Microdeletion syndromes (chromosomes 12 to 22)

INTRODUCTION — 

Chromosome deletions that span at least 5 megabases (Mb) of deoxyribonucleic acid (DNA) are usually microscopically visible on chromosome-banded karyotypes. Microdeletions, or submicroscopic deletions, are chromosomal deletions that are too small to be detected by light microscopy using conventional cytogenetic methods. Specialized testing is needed to identify these deletions. Microdeletions are typically 1 to 3 Mb long and involve several contiguous genes. The exact size and location of a microdeletion that causes a syndrome may vary, but a specific "critical region" is consistently involved. Most phenotypic effects of these microdeletions are due to haploinsufficiency of a few critical genes or, in some cases, a single gene.

This topic reviews microdeletion syndromes involving chromosomes 12 through 22. Microdeletion syndromes involving chromosomes 1 through 11 are discussed separately, as are microduplication syndromes and congenital abnormalities of the sex chromosomes. Other congenital chromosomal abnormalities, such as trisomies, are also reviewed in detail elsewhere. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microduplication syndromes" and "Sex chromosome abnormalities" and "Congenital cytogenetic abnormalities".)

OVERVIEW OF GENOMIC DISORDERS — 

Genomic disorders are diseases that result from the loss or gain of chromosomal/deoxyribonucleic acid (DNA) material. The most common and better delineated genomic disorders are divided in two main categories: those resulting from copy number losses (deletion syndromes) and copy number gains (duplication syndromes). (See "Genomic disorders: An overview".)

Copy number variations (CNVs) are submicroscopic genomic differences in the number of copies of one or more sections of DNA that result in DNA gains or losses (figure 1). Some CNVs are pathogenic and cause syndromic disorders with consistent phenotypic features, as are discussed here [1,2]. Other CNVs are associated with disease susceptibility or resistance, and the same CNV can be associated with several diverse disorders. Still other CNVs are part of physiologic genetic variation and have no recognized disease association. For example, copy number variations of the amylase gene are polymorphic and range from 2 to 17 copies in a given genome [3]. Contiguous gene syndromes can occur when CNVs affect several adjacent genes. (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Genetic variation'.)

The main mechanism that leads to disease in genomic disorders secondary to deletions and duplications is a change in the copy number of a dose-sensitive gene or genes. Other disease mechanisms include interference with imprinted genes and with regulatory elements outside genes. (See "Genomic disorders: An overview", section on 'Disease mechanisms'.)

Genomic disorders are typically detected by array comparative genomic hybridization (aCGH) (figure 2). Some laboratories may confirm gains or losses detected on an array with an independent method, such as fluorescent in situ hybridization (FISH), multiple ligation dependent probe amplification (MLPA), or quantitative polymerase chain reaction (Q-PCR), but these methods are not often performed given the robustness of the aCGH assay. Data from whole exome or whole genome sequencing can be used in conjunction with aCGH analysis to identify copy number variations [4]. (See "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Array comparative genomic hybridization' and "Tools for genetics and genomics: Cytogenetics and molecular genetics", section on 'Fluorescence in situ hybridization'.)

13q14 DELETION SYNDROME (RETINOBLASTOMA SYNDROME) — 

Chromosome 13 deletions can affect many areas of the chromosome. Children with microdeletions affecting the 13q14.11 region have an increased risk of developing retinoblastomas and pineoblastoma (MIM #613884). Intellectual disability and facial dysmorphic features also may occur and depend upon the size of the deletion [5].

Retinoblastoma is caused by mutational inactivation of both alleles of the retinoblastoma (RB1) gene that encodes a tumor suppressor, either through an RB1 germline mutation or with deletion of RB1, as is seen in patients with 13q deletion. Once one of the RB1 alleles is rendered inactive by a deletion encompassing this gene, the risk increases for the remaining RB1 gene to acquire a mutation, which leads to biallelic inactivation and the origin of a retinoblastoma in retinal tissue. This is known as the Knudson two-hit hypothesis [6].

Children with 13q14 deletion syndrome require regular dilated ophthalmologic examinations (done under anesthesia in infants and young children) to screen for retinoblastoma and brain magnetic resonance imaging (MRI) to evaluate for pineoblastoma; frequency of screening varies based upon age and disease severity (if identified) [7]. The laboratory reporting a deletion on chromosome 13 most often will highlight if the RB1 gene is involved. The evaluation and management of retinoblastoma are discussed in greater detail separately. (See "Retinoblastoma: Clinical presentation, evaluation, and diagnosis" and "Retinoblastoma: Treatment and outcome" and "Pineal gland masses", section on 'Pineoblastoma'.)

15q11.2 DELETION SYNDROME (BP1-BP2) — 

The region proximal (more centromeric) to the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) region in chromosome 15 has significant variability in the general population. The deletions and duplications of the region between breakpoints 1 and 2 (BP1-BP2) were considered benign and probably familial variations. However, several reports indicate that deletions in this region may be associated with developmental delay and behavioral abnormalities in some individuals [8-12]. A meta-analysis showed that the intelligence quotient (IQ) in persons carrying the deletion was decreased by 4.3 points [13]. In addition, the incidence of intellectual disability, schizophrenia, and epilepsy was 3.4, 2, and 2.1 percent, respectively. No increase in prevalence was seen for congenital heart disease and spectrum disorder in this population.

Many people who carry these deletions are asymptomatic, which can be attributed to nonpenetrance or the need of additional modifiers (genetic and environmental factors). There are four highly conserved genes in this region: NIPA magnesium transporter 1 (NIPA1), NIPA magnesium transporter 2 (NIPA2), cytoplasmic FMR1-interacting protein 1 (CYFIP1), and gamma-tubulin complex protein 5 (GCP5). These genes are not imprinted, and patients with this deletion have normal methylation studies for the 15q11-q13 region. These deletions should not be confused with larger deletions that cause AS or PWS. As shown in many other deletion syndromes on chromosome 15, these rearrangements occur around well-known breakpoints. These breakpoints are areas of the genome that are more prone to recombination.

15Q11-13 DELETION SYNDROMES — 

A small interstitial deletion between 15q11 and 15q13 can result in two completely different clinical syndromes depending upon the parental origin of the chromosome. A maternally derived chromosome 15 with this deletion results in Angelman syndrome (AS), whereas a paternally derived chromosome 15 with a similar deletion is associated with Prader-Willi syndrome (PWS).

15q11-13 maternal deletion (Angelman syndrome) — Angelman syndrome (AS) (MIM #105830) is a neurodevelopmental disorder characterized by severe intellectual disability, postnatal microcephaly, and a movement or balance disorder, usually in the form of gait ataxia and/or tremulous movement of limbs [14-16]. AS patients may have any combination of the following behavioral characteristics: frequent laughter or smiling; apparent happy demeanor with emotional lability; an easily excitable personality, often with hand flapping movements; hypermotoric behavior (eg, hyperkinetic or hyperactive movements); fascination with water; mouthing behaviors with drooling; and a short attention span. More than 80 percent of individuals with AS have seizures by the time they reach two years of age. Abnormal electroencephalograms (EEGs) are common with large-amplitude slow-spike waves that can be seen even in the absence of seizures. Sleep is often compromised, with frequent waking and altered sleep cycles. Reported gastrointestinal problems include constipation, gastroesophageal reflux disease, cyclic vomiting, swallowing dysfunction, and eosinophilic esophagitis [17]. Many of these manifestations continue into adolescence and adulthood, and additional features include obesity, scoliosis, anxiety, movement disorders, limited verbal communication, and self-injurious behaviors [18,19].

AS is caused by absence of the maternally inherited copy of the UBE3A gene. UBE3A maps to chromosome 15q11-q13 and encodes the E6-associated protein ubiquitin protein ligase 3A [20,21]. UBE3A is subject to genomic imprinting (ie, the differential expression of genetic information depending upon whether the information is inherited from the father or the mother). The maternally inherited copy of the UBE3A gene is functional, and the paternally inherited copy is inactive or silenced. In an unaffected individual, a functional copy or activation of UBE3A from the maternal chromosome prevents AS. (See "Principles of epigenetics" and "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)

There are four known molecular defects of UBE3A that result in AS:

●Classical deletions (approximately 5 to 7 megabases [Mb]) of maternal chromosome 15q11-q13 [22,23].

●Paternal uniparental disomy (UPD) [24], where both copies of chromosome 15 are inherited from the father, and no chromosome 15 (including UBE3A) is inherited from the mother.

●Imprinting center defects, causing the maternal chromosome to have the methylation and gene expression pattern of a paternal chromosome (which is then silenced during imprinting) [25,26].

●Point mutations in UBE3A, which produce no functional gene product [27].

Deletions account for over 70 percent of cases of AS. There are several breakpoints (BPs; chromosomal regions prone to rearrangements) surrounding the 15q11-q13 region known as BP1, BP2, and BP3. Based upon these BPs, deletions in this region can be subclassified into class I and class II deletions. Class I deletions are larger and extend from BP1 to BP3, while class II deletions extend from BP2 to BP3 [22]. Patients with class I deletions tend to have greater disease severity when compared with those who have class II deletions, and greater difficulties in expressive language, need for more antiseizure medications, and a higher incidence of autism spectrum disorder [28].

If AS is suspected, the workup should include methylation studies first, followed by chromosome microarray (array comparative genomic hybridization [aCGH]). If methylation studies are informative for AS, the next step is to obtain a chromosome microarray to determine if the patient has a class I or class II deletion. If the chromosome microarray array is negative, additional options include performing UPD studies to determine if the patient has paternal UPD by using microsatellite DNA markers or, if available, single nucleotide polymorphisms (SNPs) arrays. If a SNPs array or composite array is used, it is usually possible to determine whether there is UPD by analysis of the SNPs data in the AS/PWS critical region; in fact, most chromosome microarrays include analysis of SNPs. If UPD studies are negative, imprinting center studies are warranted. Imprinting center abnormalities can be a result of deletions that are familial and potentially inherited. They can also be the result of epimutations (ie, heritable changes in gene expression that do not alter the DNA sequence) that are sporadic and have a low recurrence risk. Sometimes epimutations are postzygotic, resulting in mosaicism [25,28-30]. If the methylation studies are negative and suspicion for AS remains, sequencing studies for UBE3A should be obtained.

Screening and monitoring include developmental evaluations and EEG to assess for seizures. The EEG is often abnormal; therefore, the author suggests obtaining an EEG after one year of age in all children with AS. Patients should also be evaluated for feeding problems and gastroesophageal reflux. Referrals to physical, occupational, and speech therapy are recommended. Augmentative communication methods may be beneficial. Melatonin and/or clonidine may alleviate severe sleep disturbances. Patients with AS who have mild seizures may respond well to the use of clonazepam. There are advances that promise to change the treatment paradigm using antisense oligonucleotide therapies to reactivate the expression of the paternal allele in the imprinted regions of the brain as well as gene therapy using viral vectors [31]. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Developmental-behavioral surveillance and screening in primary care" and "Pharmacotherapy for insomnia in adults", section on 'Melatonin'.)

15q11-13 paternal deletion (Prader-Willi syndrome) — PWS (MIM #176270) is characterized by hypotonia, poor feeding and failure to thrive in infancy but increased appetite and obesity in children and adults, genital hypoplasia, small hands and feet, and distinctive facial features (eg, almond-shaped eyes, narrowed bifrontal diameter, thin upper lip). Mild intellectual disability occurs in two-thirds of cases.

Although the exact gene(s) responsible for PWS is still unknown, two reports have identified possible contributory causes. In patients with PWS and autism spectrum disorder, truncating mutations in the MAGE family member L2 (MAGEL2) gene have been identified that encode an ubiquitin ligase enhancer involved in endosomal protein recycling [32]. Although MAGEL2 may contribute to the PWS phenotype, the role of this gene in PWS is still unclear [33]. In addition, deletions of the small nucleolar ribonucleic acid (snoRNA) HBII-85 cluster have been reported in PWS [34]. Loss involving another nucleolar RNA, the noncoding modifying or guide RNA SNORD116 in the hypothalamus, is likely the cause for hyperphagia in PWS [35,36]. (See "Prader-Willi syndrome: Management" and "Prader-Willi syndrome: Clinical features and diagnosis".)

15q13.3 DELETION SYNDROME — 

This 1.5 megabase (Mb) microdeletion (MIM #612001) has a variable phenotype and extends between breakpoints 4 and 5 (BP4 and BP5), which are adjacent and distal to BP1 and BP3 involved in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) deletions [37-41]. Clinical manifestations include mild to severe intellectual disabilities, seizures/epilepsy, behavioral abnormalities, autism spectrum disorder, schizophrenia, hypotonia, and visual impairment. The region contains six genes, but the cholinergic receptor gene nicotinic alpha 7 subunit (CHRNA7) appears to be linked to seizures and the clinical phenotype. Some authors hypothesize that this deletion alone is not sufficient to cause disease and that other abnormalities or modifiers are needed. Several patients whose deletion involves Kruppel-like factor 13 (KLF13), a gene located in the critical region, have congenital heart defects [39]. Another gene in the region OTUD7A may be a potential contributor [42,43]. OTUD7A plays a critical role in brain function and is localized to dendrites in cortical neurons [42,43].

Screening and monitoring include formal developmental and psychologic evaluations and electroencephalogram (EEG). Echocardiography should also be obtained if clinical examination is suspicious for congenital heart disease (eg, pathologic murmur). Patients may benefit from physical, occupational, and speech therapy. (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Developmental-behavioral surveillance and screening in primary care" and "Suspected heart disease in infants and children: Criteria for referral" and "Evaluation of suspected critical congenital heart disease (CHD) in the newborn".)

15q15.3 DELETION SYNDROME — 

This is an uncommon contiguous gene deletion syndrome (MIM #611102). The main clinical features associated with this syndrome are sensorineural hearing loss and male infertility due to sperm dysmotility [44]. The disease is autosomal recessive and is caused by haploinsufficiency of cation channel sperm associated 2 (CATSPER2) and stereocilin (STRC), two genes included in the deleted region that are expressed in the sperm and inner ear, respectively. Males who inherit two CATSPER2-STRC deletions (one from each parent) are infertile and deaf [45]. Females who inherit two CATSPER2-STRC deletions are deaf.

Hearing evaluations should be performed in patients who are homozygous for this deletion. The hearing loss is prelingual (ie, occurs prior to language development) and often detected during the newborn hearing screen. Males should also be tested for infertility during adolescence or young adulthood. (See "Hearing loss in children: Screening and evaluation" and "Evaluation of hearing loss in adults" and "Approach to the male with infertility".)

15q24 DELETION SYNDROME — 

This rare deletion disorder ranges from 1.7 to 3.9 megabases (Mb) in size. The core cognitive features of the 15q24 microdeletion syndrome, including developmental delays and severe speech problems, are largely due to deletion of genes in a critical region that encompasses 1.1 Mb [46].

The majority of breakpoints (eg, areas of the genome that are more prone to recombination) lie within segmental duplication (SD) blocks. The region is surrounded by multiple locus control regions (LCRs) that control chromatin structure and amplify expression of linked genes.

The syndrome is characterized by mild to moderate intellectual disability, growth retardation, microcephaly, digital abnormalities, hypospadias, and connective tissue abnormalities (loose joints; MIM #613406) [47-49]. Patients have distinctive dysmorphic features including a receding hairline, hypertelorism, epicanthal folds, broad inner aspect of the eyebrows, downslanting palpebral fissures, broad nasal bridge, long smooth philtrum, thin upper lip, and a full lower lip. Skeletal findings include delayed bone age, brachydactyly, and broad phalanges with distal hypoplasia. Genital anomalies include hypospadias, micropenis, and a small scrotum. Congenital diaphragmatic hernia has been frequently reported in this deletion [50]. Other, less frequent anomalies can include intestinal atresia, imperforate anus, hearing loss, growth hormone deficiency, cardiovascular anomalies, and meningomyelocele [46].

Cytochrome P450 family 11 subfamily A member 1 (CYP11A1) maps to the region and encodes cytochrome P450 side-chain cleavage enzyme (P450scc), which converts cholesterol to pregnenolone, the initial and rate-limiting step in the production of progesterone. Deletion of this gene may be responsible for the genital abnormalities in males, as complete absence of this gene causes sex reversal in males and congenital adrenal insufficiency. Other deleted genes include a number of enzymes involved in glycosylation. In this case, loss of both copies is usually required to exhibit symptoms; thus, this deletion may uncover recessive phenotypes. Other genes potentially responsible for this phenotype includes complexin 3 (CPLX3), a regulator of neurotransmitter release that is expressed in the brain and eye, and semaphorin 7A (SEMA7A), a gene that mediates peripheral and central axon growth required during neuronal development [51].

Heterozygous pathogenic variants leading to haploinsufficiency of SIN3 transcription regulator (SIN3), a gene located in this region, has been reported in association with Witteveen-Kolk syndrome. This syndrome presents with developmental and speech delays, autistic features, and seizures. Affected patients present with a broad forehead, long face, downslanting palpebral fissures, flat or depressed nasal bridge, large fleshy ears, long and smooth philtrum, small mouth, and pointed chin. In addition, other features include microcephaly, hypermobile joints, short stature, and small hands and feet. Brain anomalies include migration defects, enlarged ventricles, and abnormalities of the corpus callosum. Many of these features overlap with those associated with 15q24 deletions [52].

Screening and monitoring include formal developmental evaluation and skeletal survey to uncover skeletal anomalies. Males may need endocrine evaluations, and other imaging studies to evaluate for diaphragmatic hernias. Patients may benefit from physical, occupational, and speech therapy. Brain imaging, echocardiogram, hearing evaluation, and ophthalmologic evaluation are other screenings that may be performed at the time of diagnosis. Growth and feeding should be closely monitored. (See "Developmental-behavioral surveillance and screening in primary care" and "Skeletal dysplasias: Approach to evaluation" and "Diagnostic approach to children and adolescents with short stature" and "Vision screening and assessment in infants and children".)

16p13.3 DELETION SYNDROME (RUBINSTEIN-TAYBI SYNDROME) — 

A submicroscopic deletion that includes the cAMP response element-binding protein (CREB) binding protein gene, CREBBP or CBP, located on chromosome 16 at p13.3, has been identified in approximately 10 percent of individuals with Rubinstein-Taybi syndrome (RTS; MIM #180849) [53,54]. This clinical entity is characterized by prenatal and postnatal growth restriction, microcephaly, dysmorphic features, broad thumbs and toes, and intellectual disability [55-59]. Facial features include highly arched eyebrows, long eyelashes, beaked nose with prominent septum extending below nares, downslanting palpebral fissures, high-arched palate, and micrognathia. The thumbs are broad and radially deviated, and the toes are also quite broad and internally deviated. The incisors may have talon cusps. Hirsutism is commonly seen. Congenital heart disease is seen in one-third of patients. Eye abnormalities may include glaucoma, cataracts, and strabismus.

Mutation of the CBP gene has been detected in approximately 40 percent of affected individuals with RTS. Mutations in another gene, E1A binding protein p300 (EP300), account for a small number of cases [60,61]. Other yet unknown genes may also be responsible for this disorder because approximately 50 percent of individuals with clinical features consistent with RTS do not have a detectable deletion or mutation in CBP or EP300.

Screening and monitoring include developmental and ophthalmologic evaluations. An echocardiogram should be performed to evaluate for congenital heart disease. (See "Developmental-behavioral surveillance and screening in primary care" and "Vision screening and assessment in infants and children" and "Suspected heart disease in infants and children: Criteria for referral" and "Evaluation of suspected critical congenital heart disease (CHD) in the newborn".)

16p13.11 DELETION SYNDROME — 

A recurrent 1.65 megabases (Mb) deletion of this region is associated with intellectual disabilities and multiple congenital anomalies. Clinical findings include developmental delay (motor, speech, and language delays), as well as behavioral/psychiatric problems. Patients with this deletion also have microcephaly, short stature, and epilepsy [62-64]. Mild dysmorphic features are present but without a specific pattern. Polymicrogyria was reported in one patient. It is reported as one of the most prevalent deletions predisposing patients to idiopathic epilepsy [63,65].

Screening includes formal developmental evaluations, electroencephalogram (EEG), and, in the presence of microcephaly, brain MRI studies to look for central nervous system (CNS) anomalies (eg, polymicrogyria and other neuronal migration defects).

16p12.2 DELETION SYNDROME — 

This deletion has variable clinical findings and is not a recognized syndrome given the degree of variability. It encompasses 520 kb in the area comprised by coordinates 21,948,445-22,430,805 in the reference genome GRCHc37/hG19. The most common features associated with this deletion are developmental delay/intellectual disability, speech delays, epilepsy, autism spectrum disorder, psychiatric disorders (eg, depression, schizophrenia, mood disorders, alcoholism), mild dysmorphic features without a specific pattern, sleep disturbances, and congenital heart defects (hypoplastic left heart, ventricular septal defect [VSD], bicuspid aortic valve, aortic stenosis, patent foramen ovale [PFO], patent ductus arteriosus [PDA]). It is not uncommon to find a family history of learning disorders [66].

Screening includes comprehensive developmental evaluations and echocardiogram. Referral for physical, occupational, and speech therapy is recommended. Parental testing and testing of other relatives at risk for the 16p12.2 deletion is also recommended.

16p11.2 DELETION SYNDROME — 

This deletion in 16p11.2 spans almost 600 kb at position 29.5 to 30.1 megabases (Mb) [67]. It is recurrent in size (ie, the same in size in different individuals) due to flanking segments that mediate these rearrangements. Clinical findings include variable levels of intellectual disability with a high incidence of language delay (expressive more so than receptive) [50,68-72]. It is one of the most common deletions predisposing to neurodevelopmental and neuropsychiatric problems and is considered one of the most common recurrent genomic disorders (ie, affecting the same DNA region in the population) associated with autism spectrum disorder [71]. Some studies have shown that up to 55 percent of patients with this deletion met criteria for autism spectrum disorder, and the frequency of this microdeletion is approximately 0.6 percent in patients with the disorder [73,74]. Functional magnetic resonance imaging (fMRI) mapping studies have revealed that carriers of this deletion have an impairment in prefrontal brain connectivity leading to weaker frontoparietal region coupling that ultimately results in sociocognitive impairments [75]. The deletion interval includes the MAPK3 gene that encodes mitogen-activated protein kinase 3 (also called extracellular signal-regulated kinase 1 [ERK1]). Mutations that regulate ERK pathways have been implicated in neurocognitive disorders and autism spectrum disorder [76].

Other data indicate that this deletion may contribute to other behavioral and psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, and panic disorder [73,77]. Some patients with this deletion have been diagnosed with cervicothoracic syringomyelia [78] and are also at higher than average risk for seizures and/or have abnormal findings on electroencephalogram (EEG). Obesity may also be part of the phenotypic presentation. There are several reported cases of patients with a smaller deletion, approximately 200 kb, distal to the classical deletion (coordinates 29.7 to 29.9 Mb) who present with class 2 obesity [79,80].

Screening includes formal developmental and neuropsychiatric evaluations, including assessment for autism spectrum disorder. Spinal MRI may be required to diagnose syringomyelia as it can present without symptoms. Other screening and monitoring include speech and hearing evaluation, EEG, and monitoring of weight gain and overall growth. (See "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis" and "Autism spectrum disorder in children and adolescents: Screening tools" and "Developmental-behavioral surveillance and screening in primary care", section on 'Approach to surveillance'.)

17p13.3 DELETION SYNDROMES — 

There are several possible deletions in the 17p13.3 region, and the clinical manifestations depend upon the size and genes involved. Larger deletions of the distal short arm of chromosome 17 are responsible for Miller-Dieker syndrome (MDS). These deletions involve platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (PAFAH1B1; the lissencephaly gene formerly known as LIS1). There are more distal deletions that encompass the gene that encodes tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE), which do not involve PAFAH1B1 and have a distinct clinical phenotype [81].

17p13.3 deletion including PAFAH1B1 (Miller-Dieker syndrome) — MDS (MIM #247200) is a contiguous gene deletion syndrome that is characterized by lissencephaly, growth restriction, and dysmorphic features [82-86]. Haploinsufficiency of LIS1 (now called PAFAH1B1) due to point mutations or deletions is causative of lissencephaly, a generalized agyria-pachygyria brain malformation that results from an arrest of neuronal migration at 9 to 13 weeks gestation [87,88]. (See "Microcephaly in infants and children: Etiology and evaluation", section on 'Neuroanatomic abnormalities'.)

The craniofacial features seen in MDS include a prominent forehead, bitemporal hollowing, short nose with upturned nares, protuberant upper lip, thin vermilion border, and small jaw [89]. The clinical course of these patients is marked by failure to thrive, severe psychomotor retardation, opisthotonos, seizures, and death early in life, with very few children reaching 10 years of age. (See "Infantile epileptic spasms syndrome: Etiology and pathogenesis", section on 'CNS malformations' and "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Lissencephaly'.)

Some patients have smaller deletions or mutations involving PAFAH1B1 that are associated with isolated lissencephaly (LIS type 1 or classic lissencephaly; MIM #607432) [90,91].

Patients should undergo formal developmental evaluation. Brain MRI studies are recommended to delineate the degree of lissencephaly and structural central nervous system (CNS) abnormalities. Neurologic evaluation and electroencephalogram (EEG) are recommended to assess for and manage seizures. Swallowing evaluations are usually necessary, and patients may need an intragastric or transpyloric feeding tube. (See "Developmental-behavioral surveillance and screening in primary care" and "Seizures and epilepsy in children: Classification, etiology, and clinical features", section on 'Neurodevelopmental lesions' and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Overview of enteral nutrition in infants and children" and "Enteral feeding: Gastric versus post-pyloric".)

17p13.3 deletion including YWHAE — A series of patients with deletions including a gene that encodes tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein epsilon (YWHAE), but not PAFAH1B1, presented with significant growth restriction, cognitive impairment, shared craniofacial features, and variable structural abnormalities of the brain, but no lissencephaly [92]. One patient in this group did not have growth restriction. CRK proto-oncogene, adaptor protein (CRK) appears to be the gene responsible for growth restriction [93]. YWHAE is believed to be responsible for the brain findings.

Features of this microdeletion syndrome include prenatal and postnatal growth retardation, macrocephaly, and dysmorphic features including a prominent forehead, downslanting palpebral fissures, epicanthal folds, broad nasal root, low-set ears, cleft palate, and eye abnormalities. Seizures have been reported. MRI studies show microcysts in the white matter and corpus callosum, ventricular dilatation, enlargement of subarachnoid spaces, and Chiari type I malformation [81,89,93].

Patients should undergo formal developmental evaluation. Brain MRI is recommended to determine the presence of structural CNS abnormalities. Neurologic evaluation with EEG and ophthalmologic evaluation are also recommended. (See "Developmental-behavioral surveillance and screening in primary care" and "Seizures and epilepsy in children: Classification, etiology, and clinical features", section on 'Neurodevelopmental lesions' and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Vision screening and assessment in infants and children".)

17P11.2 DELETION SYNDROMES — 

Deletions in 17p11.2 can be associated with different conditions. Deletions involving the peripheral myelin protein 22 (PMP22) gene is associated with hereditary neuropathy with liability to pressure palsy (HNPP), while those involving the retinoic acid-induced 1 (RAI1) gene are associated with Smith-Magenis syndrome (SMS).

17p11.2 deletion including PMP22 (Hereditary neuropathy with liability to pressure palsy) — HNPP (MIM #162500) is an autosomal dominant entity characterized by recurrent mononeuropathy, typically associated with minor compression or trauma [94]. It is associated with deletions in 17p11.2 involving the peripheral myelin protein 22 (PMP22) gene. Population studies using chromosome microarrays suggest that many individuals harboring this deletion remain undiagnosed. Use of protective gear when practicing sports, protective pads at pressure points, and avoidance of repetitive movements or activities may prevent nerve trauma. (See "Overview of hereditary neuropathies", section on 'Hereditary neuropathy with liability to pressure palsy'.)

17p11.2 deletion including RAI1 (Smith-Magenis syndrome) — This deletion of chromosome 17p11.2 (image 1) involves the retinoic acid-induced 1 (RAI1) gene that is suspected to be a transcriptional regulator. Both microdeletions and mutations of RAI1 can cause SMS (MIM #182290) [95-100]. The circadian defect seen in this disorder is due to disruption of transcription of the circadian locomotor output cycles kaput (CLOCK) gene [101].

The syndrome is characterized by brachycephaly, midface hypoplasia, prognathism, hoarse voice, speech delay with or without hearing loss, psychomotor and growth retardation, cutaneous features, and behavior problems [102-105]. Feeding problems are seen in infants, along with hypotonia and sometimes lethargy. Patients have mild to moderate intellectual disability and autism spectrum disorder.

Sleep problems are often significant and include difficulty falling asleep, shortened sleep cycles, frequent and prolonged nocturnal awakenings (altered rapid eye movement [REM] sleep), excessive daytime sleepiness, daytime napping, snoring, and bedwetting [106]. Sleep problems appear to be due to an inversion of melatonin secretion. Tasimelteon has been approved by the US Food and Drug Administration and European Medicines Agency for the treatment of non-24-hour sleep-wake disorder in individuals with SMS [107].

Behavioral abnormalities include head banging, hand and wrist biting, onychotillomania (pulling own nails), excessive nose picking, and polyembolokoilomania (inserting objects in body orifices) [103]. Self-hugging is also a typical behavior. Poor sleep can contribute to behavior problems. Electroencephalograms (EEGs) are frequently abnormal but are not associated with overt seizures. (See "Assessment of sleep disorders in children".)

Some patients display neurologic signs, such as decreased or absent deep tendon reflexes, pes planus or pes cavus, decreased sensitivity to pain, and decreased leg muscle mass suggestive of peripheral neuropathy [108]. The deletion in these patients involves the peripheral myelin protein 22 (PMP22) gene. Other common problems include hearing loss and, in some cases, hyperacusis, short stature, scoliosis, velopharyngeal insufficiency, and ocular abnormalities (iris anomalies, microcornea). (See '17p11.2 deletion including PMP22 (Hereditary neuropathy with liability to pressure palsy)' above.)

Elevated cholesterol and triglycerides are common. Hypothyroidism is reported in up to half of these patients [109].

Screening laboratory studies include thyroid function tests and lipid panel. Patients should undergo a formal developmental evaluation. Swallowing evaluation is indicated in infants with feeding problems. Ophthalmologic and hearing evaluations are important. Cardiac evaluations including echocardiography are recommended to rule out structural anomalies. (See "Developmental-behavioral surveillance and screening in primary care" and "Vision screening and assessment in infants and children" and "Hearing loss in children: Screening and evaluation" and "Neonatal oral feeding difficulties due to sucking and swallowing disorders".)

Neuroimaging, sleep, and EEG studies are strongly recommended. In patients with large deletions, nerve conduction velocity studies are recommended to evaluate for hereditary neuropathy with liability to pressure palsy (HNPP). (See "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Overview of polysomnography in infants and children" and "Overview of hereditary neuropathies", section on 'Hereditary neuropathy with liability to pressure palsy'.)

Patients may benefit from occupational, physical, and speech therapy. Management of sleep and behavioral abnormalities may require psychotropic medications. Additional options including medications that counteract the inversion of melatonin secretion are discussed in greater detail separately. (See "Medical disorders resulting in problem sleeplessness in children", section on 'Melatonin'.)

17q12 DELETION SYNDROME — 

This deletion is recurrent in size (ie, the same in size in different individuals) due to flanking segments that mediate these rearrangements and spans approximately 1.5 megabases (Mb) [110,111]. The critical gene in this region is the hepatocyte nuclear factor-1-beta (HNF1B), also called transcription factor 2 (TCF2) [112]. Clinical findings include congenital kidney anomalies (multicystic kidney disease) and maturity-onset diabetes of the young type 5 (MODY5; MIM #137920). Cognitive impairment and central nervous system (CNS) abnormalities may be part of the clinical spectrum [111]. This deletion also confers a higher risk for autism spectrum disorder and schizophrenia [113]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Hepatocyte nuclear factor-1-alpha' and "Kidney cystic diseases in children".)

The reciprocal duplication appears to be associated with an increased risk for epilepsy, but the extent of the clinical consequences is not yet clear.

Screening studies include kidney ultrasound and brain MRI. Referral to an endocrinologist is recommended for management of diabetes. (See "Management of type 2 diabetes mellitus in children and adolescents".)

17q21.31 DELETION SYNDROME — 

This deletion involves the gene encoding microtubule associated protein tau (MAPT) and is associated with a common inversion polymorphism, known as the H2 inversion, in at least one parent. This inversion appears to mediate aberrant recombination events leading to the deletion. It was originally thought that the MAPT gene encoding MAPT was the gene causative for this disorder [114,115]. However, it was subsequently determined that this disorder is due to haploinsufficiency of the KAT8 regulatory nonspecific lethal [NSL] complex subunit 1 (KANSL1) gene [116,117]. KANSL1 is a regulator of a chromatin modifier, KAT8, that effects gene expression. As such, this condition is now known as KANSL1-related intellectual disability syndrome [118].

Clinically, this microdeletion is associated with mild to severe intellectual disability, hypotonia, and characteristic facies [114,115,119-122]. Hypotonia is also associated with poor sucking and feeding difficulties early on in infancy. Craniofacial features include a long face, large ears, and tubular or pear-shaped nose with a bulbous nasal tip. Other features include seizures in over half of cases, cardiac defects (septal defects), cryptorchidism in almost 80 percent of males, and skeletal anomalies (slender lower limbs, hip dislocation, feet deformities, and scoliosis). Patients typically have a friendly disposition, sometimes with frequent laughing that is reminiscent of Angelman syndrome (AS). Problems with attention span and hyperactivity are also reported.

Management of these patients includes developmental evaluations, an echocardiogram to examine for cardiac defects, brain MRI, electroencephalogram (EEG), and referral to neurology for the evaluation and management of seizures, if present. Physical, occupational, and speech therapy are helpful, particularly for issues with hypotonia and feeding. Patients may also benefit from augmentative communication methods. (See "Developmental-behavioral surveillance and screening in primary care" and "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Seizures and epilepsy in children: Initial treatment and monitoring".)

18p DELETION SYNDROME — 

The estimated frequency of 18p deletion syndrome is 1 in 50,000 liveborn infants, with more females than males affected [123]. Deletions can range in size from the whole short arm of chromosome 18 to microdeletions. The terminal deletion occurs de novo in approximately two-thirds of cases. The remaining cases are due to a de novo unbalanced translocation with loss of the 18p, malsegregation of parental chromosome rearrangement (ie, balanced translocation or inversion), or a ring chromosome 18 [124]. Familial transmission of the del(18p) syndrome has been reported. The larger 18p deletions can usually be diagnosed by conventional cytogenetic analysis but are often detected by array comparative genomic hybridization (aCGH) testing.

The phenotype is variable, depending upon the size and location of the deleted region. Major clinical features may include hypotonia, short stature, microcephaly and brachycephaly, a round face with short philtrum, palpebral ptosis, large ears with detached pinnae, downturned corners of the mouth, and mild to moderate cognitive impairment with speech delay [123,125,126]. Approximately 10 to 15 percent of patients present with holoprosencephaly (HP) [123,127]. Some patients with HP may present with bilateral cleft lip and palate, while others may display a single maxillary central incisor, a subtle manifestation of HP. Mutations in the TGFB-induced factor (TGIF) gene that is located in 18p11.3 are associated with HP, but not all patients with deletion of TGIF have HP, indicating a more complex interaction. Approximately 10 percent of patients may present with congenital heart defects [128]. Severe keratosis pilaris and ulerythema ophryogenes [129], autoimmune disease [126,130], and antibody deficiencies [131] have also been reported.

Patients with this deletion should have a brain MRI to assess for HP and other central nervous system (CNS) abnormalities. An echocardiogram should be obtained if clinically indicated. Other recommended clinical interventions include physical therapy for hypotonia and speech therapy for language impairment. (See "Developmental-behavioral surveillance and screening in primary care" and "Overview of craniofacial clefts and holoprosencephaly" and "Suspected heart disease in infants and children: Criteria for referral" and "Evaluation of suspected critical congenital heart disease (CHD) in the newborn".)

20p11 DELETION SYNDROME (ALAGILLE SYNDROME) — 

Alagille syndrome (MIM #118450) is mostly due to mutations in Jagged-1 (JAG1) gene, but some patients have a microdeletion that includes this entire gene [132]. This syndrome is characterized by paucity of interlobular bile ducts, chronic cholestasis, cardiac anomalies, butterfly vertebrae, posterior embryotoxon of the eye, and dysmorphic facies. Alagille syndrome is covered in greater detail separately. (See "Inherited disorders associated with conjugated hyperbilirubinemia", section on 'Alagille syndrome'.)

22q11.2 DELETION SYNDROMES (DiGEORGE SYNDROME/VELOCARDIOFACIAL SYNDROME) — 

This region in chromosome 22 is surrounded by low-copy repeats known as LCR22-1 through 6. The classic velocardiofacial syndrome (VCFS)/DiGeorge deletion is approximately 3 megabases (Mb) and includes the T-box transcription factor 1 (TBX1) gene between LCR22-1 and LCR22-3 [133].

Approximately 80 to 90 percent of patients with DiGeorge syndrome (MIM #188400) have microdeletions involving chromosome 22q11 (ie, 22q11.21-q11.23). This syndrome is characterized by abnormalities in the development of the third and fourth branchial arches, resulting in hypoplasia of the thymus and/or parathyroid gland, conotruncal cardiac defects, and facial dysmorphism. Clinical manifestations may include neonatal hypocalcemia and susceptibility to infection, as well as a predisposition to autoimmune diseases later in life. Mild to moderate learning difficulties are common.

VCFS has some overlapping features with DiGeorge syndrome, such as conotruncal cardiac defects and facial abnormalities, and is also caused by interstitial deletions of 22q11. Molecular deletions are detected in 90 percent of individuals, while cytogenetically visible deletions are observed in approximately 15 to 30 percent of cases.

The clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "DiGeorge (22q11.2 deletion) syndrome: Epidemiology and pathogenesis" and "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis".)

22q11.2 DISTAL DELETION SYNDROME — 

A number of deletions occur distally to the classic velocardiofacial syndrome (VCFS)/DiGeorge 22q11.2 deletion (MIM #611867) [134-136], including one between LCR22-4 and LCR22-6 of approximately 2.1 megabases (Mb) and another between LCR22-5 and LCR22-6 spanning 1.4 Mb. All patients with these deletions present with characteristic dysmorphic features, a history of prematurity, prenatal and postnatal growth restriction that may correct in childhood, developmental delay/learning disabilities, and mild skeletal abnormalities. Craniofacial features include arched eyebrows, deep-set eyes, a smooth philtrum, a thin upper lip, hypoplastic alae nasi, and a small, pointed chin. A few patients have cardiovascular malformations (truncus arteriosus, bicuspid aortic valve).

Management of these patients includes developmental evaluations, an echocardiogram to examine for cardiac defects, and occupational and speech therapy. (See "Developmental-behavioral surveillance and screening in primary care" and "Suspected heart disease in infants and children: Criteria for referral" and "Evaluation of suspected critical congenital heart disease (CHD) in the newborn".)

22q13.3 DELETION SYNDROME (PHELAN-MCDERMID SYNDROME) — 

Deletions of distal 22q13.3 (MIM #606232) are associated with generalized hypotonia, global developmental delay, severe speech delay, and normal to advanced growth [137-141]. The deletion encompasses the SHANK3 gene (SH3 and multiple ankyrin repeat domains 3) that is responsible for the neurologic findings [142,143]. This deletion is also associated with severe expressive language delays and autism spectrum disorder. Clinical features also include mouthing behaviors and tolerance to pain. Some individuals may have severe sleep disturbance, including difficulty with falling asleep, staying asleep, hypersomnias, and parasomnias.

Formal developmental and autism spectrum disorder evaluations are recommended. Management includes occupational and speech therapy. Patients may benefit from augmentative communication methods. (See "Developmental-behavioral surveillance and screening in primary care" and "Autism spectrum disorder in children and adolescents: Evaluation and diagnosis".)

SUMMARY AND RECOMMENDATIONS

●Microdeletions – Microdeletions, or submicroscopic deletions, are chromosomal deletions that are too small to be detected by light microscopy using conventional cytogenetics methods. They can be pathogenic or part of physiologic genetic variation. The exact size and location of a microdeletion that causes a syndrome may vary, but a specific "critical region" is consistently involved. Most phenotypic effects of these microdeletions are due to haploinsufficiency of a few critical genes or, in some cases, a single gene. Genomic disorders, including microdeletions, are typically detected by array comparative genomic hybridization (aCGH) (figure 2). (See 'Introduction' above and 'Overview of genomic disorders' above.)

●Common microdeletion syndromes

•15q11-13 deletion syndromes – 15q11-13 deletion syndromes are some of the most common microdeletions. A paternally derived chromosome 15 with this deletion results in Prader-Willi syndrome (PWS; MIM #176270), whereas a maternally derived chromosome 15 with a similar deletion is associated with Angelman syndrome (AS; MIM #105830).

-PWS is characterized by hypotonia; poor feeding in infancy with failure to thrive but increased appetite and obesity in children and adults; genital hypoplasia; small hands and feet; and distinctive facial features. (See '15q11-13 paternal deletion (Prader-Willi syndrome)' above.)

-AS is a neurodevelopmental disorder characterized by severe to profound intellectual disability, postnatal microcephaly, and a movement or balance disorder, usually in the form of gait ataxia and/or tremulous movement of limbs. Patients also often have seizures and characteristic behaviors. (See '15q11-13 maternal deletion (Angelman syndrome)' above.)

•22q11.2 deletion syndromes (DiGeorge syndrome and velocardiofacial syndrome) – More than 90 percent of patients with DiGeorge syndrome (MIM #188400) have microdeletions involving chromosome 22q11.2. This syndrome is characterized by abnormalities in the development of the third and fourth branchial arches, resulting in hypoplasia of the thymus and/or parathyroid gland, conotruncal cardiac defects, and facial dysmorphism. Clinical manifestations may include neonatal hypocalcemia, susceptibility to infection, mild to moderate learning difficulties, as well as a predisposition to autoimmune diseases later in life.

Velocardiofacial syndrome (VCFS) has some overlapping features with DiGeorge syndrome, such as conotruncal cardiac defects and facial abnormalities, and is also caused by interstitial deletions of 22q11. (See '22q11.2 deletion syndromes (DiGeorge syndrome/velocardiofacial syndrome)' above.)

•16p11.2 deletion syndrome – 16p11.2 deletion syndrome is one of the most common recurrent genomic disorders associated with neurodevelopmental, neuropsychiatric, and autism spectrum disorders. It shows incomplete penetrance and variable expressivity. Clinical findings include variable levels of intellectual disability with a high incidence of language delay, expressive more so than receptive. (See '16p11.2 deletion syndrome' above.)

●Other microdeletion syndromes – These include 13q14 deletion syndrome, which is associated with retinoblastoma, and 20p11 deletion syndrome, which is associated with cholestasis, among other syndromes. (See '13q14 deletion syndrome (Retinoblastoma syndrome)' above and '20p11 deletion syndrome (Alagille syndrome)' above.)

Microdeletions on chromosomes 1 through 11 are discussed elsewhere. (See "Microdeletion syndromes (chromosomes 1 to 11)".)