit, in our patient within a general cognitive disability, a discrepancy between nonverbal and verbal skills was observed, confirming the peculiar vulnerability of language development under brain Cr depletion.

A Genotype-First Approach for the Molecular and Clinical Characterization of Uncommon De Novo Microdeletion of 20q13.33

BackgroundSubtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features.Methodology/Principal FindingsWe characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions.Conclusions/SignificanceBased on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development.

Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment

Genome-wide high-resolution array analysis is rapidly becoming a reliable method of diagnostic investigation in individuals with mental retardation and congenital anomalies, leading to the identification of several novel microdeletion and microduplication syndromes. We have identified seven individuals with duplication on chromosome 14q11.2q13.1, who exhibited idiopathic developmental delay and cognitive impairment, severe speech delay, and developmental epilepsy. Among these cases, the minimal common duplicated region on chromosome 14q11.2q13.1 includes only three genes, FOXG1, C14orf23, and PRKD1. We propose that increased dosage of Forkhead Box G1 (FOXG1) is the best candidate to explain the abnormal neurodevelopmental phenotypes observed in our patients. Deletions and inactivating mutations of FOXG1 have been associated with a Rett-like syndrome characterized by hypotonia, irritability, developmental delay, hand stereotypies, and deceleration of head growth. FOXG1, encoding a brain-specific transcription factor, has an important role in the developing brain. In fact, in vivo studies in chicken brain demonstrated that overexpression of FOXG1 results in thickening of the neuroepithelium and outgrowth of the telencephalon and mesencephalum, secondary to a reduction in neuroepithelial cell apoptosis.

Chiari I malformation, delayed gross motor skills, severe speech delay, and epileptiform discharges in a child with FOXP1 haploinsufficiency

Human FOXP2 deficiency has been identified as a cause of hereditary developmental verbal dyspraxia. Another member of the same gene family, FOXP1, has expression patterns that overlap with FOXP2 in some areas of the brain, and FOXP1 and FOXP2 have the ability to form heterodimers. These findings suggest the possibility that FOXP1 may also contribute to proper speech development. However, no such role of FOXP1 has been established to date. Recently, a child was reported who presented with a 3p13-14.1 deletion of four genes, including FOXP1, and a constellation of deficits that included speech delay. In this study, we report the case of a patient with a single deletion of FOXP1. This patient presented with speech and motor developmental delays, a Chiari I malformation, and epileptiform discharges. The nature of the speech deficit is different from the primary oromotor verbal dyspraxia found in patients with FOXP2 deficiency. The patient's developmental deficits may support a role for FOXP1 in the development of verbal and motor skills.

Association of Syndromic Mental Retardation and Autism with 22q11.2 Duplication

We describe a 5.3-year-old girl with autism, mental retardation, hypotonia, marked speech delay, and mild dysmorphic features with a 22q11.2 duplication. Her mother carries the same duplication and presents cleft palate, and normal intelligence. The clinical and behavioural phenotype of this relatively new syndrome is very heterogeneous, with high variability also in the familiar cases. Up till now, about 50 cases of 22q11.2 duplication have been reported, but only three of them are associated with autistic disorders. We propose that in addition to 22q13.3 deletion syndrome, also 22q11.2 duplication should be suspected in a patient with unspecified dysmorphisms, mental retardation, autism, hypotonia, and severe speech delay.

Language and Cognitive Development of Children Who Have Williams Syndrome or Duplication of the Williams Syndrome Region

Language and Cognitive Development of Children Who Have Williams Syndrome or Duplication of the Williams Syndrome Region

Establishing Derived Manding for Specific Amounts with Three Children: An Attempt at Synthesizing Skinner’s Verbal Behavior with Relational Frame Theory

Participants were 2 typically developing children, aged 9 and 10 years, and 1 child, aged 4 years, with a reported severe speech delay. Five specific mand functions were trained such that participants learned to mand for the delivery or removal of tokens to the value of −2, −1, 0, +1, and +2, by presenting an arbitrary stimulus (A1, A2, A3, A4, and A5, respectively). The A stimuli were then incorporated into a series of interrelated conditional discriminations (A1–B1, B1–C1, A2–B2, B2–C2, A3–B3, B3–C3, A4–B4, B4–C4, A5–B5, B5–C5). Subsequent tests determined if participants derived 5 specific mands, presenting C1, C2, C3, C4, and C5 as mands for −2, −1, 0, +1 and +2 tokens. Three participants demonstrated derived manding, and derived manding altered in accordance with newly trained relations across two reversal procedures.

Molecular karyotyping is important in determining the cause of behavioural phenotypes

Background: The cytogenetic delineation and behavioural phenotype of syndromes has evolved from the chromosome level, through FISH (microdeletions syndromes, such as PWS, VCFS, SMS, del1p36) to molecular karyotyping (array CGH). The new syndromes being outlined in recent years account for rarer microdeletions and microduplications, in which the behavioural phenotype is not always well characterized. Method: We have screened by array CGH more than 2000 patients, of which almost 400 have cytogenetic imbalances. We present a subset of these patients, in which the behaviour was an important component of the motivation for molecular karyotyping. Results: Three case studies: 1) A boy with severe feeding problems, speech delay, stereotypic and autistic behaviour. He is dysmorphic and has an intellectual disability. Molecular karyotyping showed a de novo microdeletion of chromosome 15q13.2. 2) A 3‐year old girl with difficult behaviour, including negative vocalizations, aggression and repetitive rocking. She has poor weight gain, difficulty in falling asleep and wakes early. She is dysmorphic, has a developmental IQ of 67, a paternally inherited microdeletion of chromosome 9p21.3 and a de novo microduplication of chromosome 17p11.2. 3) A 5‐year old girl with intellectual disability who participates in interactive play but remains slow in task execution. Her balance is poor when standing and walking, She does not evidence satiety for food and constantly air‐swallows. Molecular karyotyping revealed a de novo microdeletion of chromosome 9qter. Conclusion: The molecular karyotyping results encourage its use in finding the cause of intellectual disability. With the assistance of international collaboration via common databases, such as Decipher, pinpointing and understanding the underlying genes contributing to the overall clinical picture, especially behaviour, will become a reality.

Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development

The severe mental retardation and speech deficits associated with 22q13 terminal deletions have been attributed in large part to haploinsufficiency of SHANK3, which maps to all 22q13 terminal deletions, although more proximal genes are assumed to have minor effects. We report two children with interstitial deletions of 22q13 and two copies of SHANK3, but clinical features similar to the terminal 22q13 deletion syndrome, including mental retardation and severe speech delay. Both these interstitial deletions are completely contained within the largest terminal deletion, but do not overlap with the nine smallest terminal deletions. These interstitial deletions indicate that haploinsufficiency for 22q13 genes other than SHANK3 can have major effects on cognitive and language development. However, the relatively mild speech problems and normal cognitive abilities of a parent who transmitted her identical interstitial deletion to her more severely affected son suggests that the phenotype associated with this region may be more variable than terminal deletions and therefore contribute to the relative lack of correlation between clinical severity and size of terminal deletions. The phenotypic similarity between the interstitial deletions and non-overlapping small terminal 22q13 deletions emphasizes the general nonspecificity of the clinical picture of the 22q13 deletion syndrome and the importance of molecular analysis for diagnosis.

Otologic Manifestations of Hunter Syndrome and Their Relationship with Speech Development

The excessive storage of mucopolysaccharide in Hunter syndrome leads to various otologic manifestations. We interviewed 19 patients with Hunter syndrome to assess their otologic problems, and conducted audiologic tests and temporal bone CT. Patients with the intermediate or severe form exhibited severe speech delay by more than 2 years (12/14 patients). However, in patients with the mild form (5/5), speech development was not much disturbed (2/5), although otoscopic findings were similar. The hearing threshold determined by the auditory brainstem response differed significantly between the mild and intermediate/severe forms (p < 0.05). Therefore, patients with the mild form may benefit from active otologic intervention such as VT insertion, amplification, and speech therapy.

Muskuläre Hypotonie, Entwicklungsretardierung, Sprachentwicklungsstörung und geringgradige Dysmorphiezeichen: 22q13-Deletions-Syndrom (Phelan-McDermid-Syndrom) als wichtige Differenzialdiagnose

Clarifying the cause of global developmental and speech delay is of considerable significance in pediatrics. We present the clinical phenotype of the 22q13 deletion syndrome - also known as Phelan-McDermid syndrome - and show the diagnostic options. We report on a female patient with muscular hypotonia, tall stature, minor facial dysmorphism, retarded motor and mental development, and severe speech delay. Chromosomal analysis was performed first on peripheral lymphocytes on GTG-banded chromosomes. Fluorescence in situ hybridization (FISH) analysis was carried out using the dual-color LSI DiGeorge/VCFS Region Probe (TUPLE1, N25) (Vysis/Abbott) and the subtelomeric probe tel 22q13.3 (Tel Vysion 22q). The analysis of metaphase chromosomes at 450 band resolution showed a normal female karyotype 46,XX. FISH analysis revealed a 22q13 deletion. Muscular hypotonia and developmental delay are non-specific findings observed in many genetic syndromes. In association with severe speech delay and normal or advanced growth pediatricians should consider 22q13 deletion syndrome as a potential cause and initiate a genetic examination.

Severe Speech Delay as the Presenting Symptom of Guanidinoacetate Methyltransferase Deficiency

Guanidinoacetate methyltransferase deficiency typically presents with muscular hypotonia, global developmental delay, extrapyramidal signs, and seizures during infancy and childhood. The authors report a 5-year-old child with guanidinoacetate methyltransferase deficiency who presented with severe speech delay, emphasizing the importance of an early screening for disorders of creatine synthesis and transport in every infant or child with isolated speech delay of unknown cause.

Elective mutism, generalized seizures, developmental delay, mild mental retardation, dysmorphic features and renal dystopia in a 13-year-old boy - a case report

Introduction: Elective Mutism (EM) is an underdiagnosed psychiatric disorder in children of unclear prevalence. Anxiety is considered as the main aetiological factor. Several risk factors have been identified to promote the manifestation of EM. Complicating the clinical picture is the fact that children with EM represent a heterogeneous group with a number of additional childhood disorders. Case report: We report on a 13-year-old boy with increasing lethargy and inactivity, reduced verbal communication and oppositional-defiant and aggressive behaviour in the family setting. His past medical history reported a renal dystopia, severe speech and motor developmental delay and generalized seizures. He suffered from nocturnal enuresis until the age of 11. His cognitive abilities were impaired and have been rated as a state of mild mental retardation. Distinctive abnormalities of his facial features were suggestive for a genetic aetiology. During our psychiatric assessment he demonstrated excessive shyness and answered questions at most with one whispered word. Evaluation using self-rating scales revealed high scores of social anxiety and depression. His anxious and avoidant behaviour has been observed since kindergarten, where he remained inactive and mute, suffering from intense separation anxiety. He hardly communicated verbally in the classroom during primary school, only interacting and communicating with peers when considering himself being unheard and unobserved by adults. At home he spoke uninhibited with his family. Combined cognitive-behavioural and speech therapy treatment focusing on reducing anxiety and promoting verbal communication proved effective but revealed considerable expressive and receptive language deficits.

A new syndrome with growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate

We report on two new Brazilian cases and reviewed two previously reported patients with a characteristic combination of signs including mandibulofacial dysostosis, a clinical suggestion of trigonocephaly, microcephaly, unusual ears with skin tags, and cleft palate. Follow-up of these patients revealed growth and mental retardation, and severe language and speech delay. A review of the literature and database programs did not find any syndromes that matched this constellation of findings. We believe that this combination of signs represents a new mandibulofacial dysostosis syndrome whose etiology is unknown.

Characterization of two supernumerary marker chromosomes in a patient with signs of Klinefelter syndrome, mild facial anomalies, and severe speech delay*

A boy with signs of Klinefelter syndrome, mild facial dysmorphic features, and severely retarded speech development displayed a female karyotype with mosaicism for two marker chromosomes 48,XX,+mar1,+mar2[68]/47,XX,+mar1[19]/47,XX,+mar2[6]/46,XX[8]. Using chromosomal microdissection, locus-specific fluorescence in situ hybridization (FISH), and PCR with several Y-chromosome markers, the larger supernumerary marker chromosome (SMC) was characterized as a ring Y-chromosome. Detection of the SRY-region explained the male phenotype. The smaller second marker chromosome contained the pericentromeric region of chromosome 8. We suggest that the co-occurrence of a partial Y-chromosome and partial trisomy 8 explain the severe speech delay and the facial dysmorphic features.

X‐Linked creatine transporter deficiency in two patients with severe mental retardation and autism

We describe the first two unrelated Spanish patients with creatine transporter deficiency initially identified by brain proton magnetic resonance spectroscopy (MRS). The clinical phenotype was characterized by severe mental retardation, epilepsy, autism, severe speech delay and absence of brain creatine by MRS. Urine creatine/creatinine ratio was increased and creatine uptake in fibroblasts was impaired in both patients. On DNA sequence analysis of the SLC6A8/creatine transporter gene, one hemizygous mutation was found in each patient: one mutation was novel and consisted of a deletion of two nucleotides c.878-879delTC in exon 5, resulting in a frameshift (p.Lys293fsX3), and in the other patient a known deletion of three nucleotides 1222-1224delTTC in exon 8 resulting in p.Phe408del. Creatine treatment for one year failed to improve the neurological symptoms and was associated with a striking increase in body weight in both patients (13 and 16 kg, respectively).

Hearing assessment in pre-school children with speech delay

Objective The purpose of this study was to detect any underlying hearing loss among the healthy pre-school children with speech delay. Methods 76 children, aged from 1 to 5 years, underwent a thorough audiological examination consisting of tympanometry, free field testing, otoacoustic emission recordings and auditory brainstem responses (ABRs). If hearing was normal, then they were evaluated by a child neurologist–psychiatrist. Results According to our findings, the children were classified into 3 groups; those with normal hearing levels (group I, 52 children, 68.4%), sensorineural hearing loss (group II, 22 children, 28.9%) and conductive hearing loss (group III, 2 children, 2.6%). In group I, speech delay was attributed to pervasive developmental disorder (PDD), which represents high-functioning autistic children (37 cases). Other causes were specific language impairment (SLI)-expressive (3 cases), bilingualism (2 cases), and unknown etiology (10 cases). More than half (59%) of the children diagnosed with PDD evidenced significant language impairment limited to more than two words. Children with SLI-expressive and bilingualism used a maximum of two words. In group II, 13 children suffered from profound hearing loss in both ears, 3 from severe, 3 had profound hearing loss in one ear and severe in the other, 2 from moderate, and 1 had moderate in one ear and severe in the other. No child had mild sensorineural hearing loss. The children with profound hearing loss in at least one ear had total language impairment using no word at all (10 cases), or a maximum of two words (6 cases). When hearing loss was moderate to severe, then the speech vocabulary was confined to several words (more than two words—6 cases). Only two children suffering from conductive hearing loss both presented with complete lack of speech. Conclusion A great number of healthy pre-school children with speech delay were found to have normal hearing. In this case, the otolaryngologist should be aware of the possible underlying clinical entities, especially of psychiatric nature. The children with profound sensorineural hearing loss exhibited more severe speech delay than those with moderate to severe. Regardless of etiology, the early identification and intervention contribute to positive outcome in this critical period of childhood for language development.

A Subtype of Speech Delay Associated With Developmental Psychosocial Involvement

This report presents findings supporting the hypothesis of a clinically relevant subtype of childhood speech sound disorder, provisionally titled speech delay-developmental psychosocial involvement (SD-DPI). Conversational speech samples from 29 children who met inclusionary criteria for SD-DPI were selected from a case record archive at a university speech clinic for children. Participants with SD-DPI had been characterized by speech clinicians and caregivers as having speech delay with psychosocial issues that required attention in the course of at least 1 semester of speech treatment. The 29 participants were divided into 2 subgroups, based on clinicians' and parents' records indicating either approach-related negative affect (n = 23) or withdrawal-related negative affect (n = 6). Each participant with SD-DPI was matched by age, gender, and type of speech involvement to 3 comparison speakers with speech delay of unknown origin (n = 87). Analyses of the conversational speech samples indicated that in comparison with participants in the control group, those with SD-DPI had significantly more severe speech delay, averaging approximately 7% to 10% lowered speech competence in conversation. The clinical prevalence of SD-DPI was estimated at approximately 12% of children referred to the university speech clinic in the present study. The authors interpret the present findings to indicate that approach-related or withdrawal-related negative affect, negative emotionality or mood, and decreased task persistence or attention are risk factors for increased severity of expression of speech delay.