Recognizable Patterns of Malformation

Chromosomal Abnormality Syndromes Identifiable on Routine Karyotype

Down Syndrome (Trisomy 21 Syndrome)Hypotonia, Flat Facies, Slanted Palpebral Fissures, Small Ears

Down’s report in 1866 on the ethnic classification of idiots stated that a “large number of congenital idiots are typical Mongols,” and he set forth the clinical description of the Down syndrome. The textbook by Penrose and Smith provides an overall appraisal of this disorder that has an incidence of 1 in 660 newborns, making it the most common chromosomal trisomy in humans.


  • General. Hypotonia with a tendency to keep the mouth open and protrude the tongue, diastasis recti, hyperflexibility of joints, relatively small stature with awkward gait, increased weight in adolescence.

  • Central Nervous System. Intellectual disability.

  • Craniofacial. Brachycephaly; mild microcephaly with upslanting palpebral fissures; thin cranium with late closure of fontanels; hypoplasia to aplasia of frontal sinuses, short hard palate; small nose with low nasal bridge and a tendency to have inner epicanthal folds.

  • Eyes. Speckling of iris (Brushfield spots) with peripheral hypoplasia of iris; fine lens opacities by slit lamp examination (59%); refractive error, mostly myopia (70%); nystagmus (35%); strabismus (45%); blocked tear duct (20%); acquired cataracts in adults (30% to 60%).

  • Ears. Small; overfolding of angulated upper helix; sometimes prominent; small or absent earlobes; hearing loss (66%) of conductive, mixed, or sensorineural type; fluid accumulation in middle ear (60% to 80%).

  • Dentition. Hypoplasia, irregular placement, fewer caries than usual, periodontal disease.

  • Neck. Short with loose folds of skin.

  • Hands. Relatively short metacarpals and phalanges; hypoplasia of midphalanx of fifth finger (60%) with clinodactyly (50%), a single crease (40%), or both; simian crease (45%); distal position of palmar axial triradius (84%); ulnar loop dermal ridge pattern on all digits (35%).

  • Feet. Wide gap between first and second toes, plantar crease between first and second toes, open field dermal ridge patterning in hallucal area of the sole (50%).

  • Pelvis. Hypoplasia with outward lateral flare of iliac wings and shallow acetabular angle.

  • Cardiac. Anomaly in approximately 40%; endocardial cushion defect, ventricular septal defect, patent ductus arteriosus, auricular septal defect, and aberrant subclavian artery, in decreasing order of frequency; mitral valve prolapse with or without tricuspid valve prolapse and aortic regurgitation by 20 years of age; risk for regurgitation after 18 years of age.

  • Skin. Cutis marmorata, especially in extremities (43%); dry, hyperkeratotic skin with time (75%); infections in the perigenital area, buttocks, and thighs that begin as follicular pustules in 50% to 60% of adolescents.

  • Hair. Fine, soft, and often sparse; straight pubic hair at adolescence.

  • Genitalia. Relatively small penis and decreased testicular volume; primary gonadal deficiency is common and progressive from birth to adolescence and is definitely present in adults. Although rare, cases of fertility in females have been reported; no male has reproduced.

Occasional Abnormalities

Seizures (< 9%); keratoconus (6%); congenital cataract (3%); low placement of ears; webbed neck; two ossification centers in manubrium sterni; funnel or pigeon breast; tracheal stenosis with hourglass trachea and midtracheal absence of tracheal pars membranacea; gastrointestinal tract anomalies (12%), including tracheoesophageal fistula; duodenal atresia; omphalocele; pyloric stenosis; annular pancreas; Hirschsprung disease; and imperforate anus. Incomplete fusion of vertebral arches of lower spine (37%); only 11 ribs; atlantoaxial instability (12%); posterior occipitoatlantal hypermobility (8.5%); abnormal odontoid process (6%); hypoplastic posterior arch C1 (26%). Hip abnormality (8%), including dysplasia, dislocation, avascular necrosis, or slipped capital femoral epiphyses; syndactyly of second and third toes; prune belly anomaly. The incidence of leukemia is approximately 1 in 95, or close to 1%. Thyroid disorders are more common, including athyreosis, simple goiter, and hyperthyroidism. Cholelithiasis in children and gallbladder disease in adults. Fatal perinatal liver disease has been reported.

Natural History

Muscle tone tends to improve with age, whereas the rate of developmental progress slows with age. For example, 23% of a group of children with Down syndrome who were younger than 3 years had a developmental quotient above 50, whereas none of those in the 3- to 9-year group had intelligence quotients above 50. Although the IQ range is generally said to be 25 to 50, with an occasional individual above 50, the mean IQ for older patients is 24. Fortunately, social performance is usually beyond that expected for mental age, averaging 3⅓ years above mental age for the older individuals. Generally “good babies” and happy children, individuals with Down syndrome tend toward mimicry, are friendly, have a good sense of rhythm, and enjoy music. Mischievousness and obstinacy may also be characteristics, and 13% have serious emotional problems. Coordination is often poor, and the voice tends to be harsh. Early developmental enrichment programs for Down syndrome children have resulted in improved rate of progress during the first 4 to 5 years of life. Whether such training programs will appreciably alter the ultimate level of performance remains to be determined.

Obstructive sleep apnea has a prevalence ranging from between 55% and 97%. Growth is relatively slow; during the first 8 years, secondary centers of ossification are often late in developing. However, during later childhood, the osseous maturation is more “normal,” and final height is usually attained around 15 years of age. The prevalence of obesity in children and young people as measured by body mass index (BMI) is 52% of males and 40% of females. Adolescent sexual development is usually somewhat less complete than normal. Because thyroid dysfunction is common and can be easily missed, periodic thyroid function studies should be performed starting in infancy at 6 to 8 weeks and again at the 4-month check-up. Affected individuals have an increased risk for autoimmune disease. Life expectancy is 58.6 years, and 25% live beyond 62.9 years. Alzheimer’s disease is common. By 60 years of age, 50% to 70% of affected individuals develop dementia. The major cause for early mortality is congenital heart defects. Mortality from respiratory disease, mainly pneumonia, as well as other infectious diseases, is much higher than in the general population. Although leukemia has frequently appeared on death certificates of affected individuals, other neoplasms were listed less than one tenth as often as expected. Neutrophilia, thrombocytopenia, and polycythemia are common. Of newborns, 10% present with a transient myeloproliferative disorder characterized by a clonal population of megakaryo blasts. Low-grade problems that occur frequently are chronic rhinitis, conjunctivitis, and periodontal disease as well as a high risk of respiratory syncytial virus hospitalization continuing past the first year of life. Immunologic dysfunction, including both T-cell and B-cell derangement, has been demonstrated, as has the frequent occurrence of hepatitis B surface antigen carrier state. Therefore, hepatitis B virus (HBV) vaccination is advised.

Although asymptomatic atlantoaxial dislocation occurs in 6.8% to 27% of individuals with Down syndrome, symptoms referable to compression of the spinal cord are rare. The literature regarding radiographic screening for this finding is controversial. No study to date has documented that radiographic findings can predict which children will develop neurologic problems. Any child with Down syndrome who develops changes in bowel or bladder function, neck posturing, or loss of ambulatory skills should be evaluated carefully with plain roentgenograms of the cervical spine. The majority of patients develop symptoms before 10 years of age, when the ligamentous laxity is most severe. The Faculty of Sport and Exercise Medicine United Kingdom have concluded that plain radiography cannot be currently recommended to screen for asymptomatic atlantoaxial instability (AAI). They do recommend that individuals with Down syndrome who are undergoing a sport preparticipation screening should have frequent neurologic examinations checking for gait disturbances, neck movements tendon reflexes, and plantar responses as well as asking the following questions: (1) Is there evidence of progressive myopathy? (2) Is there poor head/neck control? (3) Does neck flexion allow the chin to rest on the chest? The Committee on Genetics of the American Academy of Pediatrics has published health supervision guidelines for children with Down syndrome that offer recommendations for follow-up of affected children.


The etiology of Down syndrome is trisomy for all of, or a large part of, chromosome 21. The combined results of 11 unselected surveys totaling 784 cases showed the following relative frequencies of particular types of chromosomal alteration for Down syndrome: Full 21 trisomy (94%), 21 trisomy/normal mosaicism (2.4%), translocation cases (with about equal occurrence of D/G, and G/G translocations) (3.3%).

Faulty chromosome distribution leading to Down syndrome is more likely to occur at older maternal age, as shown in the following figures of incidence for Down syndrome at term delivery for particular maternal ages: 15 to 29 years, 1 in 1500; 30 to 34 years, 1 in 800; 35 to 39 years, 1 in 270; 40 to 44 years, 1 in 100; and over 45 years, 1 in 50.

Although the general likelihood for recurrence of Down syndrome is 1%, the principal task in giving recurrence risk figures to parents is to determine whether the child with Down syndrome is a translocation case with a parent who is a translocation carrier and thereby has a relatively high risk for recurrence. The likelihood of finding a translocation in the child with Down syndrome of a mother younger than 30 years is 6% of such cases only one of three will be found to have a translocation carrier parent. Therefore, the estimated probability that either parent of a baby with Down syndrome born of a mother younger than 30 years is a translocation carrier is 2% versus 0.3% when the baby with Down syndrome is born of a mother older than 30 years. Having excluded a translocation carrier parent, the risk for recurrence may be stated as about 1%. There is also the suggestion that the recurrence of a different trisomy subsequent to a previous trisomy 21 may also be increased. Although a low figure, it is enough to justify prenatal diagnosis for any future pregnancy. The recurrence risk for the rare translocation carrier parent will depend on the type of translocation and the gender of the parent. Mosaicism usually leads to a less severe phenotype. Any degree of intellectual ability from normal or nearly normal to severe retardation is found, and this does not always correlate with the clinical phenotype. Patients with the features of Down syndrome and relatively good performance are likely to have mosaicism (which is not always easy to demonstrate).


Down syndrome.

A–C, Young infant. Flat facies, straight hair, protrusion of tongue, single crease on inturned fifth finger.


A and B, Upslanting palpebral fissures. Low nasal bridge with upturned nares.

Courtesy Dr. Lynne M. Bird, Children’s Hospital, San Diego, California.


A, Brushfield spots. B, Loose nuchal skin. C, Wide space between toes 1 and 2. D, Poor tone. E and F, Accentuation of typical face when crying.


  • Down JLH. Observations on an ethnic classification of idiots. Clinical Lecture Reports, London Hospital. 1866;3:259.

  • Richards BW, et al. Cytogenetic survey of 225 patients diagnosed clinically as mongols. J Ment Defic Res. 1965;9:245.

  • Hall B. Mongolism in newborn infants. Clin Pediatr. 1966;5(4).

  • Penrose LS, Smith GF. Down’s Anomaly. Boston: Little, Brown; 1966.

  • Davidson RG. Atlantoaxial instability in individuals with Down syndrome: a fresh look at the evidence. Pediatrics. 1988;81:857.

  • Pueschel SM. Atlantoaxial instability and Down syndrome. Pediatrics. 1988;81:879.

  • Pueschel SM. Clinical aspects of Down syndrome from infancy to adulthood. Am J Med Genet. 1990;52(Suppl 7).

  • Ugazio AG, et al. Immunology of Down syndrome: a review. Am J Med Genet. 1990;(Suppl 7):204.

  • Pueschel SM, et al. A longitudinal study of atlantodens relationships in asymptomatic individuals with Down syndrome. Pediatrics. 1992;89:1194.

  • Bull MJ. American Academy of Pediatrics Committee on Genetics. Health supervision for children with Down syndrome. Pediatrics. 2011;128:393. Reaffirmed January 2018.

  • Yang Q, et al. Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study. Lancet. 2002;359:1019.

  • Tyler CV, et al. Increased risk of symptomatic gallbladder disease in adults with Down syndrome. Am J Med Genet. 2004;130A:351.

  • Wiseman FK, et al. Down syndrome—recent progress and future prospects. Hum Mol Genet. 2009;18:R75.

  • De Souza E, et al. Recurrence risks for trisomies 13, 18 and 21. Am J Med Genet. 2009;149:2716.

  • Gryt V, et al. National cohort study showed that infants with Down syndrome faced a high risk of hospitalization for respiratory syncytial virus. Acta Pediar. 2017;106:1519.

  • Sport pre-participation screening for asymptomatic atlanto-axial instability in Down syndrome patients. .

  • Capone GT, et al. Co-occurring medical conditions in adults with Down syndrome: a systematic review toward the development of health guidelines. Am J Med Genet. 2018;176A:116.

Trisomy 18 Syndrome

Clenched Hand, Short Sternum, Low-Arch Dermal Ridge Patterning on Fingertips

This condition was first recognized as a specific entity in 1960 by discovery of the extra 18 chromosome in babies with a particular pattern of malformation (Edwards et al., Patau et al., and Smith et al.). It is the second most common chromosomal trisomy syndrome, with an incidence of approximately 0.3 per 1000 newborn babies. There is a 3-to-1 preponderance of females to males. Several good reviews set forth a full appraisal of this syndrome. More than 130 different abnormalities have been noted in the literature on patients with the trisomy 18 syndrome, and therefore the listing of abnormalities has been divided into those that occur in 50% or more of patients, in 10% to 50% of patients, and in less than 10% of patients.

Abnormalities Found in 50% or More of Patients

  • General. Feeble fetal activity, weak cry, altered gestational timing; one-third premature, one-third postmature; polyhydramnios, small placenta, single umbilical artery, growth deficiency; mean birthweight, 2340 g; hypoplasia of skeletal muscle, subcutaneous and adipose tissue; intellectual disability; hypertonicity (after neonatal period); diminished response to sound; complex partial seizures and generalized tonic-clonic seizures that are often difficult to control.

  • Craniofacial. Prominent occiput, narrow bifrontal diameter; low-set, malformed auricles; short palpebral fissures; small oral opening, narrow palatal arch; micrognathia.

  • Hands and Feet. Clenched hand, tendency for overlapping of index finger over third, fifth finger over fourth; absence of distal crease on fifth finger with or without distal creases on third and fourth fingers; low-arch dermal ridge pattern on six or more fingertips; hypoplasia of nails, especially on fifth finger and toes; short hallux, frequently dorsiflexed.

  • Thorax. Short sternum, with reduced number of ossification centers; small nipples.

  • Abdominal Wall. Inguinal or umbilical hernia and/or diastasis recti.

  • Pelvis and Hips. Small pelvis, limited hip abduction.

  • Genitalia. Male: cryptorchidism.

  • Skin. Redundancy, mild hirsutism of forehead and back, prominent cutis marmorata.

  • Cardiac. Ventricular septal defect, auricular septal defect, patent ductus arteriosus.

Abnormalities Found in 10% to 50% of Cases

  • Craniofacial. Wide fontanels, microcephaly, hypoplasia of orbital ridges; inner epicanthal folds, ptosis of eyelid, corneal opacity, retinal folds, retinal hypopigmentation, dysplasia and areas of hemorrhage and gliosis; cleft lip, cleft palate, or both.

  • Hands and Feet. Ulnar or radial deviation of hand, hypoplastic to absent thumb, simian crease; equinovarus, rocker-bottom feet, syndactyly of second and third toes.

  • Thorax. Relatively broad, with or without widely spaced nipples.

  • Genitalia. Female: hypoplasia of labia majora with prominent clitoris.

  • Anus. Malposed or funnel-shaped anus.

  • Cardiac. Bicuspid aortic and/or pulmonic valves, nodularity of valve leaflets, pulmonic stenosis, coarctation of aorta.

  • Lung. Malsegmentation to absence of right lung.

  • Diaphragm. Muscle hypoplasia with or without eventration.

  • Abdomen. Meckel diverticulum, heterotopic pancreatic and/or splenic tissue, omphalocele, incomplete rotation of colon.

  • Renal. Horseshoe defect, ectopic kidney, double ureter, hydronephrosis, polycystic kidney.

Abnormalities Found in Less Than 10% of Cases

  • Central Nervous System. Facial palsy, paucity of myelination, microgyria, cerebellar hypoplasia, defect of corpus callosum, hydrocephalus, Dandy-Walker malformation, pyramidal tract abnormalities meningomyelocele.

  • Craniofacial. Wormian cranial bones, shallow elongated sella turcica; slanted palpebral fissures, hypertelorism, colobomata of iris, cataract, microphthalmos; choanal atresia.

  • Hands. Syndactyly of third and fourth fingers, polydactyly, short fifth metacarpals, ectrodactyly.

  • Other Skeletal. Radial aplasia, incomplete ossification of clavicle, hemivertebrae, fused vertebrae, short neck, scoliosis, rib anomaly, pectus excavatum, dislocated hip.

  • Genitalia. Male: hypospadias, bifid scrotum; female: bifid uterus, ovarian hypoplasia.

  • Cardiovascular. Anomalous coronary artery, transposition, tetralogy of Fallot, coarctation of aorta, dextrocardia, aberrant subclavian artery, intimal proliferation in arteries with arteriosclerotic change and medial calcification.

  • Abdominal. Pyloric stenosis, extrahepatic biliary atresia, hypoplastic gallbladder, gallstones, imperforate anus.

  • Renal. Hydronephrosis, polycystic kidney (small cysts), Wilms tumor.

  • Endocrine. Thyroid or adrenal hypoplasia.

  • Other. Hemangiomata, thymic hypoplasia, tracheoesophageal fistula, thrombocytopenia; tumors, primarily liver and kidney.

Natural History

Babies with the trisomy 18 syndrome are usually feeble and have a limited capacity for survival. Resuscitation is often performed at birth, and these babies may have apneic episodes in the neonatal period. Poor sucking capability may necessitate nasogastric tube feeding, but even with optimal management, these babies fail to thrive. Fifty percent die within the first week, and many of the remaining die in the next 12 months. Median survival time is 14.5 days. Only 5% to 10% survive the first year, typically with severe intellectual disability. Although most children who survive the first year are unable to walk in an unsupported fashion and verbal communication is usually limited to a few single words, it is important to realize that some older children with trisomy 18 smile, laugh, and interact with and relate to their families. All achieve some psychomotor maturation and continue to learn. There are at least 10 reports of affected children older than 10 years. Once the diagnosis has been established, limitation of extraordinary medical means for prolongation of life should be seriously considered. However, the personal feelings of the parents and the individual circumstances of each infant must be taken into consideration. Baty and colleagues documented the natural history of this disorder. For children who survived, the average number of days in the neonatal intensive care unit was 16.3, the average number of days on a ventilator was 10.1, and 13% had surgery in the neonatal period. There was no evidence for an increase in adverse reactions to immunizations. Growth curves for length, weight, and head circumference are provided in that study.


The etiology of this disorder is trisomy for all or a large part of the number 18 chromosome. The great majority of cases have full 18 trisomy, the result of faulty chromosomal distribution, which is most likely to occur at older maternal age; the mean maternal age at birth of babies with this syndrome is 32 years. Translocation cases, the result of chromosomal breakage, can be excluded only by chromosomal studies. When such a case is found, the parents should also have chromosomal studies to determine whether one of them is a balanced translocation carrier with high risk for recurrence in future offspring. There is an increased risk of trisomy 18 subsequent to a previous pregnancy with trisomy 18 (RR = 3.1), the increase being greater for women younger than age 35 at the previous trisomic pregnancy.

Mosaicism for an additional chromosome 18 leads to a longer survival and any degree of variation between a normal child and the full pattern of malformation. Recurrence risk for individuals with mosaic trisomy 18 has been variable. Four of 12 affected individuals older than 20 years have given birth to or fathered a child with complete trisomy 18, and an additional 3 have had a combined total of 5 healthy children.

Partial trisomy 18: Trisomy of the short arm causes a very nonspecific clinical picture and mild or no intellectual disability. However, partial seizures have been seen. Cases with familial trisomy of the short arm, centromere, and proximal one-third of the long arm show features of trisomy 18, although not the full pattern. Trisomy for the entire long arm is clinically indistinguishable from full trisomy 18. Trisomy for the distal one-third to one-half of the long arm leads to a partial picture of trisomy 18 with longer survival and less profound intellectual disability. In early childhood the patients resemble trisomy 18 cases, whereas adolescents and adults display a more nonspecific pattern of malformation, including prominent orbital ridges, broad and prominent nasal bridge, everted upper lip, receding mandible, poorly modeled ears, short neck, and long, hyperextendible fingers. Muscular tone tends to be decreased, intellectual disability is severe, and about one-third of the patients suffer from seizures.


Trisomy 18 syndrome.

A and B, Note hypertonicity evident in the clenched hands and crossed legs; note the narrow pelvis. C and D, Hypoplastic supraorbital ridges; prominent occiput; low-set, slanted, malformed auricle.


A, Clenched hand with index finger overlying third; hypoplasia of fingernails. B, Dorsiflexed short hallux. C, Prominent calcaneus and postaxial polydactyly.


A–C, Older child with trisomy 18 syndrome.

Courtesy Dr. Lynne M. Bird, Children’s Hospital, San Diego. California


  • Edwards JH, et al. A new trisomic syndrome. Lancet. 1960;1:787.

  • Patau K, et al. Multiple congenital anomaly caused by an extra autosome. Lancet. 1960;1:790.

  • Smith DW, et al. A new autosomal trisomy syndrome. J Pediatr. 1960;57:338.

  • Smith DW. Autosomal abnormalities. Am J Obstet Gynecol. 1964;90:1055.

  • Rasmussen S, Wong LY, Yang Q, et al. Population-based analysis of mortality in trisomy 13 and trisomy 18. Pediatrics. 2003;111:777.

  • Tucker ME, et al. Phenotypic spectrum of mosaic trisomy 18: two new patients, a literature review, and counseling issues. Am J Med Genet. 2007;143A:505.

  • De Souza E, et al. Recurrence risk for trisomies 13, 18, and 21. Am J Med Genet. 2009;149A:2716.

  • Baty BJ, et al. Natural history of trisomy 18 and trisomy 13: I: growth, physical assessment, medical histories, survival and recurrence risk. Am J Med Genet. 1994;49:175.

  • Baty BJ, et al. Natural history of trisomy 18 and trisomy 13: II: psychomotor development. Am J Med Genet. 1994;49:189.

  • Myata H, et al. Pyramidal tract abnormalities in the human fetus and infant with trisomy 18 syndrome. Neuropathology. 2014;34:219.

  • Verrotti A, et al. Epilepsy and chromosome 18 abnormalities: a review. Seizure. 2015;32:78.

  • Satge D, et al. A tumor profile in Edwards syndrome (trisomy18). Am J Med Genet. Part C (Seminars in Medical Genetics). 2016;172C:296.

Trisomy 13 Syndrome (Patau Syndrome)

Defects of Eye, Nose, Lip, and Forebrain of Holoprosencephaly Type; Polydactyly; Narrow Hyperconvex Fingernails; Skin Defects of Posterior Scalp

Apparently described by Bartholin in 1657, this syndrome was not generally recognized until its trisomic etiology was discovered by Patau and colleagues in 1960. The incidence is approximately 1 in 5000 births.

Abnormalities Found in 50% or More of Patients

  • Central Nervous System. Holoprosencephaly type defect with varying degrees of incomplete development of forebrain and olfactory and optic nerves; minor motor seizures, high incidence of spasms and photo-induced myoclonic jerks, often with hypsarrhythmic electroencephalography (EEG) pattern; apneic spells in early infancy; severe intellectual disability.

  • Hearing. Apparent deafness (defects of organ of Corti in the two cases studied).

  • Cranium. Moderate microcephaly with sloping forehead, wide sagittal suture and fontanels.

  • Eyes. Microphthalmia, colobomata of iris, or both; retinal dysplasia, often including islands of cartilage.

  • Mouth. Cleft lip (60% to 80%), cleft palate, or both.

  • Auricles. Abnormal helices, with or without low-set ears.

  • Skin. Capillary hemangiomata, especially forehead, localized scalp defects in parieto-occipital area; loose skin, posterior neck.

  • Hands and Feet. Distal palmar axial triradii, simian crease, hyperconvex narrow fingernails, flexion of fingers with or without overlapping and camptodactyly, polydactyly of hands and sometimes feet, posterior prominence of heel.

  • Other Skeletal. Thin posterior ribs with or without missing rib, hypoplasia of pelvis with shallow acetabular angle.

  • Cardiac. Abnormality in 80% with ventricular septal defect, patent ductus arteriosus, auricular septal defect, and dextroposition, in decreasing order of frequency.

  • Genitalia. Male: cryptorchidism, abnormal scrotum; female: bicornuate uterus.

  • Hematologic. Increased frequency of nuclear projections in neutrophils, unusual persistence of embryonic and/or fetal type hemoglobin.

  • Other. Single umbilical artery, inguinal or umbilical hernia.

Abnormalities Found in Less Than 50% of Patients

  • Growth. Prenatal onset of growth deficiency; mean birthweight, 2480 g.

  • Central Nervous System. Hypertonia, hypotonia, agenesis of corpus callosum, hydrocephalus, fusion of basal ganglia, cerebellar hypoplasia, meningomyelocele.

  • Eyes. Shallow supraorbital ridges, upslanting palpebral fissures, absent eyebrows, hypotelorism, hypertelorism, anophthalmos, cyclopia.

  • Nose, Mouth, and Mandible. Absent philtrum, narrow palate, cleft tongue, micrognathia.

  • Hands and Feet. Retroflexible thumb, ulnar deviation at wrist, low-arch digital dermal ridge pattern, fibular S-shaped hallucal dermal ridge pattern, syndactyly, cleft between first and second toes, hypoplastic toenails, equinovarus, radial aplasia.

  • Cardiac. Anomalous pulmonary venous return, overriding aorta, pulmonary stenosis, hypoplastic aorta, atretic mitral and/or aortic valves, bicuspid aortic valve, medial defects of the small pulmonary arteries.

  • Abdominal. Omphalocele, heterotopic pancreatic or splenic tissue, incomplete rotation of colon, Meckel diverticulum.

  • Renal. Polycystic kidney (31%), hydronephrosis, horseshoe kidney, duplicated ureters.

  • Genitalia. Male: hypospadias; female: duplication and/or anomalous insertion of fallopian tubes, uterine cysts, hypoplastic ovaries.

  • Other. Thrombocytopenia, situs inversus of lungs, cysts of thymus, calcified pulmonary arterioles, large gallbladder, radial aplasia, flexion deformity of large joints, diaphragmatic defect.

Natural History

The median survival for children with this disorder is 7 days; 91% die within the first year. Survivors have severe intellectual disability, often seizures, and fail to thrive. Only one adult, 33 years of age, has been reported. Because of the high infant mortality rate, surgical or orthopedic corrective procedures should be withheld in early infancy to await the outcome of the first few months. Furthermore, because of the severe brain defect, limitation of extraordinary medical means to prolong the life of individuals with this syndrome should be seriously considered. However, it is important to emphasize that each case must be taken on an individual basis. The individual circumstances of each child, as well as the personal feelings of the parents, must be acknowledged. Baty and colleagues documented the natural history of this disorder. For children who survived in their study, the average number of days in the neonatal intensive care unit was 10.8, average number of days on a ventilator was 13.3, and 23% had surgery in the neonatal period. There was no evidence for an increase in adverse reactions to immunizations. Growth curves are provided in that study. The Tracking Rare Incidence Syndromes (TRIS) project was established in 2007 to collect and analyze parent-provided data on a range of rare trisomy-related topics, such as trisomy 13, and seeks to make this information available to families and interested educational, medical, and therapeutic professionals.


The etiology for this disorder is trisomy for all or a large part of chromosome 13. Older maternal age has been a factor in the occurrence of this aneuploidy syndrome. There is an increased risk of trisomy 13 subsequent to a previous pregnancy with trisomy 13 (RR = 9.5), the increase being greater for women younger than age 35 at the previous trisomic pregnancy. As with Down syndrome, chromosomal studies are indicated on babies with 13 trisomy syndrome to detect the patient with a rare translocation having a balanced translocation parent for whom the risk of recurrence would be of major concern.

Cases with trisomy 13 mosaicism most often show a less severe clinical phenotype with every degree of variation, from the full pattern of malformation seen in trisomy 13 to a near-normal phenotype. Survival is usually longer. The degree of intellectual disability varies.

Partial trisomy for the proximal segment (13pterq14) is characterized by a nonspecific pattern, including a large nose, short upper lip, receding mandible, fifth finger clinodactyly, and, in most cases, severe intellectual disability. The overall picture shows little similarity to that of full trisomy 13, and survival is not significantly reduced.

Partial trisomy for the distal segment (13q14qter) has a characteristic phenotype associated with severe intellectual disability. The facies is marked by frontal capillary hemangiomata, a short nose with upturned tip, and elongated philtrum, synophrys, bushy eyebrows and long, incurved lashes, and a prominent antihelix. Trigonocephaly and arrhinencephaly have occasionally been seen. Approximately one-fourth of the patients die during early postnatal life.


The defects of midface, eye, and forebrain, which occur in variable degree as a feature of this syndrome, appear to be the consequence of a single defect in the early (3 weeks) development of the prechordal mesoderm, which not only is necessary for morphogenesis of the midface but also exerts an inductive role on the subsequent development of the prosencephalon, the forepart of the brain. This type of defect has been referred to as holoprosencephaly or arrhinencephaly and varies in severity from cyclopia to cebocephaly to less severe forms.


A–F, Two newborn children with trisomy 13 syndrome. Note sloping forehead with variable defect in facial development.


A and B, Note hyperconvex nails and postaxial polydactyly. C, Aplasia cutis congenita over posterior occiput. D, Scrotalization of the phallus.


  • Patau K, et al. Multiple congenital anomaly caused by an extra chromosome. Lancet. 1960;1:790.

  • Warburg M, Mikkelsen M. A case of 13–15 trisomy or Bartholin-Patau’s syndrome. Acta Ophthalmol. 1963;41:321.

  • Smith DW. Autosomal abnormalities. Am J Obstet Gynecol. 1964;90:1055.

  • Warkany J, Passarge E, Smith LB. Congenital malformations in autosomal trisomy syndromes. Am J Dis Child. 1966;112:502.

  • Goldstein H, Nielsen KG. Rates and survival of individuals with trisomy 13 and 18: data from a 10-year period in Denmark. Clin Genet. 1988;34:366.

  • Baty BJ, et al. Natural history of trisomy 18 and trisomy 13: I. Growth, physical assessment, medical histories, survival and recurrence risk. Am J Med Genet. 1994;49:175.

  • Baty BJ, et al. Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. Am J Med Genet. 1994;49:189.

  • Rasmussen SA, et al. Population-based analysis of mortality in trisomy 13 and trisomy 18. Pediatrics. 2003;111:777.

  • De Souza E, et al. Recurrence risks for trisomies 13, 18 and 21. Am J Med Genet. 2009;149A:2716.

  • Bruns D, et al. Birth history, physical characteristics, and medical survivors with full trisomy 13. Am J Med Genet. 2011;155A:2634.

  • Tahara M, et al. Medial defects of the small pulmonary arteries in fatal pulmonary hypertension in infants with trisomy 13 and trisomy 18. Am J Med Genet. 2014;164A:319.

  • Spagnoli C, et al. Epileptic spasms and early-onset photosensitive epilepsy in Patua syndrome: an EEG study. Brain Dev. 2015;37:704.

Trisomy 8 Syndrome (Trisomy 8/Normal Mosaicism)

Thick Lips, Deep-Set Eyes, Prominent Ears, Camptodactyly

Most cases are mosaic for trisomy 8/normal. The abnormal cell line frequently disappears from lymphocytes with increasing age and can only be demonstrated in skin fibroblasts. More than 100 cases have been reported.


  • Growth. Variable, from small to tall.

  • Performance. Mild to severe intellectual disability with a tendency toward poor coordination.

  • Craniofacial. Tendency toward prominent forehead, deep-set eyes, strabismus, hypertelorism with broad nasal root and prominent nares, full lips, everted lower lip, micrognathia, high-arched palate, cleft palate, and prominent cupped ears with thick helices.

  • Limbs. Camptodactyly of second through fifth fingers and toes, limited elbow supination, deep creases in palms and soles, single transverse palmar crease, major joint contracture, abnormal nails.

  • Other. Long, slender trunk; abnormal scapula, abnormal sternum, short or webbed neck; narrow pelvis; hip dysplasia; widely spaced nipples; ureteral-renal anomalies; cardiac defects.

Occasional Abnormalities

Absent patellae, pili bifurcati, conductive deafness, seizures, vertebral anomaly (bifid vertebrae, extra lumbar vertebra, spina bifida occulta), scoliosis, cryptorchidism, uterus didelphys, jejunal duplication, agenesis of corpus callosum, hypoplastic anemia, leukopenia, coagulation factor VII deficiency, myelodysplastic syndrome and/or leukemia, Wilms tumor, nephroblastoma, mediastinal germ cell tumor, gastric leiomyosarcoma, placental-site trophoblastic tumor, Behcet syndrome (systemic inflammatory disease of unknown etiology characterized clinically by recurrent oral ulcers, genital ulcers, eye lesions, and skin lesions).

Natural History

The natural history largely depends on the severity of intellectual disability. There appears to be a lack of correlation between the phenotype and the percentage of trisomic cells.


The etiology for this disorder is trisomy 8, the majority of patients being mosaics. Apparently, full trisomy 8 is, in most cases, an early lethal disorder.


Amiable, tall individual at 4 years and at 16 years who has trisomy 8/normal mosaicism, with a normal karyotype from cultured leukocytes but trisomy 8 in skin fibroblast cells. He has a moderate hearing deficit and an IQ estimated in the 70s. He is quite active and skates, swims, and bowls. Note the facies, the small, widely spaced nipples, and the general body stance. There is some limitation of full extension of the fingers, which are partially webbed, and limited extension of the right elbow. There is hypoplasia of the supraspinatus, trapezius, and upper pectoral musculature.

Courtesy Dr. G. Howard Valentine, War Memorial Children’s Hospital, London, Ontario.


Boy with trisomy 8/normal mosaicism.

From Riccardi VM, et al: J Pediatr 77:664, 1970, with permission.


Intellectually disabled 10-year-old boy with trisomy 8/normal mosaicism. Note the prominent ears.

From De Grouchy J, et al: Ann Genet 14:69, 1971, with permission.


Note deep creases on palms and soles.


  • Stalder GR, Buhler EM, Weber JR. Possible trisomy in chromosome group 6–12. Lancet. 1963;1:1379.

  • Schinzel A, et al. Trisomy 8 mosaicism syndrome. Helv Pediatr Acta. 1974;29:531.

  • Riccardi VM. Trisomy 8: an international study of 70 patients. Birth Defects. 1977;XIII(3C):171.

  • Kurtyka ZE, et al. Trisomy 8 mosaicism syndrome. Clin Pediatr. 1988;27:557.

  • Breslau-Siderius LJ, et al. Pili bifurcati occurring in association with the mosaic trisomy 8 syndrome. Clin Dysmorphol. 1996;5:275.

  • Becker K, et al. Constitutional trisomy 8 and Behcet syndrome. Am J Med Genet. 2009;149A:982.

Trisomy 9 Mosaic Syndrome

Joint Contractures, Congenital Heart Defects, Low-Set Malformed Ears

In 1973 Haslam and colleagues reported the first case of trisomy 9 mosaicism. In the same year Feingold and colleagues reported the first example of a child with full trisomy 9 using blood lymphocytes.


  • Growth. Prenatal onset of growth deficiency.

  • Performance. Severe intellectual disability.

  • Craniofacial. Sloping forehead with narrow bifrontal diameter; upslanting, short palpebral fissures, deeply set eyes; prominent nasal bridge with short root, small fleshy tip, and slit-like nostrils; prominent lip covering receding lower lip; micrognathia, low-set, posteriorly rotated, misshapen ears.

  • Skeletal. Joint anomalies, including abnormal position and/or function of hips, knees, feet, elbows, and digits; kyphoscoliosis; narrow chest; hypoplasia of sacrum, iliac wings, and pubic arch; hypoplastic phalanges of toes.

  • Other. Congenital heart defects in approximately two-thirds of cases.

Occasional Abnormalities

Subarachnoid cyst, choroid plexus cyst, cystic dilatation of fourth ventricle with lack of midline fusion of cerebellum, hydrocephalus, lack of gyration of cerebral hemispheres, meningocele, microphthalmia, corneal opacities, Peters anomaly, absence of optic tracts, preauricular tags, hearing loss, facial asymmetry, short neck, cleft lip and/or palate, velopharyngeal insufficiency, bile duct proliferation in absence of a demonstrable stenosis or atresia, gastroesophageal reflux, triphalangeal thumbs, punctate mineralization in developing cartilage, 13 ribs and 13 thoracic vertebrae. Diaphragmatic hernia. Nonpitting edema of legs, multiple pilomatricomas (benign neoplasms of hair matrix cells), simian crease, nail hypoplasia. Genitourinary anomalies, including hypoplastic external genitalia, XX sex reversal, cryptorchidism, cystic dilatation of renal tubules, diverticulae of bladder, hydronephrosis, and hydroureter.

Natural History

The majority of patients die during the early postnatal period. In those who survive, failure to thrive and severe motor and intellectual disability are the rule. However, several children walk unassisted, display social action skills, develop minimal speech, and are able to care for some or all of their daily care needs (e.g., dressing, feeding).


The etiology of this disorder is trisomy for chromosome 9. The incidence and severity of malformations and intellectual disability correlate with the percentage of trisomic cells in the different tissues.


Facial features of a 22-week fetus with trisomy 9 syndrome. Note the sloping forehead, broad and prominent nasal bridge, prominent upper lip covering receding lower lip, and micrognathia.

Courtesy Prof. JC Ferreres, Hospital Vall d’Hebron, Barcelona, Spain.


A, Stillborn at term with mosaic trisomy 9. Note growth retardation as well as multiple contractures with extended elbows, flexed hips and knees. A and B, Facial features include short palpebral fissures, deeply set eyes; prominent nasal bridge with short root, small fleshy tip, and slit-like nostrils; prominent lip covering receding lower lip; micrognathia, low-set, posteriorly rotated, and misshapen ears. C, Note extended wrist with clenched hands and hypoplastic nails.


  • Feingold M, et al. A case of trisomy 9. J Med Genet. 1973;10:184.

  • Haslam RHA, et al. Trisomy 9 mosaicism with multiple congenital anomalies. J Med Genet. 1973;10:180.

  • Bowen P, et al. Trisomy 9 mosaicism in a newborn infant with multiple malformations. J Pediatr. 1974;85:95.

  • Akatsuka A, et al. Trisomy 9 mosaicism with punctate mineralization in developing cartilages. Eur J Pediatr. 1979;131:271.

  • Frohlich GS. Delineation of trisomy 9. J Med Genet. 1982;19:316.

  • Kamiker CP, et al. Mosaic trisomy 9 syndrome with unusual phenotype. Am J Med Genet. 1985;22:237.

  • Levy I, et al. Gastrointestinal abnormalities in the syndrome of mosaic trisomy 9. J Med Genet. 1989;26:280.

  • Bruns D. Presenting physical characteristics, medical conditions, and developmental status of long-term survivors with trisomy 9 mosaicism. Am J Med Genet. 2011;155:1033.

Triploidy Syndrome and Diploid/Triploid Mixoploidy Syndrome

Large Placenta with Hydatidiform Changes, Growth Deficiency, Syndactyly of Third and Fourth Fingers

Triploidy, a complete extra set of chromosomes, is estimated to occur in approximately 2% of conceptuses. Most are lost as miscarriages, accounting for approximately 20% of all chromosomally abnormal spontaneous abortuses. Two distinct phenotypes occur. One (with two paternal and one maternal set of chromosomes) is associated with a well-grown fetus and an abnormally large placenta consistent with a partial hydatidiform mole; the other (with two maternal and one paternal set of chromosomes) is associated with a severely growth-deficient fetus with relative macrocephaly and a small noncystic placenta.

Infrequently, triploid infants survive to be born after 28 weeks’ gestation with severe intrauterine growth retardation. Instances of diploid/triploid mixoploidy are less frequent. Asymmetric growth deficiency with mild syndactyly and occasional genital ambiguity in 46,XX/69,XXY individuals are the important diagnostic features in mixoploid individuals.

Abnormalities Found in 50% or More of Cases

  • Placenta. Large, with a tendency toward hydatidiform changes.

  • Growth. Disproportionate prenatal growth deficiency that affects the skeleton more than the cephalic region; in mixoploid individuals, skeletal growth may be asymmetric.

  • Craniofacial. Dysplastic calvaria with large posterior fontanel; ocular hypertelorism with eye defects, ranging from colobomata to microphthalmia; low nasal bridge; low-set, malformed ears; micrognathia.

  • Limbs. Syndactyly of third and fourth fingers, simian crease, talipes equinovarus.

  • Cardiac. Congenital heart defect (atrial and ventricular septal defects).

  • Genitalia. Male: hypospadias, micropenis, cryptorchidism, Leydig cell hyperplasia.

  • Other. Brain anomalies, including hydrocephalus and holoprosencephaly; adrenal hypoplasia; renal anomalies, including cystic dysplasia and hydronephrosis.

Abnormalities Found in Less Than 50% of Cases

Aberrant skull shape; choanal atresia; cleft lip and/or palate; iris heterochromia; patchy cutaneous hyperpigmentation, hypopigmentation, or a mixture of both (referred to as pigmentary dysplasia); meningomyelocele; macroglossia; omphalocele or umbilical hernia; biliary tract anomalies, including aplasia of the gallbladder; incomplete rotation of colon; proximally placed thumb; clinodactyly of fifth finger; splayed toes.

Natural History

Partial hydatidiform molar pregnancies associated with a triploid fetus should not raise concern regarding the development of choriocarcinoma. All cases of full triploidy either have been stillborn or have died in the early neonatal period, with 5 months being the longest recorded survival. Individuals with diploid/triploid mixoploidy usually survive and manifest some degree of psychomotor retardation, as well as learning disorders, seizures, short stature, truncal obesity, syndactyly, scoliosis, and asymmetry. Because of body asymmetry, patients with mixoploidy may require a heel lift for the shorter leg to prevent compensatory scoliosis; some of these individuals may resemble those having Russell-Silver syndrome. Diagnosis of mixoploidy usually requires skin fibroblast cultures, because the triploid cell line may have disappeared from among peripheral blood leukocytes. The degree of skeletal asymmetry does not appear to correspond to the proportions of triploid cells present.


In 69% of cases the extra set of chromosomes is paternally derived. However, the two most common mechanisms of origin are attributable to maternal factors: first, dispermy or double fertilization owing to failure of the zone reaction, which normally prevents polyspermy; and second, a failure of meiosis II leading to a diploid egg. Approximately 60% of the cases have been XXY, with most of the remainder being XXX. It is not unusual for more than one X chromosome to remain active in triploidy. Older maternal age has not been a factor, and no data indicate an increased risk of recurrence, such as that seen for chromosomal disorders caused by nondisjunction. In several instances, a triploid pregnancy has been followed or preceded by a molar pregnancy.


A and B, Stillborn infant with triploidy showing relatively large-appearing upper head in relation to very small face and 3-4 syndactyly of the fingers.


A–D, Severely growth-retarded 20-week fetus with 69,XXY karyotype. Note the meningomyelocele and 3-4 syndactyly. This phenotype is consistent with two paternal chromosomal copies and one maternal chromosomal copy. The most common form of triploidy, it typically results in a growth-retarded fetus with a large hydatidiform placenta.


A–C, Infant with asymmetric growth deficiency (right side smaller), syndactyly of third and fourth fingers, and mild developmental delay who has triploid/diploid mixoploidy syndrome that is evident only in cultured fibroblasts.

Courtesy Dr. John M. Graham, Cedars-Sinai Medical Center, Los Angeles, California.


  • Book JA, Santesson B. Malformation syndrome in man associated with triploidy (69 chromosomes). Lancet. 1960;1:858.

  • Ferrier P, et al. Congenital asymmetry associated with diploid-triploid mosaicism and large satellites. Lancet. 1964;1:80.

  • Niebular E. Triploidy in man: cytogenetical and clinical aspects. Humangenetik. 1974;21:103.

  • Wertelecki W, Graham JM, Sergovich FR. The clinical syndrome of triploidy. Obstet Gynecol. 1976;47:69.

  • Jacobs PA, et al. The origin of human triploids. Ann Hum Genet. 1978;42:49.

  • Poland BJ, Bailie DL. Cell ploidy in molar placental disease. Teratology. 1978;18:353.

  • Jacobs PA, et al. Late replicating X chromosomes in human triploidy. Am J Hum Genet. 1979;31:446.

  • Graham JM, et al. Diploid-triploid mixoploidy: clinical and cytogenetic aspects. Pediatrics. 1981;68(23).

  • Wulfsberg EA, et al. Monozygotic twin girls with diploid/ triploid chromosome mosaicism and cutaneous pigmentary dysplasia. Clin Genet. 1991;39:370.

  • Zaragoza MV, et al. Parental origin and phenotype of triploidy in spontaneous abortions: predominance of diandry and association with the partial hydatidiform mole. Am J Hum Genet. 2000;66:1807.

  • Joergenaen MW, et al. Triploid pregnancies: genetic and clinical features of 158 cases. Am J Obstet Gynecol. 2014;211. 370.e1–19.

Deletion 3p Syndrome

Low IQ Growth Deficiency, Ptosis, Postaxial Polydactyly

Partial deletion of the distal part of the short arm of chromosome 3 was first reported by Verjaal and De Nef in 1978. Many cases have subsequently been reported. In most cases the disorder has arisen de novo . Although typically a terminal deletion with breakpoints at chromosome band 3p25, more recent molecular studies have shown the location of the 3p breakpoint to be variable.


  • Growth. Prenatal onset of growth deficiency, most striking postnatally.

  • Performance. Severe to profound intellectual disability, hypotonia.

  • Craniofacial. Microcephaly with flat occiput, synophrys, epicanthal folds, ptosis, short palpebral fissures, prominent nasal bridge, small nose with anteverted nares, long philtrum, malformed ears, micrognathia, downturned corners of mouth.

  • Other. Postaxial polydactyly of hands and, less frequently, feet.

Occasional Abnormalities

Trigonocephaly with prominent metopic sutures, agenesis of corpus callosum, cerebellar hemangioblastoma, upslanting palpebral fissures, ocular hypertelorism, preauricular pits or fistula, cleft palate; cardiac defects, including ventricular septal defect (two patients) and one patient with double mitral valve, atrioventricular canal defect, and tricuspid atresia; inguinal and/or umbilical hernia, hiatal hernia, common mesentery, anteriorly placed anus; renal anomalies, including pelvic and/or cystic kidney; cryptorchidism; scoliosis.

Natural History

Nasogastric tube feeding because of poor suck is often required. Persistent central and obstructive apnea is common with frequent pneumonia. Gastroesophageal reflux and profound failure to thrive often occur. Limited life span is typical; however, survival into adulthood has been reported. Many survivors are blind and deaf and interact only minimally with their environment.


This disorder is caused by partial deletion of the short arm of chromosome 3. Most cases are terminal deletions with breakpoints at 3p25. However, the 3p breakpoint has recently been shown to be variable. In one case an interstitial deletion at 3p25-p26, thought to be the smallest 3p deletion associated with the characteristic phenotype, was reported. In the vast majority of cases, the deletion has occurred de novo .


In that the gene responsible for Von Hippel-Lindau (VHL) syndrome localizes to 3p25-26, it has been suggested that individuals with del(3p) syndrome may be at increased risk for central nervous system and visceral tumors associated with VHL. However, only one patient, a 24-year-old female, has been described with del 3p26.3-25.3, who developed a cerebellar hemangioblastome, the most common tumor associated with VHL syndrome.

Jun 28, 2021 | Posted by in PEDIATRICS | Comments Off on Recognizable Patterns of Malformation
Premium Wordpress Themes by UFO Themes