DiagnosisClinical Diagnosis2q37 microdeletion syndrome is suspected in individuals with the following characteristics: Developmental delay/intellectual disabilityBrachymetaphalangy of digits 3-5 (often digit 4 alone), referred to as type E brachydactyly Short stature Obesity Hypotonia Characteristic facial appearance: Round face (variable) Frontal bossing Arched eyebrows Deep-set eyes Upslanted palpebral fissures Epicanthal folds Hypoplastic alae nasi Prominent columella Thin upper lip Minor ear anomalies Autism or autism spectrum disorder Joint hypermobility/dislocation, scoliosis Note: When present together, the first four features (developmental delay/intellectual disability, brachymetaphalangy of digits 3-5, short stature, obesity) are often referred to as the Albright hereditary osteodystrophy (AHO)-like phenotype.Other structural anomalies Seizures Congenital heart disease (atrial/ventricular septal defects, PDA) CNS abnormalities (hydrocephalus, dilated ventricles) Umbilical/inguinal hernia Tracheomalacia Situs abnormalities Gastrointestinal abnormalities Renal malformations Other clinical findings Eczema Osteopenia Behavioral problems (hyperactivity, attention deficits) Neoplasms. Wilms tumor TestingCytogenetic testing. Chromosome analysis confirms the diagnosis of 2q37 microdeletion syndrome in 80%-85% of affected individuals. In about 15%-20% of cases, the conventional karyotype is normal because of the small size of the deleted region [Shrimpton et al 2004, Aldred 2006, Lacbawan et al 2006]. 2q37 microdeletions (deletions that are not visible with routine cytogenetics) have been reported in persons with the AHO-like phenotype [Bijlsma et al 1999, Chassaing et al 2004]. Small terminal deletions of 2q may be missed on routine cytogenetic studies, and microdeletions may be undetectable unless more detailed deletion/duplication analysis is employed (Table 1: footnotes 2-4).Some individuals with the 2q37 microdeletion syndrome have chromosomal rearrangements involving 2q37, including chromosome 2 inversion, ring chromosome 2, or translocation between chromosome 2 and another chromosome that results in deletion of 2q37. Molecular Genetic TestingGenes. The largest reported telomeric deletion in the 2q37 chromosomal region is about 10 Mb while the smallest is frequently around 3 to 4 Mb [Aldred 2006, Lacbawan et al 2006]. The smallest terminal deletion reported to date was 2.7 Mb [Williams et al 2010], although an individual with developmental delay with dysmorphic features had a paternally inherited 1.6-Mb terminal deletion [Balikova et al 2007]. Most likely, deletion of the genes in this chromosome region is the genetic defect known to be associated with microdeletion 2q37 syndrome. Several individuals with features of the 2q37 microdeletion syndrome have been found to have either isolated intragenic mutations of HDAC4 or decreased HDAC4 expression without a contiguous gene deletion, leading to the proposal that mutations in HDAC4 are causative of most of the syndromic features of the 2q37 microdeletion syndrome [Williams et al 2010, Morris et al 2012]. See Molecular Genetics for further discussion of candidate genes in the region.Clinical testing Table 1. Summary of Genetic Testing Used in 2q37 Deletion SyndromeView in own windowGenetic Defect in 2q37 RegionTest MethodMutation Detection Frequency by Test Method ^{1Test AvailabilityDeletion or chromosomal rearrangement involving 2q37 Cytogenetic analysis 80%-85% ClinicalDeletion / duplication analysis 2>99% 3, 4, 5Clinical HDAC4 mutation in absence of 2q37 deletion / rearrangementHDAC4 sequence analysis 6Unknown, but rare1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.3. Subtelomeric 2q probes are commercially available. A subtelomeric FISH probe should confirm the vast majority of chromosome 2q37 deletions. Theoretically, an interstitial 2q37 deletion could be missed if the subtelomeric sequence is present [Aldred et al 2004, Chaabouni et al 2006].4. Chromosomal microarray (CMA) using BAC clones confirmed a cryptic unbalanced translocation involving 2q37.2 in a spontaneously aborted fetus after cultured embryonic tissue failed to grow [Bruyere et al 2003]. Most 2q37 microdeletions are detectable with commercially available CMA, although more precise mapping of the deleted region is typically performed only on a research basis [Aldred et al 2004; Shrimpton et al 2004; Lacbawan et al, unpublished]. 5. Although submicroscopic deletions are demonstrated using FISH or CMA, concurrent duplication/deletion may be missed by FISH study [Lacbawan et al 2006]. 6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.Testing StrategyTo confirm/establish the diagnosis of 2q37 microdeletion in a proband, the following testing should be performed:First alternativeDeletion/duplication analysis could be performed first, as it will detect large deletions, microdeletions, and microduplications of the 2q37 region. In addition, it would screen for other microdeletion/microduplication syndromes (e.g., Smith-Magenis syndrome) that have overlapping clinical features with the 2q37 microdeletion syndrome.
Note: Deletion/duplication analyses (e.g., CMA) typically do not directly evaluate chromosomal structure; thus, when results suggest an unbalanced translocation or a ring chromosome, conventional cytogenetic studies are needed to confirm these structural chromosome anomalies.Second alternativeFor familial cases where other chromosomal rearrangements may be present, karyotype (i.e., routine cytogenetic study) should be done.If the chromosome study is normal but the index of suspicion is high, targeted deletion analysis of the 2q37 region may be performed.If the proband has clinical features of the 2q37 microdeletion syndrome but no microdeletion or chromosome anomaly involving 2q37 is found on the above testing, sequence analysis of HDAC4 could be considered.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion or mutation in the proband and/or of balanced carrier status in a parent. Genetically Related (Allelic) DisordersThe 2q37 microdeletion syndrome may present with a broad spectrum of clinical findings. Prior to the clinical introduction of chromosomal microarray, subtelomeric FISH identified 2q37 deletions in a number of individuals referred for developmental delay/intellectual disability with or without other dysmorphic features [Anderlid et al 2002, Sogaard et al 2005, Ravnan et al 2006]. The 2q37 microdeletion syndrome phenotype was not clearly described in any of these individuals. A pilot study of children with autism reported one nondysmorphic child with a normal examination and a subtelomeric deletion of 2q [Wolff et al 2002]. Similarly, in a large cohort of more than 400 autistic individuals, Reddy [2005] reported a child with autism and macrocephaly who had a 2q37 deletion identified by FISH. Further molecular characterization of these individuals would be helpful.}

Natural HistoryThe 2q37 microdeletion syndrome may present with a broad spectrum of clinical findings as described below [Smith et al 2001, Casas et al 2004, Chassaing et al 2004, Lacbawan et al 2005, Aldred 2006, Chaabouni et al 2006, Lacbawan et al 2006, Kitsiou-Tzeli et al 2007].In individuals with isolated microdeletion 2q37 (i.e., those without an unbalanced translocation), functional outcome was affected by the presence of autism, developmental delay, and/or major congenital anomalies.The phenotype observed in individuals with 2q37 microdeletion syndrome seems variable in earlier reports because the molecular breakpoints were not defined.The published female-to-male ratio is greater than one. Developmental delay. Most affected individuals have mild-moderate developmental delay. However, one individual with delayed developmental milestones was reported to work as a librarian's assistant and a second individual was a college student with autism and average-range cognitive function. Autism or autism spectrum disorder. 2q37 microdeletions are common in individuals with syndromic autism [Jacquemont et al 2006]. Approximately one third of those reported with 2q37 microdeletion syndrome have autism or autistic features, which show significant variation among individuals. Nonetheless, no behavioral phenotype appears to be specific to the 2q37 microdeletion syndrome. Brachymetaphalangy. Short metacarpals/metatarsals of digits 3-5, often of digit 4 alone, are present in more than half of reported cases. No functional implications are associated with the shortened digit(s). Brachymetaphalangy may not be clinically apparent in young children, though this feature has been described in several children under age one year. Growth. The incidence of short stature is increased in individuals with 2q37 microdeletion syndrome. Failure to thrive is sometimes reported in affected infants. Obesity. Obesity may be noted in childhood. The prevalence of obesity appears to increase with age. Hypotonia. A significant number of individuals with 2q37 microdeletion syndrome have hypotonia and feeding difficulties. Genu valgum/recurvatum and pes planus are also common. Characteristic facial appearance and other dysmorphic features. The typical facial characteristics include thin, arched eyebrows with deeply set eyes, hypoplastic nares, prominent columella, thin vermilion border, and minor ear dysmorphism with or without round face. The facial phenotype can be subtle, and may not be easily recognized by less experienced clinicians. Use of stereophotogrammetry has been shown to be able to distinguish the facial phenotype. Low-set, hypoplastic nipples are often seen. Joint hyperextensibility and skin hyperlaxity may be observed.Seizures of some type, including grand mal, partial, and myoclonic, have been noted in approximately 20%-35% of reported cases; very little clinical information is provided in most reports. Eczema. Moderate-to-severe eczema has been reported in a few individuals. Osteopenia. Though osteopenia is not well known to be associated with 2q37 deletion, a number of affected individuals have had osteopenia on further radiologic studies. Clinical implications have not been described. Gastroesophageal reflux (GER). Moderate-to-severe GER can occur, and can be severe enough to necessitate surgical intervention. Wilms tumor. Three individuals with isolated 2q37 microdeletion syndrome and Wilms tumor have been reported [Conrad et al 1995, Olson et al 1995, Viot-Szoboszlai et al 1998]. All three children presented before age two years. Olson et al [1995] reported another individual with an unbalanced translocation der(2)t(2;15)(q37;q22) and Wilms tumor. An individual with a 46,XY,add(2)(q35) karyotype and Wilms tumor was reported by Jones et al [2011]. Both individuals presented between age two and age three years. However, screening of a large cohort of individuals with 2q terminal deletions did not find other individuals with Wilms tumor. Jones and colleagues estimate a 1% risk of Wilms tumor in individuals with 2q deletions. Other structural anomalies [Reddy et al 1999, Lehman et al 2001, Aldred 2006, Masumoto et al 2006]: Cleft palate Congenital hearing loss Congenital heart disease (typically atrial/ventricular septal defects) Situs abnormalities Renal malformations including horseshoe kidney CNS abnormalities including separate cases reported with holoprosencephaly, agenesis of the corpus callosum, and hydrocephalus Gastrointestinal abnormalities, including hiatal hernia, pyloric stenosis, malrotation, anal atresia, and esophageal atresia Joint hypermobility/dislocation and scoliosis Umbilical/inguinal hernia Life span. The presence of congenital malformations appears to be the single greatest factor in determining life expectancy. Few older adults have been reported with 2q37 microdeletion syndrome; however, the authors anticipate that this will change as more individuals are ascertained with the use of subtelomeric FISH and CMA studies and longitudinal data are collected on those with the disorder. The literature continues to demonstrate that the vast majority of individuals with this syndrome do not have a shortened life span.

Genotype-Phenotype CorrelationsPenetrance is complete in the 2q37 microdeletion syndrome; however, phenotypic variability is observed. Using both cytogenetic and molecular analyses, deletion size does not appear to correlate well with phenotype. Brachymetaphalangy is observed in approximately half of individuals with deletions of the Albright hereditary osteodystrophy (AHO)-like critical region containing HDAC4 [Aldred et al 2004]. Further genotype-phenotype correlations have not been established. A parent-of-origin effect has not been convincingly demonstrated.

Differential DiagnosisAlbright hereditary osteodystrophy (AHO) is characterized by obesity, short stature, brachydactyly, subcutaneous ossifications, and intellectual disability. Most individuals with AHO have an inactivating mutation in GNAS, the gene encoding the alpha subunit of a G-protein. Maternally inherited mutations are associated with resistance to parathyroid hormone (PTH) (known as pseudohypoparathyroidism type 1A), thyroid stimulating hormone (TSH), and gonadotropins. Paternally inherited mutations are associated only with AHO (also known as pseudopseudohypoparathyroidism). The clinical overlap between AHO/pseudopseudohypoparathyroidism and the 2q37 microdeletion syndrome may be substantial [Aldred et al 2004, Aldred 2006]. The authors are not aware of any individuals with the 2q37 microdeletion syndrome who had subcutaneous calcifications or hormone resistance, both of which can be seen in AHO.Smith-Magenis syndrome. Phenotypic overlap with Smith-Magenis syndrome was clearly demonstrated by Williams et al [2010]. Kabuki syndrome. Two individuals with phenotypic features suspicious for Kabuki syndrome had chromosomal rearrangements that included 2q37 deletion [Cusco et al 2008]. CHARGE syndrome. Two children in a family with an unbalanced translocation between 2q and 21q resulting in a 2q37 microdeletion presented with choanal atresia and were initially misdiagnosed as having CHARGE syndrome [Fernandez-Rebollo et al 2009]. Type E brachydactyly (metacarpal 3-5 shortening) has been described in Turner syndrome. HOXD13 mutations have been reported in a skeletal malformation syndrome with overlap between brachydactyly types D and E [Johnson et al 2003]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with the 2q37 microdeletion syndrome, the following evaluations are recommended:Complete medical history to include evidence of any congenital malformations, seizure disorder, or behavioral problems Complete physical and dysmorphology examination Determination of head circumference, height, weight, and other anthropometric measurements Specialty evaluation of obesity or failure to thrive Multidisciplinary developmental and neurologic evaluation to assess motor and cognitive skills as well as autism, autism spectrum behaviors, and other behavioral issues Echocardiogram to evaluate for congenital cardiac anomaly Renal ultrasound examination to evaluate for possible Wilms tumor, renal malformation, or other renal problems Ophthalmology evaluation for strabismus and/or refractive errors Audiologic assessment for possible hearing loss Brain imaging studies (MRI, CT scan) in individuals with abnormal neurologic findings EEG for evaluation of seizures and treatment monitoring X-ray to evaluate for the presence of scoliosis and skeletal anomalies examination. While the clinical implications of osteopenia have not been studied in the 2q37 microdeletion syndrome, clinicians should be aware that this is a common finding. X-rays should be performed at diagnosis and should be repeated as warranted by clinical examination. The youngest individual with osteopenia in the authors' series is age three years. Medical genetics consultationTreatment of ManifestationsDepending on the age and presenting concerns of the individual with the 2q37 microdeletion syndrome, care from specialists in the following areas is often necessary: medical genetics, speech pathology, occupational and physical therapy, child development, neurology, cardiology, gastroenterology, nutrition/feeding in cases of failure to thrive, ophthalmology, and audiology.Medical care may be coordinated by a medical geneticist or other health care professional skilled at managing patients with complex needs.Infants benefit from enrollment in an early-intervention program. Most school-age children benefit from an individualized educational program (IEP) with input from a multi-specialty group of physical, occupational, and speech therapists with pediatric assessment.Prevention of Secondary ComplicationsAt this time, it is not known why many individuals with the 2q37 microdeletion syndrome are obese. To the extent that it is feasible, the authors recommend an active lifestyle and good dietary habits to help avoid development of obesity.SurveillanceJones et al [2011] suggested that individuals with 2q deletions sparing 2q37.1 likely have a less than 5% risk of developing Wilms tumor; therefore, they do not recommend surveillance for the development of Wilms tumor in these individuals. Wilms tumor screening can be considered for individuals with deletions including 2q37.1, although screening intervals are not delineated. Wilms tumor screening protocols in individuals with WAGR syndrome and Beckwith-Wiedemann syndrome include abdominal ultrasounds every three months until mid-childhood [Beckwith 1998]. The practitioner caring for an infant or young child with a 2q37 deletion is encouraged to monitor the literature for updates.When the 2q37 microdeletion is identified in early childhood, screening for the development of renal cysts at age four years and again at puberty is suggested [Falk & Casas 2007].The following are also appropriate:Ongoing routine pediatric care Periodic reevaluation by a medical geneticist to provide new recommendations and information about the syndrome Periodic neurodevelopmental and/or developmental/behavioral pediatric evaluation to assist in the management of cognitive and behavioral problemsEvaluation of Relatives at RiskIt is reasonable to perform genetic testing of any young child at risk, so that Wilms tumor surveillance can be considered in those with a deletion that includes 2q37.1. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. 2q37 Microdeletion Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNot applicable2q37Not applicable HDAC42q37​.3Histone deacetylase 4HDAC4 @ LOVDHDAC4Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for 2q37 Microdeletion Syndrome (View All in OMIM) View in own window 600430BRACHYDACTYLY-MENTAL RETARDATION SYNDROME; BDMR 605314HISTONE DEACETYLASE 4; HDAC4Molecular Genetic PathogenesisProposed candidate genes responsible for the Albright hereditary osteodystrophy (AHO)-like phenotype in individuals with 2q37 microdeletion syndrome include the following:Chaabouni et al [2006] initially narrowed the critical region for the AHO-like phenotype to an approximately 2-Mb interstitial region at 2q37.3 containing HDAC4, GPC1, and STK25. HDAC4. In 2010, Williams et al published two AHO-like cases with apparently isolated intragenic inactivating mutations of HDAC4. They proposed HDAC4 as the gene in which mutation caused the syndromic features of the 2q37 microdeletion syndrome (see OMIM 605314 for a summary of the allelic variants identified in these two cases). Recently, an individual with a cryptic balanced translocation between chromosomes 2q37 and 10q26 was found to have mild features of the 2q37 microdeletion syndrome. HDAC4 expression was 67% compared to expression in control individuals. This individual’s son, who had an unbalanced translocation resulting in a 9.84 Mb deletion of 2q37.1, was found to have a more severe phenotype and 23% expression of HDAC4 compared to control individuals [Morris et al 2012]. HDAC4 has 27 exons (NM_006037.3) and encodes a protein of 1084 amino acids (NP_006028.2).Three individuals with Wilms tumor and constitutional 2q37 or 2q37.1 deletion (without other chromosome anomalies) have been reported [Conrad et al 1995, Olson et al 1995, Viot-Szoboszlai et al 1998]. Since 2q37.1 is centromeric to HDAC4, it is hypothesized that there is a tumor-suppressor gene at 2q37.1, and that individuals with “larger” chromosome deletions involving 2q37.1 may be at increased risk of developing Wilms tumor. Drake et al [2009] studied a series of sporadic Wilms tumors and found evidence of a tumor suppressor role for a 360-kb critical region containing DIS3L2 and adjacent noncoding microRNA miR-562. Astuti et al [2012] subsequently identified DIS3L2 mutations in individuals with Perlman syndrome, a Wilms tumor predisposition syndrome. Genome-wide linkage studies have shown an autism susceptibility region on 2q37 [International Molecular Genetic Study of Autism Consortium 2001, Morrow et al 2008]. Proposed candidate genes responsible for the autistic features in individuals with 2q37 microdeletion syndrome include the following: KIF1A, previously known as ATSV, is an axonal transporter of syntaptic vesicles [Smith et al 2001, Devillard et al 2010]. FARP2, HDLBP, and PASK were identified as candidate genes because of their structural and functional relation to pathways in neuronal and skeletal pathways. All three were downregulated in an individual with a 3.5-Mb deletion and autism, compared to family members and healthy controls [Felder et al 2009]. FARP2 is a GTPase involved in neurite growth and axonal guidance. Vigilin (high density lipoprotein –binding protein, HDLBP) is a multi-KH-domain containing protein in cholesterol metabolism and structurally similar to FMR1 (Fragile X); PASK (Pas-domain serine/threonine kinase) is a kinase important in normal axonal ensheathment. Lukusa et al [2004] considered CENTG2, now known as AGAP1, a candidate gene for autism. Wassink et al [2005] confirmed deletion of this gene in an autistic female with a cytogenetically visible 2q37 deletion, AHO-like features, and normal intelligence. AGAP1 is expressed in the fetal and adult brain and is involved in endocytic trafficking [Nie et al 2002].