Pediatric Annals

Special Issue Article 

An Update on Common Chromosome Microdeletion and Microduplication Syndromes

Paula Goldenberg, MD, MSW, MSCE

Abstract

This review summarizes common microdeletion and microduplication syndromes and highlights important updates in patient-care needs for people with these conditions (22q11.2, 7q11.23, 17p11.2, and 16p11.2). These conditions are in chromosomal “hotspots” and have an estimated prevalence of 1 in 1,000 to 1 in 25,000. Some conditions have possible increased or decreased genetic risk of schizophrenia (22q11.2 deletion and duplication), or risk of aortic dilation (7q11.23 duplication) versus aortic stenosis (7q11.23 deletion). Many of these conditions are associated with developmental delay, autism, and/or multiple congenital anomalies and would not be detected with a karyotype. Chromosomal microarray analysis will detect all these conditions with a single screening test, allowing for the appropriate diagnosis and management of these patients. [Pediatr Ann. 2018;47(5):e198–e203.]

Abstract

This review summarizes common microdeletion and microduplication syndromes and highlights important updates in patient-care needs for people with these conditions (22q11.2, 7q11.23, 17p11.2, and 16p11.2). These conditions are in chromosomal “hotspots” and have an estimated prevalence of 1 in 1,000 to 1 in 25,000. Some conditions have possible increased or decreased genetic risk of schizophrenia (22q11.2 deletion and duplication), or risk of aortic dilation (7q11.23 duplication) versus aortic stenosis (7q11.23 deletion). Many of these conditions are associated with developmental delay, autism, and/or multiple congenital anomalies and would not be detected with a karyotype. Chromosomal microarray analysis will detect all these conditions with a single screening test, allowing for the appropriate diagnosis and management of these patients. [Pediatr Ann. 2018;47(5):e198–e203.]

Pediatricians typically identify concerns for developmental delay, autism, possible congenital anomalies, failure to thrive, and short stature during newborn and well-child examinations. They are often the first provider to suspect a genetic syndrome in their patients, initiating further evaluation with additional testing or referral to subspecialists.

Chromosomal microdeletions and microduplications can frequently be the underlying etiology; thus, the microarray test is recommended in practice guidelines for the testing of many of these initial presenting findings.1–3 Yet, many providers in busy practices may not be aware of recommended guidelines and may not have access to genetics services. In a survey of pediatric primary care providers, only 5% of 407 respondents indicated that they would refer a patient with global developmental delay to a genetics specialist.4 Of those ordering testing, 50% would send a karyotype, which would not detect the common conditions that are the subject of this article.4

This review describes common copy number variants in four chromosomal “hot spots” that can result in deletions or duplications in the 22q11.2, 7q11.23, 17p11.2, and 16p11.2 regions. Given the frequency of these conditions, it is likely that any pediatrician will have at least one patient with these disorders.

22q11.2 Deletion Syndrome (Digeorge Syndrome, Velocardiofacial Syndrome)

There is a wide range of findings associated with the prevalence of 22q11.2 deletion syndrome, which was previously thought to be present in 1 in 3,000 to 6,000 births,5 but has more recently been reported to occur in approximately 1 in 1,000 low-risk pregnancies,6 suggesting the possibility that patients on the milder end of the phenotypic spectrum are underdiagnosed. This syndrome is typically caused by a deletion of only 1.5 to 3 megabases (Mb), which is not detectable with a karyotype study.

Although general clinicians are familiar with more serious presentations of 22q11.2 deletion syndrome, such as severe hypocalcemia/hypoparathyroidism (50%–65%), cellular immune deficiency (75%), and conotruncal heart defects (75%),5 not all patients have these conditions at birth. The facial features are not striking either, consisting of hooded eyelids, upslanting palpebral fissures, thick ear helices, low-set ears, small ears, hypoplasia of the alae nasi (diminutive nostrils), bulbous nasal tip, and small mouth.5

Motor delays and speech delays are commonly seen but may not reflect overall cognitive ability, as palatal dysfunction can cause deficits in expressive speech. There is relative strength in verbal IQ and patients may have a nonverbal learning disability, usually with borderline intelligence and normal distribution. Two-thirds of patients have an IQ in the range of 55 to 85, with a mean IQ of 70.5

Many patients who are not diagnosed as infants with 22q11.2 deletion syndrome are diagnosed later in life when feeding problems, failure to thrive, palate dysfunction, developmental delay, learning problems (nonverbal learning disability), behavioral concerns, and psychiatric problems become apparent, or may be identified as an adult after having a child who is affected.7

Patients with 22q11.2 deletion syndrome can be diagnosed with microarray testing, which is recommended for multiple congenital anomalies and developmental delay.8 Certain characteristic conotruncal cardiac defects may also lead to this diagnosis, and a fluorescent in situ hybridization (FISH) or a multiplex ligation-dependent probe amplification test may be used. Patients suspected of 22q11.2 deletion who have a negative FISH test should be offered microarray testing, as there may be an atypical deletion or alternative chromosomal finding for these anomalies. Parental testing is recommended when a child is diagnosed, due to 50% recurrence risk and for syndrome-specific medical management (FISH testing is recommended if the proband's deletion includes the FISH probe genetic target).9

Psychiatric Concerns

Behavioral and psychiatric concerns are common in people with 22q11 deletion syndrome, and frequently include anxiety, depression, attention-deficit/hyperactivity disorder (ADHD), and autism.5

Schizophrenia is seen in 1 of 4 adults with 22q11.2 deletion syndrome.5 In a large cohort of people with schizophrenia in the general population, it was found that 22q11.2 deletion was present in many more people than expected, with an odds ratio of 67.7.10

Any patient with 22q11.2 deletion with unusual behavior changes or signs of psychosis (eg, hallucinations, delusions) needs to see a psychiatrist as soon as possible for early intervention, as it is reported that in individuals with first-episode psychosis have improved outcomes with early intervention.11

Health Care Management for Patients with 22q11.2 Deletion Syndrome

There are health care guidelines for pediatric patients with 22q11.2 deletion syndrome that extend through adulthood.9 Syndrome-specific annual and periodic evaluations are recommended. There are also published growth charts for children and adolescents.12

22q11.2 Duplication Syndrome

The 22q11.2 duplication is in the same location that is deleted in 22q11.2 deletion syndrome, and usually about 1.5 to 3 Mb in length. The duplication of the 22q11.2 region is seen in 1 in 850 low-risk pregnancies.

Patients diagnosed with 22q11.2 duplication syndrome may have severe congenital anomalies and developmental delays, including a 14% to 25% risk of autism.13 Yet, there are parents frequently found to also carry this duplication who are unaffected, which may extend the phenotype to apparently normal cognition, behavior, and few or no congenital anomalies.14

Two-thirds of patients with 22q11.2 duplication syndrome inherited this condition from a parent, and parental testing is recommended for this autosomal dominant condition that has a 50% recurrence risk.13,15

Health Care Management for People with 22q11.2 Duplication Syndrome

Patients with 22q11.2 duplication have a lower frequency of similar birth defects and comorbidities as patients with 22q11.2 deletion syndrome. Providers are recommended to follow the 22q11.2 deletion syndrome guidelines13 for care of patients with 22q11.2 duplication syndrome.

Possible Reduced Risk of Schizophrenia in Patients with 22q11.2 Duplication Syndrome

Two large population studies of patients with schizophrenia have found lower numbers of people with 22q11.2 duplications than expected, potentially conferring an odds ratio of 0.14 to 0.15.10,16 This duplication is one of the first identified potential protective genetic factors that may reduce genetic risk of schizophrenia.

7q11.23 Deletion (Williams Syndrome)

Williams syndrome is caused by a microdeletion of 1.5 to 1.78 Mb in 7q11.23. It is estimated to occur in 1 in 10,000 people.17 The facial features may be subtle, especially in infants, and include periorbital puffiness, low nasal bridge, upturned nose, long philtrum, full lips, and wide mouth.17 Patients with Williams syndrome have an appealing, outgoing personality and empathy for the emotions of others, yet struggle with anxiety, phobias, hyperacusis, and ADHD.17 Although most people with Williams syndrome have mild intellectual disability, there is a range of cognitive ability. The typical neurocognitive profile shows relative strength in verbal short-term memory and language, and relative weakness in visuospatial ability.17

The deletion of the gene ELN, encoding elastin, is associated with cardiovascular anomalies including supravalvular aortic stenosis (70%), peripheral pulmonary stenosis, renal artery stenosis, thoracic and abdominal aortic stenosis, and hypertension (50%).17 Familial supravalvular aortic stenosis is an autosomal dominant condition with isolated cardiac and vascular features of Williams syndrome caused by mutations of ELN (supravalvular aortic stenosis, pulmonary valvular stenosis, and pulmonary artery stenosis) without other features of Williams syndrome.

Endocrine and growth concerns are common in patients with Williams syndrome, including hypercalcemia (5%–50%),17 which is typically mild but can be more severe in infants; nephrocalcinosis is present in a minority of patients.14 Other endocrine concerns include subclinical hypothyroidism (30%), early menarche, impaired glucose tolerance (possibly in 90% of adults), with obesity as a significant risk factor.

Patients with Williams syndrome may be diagnosed with microarray testing for multiple congenital anomalies, developmental delay, dysmorphic features, or growth difficulty (failure to thrive and/or short stature).

The recurrence risk of Williams syndrome is low if neither parent is affected. Parents who have features of Williams syndrome should have genetic testing.

Anesthesia Risk

Patients with Williams syndrome are at risk of sudden cardiac arrest with anesthesia. Risk factors for susceptibility include age younger than 3 years and biventricular outflow obstruction.18 Sudden cardiac arrest may occur up to 24 hours after an operative procedure, and there is controversy regarding same-day surgery in people with Williams syndrome.19 There are existing guidelines stratifying anesthesia risk for people with Williams syndrome.19

Diabetes Risk

Glucose tolerance screening is recommended beginning in the second or third decade, for early detection of impaired glucose tolerance.17,20

Health Care Management for Patients with Williams Syndrome

There are health management scheduled surveillance guidelines for people with Williams syndrome that include syndrome-specific growth charts.21

7q11.23 Duplication Syndrome

The 7q11.23 duplication syndrome is caused by a 1.5-Mb duplication in the same location as the deletion in people with Williams syndrome. Nearly all people with 7q11.23 duplication have developmental delay, intellectual disability, autism spectrum disorder, and speech-language delays.22 Medical problems include hypotonia (58%), seizures (20%), anxiety (72%), constipation (66%), patent ductus arteriosus (15%), and renal anomalies (18%).22 Characteristic physical features include brachycephaly, macrocephaly, broad forehead, facial asymmetry, straight eyebrows, short philtrum, and broad nasal tip.22

The 7q11.23 duplication syndrome is usually diagnosed by microarray testing, and it is inherited from a parent who is affected in 27% of cases.22 Parental testing is recommended when offspring are identified as having 7q11.23 duplication syndrome.

Aortopathy

Nearly half of all people with 7q11.23 duplication have aortic root, sinotubular junction, or ascending aorta dilation detected with screening echocardiogram.22,23 This finding is especially interesting as it raises the possibility of elastin dosage excess as a possible etiology of aortic dilation in comparison with people with Williams syndrome who have supravalvular aortic stenosis. Echocardiograms are recommended in any person who has been diagnosed, and cardiologic surveillance is advised.22,23

17p11.2 Deletion Syndrome (Smith-Magenis Syndrome)

Smith-Magenis syndrome (SMS) is caused by a 3.5-Mb deletion (95%) or by a mutation of a gene in this deletion region, retinoic acid-induced gene 1 (RAI1; 5%). SMS has an estimated prevalence of 1 in 25,000.24 Clinical features include a broad square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanting palpebral fissures, deep set eyes, broad nasal bridge, and short broad hands. Infants with SMS have been described as angelic and quiet babies with increased sleepiness and daytime napping.24 Infants are typically not diagnosed unless they have congenital anomalies such as heart defects (35%). Global developmental delay is observed in later infancy, and most patients with SMS have moderate intellectual disability and autism spectrum disorders (90%). Severe behavioral problems include self-injury, aggression, pulling off nails (onychotillomania), and inserting objects into body orifices (polyembolokoilamania). Patients may also clasp their hands or hug themselves to express happy feelings.24

Patients with SMS may be diagnosed with microarray or by RAI1 sequencing and deletion/duplication analysis. SMS is typically de novo and unlikely familial unless a parent has some features of SMS. There are rare reports of parents with low-level mosaicism of the SMS deletion who subsequently had a child with nonmosaic SMS.24

Sleep Cycle in Patients with Smith-Magenis Syndrome

Sleep problems are reported in 95% of patients with SMS. Typically, infants with SMS nap more frequently than other infants.24 By age 18 months these children may have severe sleep problems, including delayed onset of sleep, frequent and prolonged awakenings, and excessive daytime sleepiness.24 Patients may be awake for much of the night, reducing sleep for caregivers, so families sometimes use an enclosed bed system.

Melatonin is sometimes used for treatment given the apparent reversal of circadian cycle in children with SMS, and lower doses may be more effective.25

17p11.2 Duplication Syndrome Potocki-Lupski Syndrome

The chromosomal cause of Potocki-Lupski syndrome (PLS) is typically a 3.7-Mb duplication of the same region that is deleted in people with SMS, including RAI1. Typically, patients may have mild hypotonia at birth, poor feeding, and failure to thrive. Congenital heart defects (40%) and sleep-disordered breathing (central and obstructive sleep apnea) are also described.24 Nonspecific facial features include micrognathia and down-slanting palpebral fissures.

The developmental profile for people with PLS includes expressive (50% verbal apraxia) and receptive language delay, and patients may benefit from use of augmentive communication devices.24 As with SMS, there is typically moderate intellectual disability, with some in the borderline or average range. Behaviorally, patients with duplication of RAI1 may have symptoms of autism spectrum disorder.26

Genetic testing approaches for PLS diagnosis include microarray and RAI1 deletion/duplication testing. Most patients are diagnosed with microarray screening for developmental delay. Testing of parents of a proband is recommended as there is a wide phenotypic spectrum, and there is a 50% recurrence risk if a parent has the duplication.24

Sleep Disturbance in Patients with PLS

Parents of children with PLS are typically not aware of sleep problems in their children, but in one study 14 of 16 patients were found to have central and/or obstructive sleep apnea.24

Aortic Dilation

All patients should have an echocardiogram at diagnosis, and aortic dilation has been reported in patients with PLS, regardless of whether there is the presence of a heart defect or history of cardiothoracic surgery. Patients who are not observed by a cardiologist are recommended to have echocardiograms every 2 to 3 years during childhood, and every 4 to 5 years during adulthood.24

16P11.2 Deletion Syndrome

The 16p11.2 deletion syndrome is caused by a recurrent 593-kilobase (kB) deletion, most typically diagnosed with microarray testing for genetic etiologies of developmental delay, intellectual disability, or autism spectrum disorder. It is estimated to be present in 3 in 10,000 people, and in approximately 1% of people with a diagnosis of autism.27 Cognition can range from intellectual disability to average IQ, with those in the average range more typically having language delay (70%) or autism spectrum disorder (20%). Full-scale IQ is typically 26 points lower than in unaffected family members.28 Other conditions commonly seen are seizures (20%), psychiatric conditions, and obesity.28

There are no characteristic facial features to assist with identification of people at risk of 16p11.2 deletion. Patients commonly have macrocephaly and sacral pits.27

Most people have de novo deletions of 16p11.2. Parental testing is recommended, as 20% of deletions are inherited and the transmitting parent is typically unaffected.29

Paroxysmal Kinesigenic Dyskinesia

This condition is characterized by attacks of dystonia, chorea, ballismus, or athetosis triggered by sudden movement. It has been seen in some people with 16p11.2 deletion.30 Familial paroxysmal kinesigenic dyskinesia is a known condition caused by mutations of PRRT2, a gene in the deletion region of 16p11.2.31

16p11.2 Duplication Syndrome

The 16p11.2 duplication is a reciprocal duplication (593 kB) reported in people with developmental delays or autism spectrum disorder. In contrast to 16p11.2 deletion, patients with 16p11.2 duplication are underweight, with typical body mass index lower than familial controls.32 Intelligence is approximately 26 full-scale IQ points lower than in family members who are not unaffected. Epilepsy (19%) and autism (20%) are commonly seen.33

The 16p11.2 duplication is frequently familial, so parents should have genetic testing when an affected child is diagnosed.

Risk of Schizophrenia

There is increased risk of schizophrenia (odds ratio, 10.79) in people with microduplication of 16p11.2. This microduplication is also associated with an increased risk of schizophrenia10,34 in general population studies. The 16p11.2 duplication was the second highest genetic risk factor after 22q11.2 deletion.10

Discussion

It is highly likely that patients with the above-described conditions are being managed by general pediatricians, and that children with these conditions would be more prevalent in developmental, child neurology, and psychiatry clinics regardless of whether their genetic diagnosis had been made. Microarray testing, as recommended by the American Academy of Pediatrics,35 the American College of Medical Genetics and Genomics,8 and the American Academy of Neurology,36 will identify people with the aforementioned deletions and duplications.

Identification of an underlying diagnosis for these findings can potentially improve medical care through identification of previously unknown comorbidities, inform recurrence risk in future pregnancies, and alert providers to syndrome-related risks such as autism, schizophrenia, and developmental delay.

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Authors

Paula Goldenberg, MD, MSW, MSCE, is a Medical Geneticist, Massachusetts General Hospital, Medical Genetics; and an Assistant Professor, Harvard Medical School.

Address correspondence to Paula Goldenberg, MD, MSW, MSCE, Massachusetts General Hospital, 175 Cambridge Street, Room 505, Boston, MA 02114; email: pgoldenberg2@mgh.harvard.edu.

Disclosure: Paula Goldenberg is a scientific and clinical advisor for the International 22q11.2 Foundation.

10.3928/19382359-20180419-01

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