Sólveig Óskarsdóttir

Practical guidelines for managing patients with 22q11.2 deletion syndrome

A 12-year-old boy currently is followed by multiple sub-specialists for problems caused by the chromosome 22q11.2 deletion syndrome (22q11DS) (Figure). He was born via spontaneous vaginal delivery, weighing 3033 g, to a 31-year-old G3P3 mother after a full-term pregnancy complicated only by mild polyhydramnios. Family history was non-contributory. Apgar scores were 8 at 1 minute and 9 at 5 minutes. With the exception of a weak cry, the results of the infant’s initial examination were unremarkable, and he was moved to the well-baby nursery. Shortly thereafter, a cardiac murmur was noted, the cardiology department was consulted, and the child was transferred to a local tertiary care facility with a diagnosis of tetralogy of Fallot. Stable, he was discharged home at 3 days of life. Figure Mild dysmorphic facial features of a boy aged 11 years with 22q11.2DS, including a short forehead, hooded eyelids with upslanting palpebral fissures, malar flatness, bulbous nasal tip with hypoplastic alae nasi, and protuberant ears. At 5 days of life, he had jerky movements. On presentation to the local emergency department, his total calcium level was 4.7 mg/dL, and later partial hypoparathyroidism was diagnosed. At that time, a consulting geneticist suggested the diagnosis of chromosome 22q11DS. Weeks later, the family received a telephone call confirming the diagnosis with fluorescence in situ hybridization (FISH). No additional information about the diagnosis, prognosis, etiology, or recurrence risk was provided until the child was 5 months of age, when he underwent cardiac repair at a third hospital, where a comprehensive 22q11DS program was in operation. In the interim, the child had feeding difficulties requiring supplemental nasogastric tube feeds, nasal regurgitation, and gastroesophageal reflux, while the parents searched the internet for reliable information about their son’s diagnosis. Subsequent notable abnormalities and interventions included: recurrent otitis media with bilateral myringotomy tube placement at 6 months; angioplasty with left pulmonary artery stent placement after the identification of pulmonary artery stenosis with bilateral pleural effusions at age 6 years; chronic upper respiratory infections with significant T cell dysfunction requiring live viral vaccines to be held until age 7 years; velopharyngeal incompetence necessitating posterior pharyngeal flap surgery at 7 years; enamel hypoplasia and numerous caries resulting in 3 separate dental procedures under general cardiac anesthesia beginning at age 7 years; multiple cervical and thoracic vertebral anomalies with thoracic levoconvex scoliosis and upper lumbar dextroscoliosis requiring growing rod placement at age 11 years with subsequent rod extension at ages 11.5 and 12 years; postoperative hypocalcemia; short stature; constipation; and persistent idiopathic thrombocytopenia. Pertinent negative test results included normal renal ultrasound scanning and parental 22q11.2 deletion studies. On physical examination, the boy’s height and weight have consistently tracked just below the fifth percentile, with no evidence of growth hormone deficiency. His head circumference is within reference range at the 25th percentile. Dysmorphic features include: a low anterior hairline; hooded eyelids; malar flatness; normally formed but protuberant ears with attached lobes; a mildly deviated nose with a bulbous nasal tip and hypoplastic alae nasi; asymmetric crying facies with a thin upper lip; mild micrognathia; a sacral dimple; and soft tissue syndactyly of the second and third toes. Developmentally, the boy had mild delays in achieving motor milestones, sitting at 11 months and walking at 18 months. However, he exhibited significant delays in the emergence of language: he never babbled, spoke his first words at age 3 years, and only achieved full conversational speech at 7 years. However, he had relative strengths in receptive language and communicated appropriately by the use of sign language. Now quite conversant, he is mainstreamed in the seventh grade with resource room supports. Moreover, he is affable, but exhibits anxiety and perseverations. Lastly, despite numerous medical, academic, and social challenges, he participates in assisted athletics, is an avid wrestling fan, and enjoys travel. However, his exceptionally supportive parents, siblings, and extended family continue to worry about his long-term outcome and transition of care as he approaches adulthood. As demonstrated by this boy’s complicated course, practical multi-system guidelines are needed to assist the general practitioner and specialists in caring for patients with 22q11DS. Although still under-recognized, detection, including in the prenatal setting, is increasing. Moreover, the phenotypic spectrum is highly variable, and patients may present at any age. Thus, initial guidelines developed by an international panel of experts present the best practice recommendations currently available across the lifespan, with a major focus on the changing issues through childhood development.

Autism, ADHD, Mental Retardation and Behavior Problems in 100 Individuals with 22q11 Deletion Syndrome.

This study assessed the prevalence and type of associated neuropsychiatric problems in children and adults with 22q11 deletion syndrome. One-hundred consecutively referred individuals with 22q11 deletion syndrome were given in-depth neuropsychiatric assessments and questionnaires screens. Autism spectrum disorders (ASDs) and/or attention deficit/hyperactivity disorder (ADHD) were diagnosed in 44 cases. ASD was diagnosed in 23 cases of whom only 5 had autistic disorder. ADHD was diagnosed in 30 individuals. In nine of these cases with ASD or ADHD there was a combination of these diagnoses. Mental retardation (MR) with or without ASD/ADHD was diagnosed in 51 individuals. ASD, ADHD, and/or MR were present in 67 cases. Females had higher IQ than males. The results of this study showed that the vast majority of all individuals with 22q11 deletion syndrome have behavior and/or learning problems and more than 40% meet criteria for either ASD, ADHD or both. Neuropsychiatric and neuropsychological evaluations are indicated as parts of the routine clinical assessment of individuals with 22q11 deletion syndrome.

Presenting phenotype in 100 children with the 22q11 deletion syndrome

The aim of this study was to investigate and describe the presenting phenotype of children with the 22q11 deletion syndrome and to describe common clinical features that could serve as guidelines in the clinical diagnostic process preceding genetic testing. A hospital-based study of 100 consecutive children and adolescents with 22q11 deletion was initiated. The patients were divided into two groups according to age at diagnosis: before or after 2 years of age. Clinical features were grouped into a core set of eight features: cardiac defects, non-visible/hypoplastic thymus or infection problems, hypocalcaemia, feeding difficulties, cleft palate/speech-language impairment, developmental delay/learning difficulties, characteristic dysmorphic features and other malformations and deformities. The median age at diagnosis was 6.7 years. Of all patients, 26% were diagnosed in infancy and 92% had a congenital cardiac defect, whereas 54% of those diagnosed later had a cardiac defect. A cleft palate was present in 25 cases and 44 had some other malformation or deformity. All presented with a combination of many of the core features. Of those diagnosed after 2 years of age, the majority presented with speech-language impairment, developmental delay or learning difficulties and recurrent infections. Characteristic mild dysmorphic features were noticed in all children. Conclusion: In spite of variable clinical expression, children with 22q11 deletion share a number of major features and have a characteristic phenotype. A high proportion have no cardiac defect and hence a risk of diagnostic delay. Increased awareness and knowledge among general paediatricians and other specialists who meet these children early in life is needed to reduce the diagnostic delay.

Neuropsychiatric disorders in the 22q11 deletion syndrome.

Purpose: This study was undertaken with a view to establishing the occurrence of neuropsychiatric disorders in the 22q11 deletion syndrome.Methods: Thirty-two children and young adults with genetically confirmed 22q11 deletion were given comprehensive neuropsychiatric assessments.Results: Altogether, 56% had a neuropsychiatric disorder. Only 6% were of normal IQ and free of physchiatric disorder. Attention-deficit/hyperactivity disorder was diagnosed in 44% and 31% had an autism spectrum problem. In 16% criteria for both these diagnoses were met. Fifty-three percent had mental retardation, often with a test-profile suggesting a nonverbal learning disorder.Conclusion: The findings imply that a majority of children and adolescents with 22q11 deletion syndrome are in need of neuropsychiatric assessment and intervention.

Chromosome 22q11 deletion syndrome (CATCH 22): neuropsychiatric and neuropsychological aspects

Twenty children and young adults (age range 5 to 33 years, 12 females and eight males) with genetically confirmed 22q11 deletion syndrome (CATCH 22: Cardiac anomaly, Anomalous face, Thymus hypoplasia/aplasia, Cleft palate, and Hypocalcaemia), recruited from a large ongoing study, were given comprehensive assessments with a view to determining the pattern of neuropsychiatric and neuropsychological deficits thought to be part of the syndrome in many cases. IQ ranged between 46 and 100 with a mean score of 70. Half the group had an IQ < 70. In 13 individuals, attention‐deficit‐hyperactivity disorder (ADHD), mainly inattentive or combined type in most cases, and/or autism spectrum problems were diagnosed. Many participants, even among those who had an IQ within the normal range and had neither ADHD nor autistic spectrum problems, showed a characteristic and pronounced behavioural profile with low mental energy, initiation difficulties, deficits in sustained attention, and social interaction (often augmented by limited facial expression and communication and speech problems).

Disabilities and cognition in children and adolescents with 22q11 deletion syndrome

The purpose of this study was to investigate cognitive and other disabilities in children and adolescents with 22q11 deletion syndrome. Thirty-three children (15 females, 18 males; age range 3 to 19y, median 7y 6mo) with 22q11 deletion were investigated for growth, development, neurology, cognition, motor function, and participation (measured as handicap**). Half of the children had never crawled, although they had shuffled, and commencement of walking was delayed (mean 18mo, SD 6mo). Hypotonia was found in 25 and poor balance in 24 of the 33 children; 17 out of 27 had definite motor problems, including two with spastic hemiplegia. Intelligence quotient (IQ) range was 50 to 100. Eleven patients had an IQ below 70, and 15 between 70 and 84. Verbal IQ was higher than Performance IQ. Level of handicap within the study group was considered moderate, and all but one child had extra support at school. We conclude that children with 22q11 deletion syndrome have multiple neurological, motor, and cognitive problems. Although the severity and number of problems varies, the combination of impairments and disabilities results in a low level of participation.

Attention deficits in children with 22q.11 deletion syndrome

This study examined attention abilities of children with 22q.11 deletion syndrome. Thirty children (14 males, 16 females; age range 7 to 13y) were given comprehensive neuropsychological and neuropsychiatric assessments. Learning disability was found in 13 children. Superiority in verbal over performance IQ was very common. Attention-deficit-hyperactivity disorder (mainly of inattentive subtype) was diagnosed in 13 children. There appeared to be a relation between low IQ and presence of autism spectrum problems. The presence of attention deficits was clearly supported by the scores on the Child Behavior Checklist and the Conners Questionnaire. On the Becker attention tests the reaction times were significantly longer in the two visual and auditory tests, indicating that the ability to sustain attention is critically impaired in this group. A tendency of inferiority on auditory compared with visual tests was noted but there were no specific problems with the focus-execute aspect of attention.

Newborn screening for primary immunodeficiencies: beyond SCID and XLA

Primary immunodeficiencies (PID) encompass more than 250 disease entities, including phagocytic disorders, complement deficiencies, T cell defects, and antibody deficiencies. While differing in clinical severity, early diagnosis and treatment is of considerable importance for all forms of PID to prevent organ damage and life‐threatening infections. During the past few years, neonatal screening assays have been developed to detect diseases hallmarked by the absence of T or B lymphocytes, classically seen in severe combined immunodeficiencies (SCID) and X‐linked agammaglobulinemia (XLA). As described in this review, a reduction or lack of T and B cells in newborns is also frequently found in several other forms of PID, requiring supplemental investigation and involving the development of additional technical platforms in order to help classify abnormal screening results.

A prospective cross-sectional study of speech in patients with the 22q11 deletion syndrome

UNLABELLED The purpose of this study was to investigate a consecutive series of 65 participants between 3 and 33 years of age (median age of 9 years and 4 months) with a confirmed 22q11.2 deletion, in order to ascertain the frequency and severity of articulation difficulties, velopharyngeal impairment (VPI), and the level of intelligibility. The majority had velopharyngeal impairment; over half of them to such a degree that surgery had been performed or was considered necessary. A high level of correct place and manner of consonants was only found in children with the 22q11 deletion syndrome from age 6. The most misarticulated consonants were stops and fricatives. Glottal articulation assessed in words and sentences was less frequent than expected according to earlier studies. A high prevalence of reduced intelligibility at different ages indicates an obvious communication limitation in younger children, and for some individuals even as teenagers and adults. EDUCATIONAL OBJECTIVES As a result of this activity, the participant will have knowledge about the frequency and severity of: (1) articulation difficulties; (2) velopharyngeal impairment; and (3) the level of intelligibility in patients with a 22q11.2 deletion.

Language skills in 5-8-year-old children with 22q11 deletion syndrome.

BACKGROUND Language impairment and delayed language onset have been described, although not investigated in detail, in children with 22q11 deletion syndrome. AIMS To investigate different areas of language: the ability to retell a narrative, phonology, syntax and receptive vocabulary in a group of 5-8-year-old children with 22q11 deletion syndrome regardless of whether or not they had a history of speech and language difficulties. Gender differences were also investigated. METHODS & PROCEDURES Nineteen consecutively referred children with 22q11 deletion syndrome, ten girls and nine boys, between the ages of 5 and 8 years, participated in the study. The mean full-scale IQ of the group was 78. Six children had an autism spectrum disorder, attention deficit/hyperactivity disorder, or a combination of these. Three different language tests were used: (1) the Bus Story - a test of narrative speech and language; (2) an articulation test including all Swedish phonemes in different positions; and (3) the Peabody Picture Vocabulary Test - Revised (PPVT-R). OUTCOMES & RESULTS All but two children had an information score in the retelling task of 1 SD below the population mean. A negative correlation between age and the information score implied that the older the children, the more severe the problems. One child had an average sentence length within the normal limits and five children had subordinate clauses within normal limits. A median of 4% of the utterances included grammatical errors. About 50% of the children had a complete consonant inventory. The phonological process analysis implied delayed rather than deviant development. The group had a moderately low score for receptive vocabulary. CONCLUSIONS Language difficulties in all investigated areas of language were found. It is suggested that speech-language impairment is a common feature of 22q11 deletion syndrome. An implication of these results is that follow-ups of language skills are important not only for pre-school children, but also for school age children and adolescents with 22q11 deletion syndrome.