Chromosomal disorders in childhood

• Chromosomal disorders are conditions caused by an abnormal number or structure of chromosomes; most arise from errors in cell division and many are not inherited.
• Trisomy 21 (Down syndrome) is the commonest autosomal trisomy compatible with survival; Turner syndrome is the most common sex chromosome disorder in females.
• The table in this topic compares the ten common syndromes by genetic abnormality, presentation, and the diseases for which children are screened.
• Risk rises mainly with maternal age for trisomies, and prenatal screening now combines ultrasound, serum markers, cell-free DNA, and invasive tests.
• Most of these disorders need lifelong, multidisciplinary follow-up, and children should be screened systematically for the complications that each syndrome carries.

By the end of this page you should be able to:

1. Name the genetic abnormality behind each of the common childhood chromosomal syndromes.
2. Explain why advanced maternal age increases trisomy risk and how prenatal screening and diagnostic testing differ.
3. Choose between karyotype and chromosomal microarray for a given clinical question.
4. Explain what a Robertsonian translocation is and how it changes recurrence risk.
5. Outline the health surveillance schedule recommended for children with Down syndrome.
6. Counsel a family about inheritance, recurrence and the options after a prenatal screen.

A chromosomal disorder is any condition caused by a change in the number or structure of chromosomes. The normal human cell carries 46 chromosomes: 22 pairs of autosomes and one pair of sex chromosomes. ^[2] Errors in cell division produce numerical abnormalities (aneuploidy, meaning one chromosome too many or one too few) or structural abnormalities (deletions, translocations, inversions and rings). ^[2] Constitutional abnormalities are present in every cell from conception; acquired ones arise after birth in a clone of cells and usually cause cancer.

Numerical abnormalities are the most common. Trisomy means three copies of a chromosome; monosomy means only one. Most autosomal aneuploidies are lethal before birth; only trisomies 21, 18 and 13 and abnormalities of the sex chromosomes are common among live-born children. ^[2] Structural abnormalities rearrange pieces of chromosomes; the most important for this topic is the Robertsonian translocation, which fuses two acrocentric chromosomes at their centromeres. ^[2]

Chromosomal abnormalities occur in about 0.5% to 1% of live-born infants and in nearly 5% of stillbirths. ^[2] Aneuploidy overall develops in 5% to 10% of all pregnancies and is the leading cause of miscarriage and congenital malformation. ^[2] About 0.4% to 0.9% of newborns have a chromosomal abnormality that is detectable on testing, and about half of them have an abnormal phenotype. ^[2]

Down syndrome (trisomy 21) is by far the most common viable autosomal trisomy, with an estimated incidence of 1 in 700 to 1 in 800 live births. ^[2] Its incidence in embryos is much higher, but an estimated 50% to 75% of affected fetuses are lost through miscarriage before term. ^[1] Trisomy 18 (Edwards syndrome) occurs in about 1 in 3,000 to 1 in 5,000 live births and is the second most common autosomal trisomy; trisomy 13 (Patau syndrome) in about 1 in 10,000 to 1 in 20,000. ^[2][3][4] Turner syndrome occurs in about 1 in 2,000 to 1 in 2,500 live female births, and Klinefelter syndrome in 1 in 500 to 1 in 1,000 male births. ^[2][5][6] Cri-du-chat (5p deletion) has an incidence of about 1 in 15,000 to 1 in 50,000 live births, Williams syndrome of 1 in 7,500 to 1 in 20,000, and DiGeorge (22q11.2 deletion) of about 1 in 2,000 to 1 in 4,000 live births. ^[7][8][9] Prader-Willi syndrome affects about 1 in 10,000 to 1 in 30,000 individuals; Angelman syndrome affects 1 in 12,000 to 1 in 20,000. ^[10][11] Sex chromosome aneuploidies collectively reach about 1 in 400 newborns. ^[13]

The single most consistent risk factor is advanced maternal age. Trisomies arise mainly from nondisjunction during meiosis, and most (often more than 90% in trisomy 13, 18 and 21) are of maternal origin. ^[2][4] The rate of trisomy 21 rises nearly exponentially after 35 years of maternal age, climbing from 10% to 20% up to more than 60% of cases at the cellular level described in reviews (the absolute risk to the pregnancy is far lower). ^[2] This is because the human oocyte arrests in meiosis for decades before completion, and the machinery that separates chromosomes becomes less reliable with time. Sex chromosome aneuploidies behave differently: at least half are paternal in origin, and they are not linked to maternal age. ^{[2] [7][9]}

Other named risk factors are a previous trisomic pregnancy, aberrant recombination, folic acid deficiency, obesity, smoking and radiation exposure, although maternal age is the dominant one. ^[2] About 95% of Down syndrome cases come from meiotic nondisjunction; 3% to 4% from Robertsonian translocations, usually between chromosomes 14 and 21; and 1% to 2% from mosaicism (postzygotic error). ^[1] For trisomy 13, about 91% are maternal nondisjunction; the rest include Robertsonian translocations and mosaicism. ^[4] For trisomy 18, about 94% are complete trisomy, less than 5% mosaic and 2% partial, the latter often from an unbalanced translocation in one parent. ^[3]

Most deletion syndromes (22q11.2, 5p, 7q11.23, Prader-Willi, Angelman) arise de novo; 6% to 10% of 22q11.2 deletions are inherited from a mildly affected parent in an autosomal dominant pattern, and imprinting centre defects in Prader-Willi and Angelman syndromes can also be inherited. ^[9][10][11] Turner syndrome is usually a de novo loss or partial loss of an X chromosome with negligible recurrence risk in most families. ^[5]

The table summarises the genetic abnormality, the presentation a student is most likely to be asked about, the main associated diseases, and the screening that follows from them.

Most childhood chromosomal disorders start with a failure of chromosome segregation. In meiosis, the paired chromosomes fail to separate (nondisjunction) or separate unevenly, so one gamete receives 24 chromosomes instead of 23. ^[2] Because the oocyte stays in meiosis I for years, the checkpoint mechanisms that hold chromosome pairs together weaken with age, which is why trisomy risk climbs after 35. ^[2]

Once a zygote has an extra chromosome, gene dosage imbalance distorts development: the excess copies of genes on the extra chromosome are over-expressed, disrupting pathways in heart, brain, bone and endocrine organs. ^[1] Each syndrome's phenotype reflects the genes on the chromosome (or region) that is altered. Trisomy 21 involves duplicated genes on chromosome 21, including amyloid precursor protein (APP), which explains the near-universal brain pathology of Down syndrome and the high frequency of dementia by age 60. ^[1] Trisomy 13 and 18 involve very gene-rich regions with high mortality because there are relatively few tolerable duplications. ^[2] Sex chromosome disorders are milder because one X is normally inactivated in females and Y carries few genes, although haploinsufficiency of the SHOX gene in the pseudoautosomal region contributes to short stature in Turner and tall stature in Klinefelter. ^[5][6] Microdeletion syndromes are contiguous gene syndromes: loss of a small region removes several genes at once, so the phenotype depends on which region is lost. ^[7] Prader-Willi and Angelman syndromes show genomic imprinting: expression of genes in 15q11.2-q13 depends on the parent of origin, so the same deletion produces Prader-Willi if paternal and Angelman if maternal. ^{[10][11] [8]}

A chromosomal diagnosis sometimes presents in the neonatal period with dysmorphic features, hypotonia, a heart murmur or feeding difficulty; sometimes it is not suspected until growth failure, delayed puberty or infertility brings the patient to clinic years later. Useful history questions include pregnancy history (increased nuchal translucency, cardiac or renal anomalies, abnormal screening), early feeding problems, recurrent infections, developmental delay, seizures, sleep and behaviour, and a family history of miscarriage, stillbirth or learning disability. ^{[1][5][6][11]}

For Turner syndrome, late diagnosis is common: many cases are diagnosed at 10 to 17 years, with primary amenorrhoea. ^[5] For Klinefelter syndrome, about two-thirds remain undiagnosed, and diagnosis often happens at a mean age around 30 years during infertility evaluation. ^[6] For Angelman syndrome, diagnosis is usually made at about 2 years, with deletions found at a mean of 1.7 years and non-deletion mechanisms at 2.9 years. ^[11]

Neonates with Down syndrome may have hypotonia, characteristic facies (upslanting palpebral fissures, flat nasal bridge, single transverse palmar crease), congenital heart disease and duodenal atresia. ^[1] Trisomy 18 shows clenched hands with overlapping fingers, rocker-bottom feet and micrognathia; trisomy 13 shows holoprosencephaly, cleft lip or palate, postaxial polydactyly and microphthalmia. ^[2][3][4] Turner girls may have lymphoedema at birth, a webbed neck, low posterior hairline, shield chest and short stature; Klinefelter boys may be tall with long limbs and small firm testes. ^[5][6] Cri-du-chat infants produce the characteristic high-pitched cry with moon facies and hypotonia; Williams syndrome shows the "elfin" facies and often a heart murmur; DiGeorge syndrome shows conotruncal congenital heart disease, velopharyngeal dysfunction and hypocalcaemia. ^[7][8][9]

Within the syndromes above, several mimics are important: mosaic forms in which a normal cell line coexists with an abnormal one and produces a much milder picture; partial or microdeletion forms that lack the full phenotype; and other syndromes that look similar, such as Noonan syndrome (which shares webbed neck, short stature and cardiac lesions with Turner syndrome but occurs in both sexes), fetal alcohol syndrome, CHARGE syndrome and Wolf-Hirschhorn syndrome. ^[5][7][9] The diagnostic test must match the question, because a child with a normal karyotype but a small deletion will be diagnosed only by microarray.

A karyotype is the full chromosomal complement, usually prepared from cultured lymphocytes and stained, so that each chromosome can be counted and inspected for structural rearrangements. ^[2] It reliably identifies aneuploidy and structural rearrangements larger than 5 Mb, and it is the first-line confirmatory test for any suspected numerical or large structural chromosomal abnormality. ^[2] It takes about 1 to 2 weeks because cells must be cultured. ^[2] Amniocentesis achieves a diagnostic rate of about 99.4% and chorionic villus sampling about 97.8%, but both carry a small risk of pregnancy loss. ^[2]

Chromosomal microarray (CMA) identifies sub-chromosomal deletions and duplications down to 50 to 100 kb, is the gold standard for microdeletion syndromes such as 22q11.2, and is preferred when the fetal phenotype suggests a syndrome or when a structural anomaly is found. ^[13] It does not require dividing cells, gives faster results, and identified a clinically important copy number variant in 1.7% of fetuses with normal ultrasound and karyotype in one large study. ^[13] It cannot, however, detect balanced translocations or inversions, which only a karyotype reveals. ^[13]

Screening in pregnancy follows a logical ladder. First-trimester combined screening combines nuchal translucency (measured at 11 to 14 weeks) with pregnancy-associated plasma protein A and free beta-hCG, and detects about 87%, 85% and 82% of Down syndrome at 11, 12 and 13 weeks respectively. ^[12] Nuchal translucency alone changes the risk of trisomy 21 with a detection rate of about 70%, and an increased measurement is also seen in trisomies 13 and 18, Turner syndrome and congenital heart disease. ^[1]

Cell-free DNA (cfDNA) screening, introduced for aneuploidy in 2011, measures fetal and placental DNA fragments in maternal blood. ^[13] Multiple societies now recommend that cfDNA screening for common aneuploidies (trisomies 21, 18 and 13) be offered to all pregnant patients. ^[12] Compared with serum analyte screening it is more sensitive and specific: about 98.9% sensitivity and 99.9% specificity for trisomy 21, 94.1% and 99.9% for trisomy 18, and 100% and 99.9% for trisomy 13. ^[13] Positive predictive values vary: cfDNA for trisomy 18 alone had a positive predictive value of about 60.7% when used on its own, rising to 100% when combined with ultrasound. ^[3] For sex chromosome aneuploidies, the positive predictive value in cfDNA varies widely, from about 14.5% for Turner to about 97.7% for Klinefelter, because these conditions are rarer and can be confounded by maternal X-chromosome inactivation or mosaicism. ^[13] Most societies do not recommend routine cfDNA screening for microdeletions because positive predictive values are low; diagnostic testing with microarray is the right route when copy number variants are the concern. ^[13]

A positive screening result is not a diagnosis. It should be followed by genetic counselling, detailed ultrasound and the offer of diagnostic testing with chorionic villus sampling (from 10 to 13 weeks) or amniocentesis (from about 15 weeks). ^[12] The miscarriage risk of these invasive tests is low, around 0.1% to 0.3% in modern cohorts, although older textbook figures quote 0.5% to 1%. ^[13][1] Amniocentesis (rather than chorionic villus sampling) is preferred if a rare autosomal trisomy is suspected, because confined placental mosaicism is common for those. ^[13]

The following flowchart shows how screening leads to diagnosis.

A Robertsonian translocation is the fusion of two acrocentric chromosomes at their centromeres, with loss of both short arms but formation of a single chromosome carrying both long arms. ^[2] (Acrocentric chromosomes are 13, 14, 15, 21 and 22; their short arms carry only ribosomal RNA genes.) The carrier usually has 45 chromosomes but is phenotypically normal, because almost no essential genetic material is lost.

The problem is in gametogenesis. A carrier of a 14;21 (or 13;14) translocation can produce gametes with 24 chromosomes, and conception with an unbalanced gamete can produce an embryo with trisomy 21; there is also a high risk of miscarriage. ^[1][2] For a parent who already has a child with an unbalanced translocation, recurrence risk can be as high as 20% in subsequent pregnancies in translocation cases. ^[3] In the de novo (standard) trisomy, recurrence risk after one affected child is low (about 1% for trisomy 18, and 0.5% to 1% for complete trisomy 18). ^[3] The carrier frequency of Robertsonian translocations in the general population is about 1 in 1,000. ^[2]

This distinction determines counselling. Karyotyping of both parents is therefore recommended when a child has Down syndrome caused by a translocation, as the recurrence risk and the advice differ completely between an inherited translocation and de novo nondisjunction. ^[1]

Management of every one of these syndromes is supportive and individualised, coordinated through a family-centred medical home, but a few cross-cutting principles apply.

Genetic counselling. Families should be told plainly that most chromosomal abnormalities are random events in gamete formation, that they are not the parents' fault, and that they could not have been prevented. ^[6] For a couple who have had an affected child, parental karyotype determines recurrence risk. Where an inherited translocation is found, the extended family (parents' siblings) may also be carriers. ^[1][3] For Prader-Willi and Angelman syndromes the recurrence risk is below 1% for deletions and uniparental disomy, but up to 50% for inherited imprinting defects or UBE3A variants. ^[10][11] For Turner and Klinefelter syndromes, recurrence risk is negligible in most families. ^[5][6]

Prenatal options. Parents should know that non-invasive prenatal testing is screening, not diagnosis; that a screen-positive result requires confirmatory chorionic villus sampling or amniocentesis; and that trisomy 13 is the syndrome most likely to be missed clinically before birth. ^[12][4] Amniocentesis is the preferred confirmatory test when confined placental mosaicism is a concern, and karyotype is needed to detect balanced rearrangements. ^[13]

For each syndrome, early and lifelong surveillance is the intervention. Details for Down syndrome are set out below; for trisomies 13 and 18, paediatric guidelines now recommend active resuscitation in the delivery room (rather than withholding care on diagnosis alone), with individualised, family-centred planning. ^[3][4]

Children with Down syndrome benefit from the most structured and best evidenced surveillance programme, so it is a useful template to learn. ^[1] The following schedule summarises current recommendations.

Growth. Use Down-specific growth charts for weight, length and head circumference, and Down-specific body mass index charts from 2 to 10 years, switching to standard charts thereafter. ^[1]

Cardiac. Every newborn with Down syndrome should have an echocardiogram, regardless of prenatal imaging, with cardiology follow-up according to findings. ^[1] Up to 50% of infants have congenital heart defects, most often atrioventricular septal defects (about 40% of cardiac lesions) or ventricular septal defects (about 32%). ^[1]

Thyroid. Newborn screening is reviewed, thyroid stimulating hormone is measured at 6 and 12 months and then annually, and every 6 months if thyroid autoantibodies are detected. ^[1]

Hearing. Ear-specific audiology in the first month, repeated at 6 months and annually thereafter. ^[1]

Ophthalmology. Examination in the first 6 months, then photoscreening at every health supervision visit or paediatric ophthalmology every 2 years. ^[1]

Haematology. Complete blood count with differential and iron studies from age 1 year and annually, with vigilance for transient abnormal myelopoiesis in neonates and later leukaemia. ^[1]

Atlantoaxial instability. Cervical spine precautions are discussed at least every 2 years, with a careful neurological history and examination at each visit. Routine neutral-position radiographs are no longer recommended in asymptomatic children. ^[1]

Sleep-disordered breathing. Ask about snoring, unusual sleep positions, apnoeic pauses and daytime sleepiness, because obstructive sleep apnoea is common and often persists after adenotonsillectomy. ^[1]

Development. Early intervention services (physiotherapy, occupational therapy, speech and language) are reviewed at every visit, with transition planning at 36 months; autism screening at 18 to 24 months is recommended, remembering that presentation may differ in Down syndrome. ^[1]

Other screening. Celiac disease screening in children with suggestive symptoms (the condition is present in about 5%); neurologic and dermatologic review; testicular palpation in boys from early childhood; family planning discussions for adolescents. ^[1]

For other syndromes the principles are the same but the targets differ: Turner syndrome needs cardiac imaging at diagnosis, renal ultrasound and lifelong blood pressure surveillance; DiGeorge syndrome needs immune evaluation, calcium monitoring and scheduled psychiatric follow-up; Prader-Willi syndrome needs strict food supervision, growth hormone therapy and endocrine screening; Angelman syndrome needs seizure and sleep management. ^{[5][9][10][11]}

Complications are predictable from the chromosome involved. In Down syndrome they include congenital heart disease (the leading cause of morbidity and mortality in early life), pulmonary hypertension, Hirschsprung disease (about 2%) and duodenal atresia, transient myeloproliferative disorder in about 10% of neonates with 20% to 30% progressing to acute megakaryoblastic leukaemia, and an overall ten-fold excess leukaemia risk. ^[1] Autoimmune conditions (thyroid, celiac disease), epilepsy, hearing and vision loss, obstructive sleep apnoea and early-onset dementia (about 50% to 70% by 60 years) are the lifelong concerns. ^[1] Life expectancy has improved markedly, from about 45% one-year survival decades ago to over 96% at one year in those without cardiac anomalies. ^[1]

Trisomy 18 and 13 remain life-limiting: in trisomy 18, 60% to 75% survive the first week and 10% to 19% survive the first year, though 30% to 50% with intensive care; in trisomy 13 postnatal mortality is about 50% in the first month and 90% in the first year. ^[3][4] Mosaic cases do better in both. Turner syndrome carries a three-fold excess mortality compared with the general population, driven by cardiovascular disease (aortic dissection or rupture is the leading cause), with median survival of about 69 years. ^[5] Klinefelter syndrome shortens life by about 5 to 6 years. ^[6] Angelman and Prader-Willi syndromes carry near-normal life expectancy with good supportive care. ^[10][11]

There is no way to prevent chromosomal disorders, but their impact can be reduced. Population screening has moved from age-plus-nuchal-translucency to cfDNA, with invasive diagnosis reserved for screen-positive or anomalous pregnancies. ^[12][13] Newborn and early childhood screening should be built into every primary care contact: thyroid, hearing and vision for Down syndrome, cardiac and renal imaging for Turner and 22q11.2, T-cell and calcium studies for DiGeorge, and seizure surveillance for Angelman. ^{[1][5][9][11]} Genetic counselling about recurrence, including offering carrier or translocation testing to parents after an affected child, is the most effective preventive step for families. ^[1][3][4]

Prenatal and newborn. When a diagnosis is suspected at birth, confirm with karyotype (or microarray for deletion syndromes), refer to clinical genetics, and start the syndrome-specific surveillance (cardiac imaging, hearing, thyroid). ^[1]

Maternal context. Counselling must be sensitive to the legal and social context of prenatal diagnosis, including the effects of local abortion law on the options parents are offered. ^[1]

Older adults. Adults with Down syndrome and other chromosomal disorders need transition to adult services, dementia screening for Down syndrome, cardiovascular and metabolic surveillance for Turner and Klinefelter, and continued attention to mental health in 22q11.2 deletion. ^[1][5][6][9]

• First-trimester ultrasound and serum testing are cheaper than cfDNA; even measuring nuchal translucency alone improves trisomy 21 detection. ^[1]
• Amniocentesis with karyotype is the affordable diagnostic gold standard; chromosomal microarray is preferable only when a deletion syndrome is suspected and funds allow. ^[2][13]
• Newborn thyroid screening, congenital heart auscultation and weight monitoring catch many of the common complications without technology. ^[1]
• Where growth hormone, thymus transplantation or cardiac surgery are unavailable, focus on nutrition, infection prevention, seizure control on basic anticonvulsants (avoiding carbamazepine, phenytoin and vigabatrin in Angelman syndrome), and family support. ^[11]
• Listen for a murmur that does not fit, a baby with dense hypotonia and a strange cry, or a girl who is very short with delayed puberty; these three clinical clues will find most cases. ^[7][5]
• Refer early to regional centres for confirmation and counselling, because karyotype availability varies by country. ^[13]

Genetic counselling; prenatal diagnosis; congenital heart disease; hypotonia in infancy; speech and language delay; short stature; epilepsy; autism spectrum disorder assessment; dementia in Down syndrome.