Deletion, Duplication, and Microduplication Syndromes Identifiable Using Molecular Technology

1p36 Deletion Syndrome (Monosomy 1p36 Deletion Syndrome)

Large Anterior Fontanel, Deep-Set Eyes, Pointed Chin

First delineated in 1997 as a recognizable pattern of malformation, monosomy 1p36 is the most commonly observed terminal deletion in the human population with an estimated prevalence of 1 in 5000.


  • Growth. Postnatal onset of growth deficiency, obesity.

  • Performance. Intellectual disability, severe in the majority of cases, although mild in a few; speech more severely affected than motor development. Expressive language absent in most patients. Behavior difficulties, including temper tantrums, self-biting, reduced social interaction, stereotypic behaviors, hyperphagia.

  • Craniofacial. Microcephaly; brachycephaly; large, late-closing anterior fontanel; straight eyebrows; epicanthal folds; prominent forehead; deep-set eyes; broad nasal root/bridge; midface hypoplasia; low-set, posteriorly rotated ears; thickened ear helices; long philtrum; pointed chin.

  • Cardiac. Structural defects in 71%, including patent ductus arteriosus, ventricular septal defect (VSD), atrial septal defect (ASD), bicommissural aortic valve, Ebstein anomaly, noncompaction cardiomyopathy, dilated cardiomyopathy in infancy.

  • Limbs/Skeletal. Brachydactyly, camptodactyly, short feet, bifid/fused/enlarged/missing ribs, scoliosis, delayed bone age.

  • Neurologic. Hypotonia; seizures with onset between 4 days and 3 years; infantile spasms associated with a hypsarrhythmic; electroencephalogram (EEG) abnormalities; central nervous system (CNS) defects, including enlarged lateral ventricles, cortical atrophy, enlarged subarachnoid space, diffuse brain atrophy, enlargement of the frontotemporal opercula, and focal pachygyria.

  • Other. Hypermetropia, hearing loss, renal anomalies, cryptorchidism, hypospadias, scrotal hypoplasia, micropenis, hypoplastic labia minora, clitoral hypertrophy.

Occasional Abnormalities

Hydrocephalus, visual inattentiveness, strabismus, myopia, nystagmus, sixth nerve palsies, cataracts, colobomas, moderate optic atrophy, cleft lip with or without cleft palate, bifid uvula, facial asymmetry, fifth finger clinodactyly, camptodactyly, hypothyroidism, kyphosis, hip dysplasia, congenital spinal stenosis, metatarsus adductus, polydactyly, shawl scrotum, imperforate anus, anteriorly placed anus, hiatal hernia, pyloric stenosis, abnormal pulmonary lobation, pemphigus vulgaris, sacral/coccygeal dimple, anterior body wall defects.

Natural History

Hypotonia occurs in the majority of neonates. Feeding problems, including poor suck and swallowing, reflux, and vomiting, are common in infancy. Hearing impairment, primarily sensorineural, is common, and visual disturbances have been observed frequently. Full-scale IQ scores are generally less than 60 and IQ less than 20 has been described. Seizures, beginning in infancy, cease in the first few years in some children, but persist, requiring long-term therapy, in others. Type II diabetes and impaired glucose tolerance owing to hyperinsulinism leading to obesity occur, although rarely. Disturbed behaviors, including temper tantrums, aggression, and self-injurious behavior are common. A majority of adolescents and adults were reported able to sit, walk, and receive nutrition orally independently. Most were able to use complex speech.


Deletion of the 1p36 chromosome region. The majority of cases are owing to a de novo terminal 1p36 deletion. Although in some cases the deletion can be detected by high-resolution karyotype, confirmation by fluorescence in situ hybridization (FISH) analysis or by array comparative genomic hybridization (CGH) is required in most. The size of the deletion does not correlate with the number of characteristic clinical features. Candidate genes that may contribute to the various phenotypes include MMP23B , GABRD , SKI , PRDM16 , KCNAB2 , RERE , UBE4B , CASZ1 , PDPN , SPEN , ECE1 , HSPG2 , and LUZP1 .


1p36 deletion syndrome.

A–C, Affected child with thickened ear helices, pointed chin, and missing distal crease on fourth finger with contracture (camptodactyly).


  • Shapira SK, et al. Chromosome 1p36 deletions: The clinical phenotype and molecular characterization of a common newly delineated syndrome. Am J Hum Genet. 1997;61:642.

  • Slavotinek A, et al. Monosomy 1p36. J Med Genet. 1999;36:657.

  • Heilstedt HA, et al. Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome. Am J Hum Genet. 2003;72:1200.

  • Gajecka M, et al. Monosomy 1p36 deletions syndrome. Am J Med Genet C. 2007;145C:346.

  • Battaglia A, et al. Further delineation of the deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation. Pediatrics. 2008;121(2):404.

  • Rosenfeld A, et al. Refinement of causative genes in monosomy 1p36 through clinical and molecular cytogenetic characterization of small interstitial deletions. Am J Med Genet A. 2010;152A:1951.

  • Brazil A, et al. Delineating the phenotype of the 1p36 deletion syndrome in adolescents and adults. Am J Med Genet. 2014;164A164:2496.

  • Shimada S, et al. Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications. Brain Develop. 2015;37:515.

  • Jordan VK, et al. 1p36 deletion syndrome. Appl Clin Genet. 2015;8:189.

2q31.1 Microdeletion Syndrome

Limb Defects, Intellectual Disability, Dysmorphic Features

The clinical phenotype was first delineated by Boles and colleagues. At least 50 patients have been reported. Haploinsufficiency of the HOXD cluster has been identified as the cause of the spectrum of limb defects.


  • Growth. Pre- and postnatal growth retardation.

  • Performance. Mild to severe intellectual disability; epilepsy.

  • Central Nervous System. Large ventricles, delayed myelination, periventricular leukomalacia, partial agenesis of corpus callosum, cortical atrophy.

  • Craniofacial. Microcephaly, narrow forehead with prominent metopic suture, short downslanting palpebral fissures, deep-set eyes, ptosis, broad eyebrows with lateral flare, small nose with bulbous tip, thin upper lip, thick and everted lower lip, low-set dysplastic ears with thickened helices and lobules, micrognathia, cleft lip with or without cleft palate, cleft palate alone.

  • Limbs. A wide range of defects. Mild digital abnormalities include camptodactyly, fifth finger clinodactyly with shortening of middle phalanges, partial to complete syndactyly, duplicated halluces, hypoplastic or absent phalanges of third/fourth/fifth fingers, nail hypoplasia, brachymetacarpia, broad first toes, and wide distance between hallux and remaining toes (sandal gap). Severe malformations include multiple fusions of carpal/tarsal and phalangeal bones, split-hand/split-foot, and monodactyly. The lower limbs tend to be more often and more severely affected than the upper limbs.

  • Ocular. Strabismus, nystagmus, cortical blindness, colobomas, refractive errors.

  • Cardiac. Septal defects, patent ductus arteriosus.

  • Genitalia. Hypoplastic male and female genitalia, hypospadias, penoscrotal transposition.

Occasional Abnormalities

Cataracts, microphthalmia, agenesis of corpus callosum, sex reversal, renal and urinary malformations. Pansynostosis of cranial sutures, myelomeningocele, hydrocephalus, contractures of large joints, hypoplasia or absence of a bone in the forearm or leg, scoliosis, hirsutism.

Natural History

Severe feeding problems and profound developmental delay can occur; early death from respiratory infection or cardiac defects has occurred in several patients. Patients with smaller deletions can have mild to moderate intellectual disability and a benign course in infancy with near-normal growth.


The deletion of this region is of variable size, ranging from a visible cytogenetic deletion to smaller submicroscopic deletions. Thus the phenotype is variable with more severe growth retardation and developmental delays, as well as multiple major and minor malformations of different systems in larger deletions. However, the deletion of the HOXD cluster and its surrounding up/downstream regulatory sequences appear to be responsible for the observed limb anomalies. Deletion of DLX1 and DLX2, two genes in the region affecting limb development in Drosophila, do not appear to determine the extent of the limb defects. The critical region covers the interval 1.5 Mb centromeric and 1 Mb telomeric to the HOXD genes. The characteristic facial appearance is associated with a 2.4-Mb locus immediately centromeric to the locus for limb anomalies. HOXD13 mutations and small microdeletions involving HOXD9-13 and EVX2 cause a specific synpolydactyly phenotype.


These deletions confirm that a diploid dose of human HOXD genes is crucial for normal growth and patterning of the limbs along the anterior-posterior axis.


2q31.1 Microdeletion syndrome.

Affected children 1 month (A), 3 months (B), and 11 years (C) of age. Note broad eyebrows with lateral flare, short palpebral fissures, ptosis, small nose with bulbous tip and hypoplastic nares, and micrognathia.

From Mitter D, et al: Am J Med Genet A 152A:1213, 2010, with permission.


2q31.1 Microdeletion syndrome.

A, Camptodactyly of the second and fifth fingers of the right hand and postaxial polydactyly, syndactyly of fingers 3 and 4, and camptodactyly of the second finger of the left hand. B, Fingers are tapered, and the thumbs are adducted and proximally placed. Note the bilateral fourth and fifth finger clinodactyly and mild syndactyly of fingers 3 and 4. C, Note the syndactyly and overlapping of the second and fourth toes. D, Long halluces, partial cutaneous syndactyly, and short distal phalanges of toes 2 through 5.

From Mitter D, et al: Am J Med Genet A 152A:1213, 2010, with permission.


Hand radiographs of patients with a 2q31.1 microdeletion syndrome.

A and B, Radiographs of a newborn showing aplasia of the second and third fingers. C, Radiographs of the left hand of the child, at 1 year of age, whose hand is pictured in Figure 2A . Note dysplastic additional phalanx with an additional metacarpal bone, accelerated bone age, and dysplastic proximal phalanges with low mineralization.

From Mitter D, et al: Am J Med Genet A 152A:1213, 2010, with permission.


Radiographs of the feet of a 15-month-old with a 2q31.1 microdeletion syndrome.

Note the broad halluces, hypoplastic or absent middle or distal phalanges, broad fifth metatarsal bone, and duplication of the proximal fifth phalanx.


  • Boles RG, et al. Deletion of chromosome 2q24-q31 causes characteristic digital anomalies: case report and review. Am J Med Genet. 1995;55:155.

  • Slavotinek A, et al. Two cases with interstitial deletions of chromosome 2 and sex reversal in one. Am J Med Genet. 1999;86:75.

  • Del Campo M, et al. Monodactylous limbs and abnormal genitalia are associated with hemizygosity for the human 2q31 region that includes the HOXD cluster. Am J Hum Genet. 1999;65:104.

  • Veraksa A, Del Campo M, McGinnis W. Developmental patterning genes and their conserved functions: from model organisms to humans. Mol Genet Metab. 2000;69:85.

  • Goodman FR, et al. A 117-kb microdeletion removing HOXD9-HOXD13 and EVX2 causes synpolydactyly. Am J Hum Genet. 2002;70:547.

  • Goodman FR. Limb malformations and the human HOX genes. Am J Med Genet. 2002;112:256.

  • Mitter D, et al. Genotype-phenotype correlation in eight new patients with a deletion encompassing 2q31.1. Am J Med Genet A. 2010;152A:1213.

  • Dimitrov B, et al. 2q31.1 microdeletion syndrome: redefining the associated clinical phenotype. J Med Genet. 2011;48:98.

  • Puvabanditsin S, et al. 2q31.1 microdeletion syndrome: case report and literature review. Clin Case Rep. 2015;3:357.

2q37 Deletion Syndrome (2qter Subtelomeric Microdeletion Syndrome)

Since the disorder was first reported by Gorski and colleagues in 1989, more than 100 cases of visible or submicroscopic deletions have been described, making this disorder one of the most frequently recognizable subtelomeric deletions.


  • Growth. Postnatal onset short stature not manifest until adulthood, obesity.

  • Performance. Mild to severe intellectual disability, hypotonia, seizures (25% to 35%), autism spectrum disorders (25% to 35%).

  • Craniofacial. Sparse hair; sparse, arched eyebrows; frontal bossing; round face with full cheeks; midface hypoplasia; deep-set eyes; epicanthal folds; upslanting palpebral fissures; depressed nasal bridge; short nose; hypoplastic, notched nares; prominent low-set columella; short philtrum; thin upper lip with hypoplastic cupid’s bow; high arched palate; microtia.

  • Limbs. Small hands and feet, short third, fourth, and fifth metacarpals (often fourth alone) and metatarsals, brachymetaphalangism, fifth finger clinodactyly, mild cutaneous syndactyly, persistent fetal fingertip pads, abnormal palmar creases.

  • Cardiac. Defects in 30%, including ventricular septal defect (VSD), atrial septal defect (ASD), aortic coarctation, hypoplastic aortic arch.

  • Other. Wide-set, distally placed, inverted nipples; supernumerary nipples; pectus carinatum and excavatum; scoliosis; intestinal malrotation; duodenal atresia; anteriorly placed anus; kidney and urinary tract anomalies; joint laxity; inguinal hernias; eczema.

Occasional Abnormalities

Microcephaly (10%), macrocephaly, hypospadias, cryptorchidism, hypoplastic gonads, bifid uterus, dilated ventricles, hydrocephalus, holoprosencephaly, subependymal cyst, cerebellar anomalies, iris coloboma, diaphragmatic hernia, dilated cardiomyopathy tracheomalacia, congenital hip dislocation, fused cervical vertebrae, supernumerary ribs, asthma, recurrent infections, Wilms tumor (<5%), alopecia, hypertrichosis, loose skin, cleft palate, hearing loss., growth hormone deficiency.

Natural History

Poor feeding and gastroesophageal reflux can lead to failure to thrive. Some patients have early overgrowth with early closure of the epiphyses and adult short stature. Affected women have occasionally given birth, but affected males have not had offspring. Screening for Wilms tumor should be considered.


Deletion size varies, ranging from visible deletions in 80% to subtelomeric cryptic deletions in 20%. Several families have shown recurrence for the deletion as a result of a parental balanced translocation (5%). Therefore, as in other subtelomeric deletions, FISH should be performed in all parents. A phenotype reminiscent of Albright hereditary osteodystrophy with short stature, obesity, and short fourth and fifth metacarpals and metatarsals seems to occur only in the distal deletions. Histone deacetylase 4 (HDAC4) is responsible for the brachymetaphalangism and intellectual disability. This phenotype occurs in 50% to 60% of individuals with the 2qter submicroscopic microdeletion syndrome. The interval for autistic behavior is 1.43 Mb in size within the 2q37 region. Wilms tumor has been reported in three patients with breakpoints at or proximal to band 2q37.1.


2q37 microdeletion syndrome.

Note the sparse hair, sparse and arched eyebrows, round face with full cheeks, midface hypoplasia, and epicanthal folds (A–C and F) ; deep-set eyes, upslanting palpebral fissures (A, D, and F) ; depressed nasal bridge, short nose (B and E) ; prominent low-set columella, thin upper lip with hypoplastic Cupid’s bow ( D and E ); and low-set ears (B and E) .

C, Courtesy Professor Bruno Dallapiccola, Ospedale Bambino Gesú, Rome, Italy.

Jun 28, 2021 | Posted by in PEDIATRICS | Comments Off on Deletion, Duplication, and Microduplication Syndromes Identifiable Using Molecular Technology
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