Alex Habel

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.

The Nature of Feeding in Infants With Unrepaired Cleft Lip and/or Palate Compared With Healthy Noncleft Infants

Objective: Feeding difficulties are reported widely in infants with cleft lip and/ or palate. There is, however, a paucity of objective information about the feeding patterns of these infants. This study compared patterns of feeding in infants with unrepaired cleft lip and palate with healthy noncleft infants of a similar age. Setting: North Thames Regional Cleft Centre. The noncleft cohort was recruited from West Middlesex University Hospital, a general hospital with similar demographics. Participants: Fifty newborn infants with nonsyndromic complete unilateral cleft lip and palate or a cleft of the soft and at least two thirds of the hard palate who were referred to the North Thames Regional Cleft Centre participated. Parents of 20 randomly selected, noncleft infants agreed to participate. Main Outcome Measures: Feeding patterns were rated using the Neonatal Oral Motor Assessment Scale. Additional objective information was collected using the Great Ormond Street Measurement of Infant Feeding (Masarei et al., 2001; Masarei, 2003). Results: Infants with nonsyndromic complete unilateral cleft lip and palate or a cleft of the soft and at least two thirds of the hard palate had less efficient sucking patterns than their noncleft peers had. They used shorter sucks (mean difference, 0.30 second; p < .0005), a faster rate of sucking (mean difference, 34.20 sucks/second; p < .0005), higher suck-swallow ratios (mean difference, 1.87 sucks/swallow; p < .0005), and a greater proportion of intraoral positive pressure generation (mean difference, 45.97% positive pressure; p < .0005). Conclusions: This study demonstrated that the sucking patterns of infants with nonsyndromic complete unilateral cleft lip and palate or a cleft of the soft and at least two thirds of the hard palate differ from those of their noncleft peers.

Management of Cleft Lip and Palate in the Developing World

This book explores the complex issues surrounding the management of cleft lip and palate in the Developing World, and aims to raise the profile of a condition commonly considered to be of only cosmetic importance in countries where infant and child mortality rates are high. It provides information and guidelines to three groups: those in the Developing World setting up programmes of cleft lip and palate care, and clinicians from developed countries delivering care in that context, as well as clinicians in the Developing World itself. The book is multidisciplinary, demonstrating the role of every member of the team, not just the surgeon, and includes contributions from charity organisations which support these cleft lip and palate programmes. Each area of clinical practice is covered, comparing typical care in developed countries with that in the Developing World, and contains practical suggestions as to how the gap may be narrowed.

Core neuropsychological characteristics of children and adolescents with 22q11.2 deletion

BACKGROUND The 22q11.2 deletion syndrome (22qDS) confers high risk for intellectual disability and neuropsychological/academic impairment, although a minority of patients show average intelligence. Intellectual heterogeneity and the high prevalence of psychiatric diagnoses in earlier studies may have obscured the prototypical neuropsychological profile in 22qDS. METHODS We examined intelligence, memory, reading and mathematical processes in 31 children/adolescents with 22qDS, selected for educational underachievement and an absence of psychiatric diagnoses, using standardised, psychometrically matched instruments that specify how typical a score is for a given intelligence quotient (IQ). RESULTS Corroborating earlier findings, verbal IQ was significantly superior to performance IQ; verbal memory and basic reading were relative strengths; and visual/spatial memory was a relative weakness. All four findings transcended performance characteristics that are typical of low-IQ individuals. Rote learning yielded the highest score; reading comprehension, numerical operations and mathematical reasoning were among the lowest-performed academic domains. Albeit in the expected direction, performance in the respective components could not be clearly differentiated from what is IQ-appropriate. CONCLUSIONS A superiority of verbal intelligence over non-verbal intelligence, relative strengths in verbal memory and basic reading, and a relative weakness in visual/spatial memory are likely to be core characteristics of children/adolescents with 22qDS, transcending performance features that are typical of individuals with low IQ.

Delayed detection of cleft palate: an audit of newborn examination

Aims: To identify prevalence of delayed detection of cleft palate, and associated factors that could lead to improved identification at neonatal clinical examination. Methods: Audit of hospital notes, parental questionnaire incorporating open ended questions, and telephone questionnaire of junior doctors in the referring hospitals incorporating fixed choice questions. Results: Of 344 cleft palate patients without cleft lip or submucous cleft palate, the day the cleft was detected was recorded in 92%. Delayed detection, after the first day, was 28% overall, distributed as 37% with isolated cleft palate and 23% with syndromic cleft palate. Narrow V shaped clefts were more likely to be delayed in detection compared with broad U shaped clefts, as were soft palate clefts compared with hard palate clefts. Five with isolated cleft palates were not detected until after the first year. Babies born at home were unlikely to be detected on day 1. Symptoms were significantly increased in the delayed detection group for feeding problems and nasal regurgitation. A telephone questionnaire of trainee paediatricians in referring units revealed that digital examination was more commonly practised than visual inspection, and few recalled receiving specific instruction on examination of the palate. Conclusion: Delayed detection of cleft palate was not uncommon, and the features of those more likely to be missed suggested digital examination was related. Trainee doctors and midwives should be instructed to inspect visually using a light and tongue depressor, then digitally if submucous cleft palate is suspected.

Syndrome-specific growth charts for 22q11.2 deletion syndrome in Caucasian children†

Growth faltering occurs frequently in infancy in the 22q11 Deletion syndrome (22q11 DS). The subsequent course of growth in childhood and outcome for final adult height lacks consensus. We analyzed 5,149 growth data points from 812 Caucasian subjects with 22q11 DS, from neonates to 37 years old. Charts were constructed for height, weight, body mass index, and head circumference (OFC) using the LMS Chart Maker program. These charts were compared with the WHO birth to 4 years growth standard and US CDC 2000 growth reference between 5 and 20 years. Starting from the 50th centile at birth, by 6–9 months of age boys mean height and weight had fallen to the 9th centile, as did girls height but their weight fell less markedly, to the 25th centile. Feeding difficulties were non‐contributory. In children under 2 years old with congenital heart disease (CHD) mean weight was −0.5 SD lighter than no CHD. Catch up growth occurred, more rapid in weight than height in boys. Up to 10 years old both sexes tracked between the 9th and 25th centiles. In adolescence, the trend was to overweight rather than obesity. At 19 years mean height was −0.72 SD for boys, −0.89 SD girls. OFC was significantly smaller than the WHO standard in infancy, between the 9th and 25th centile, rising to the 25th centile by 5 years old. Thereafter the mean was close to the 9th centile of the OFC UK growth reference, more prolonged and marked than in previous studies.

Memory in intellectually matched groups of young participants with 22q11.2 deletion syndrome and those with schizophrenia

The 22q11.2 deletion syndrome (22qDS) and schizophrenia have genetic and neuropsychological similarities, but are likely to differ in memory profile. Confirming differences in memory function between the two disorders, and identifying their genetic determinants, can help to define genetic subtypes in both syndromes, identify genetic risk factors for the emergence of psychosis, and develop pharmacological interventions for cognitive dysfunction. However, no study has compared memory function between 22qDS and schizophrenia, while indirect comparisons are confounded by marked differences in IQ between the two populations. We compared verbal and visual memory in 29 children and adolescents with 22qDS and 15 intellectually matched youths with schizophrenia using age-appropriate, directly comparable, Wechsler scales. Verbal memory was markedly superior in the 22qDS group by 21 points. There were no group differences in visual memory. The inherently low COMT activity in 22qDS merits investigation as a potential protective factor for verbal memory.