Down Syndrome
Dot Point Summary
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Down Syndrome is the commonest single chromosomal disorder
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Early recognition and diagnosis, knowledge of associated problems, appropriate supports and parental counselling are most important
Introduction
Down syndrome was first described by Langdon Down in 1886.
Despite the availability of improved antenatal diagnosis, the incidence of Down syndrome remains at around 0.78/1000 live births. The risk of Down syndrome increases with maternal age, and this is the most important risk factor. Prenatal diagnosis has traditionally been offered to women aged over 35 years. In Victoria, many women use prenatal maternal serum screening to establish their risk of Down syndrome with 80-90% sensitivity (however, this means that 10-20% of women with a 'negative' test may still have a baby with Down Syndrome). Therefore, despite these measures babies with Down syndrome are born unexpectedly, and many of these are born to women under 35 years.
Genetics
Down Syndrome is caused by a simple trisomy of chromosome 21 in 95% of cases, i.e in an affected male the karyotype would be 47, XY, +21. Of these 90% result from maternal meiotic nondysjunction of chromosome 21 in oogenesis. The recurrence risk in a subsequent pregnancy for simple trisomy 21 is low, being less than 1% in most women, and a parental karyotype is not required if an infant has simple trisomy 21 on the final karyotype result. The remainder of cases result from mosaic trisomy 21 or more complex chromosomal rearrangements and the recurrence risk for parents in the latter group may be increased.
Diagnosis
It is usually possible to make a confident clinical diagnosis in the term newborn on the basis of a combination of dysmorphic features (link). A range of well known physical findings, some less specific than others, are described, however no one physical abnormality is 100% specific for Down syndrome and the gold standard for diagnosis remains the banded karyotype. The phenotype may not be appreciated in preterm infants. If suspected a thorough examination is required. Those findings most frequently found are
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upslanting palpebral fissures (83%)
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hypotonia (76%)
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ear abnormalities (67%)
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epicanthic folds (56%)
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flat facial profile (50.9%)
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so called sandal sign with increased space between first and second toes (46%)
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brachycephaly
Those with mosaic Down syndrome may have no dysmorphic features, and go unrecognised.
A range of associated health issues occur in those with Down syndrome. Those important to the early neonatal period include
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Cardiac defects (30-40%) particularly atrioventricular canal defects
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Tetralogy of Fallot
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oesophageal atresia
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duodenal atresia
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imperforate anus
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Hirschsprung disease
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Congenital optic lens opacities (3%)
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Strabismus
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Intellectual impairment
Investigations
Chromosomal analysis should be performed whenever the diagnosis of Down syndrome is seriously entertained. The karyotype can be performed after birth on cultured lymphocytes from a blood sample (Lithium heparin blood 2-5ml). Routine blood karyotype takes 10-14 days to complete and an urgent karyotype result is unlikely to be available inside 7 days. Fluorescent in-situ hybridization (FISH) using a probe specific for the Down syndrome critical region can be processed in 48 hours when an urgent result is required. Direct communication with the on-call genetics fellow or the scientist in the cytogenetics laboratory will facilitate the laboratory confirmation of Down syndrome.
Given the frequency of cardiac defects, an echocardiogram is recommended as a routine. Formal thyroid function tests should be requested to exclude congenital hypothyroidism. Other investigations may be required, depending on clinical concerns.
Management
If the diagnosis is seriously entertained, discussion with both parents as to the likelihood of Down syndrome, on clinical grounds, should occur as soon as possible. Sufficient time should be made available for what is often, initially, a distressing diagnosis. It is advisable that, if possible, a midwife and social worker be present. If experienced staff consider that the diagnosis of Down syndrome is likely an urgent T21 FISH should be obtained. A follow up discussion with the family should occur once the FISH result is available. The clinical Genetics service is happy to be involved in counselling the parents. Once the diagnosis is made, repeated counselling will be required as this is a life long condition and the impact of the diagnosis will result in a difficult time for parents and family. Parents often work through the diagnosis and its impact at different rates.
Life threatening cardiac and GIT defects will require urgent management and consultation with the relevant on-call sub-specialist(s), and NETS.
By comparison, when a newborn has significant dysmorphic features not typical of Down syndrome, it is advised that the parents be informed of the atypical physical features and that a karyotype will be requested to exclude a chromosomal abnormality.
Referral for an early cardiology and ophthalmology consultation should be organised prior to discharge as should early follow up with a general Paediatrician and the family's general practitioner.
The Down Syndrome Association of Victoria offer considerable support and information, including a folder containing suitable information for parents of newly diagnosed children as well as a folder for health professionals.
Differential Diagnosis
Occasionally other syndromes, such as Smith-Maginnis and Zellweger syndrome have been misdiagnosed as Down syndrome.
Areas of Uncertainty
A range of non-mainstream therapies to assist with development have been recommended by various individuals and groups. A discussion regarding these practices is outside the scope of this handbook.
References
Devlin L, Morrison PJ. Accuracy of the clinical diagnosis of Down Syndrome; Ulster Med J. 2004 May: 73(1): 4-12
Fried K. A score based on eight signs in the diagnosis of Down Syndrome in the Newborn; J Ment Defic Res. 1980 Sep; 24(3):181-5
Gardner RJM and Sutherland GR: Chromosome Abnormalities and Genetic Counselling (3rd Edition). 2004 (Oxford University Press)
Hall B. Mongolism in newborn Infants. An examination of the criteria for recognition and some speculations on the pathogenic activity of the chromosomal abnormality; Clin Pediatr (Phila). 1966 Jan 5(1): 4-12
Hunter AGW: Down Syndrome in Management of Genetic Syndromes (2nd Edition), Edited by Cassidy SB and Allanson JE. 2005 (John Wiley and Sons)
Kava MP, Tullu Ms, Muranjan MN, Girisha KM. Down Syndrome: Clinical profile from India; Arch Med Res. 2004 Jan- Feb; 35(1) 31-5
Smith's Recognizable Patterns of Human Malformation 6th Ed. W.B Saunders Company 1977; Website
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