Formiga et al. (1988) reported 2 unrelated patients with an interstitial deletion of chromosome 15q. The first child showed intrauterine and postnatal growth retardation, severe psychomotor retardation, and dysmorphic facial features, including microcephaly, slight microphthalmia, hypertelorism, slanting palpebral ... Formiga et al. (1988) reported 2 unrelated patients with an interstitial deletion of chromosome 15q. The first child showed intrauterine and postnatal growth retardation, severe psychomotor retardation, and dysmorphic facial features, including microcephaly, slight microphthalmia, hypertelorism, slanting palpebral fissures, epicanthal folds, strabismus, hypopigmented irides, short nose, microretrognathia with open mouth and high-arched palate, and large ears. She also had abnormal insertion of several toes. Karyotype analysis showed a deletion of chromosome 15q22-q25. The second child had severe psychomotor retardation, hypotonia, and similar facial dysmorphism with small, slanting palpebral fissures, microphthalmia, large ears, hypopigmented irides, and microretrognathia with open mouth and arched palate. She had clinodactyly, abnormal insertion of the toes, and cardiovascular abnormalities, consisting of septal hypertrophy with dilatation of the aorta and pulmonary artery. Karyotype analysis showed a deletion of chromosome 15q21-q24. Bettelheim et al. (1998) reported 2 unrelated fetuses with significant left-sided congenital diaphragmatic hernia detected by ultrasound. One died in utero, and the other died 10 minutes after birth. Karyotype analysis showed a de novo interstitial deletion of chromosome 15q24 in the first and a deletion of chromosome 15q24-qter in the second. Cushman et al. (2005) reported 3 patients with interstitial deletions involving chromosome 15q24, including 2 with cryptic deletions and 1 with a cytogenetically visible deletion of chromosome 15q22.3-q24. All had global developmental delay and hypotonia. The 2 males had hypogonadism. Two patients were reported to have dysmorphic facial features, including epicanthal folds, strabismus, micrognathia, and cupped or notched ears, as well as digital anomalies, such as clinodactyly and tapering of the fingers. Sharp et al. (2007) reported 4 unrelated boys with mild to moderate developmental delay and dysmorphic facial features who were each heterozygous for a deletion at chromosome 15q24. Three had low birth weight, short stature, and microcephaly. Dysmorphic features included high anterior hairline, hypertelorism, downslanting palpebral fissures, broadening of the medial eyebrows, broad nasal base with flaring of the alae nasi, long smooth philtrum, and full lower lip. Three had joint laxity, 2 had scoliosis, and 3 had hypospadias. All had digital anomalies, such as long slender fingers and proximally implanted thumbs. Two had growth hormone deficiency; the other 2 were not tested. Van Esch et al. (2009) reported a 33-year-old man with severe mental retardation and a chromosome 15q24 microdeletion. Hypertelorism, broad nasal bridge, and large ears were noted in infancy. He had delayed psychomotor development and hypotonia. As a child, he had hyperactive behavior and showed aggressive outbursts, requiring institutionalization. At age 33, he was found to have a congenital diaphragmatic hernia of the Morgagni type. Dysmorphic features at that time included obesity, strabismus, downslanting palpebral fissures, long face with high forehead, long philtrum, and high-arched palate. He also had small genitals and unilateral cryptorchidism. Cytogenetic and array CGH analysis detected a de novo 3.1-Mb deletion at chromosome 15q24 with breakpoints within segmental duplication clusters. El-Hattab et al. (2009) reported 4 patients with the 15q24 deletion syndrome. All had developmental delay, short stature, hypotonia, joint laxity, digital anomalies, and characteristic facial features similar to previously reported cases. In a review of common reported features, El-Hattab et al. (2009) concluded that 15q24 deletion represents a distinct syndrome. General features include mild to severe developmental delay, hypotonia, short stature, digital anomalies, joint laxity, genital anomalies, and characteristic facial features, such as a high anterior hairline, facial asymmetry, ear malformations, broad medial eyebrows, downslanted palpebral fissures, hypertelorism, epicanthal folds, strabismus, long smooth philtrum, full lower lip, and broad nasal base. The distal extremity malformations consist of thumb anomalies, small hands with brachydactyly, clinodactyly, and foot-ankle deformities. - Chromosome 15q24 Duplication Syndrome Kiholm Lund et al. (2008) reported a 2-year-old boy with a chromosome 15q24 microduplication that was reciprocal to the minimal critical region for the chromosome 15q24 microdeletion. He had global developmental delay, hypospadias, and dysmorphic features, including low-set, posteriorly rotated ears, broad nasal bridge, hypertelorism, downslanting palpebral fissures, epicanthal folds, thick upper lip, and smooth philtrum. He also had digital anomalies with overlapping fingers and hypoplastic nails and hypotonia. Although the duplication was inherited from the healthy father, it was considered clinically significant, since the phenotype in the proband resembled the reciprocal deletion syndrome. El-Hattab et al. (2009) reported a 15-year-old boy with short stature, mild mental retardation, hypertonia, attention-deficit hyperactivity disorder, and Asperger syndrome who had a 2.6-Mb microduplication of chromosome 15q24, including the 1.75-Mb critical region. He had a long face, epicanthal folds, downslanting palpebral fissures, high nasal bridge, smooth philtrum, and full lower lip. Two sibs from a second family had a 2.11-Mb duplication of chromosome 15q24, distal to the critical region, and they showed developmental delay, axial hypotonia, tapering fingers, and characteristic facial features, such as hypertelorism, flat nasal bridge, and prominent ears. The 2 sibs inherited the duplication from their mother, who had learning disabilities.
The clinical spectrum of the 15q24 microdeletion syndrome is variable. Developmental delay and intellectual disability are the most consistent features; however, no single clinical feature is required to establish the diagnosis. ...
DiagnosisClinical Diagnosis The clinical spectrum of the 15q24 microdeletion syndrome is variable. Developmental delay and intellectual disability are the most consistent features; however, no single clinical feature is required to establish the diagnosis. Features that should prompt consideration of this diagnosis in an individual with developmental delay or intellectual disability include:Dysmorphic facial features, especially a high anterior hairline, deep-set eyes, and a triangular shaped face (see Figure 1)Markedly delayed or absent speechHypotoniaJoint laxityOcular abnormalities, especially strabismusHand and foot abnormalities: short fifth fingers; significant shortening of the fourth metacarpals and short fifth metacarpals; thumb anomalies such as proximally implanted thumbsGrowth retardation and failure to thriveHearing: conductive and sensorineural hearing lossGenital anomalies: hypospadias or micropenis in males, labial adhesions in femalesFigureFigure 1. Eight individuals with deletions in the 15q24 region. Those in panels A-F each have a deletion that includes the 1.1-Mb critical region. The individual in panel G has a large atypical deletion that includes only the proximal ~250 kb of the critical (more...)TestingCytogenetic testing. The 15q24 microdeletion cannot be identified by routine analysis of G-banded chromosomes or other conventional cytogenetic banding techniques.Molecular Genetic Testing Critical region. The diagnosis of the 15q24 microdeletion is established by demonstration of a heterozygous deletion at chromosome 15q24. The majority of 15q24 deletions identified to date involve a 1.1-Mb region between 72.2-73.3 Mb of the reference genome (NCBI Build 36 / hg18) (identified as breakpoints B and C in Figure 2). The actual size and breakpoints of the deletion vary among patients, with most deletions occurring due to non-allelic homologous recombination (NAHR) between segmental duplication blocks. FigureFigure 2. A schematic representation of the structure of the 15q24 region and the most common deletions identified in the region. Orange rectangles represent segmental duplication blocks A-E, which are though to facilitate non-allelic homologous recombination (more...)Notably, the critical region continues to be refined as patients with “atypical” deletions are identified, some of which involve only part or none of the proposed 1.1-Mb critical region but still appear to be pathogenic. Two individuals with de novo deletions just outside the proposed 1.1-Mb critical region have milder developmental delay and both developed reasonable speech; they both have dysmorphic features, and one has hand anomalies [Mefford et al 2012]. Two patients with large deletions that involve only 800 kb [Andrieux et al 2009] and 500 kb [Ng et al 2011] of the region between breakpoints B and C in Figure 2 have also been reported. The deletions in these two patients suggest that the critical region may be smaller than 1.1 Mb, though the large size of their deletions makes it difficult to know which genes are contributing to their features. Future identification of smaller, atypical deletions will continue to refine the critical region and genotype-phenotype correlations. Genes. The cognitive features of the 15q24 microdeletion syndrome, including developmental delays and severe speech problems, largely result from deletion of genes in a 1.1-Mb critical region. No single gene in which mutations cause a similar phenotype has been identified within this region. Clinical testingDeletion/duplication analysis. The 15q24 microdeletion can be detected by any number of molecular methods that determine the copy number of sequences within the deleted region. Both whole-genome and targeted approaches can be applied. Genomic microarray technologies. Array-based genomic hybridization can detect the common deletion in a proband. The ability to size the deletion depends on the type of microarray used and the density of probes in the 15q24 region. Targeted deletion analysis. Targeted methods, including fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and quantitative PCR (qPCR) can be used if the deletion is suspected clinically or for confirmation of the deletion after genomic microarray analysis. Targeted approaches can also be used to evaluate relatives of the proband for presence of the deletion. Whether or not it is possible to size the deletion depends on the number and distribution of probes in the 15q24 region. It is not possible to size the deletion routinely by use of FISH. Table 1. Summary of Molecular Genetic Testing Used in 15q24 Microdeletion View in own windowChromosomal RegionTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test Availability15q24Deletion / duplication analysis 2Deletion of 1.1-Mb critical region~100% with appropriate probesClinical1. The ability of the test method used to detect a deletion or duplication that is present in the indicated chromosomal region2. 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.Interpretation of test results. Depending on the initial test that identifies the deletion, validation of the deletion by an independent method might be warranted. If high-density genomic microarray platforms have been used for the identification of the deletion, validation of the deletion may not be necessary, as it is unlikely that more than 50-100 adjacent targets show an abnormal copy number by chance.Testing Strategy Establishing the diagnosis in a proband requires detection of the 1.1-Mb minimal critical deletion common in 15q24 microdeletion syndrome. Most microdeletions are detected by genomic microarray analysis performed as part of the evaluation of developmental delay or intellectual disability.If the 15q24 microdeletion is suspected based on the clinical features, a targeted technique (e.g., FISH, MLPA) can be employed. Note: The deletion cannot be identified by routine chromosome analysis.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the deletion in the proband and/or of balanced carrier status in a parent. At this point, all known cases have originated de novo; parents with balanced rearrangements have not yet been reported, nor have offspring of individuals with a 15q24 microdeletion who are mildly affected. However, because only a limited group of patients has been studied, a balanced rearrangement in a parent is still a possibility. Genetically Related (Allelic) Disorders Syndromic microphthalmia / Matthew Wood syndrome (recessive) (OMIM 601186). Recessive mutations in STRA6 cause a profound intellectual disability syndrome with eye abnormalities including microphthalmia and/or anophthalmia, diaphragmatic hernia, pulmonary hypoplasia, cardiac defects, and short stature [Golzio et al 2007, Pasutto et al 2007]. Congenital adrenal insufficiency (recessive) (OMIM 118485). Compound heterozygous or homozygous mutations in CYP11A1 have been reported in several persons with congenital adrenal insufficiency with partial or complete 46,XY sex reversal [Katsumata et al 2002, Hiort et al 2005, Al Kandari et al 2006, Kim et al 2008, Rubtsov et al 2009]. One individual in whom only one mutation in the gene was identified has also been reported [Tajima et al 2001]. MPI-CDG (CDG-Ib; recessive) (OMIM 602579). This autosomal recessive disorder is caused by compound heterozygous or homozygous mutations in MPI, located within the 15q24 microdeletion critical region [Jaeken et al 1998, Schollen et al 2000]. Features of MPI-CDG include chronic diarrhea, failure to thrive, protein-losing enteropathy, and coagulopathy. Unlike other types of CDG, MPI-CDG does not usually involve the central nervous system. (See Congenital Disorders of Glycosylation Overview.)Reciprocal duplication. Several individuals have been reported to have duplications of the 15q24 region that include the 1.1-Mb critical region for the 15q24 microdeletion syndrome. It is currently unclear if the 15q24 duplications represent a distinct clinical phenotype [El-Hattab et al 2010]. Two reported, unrelated individuals share some features similar to the 15q24 microdeletion syndrome, including developmental delay, digital anomalies, and dysmorphic features [Kiholm Lund et al 2008, El-Hattab et al 2009]. In contrast, the only feature shared with two additional individuals, who were more severely affected and also had secondary copy number changes, was developmental delay [El-Hattab et al 2010]. In the three instances in which inheritance was known, the duplications were inherited from mildly affected or healthy parents. Given the parental phenotypes and the finding of secondary copy number changes in some affected individuals, it is possible that these duplications are one of several factors contributing to an abnormal phenotype, or show reduced penetrance and/or variable expressivity. 15q24 duplications of the region distal to the 1.1-Mb critical deletion region have also been reported and may also contribute to variable abnormal phenotypes. Two reported families have multiple affected individuals with this duplication; persons heterozygous for this duplication showed varying degrees of developmental delay, hypotonia, and dysmorphic features; one of the families also had individuals with autism spectrum disorders [El-Hattab et al 2009, Roetzer et al 2010].
The 15q24 microdeletion syndrome has a clinically recognizable phenotype that includes developmental delay/intellectual disability, facial dysmorphisms (Figure 1), congenital malformations, and growth retardation (Table 2). Males and females are affected equally. ...
Natural HistoryThe 15q24 microdeletion syndrome has a clinically recognizable phenotype that includes developmental delay/intellectual disability, facial dysmorphisms (Figure 1), congenital malformations, and growth retardation (Table 2). Males and females are affected equally. Intellectual disability and developmental delay. All persons with a deletion involving the 1.1-Mb critical region reported to date have had mild to severe intellectual disability (ID). Delays are generally global, including gross motor skills, speech, and cognition. Motor delay, most likely related to the degree of hypotonia, is mild to moderate in most. Speech and cognitive deficits are generally more severe. Most affected individuals have severe language delays with limited language acquisition. Cognitive abilities range from mild to severe ID; most have at least moderate ID. Dysmorphic facial features are common in persons with 15q24 microdeletion syndrome and include high anterior hairline, deep-set eyes, and triangular shaped face. Other frequently reported features include long or prominent philtrum, full lower lip, epicanthal folds, and pointed chin.Ocular abnormalities have been reported in 59% of individuals, with strabismus being the most frequent. Other rare abnormalities include iris coloboma, chorioretinal coloboma anisocoria, and hypermetropia. Digital anomalies have been reported in 59% of individuals. These include short fifth fingers, significant shortening of the fourth metacarpals and short fifth metacarpals, thumb anomalies including proximally implanted thumbs, camptodactyly, hypoplastic fifth toes, and toe syndactyly.Genital anomalies are reported in approximately 30% of patients, with hypospadias and micropenis most commonly reported. Table 2. Features of 15q24 Microdeletion SyndromeView in own windowFrequency in %Features>75% of individualsDistinctive facial features (see Clinical Diagnosis) Developmental delay/intellectual disability Significant speech delay Hypotonia (childhood)50%-75%Eye abnormalities, most frequently strabismus Digital anomalies Ear anomalies (most frequently dysplastic ears) 25%-50%Joint laxity Hearing loss Abnormalities on brain MRI: • Heterotopia • Corpus callosum cysts • Enlarged ventricles • Cerebral atrophy • Hypoplastic olfactory bulbs Hypospadias and/or micropenis10%-25%Seizures Sensorineural hearing loss Conductive hearing loss<10%Heart defects Diaphragmatic hernia Bowel atresia Pierre Robin syndromeData from 32 individuals (24 male, 8 female) [Sharp et al 2007, Klopocki et al 2008, Marshall et al 2008, El-Hattab et al 2009, Masurel-Paulet et al 2009, Van Esch et al 2009, El-Hattab et al 2010, McInnes et al 2010, Ng et al 2011, Mefford et al 2012]
The most common findings in 15q24 microdeletion syndrome, developmental delay and childhood hypotonia, are frequent and relatively nonspecific indications for molecular cytogenetic analysis. However, the concurrent finding of characteristic facial dysmorphic features and hand and genital anomalies may prompt special consideration of 15q24 microdeletion syndrome. ...
Differential DiagnosisThe most common findings in 15q24 microdeletion syndrome, developmental delay and childhood hypotonia, are frequent and relatively nonspecific indications for molecular cytogenetic analysis. However, the concurrent finding of characteristic facial dysmorphic features and hand and genital anomalies may prompt special consideration of 15q24 microdeletion syndrome. Other diagnoses that may be considered in affected individuals include the following:Angelman syndrome. Clinical features seen in 15q24 microdeletion syndrome that may also be seen in Angelman syndrome include microcephaly, absent speech, growth retardation, seizures, and generally happy disposition. Fryns syndrome is characterized by diaphragmatic defects (diaphragmatic hernia, eventration, hypoplasia or agenesis); characteristic facial appearance (coarse facies, ocular hypertelorism, broad and flat nasal bridge, thick nasal tip, long philtrum, low-set and poorly formed ears, tented upper lip, macrostomia, micrognathia); distal digital hypoplasia (nails, terminal phalanges); pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia/renal cortical cysts, and/or malformation involving brain, cardiovascular system, gastrointestinal system, genitalia). Survival beyond the neonatal period has been rare. Data on postnatal growth and psychomotor development are limited; however, severe developmental delay and intellectual disability are common. Since persons with 15q24 microdeletion syndrome have been reported to have diaphragmatic hernia, Fryns syndrome should be considered in the differential diagnosis. Deletion 22q11.2 (velocardiofacial syndrome) (VCFS). The 15q24 microdeletion syndrome may be considered in persons who have not had deletion of 22q11.2 on targeted testing. Developmental delay and dysmorphic facial features are common in both syndromes.Prader-Willi syndrome (PWS). Clinical features of 15q24 microdeletion syndrome that may also be seen with PWS include severe neonatal hypotonia, seizures, global developmental delay, strabismus, upslanting palpebral fissures, and cryptorchidism. However, in contrast to PWS, childhood hyperphagia and central obesity have not been reported in 15q24 microdeletion syndrome, and behavioral problems and sleep disturbances are less common.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).
To establish the extent of disease and needs of an individual diagnosed with the 15q24 microdeletion syndrome, the following evaluations should be considered:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with the 15q24 microdeletion syndrome, the following evaluations should be considered:Ophthalmologic examinationFormal audiology evaluation to assess for sensorineural hearing lossCardiac evaluationBrain imaging in individuals with microcephaly and/or neurologic findingsExamination for genitourinary abnormalities (e.g., hypospadias or cryptorchidism in males)Comprehensive developmental assessmentConsideration of neurologic referral for any unusual movements or concern for seizuresDiscussion of results with a medical geneticist or genetic counselorTreatment of ManifestationsThe following are indicated:Routine treatment of ophthalmologic, cardiac, neurologic findingsSpeech, occupational, and physical therapiesSpecialized learning programs to meet individual needsNo specific antiepileptic or antipsychotic medications are indicatedSurveillanceAppropriate surveillance includes:Routine pediatric careRoutine developmental assessmentsMonitoring of specific identified medical issues Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management If a fetus is known to have 15q24 microdeletion syndrome, fetal echocardiogram and ultrasound examination with an attempt to visualize the palate and look for diaphragmatic hernia are recommended. Close monitoring for intrauterine growth retardation is warranted. Counseling with regard to the developmental outcomes and medical complications of the 15q24 microdeletion syndrome is appropriate. Delivery at a center with a good neonatal intensive care team is optimal, as respiratory complications and feeding difficulties may occur after delivery. 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
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. 15q24 Microdeletion: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameUnknown15q24UnknownData 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 15q24 Microdeletion (View All in OMIM) View in own window 613406CHROMOSOME 15q24 DELETION SYNDROMEMolecular Genetic Pathogenesis The 15q24 region is characterized by several segmental duplication (SD) blocks or low copy repeats [Bailey et al 2002, El-Hattab et al 2009] (see Figure 2). The SD blocks are thought to facilitate nonallelic homologous recombination (NAHR), resulting in microdeletion or duplication of the intervening region. Five SD blocks (A, B, C, D, E) have been identified as playing a role in generating recurrent 15q24 microdeletions, with the most common deletions occurring between blocks A and D (3.1 Mb), B and E (3.8 Mb), and A and C (2.6 Mb). The critical region, which lies between B and C, was identified as the smallest region of overlap among the common deletions; no one with a deletion involving only the critical region has been reported to date. The 1.1-Mb critical region between blocks B and C contains 26 genes that are well characterized in the RefSeq database. Haploinsufficiency of one or more genes in the region is thought to result in the 15q24 microdeletion syndrome phenotype; however, no mutations in a single gene from the region have yet been identified as causing a similar phenotype. Candidate genes, based on their known function, include the following:CPLX3, which is expressed in the brain and eye, regulates neurotransmitter release in mouse hippocampal neurons, and is involved in syntaxin binding;SEMA7A, a membrane-anchored semaphorin that mediates central and peripheral axon growth and is required for proper axon tract formation during development.