Chapter 9 Genetics and dysmorphology
Long Cases
Down syndrome
Down syndrome (DS) represents a common chromosomal disorder. The incidence has changed with the increase in the proportion of pregnancies diagnosed prenatally. In addition, the maternal age at parturition has changed, with more women over 35 giving birth; in 1986, 72% of babies with DS were born to younger mothers, whereas in 2004, 46% were born to younger mothers. However, the worldwide birth incidence of DS has not increased, but decreased from what it could have been by 2–18% per year. One in 350 pregnancies are affected, but only 1 in 1150 live births. Now (2010), 95% of fetuses identified with DS are terminated. In the USA, between 1989 and 2005, there was a 49% decrease between expected and observed rates, and in the UK, between 1989 and 2006, there was a 54% decrease between expected and observed rates. These trends can be attributed to availability of prenatal testing and women preferring selective terminations.
The increased risk of developing acute leukaemias in children with DS is being investigated, as transient leukaemia (TL), and the myeloid leukaemia of DS (ML DS) offer unique models to understand better the stepwise progression of leukaemia, and of gene dosage effects mediated by aneuploidy. (Aneuploid cells have an abnormal number of chromosomes: the most common aneuploidies are trisomies; most trisomies are not compatible with life, with the exception of DS and the sex chromosomal trisomies.)
History
Past treatment
• CVS: past surgery, complications thereof, plans for further operative procedures. Past interventional catheter procedures. Medications, past and present, side effects of these, monitoring levels, treatment plans for the future. Antibiotic prophylaxis for dental procedures, maintenance of dental hygiene. Compliance with treatment. Any identification bracelet. Instructions for air travel and high altitude. Any recent investigations monitoring treatment. Any recent changes in treatment regimen, and indications for these.
• GIT: past surgery, complications thereof, plans for further operative procedures. Compliance with treatment (e.g. following diet for coeliac disease). Any recent investigations monitoring treatment. Any recent changes in treatment regimen, and indications for these.
• Hearing and vision: past ear, nose and throat surgical intervention, hearing aid placement, ophthalmological intervention, glasses.
• OSA: past adenotonsillectomy, nasal mask continuous positive airway pressure (CPAP).
• Treatments for other conditions: hypothyroidism, atlantoaxial subluxation, seizures, leukaemia, arthritis, diabetes mellitus.
Current state of health
Note any of the following symptoms:
• CVS disease (fatigue, shortness of breath, cough, sweating, poor feeding, recurrent chest infections; symptoms suggesting arrhythmias, such as syncope, alteration of consciousness, dizziness, palpitations, ‘funny feeling’ in the chest, chest pain).
• GIT disease (nausea, vomiting, change in bowel habit).
• Recurrent infection (how often, what sites [usually upper or lower respiratory tract], treatment required, any prophylactic antibiotics).
• Hearing impairment (compliance/problems with hearing aids, impacted cerumen, ventilation tubes for chronic otitis media).
• Visual impairment (development of refractive disorders, keratoconus, corneal opacities, cataracts).
• Weight concerns (obesity, non-compliance with diet, exercise, or sign of hypothyroidism).
• OSA symptoms (snoring, restless sleep, daytime somnolence).
• Skin problems (in children—seborrhoeic dermatitis, palmar/plantar hyperkeratosis, xerosis; in adolescents—folliculitis [especially back, buttocks, thighs, perigenital area], fungal infections [skin and nails], atopic dermatitis).
• Oral health (level of oral hygiene, dental caries, peridontal disease, bruxism [stereotyped orofacial movements with teeth grinding], intervention for malocclusion, non-compliance with dental recommendations).
• Respiratory problems (recurrent pneumonia due to silent aspiration).
• Orthopaedic issues (limping can be due to atlantoaxial subluxation, acetabular dysplasia with subluxing hips [not more common in DS, but may appear later], slipped femoral epiphysis, arthritis or leukaemia).
• Foot problems (hallux valgus, hammer toe deformities, plantar fasciitis, pedal arthritis).
• Joint problems (polyarticular onset juvenile arthritis-like arthropathy).
• Diabetes mellitus (increased drinking or eating, weight loss, lethargy).
• Hypothyroidism (dry skin, cold intolerance, lethargy).
• Haematological neoplasia (acute lymphoblastic leukaemia [ALL] or acute non-lymphoblastic leukaemia [ANLL] occur 10–15 times more frequently in DS, with usual symptoms of pallor, bruising, fever, hepatosplenomegaly and lymphadenopathy).
• Reproductive issues in adolescents (difficulties with menstrual hygiene, use of oral contraceptives, Depo-provera, presentation of premenstrual syndrome [PMS] with temper tantrums, autistic behaviour episodes, seizures, sex education, desire to reproduce).
• Neurological issues (seizures [more frequent than general population, but less than other causes of intellectual impairment], strokes [due to cyanotic CHD, or moyamoya disease]).
Current state of behaviour
Ask about possible co-morbid psychiatric/behavioural issues:
• Symptoms of ADHD (inattention, hyperactivity, impulsivity); any treatment for these.
• Symptoms of ASD (impaired social interaction, impaired communication, behaviour patterns including preferring own company, tendency to be loner, ‘in their own world’), most problematic behaviours at present (e.g. rituals, anxiety, aggression, self-injury); any treatment for these.
• Other behavioural concerns: depression, conduct disorder, oppositional defiant disorder, aggressive behaviour; any treatment for these.
• Impact of these co-morbid issues (on family, educational facility [e.g. special school], therapists, carers).
Social history
1. DS impact on child: level of functioning in activities of daily living (ADLs), schooling (type of school, level of support from education department, therapists, academic performance, teachers’ attitudes, peer attitudes, teasing, amount of school missed and whether schooling is appropriate).
2. DS impact on parents: for example, financial situation, financial burden of disease so far, government allowances being received, marriage/partnership stability, restrictions on social life, plans for further children, genetic counselling, availability of prenatal diagnosis, contingency plans for child’s future, guardianship and power of attorney issues.
3. DS impact on siblings: for example, effect of family’s financial burden, whether siblings feel comfortable to bring friends home, whether siblings miss out on parental time, plans for siblings to act as guardians in future.
4. Social supports: for example, social worker, contact with DS parent support groups, any available respite.
5. Coping: contingency plans (e.g. plan if child develops severe febrile illness); parents’ degree of understanding regarding health supervision issues in DS.
6. Access to local doctor, paediatrician, neurodevelopmental clinic, various subspecialty clinics attended (where, how often), other clinics attended, alternative practitioner (e.g. homeopathy) involvement.
Examination
The examination of the child with DS in a long-case setting includes a full cardiological appraisal if the child has any CVS involvement, a documentation of the dysmorphic features of DS occurring in that child, plus an assessment for the development of any of numerous associated problems that may have arisen (e.g. thyroid disease, leukaemia). In addition, an assessment of function with respect to ADLs, a developmental assessment and an impression of behaviour based on direct interaction will give a complete picture, but time constraints may preclude these being assessed adequately. The approach given in Table 9.1 deals with the physical aspects of the child with DS that are able to be assessed objectively and within the time requirements. This approach can also be used in a short-case setting.
| A. Measurements |
| Height |
| Head circumference |
| Request/plot weight |
| Assess percentile charts specific for Down syndrome |
| Calculate height velocity |
| Request/plot birth parameters |
| Request/plot parents’ percentiles and ages at puberty |
| B. Systematic examination |
| The following is a selected listing of possible physical findings in children with Down syndrome—it does not include behavioural aspects |
| General inspection |
| Diagnostic facies |
| Tanner staging |
| Nutritional status |
• Scars: repairs of gastrointestinal tract anomalies (e.g. duodenal atresia, pyloric stenosis, Hirschsprung disease, omphalocoele, imperforate anus), repairs of urinary tract anomalies (e.g. vesicoureteric reflux, posterior urethral valves, other obstructive uropathy), renal transplantation (e.g. dysplastic kidneys, glomerulosclerosis), operative interventions for other associated conditions (e.g. Crohn’s disease)
• Prune-like appearance (prune belly syndrome)
• Tanner staging pubic hair (pubic hair tends to be straight)
• Quality of gait: often ‘Chaplinesque’ (externally rotated hips, flexed knees (in valgus), externally rotated tibiae)
• Limp (hip dysplasia, dislocation, avascular necrosis, slipped femoral capital epiphysis)
• Hemiplegic/circumducting gait (cerebrovascular accident [CVA] or cerebral abscess complicating cyanotic CHD)
Management issues
The following directs you to most areas of management relevant in the long case.
Cardiac disease
Around 30–50% of children with DS have CVS disease, the most common being septal defects (particularly atrioventricular (AV) canal, then VSD, then ASD), patent ductus arteriosus and tetralogy of Fallot; left-side defects are uncommon. These abnormalities are now more easily corrected, and are largely responsible for the increased life span of patients with DS. Cardiac disease may be entirely asymptomatic, so all neonates diagnosed with DS should have an echocardiogram after birth, and again at 6 weeks. The success rate for repair of septal defects is improving steadily: if not corrected, these conditions can lead to pulmonary hypertension, particularly if there is OSA, and shortened life span. Eisenmenger’s syndrome (reversal of shunting, to cause right-to-left shunt), more common in DS than in the general population, is now rare. Children with DS under 2 years of age with cyanotic CHD have an increased risk of cerebrovascular accident (CVA); they may present with seizures or acute onset hemiplegia. Children with DS over 2 years of age with cyanotic congenital heart disease (CHD) have an increased incidence of brain abscess, the severity of which relates to the degree of hypoxia. They may present with fever, headache, seizures or focal neurological signs. Around 50% of adolescents with DS syndrome and no previously known cardiac diagnosis develop mitral valve prolapse; aortic incompetence also can develop in adolescence. These are indications for continued monitoring. Despite obesity and unfavourable lipid levels in DS, the incidence of hypertension and atheroma is low. See further discussion of cardiac disease issues in the long case on cardiology (Chapter 6).
Developmental issues
Nearly all children with DS have a mild (IQ 50–70) to moderate (IQ 35–50) intellectual disability (ID). A small number have a severe ID, with an IQ in the 20–35 range. The IQ alone gives little clue as to function. Language milestones are slower to develop; aspects affected include articulation, expression, comprehension, phonological awareness, syntax and semantics, with reading being a relative strength. In around two thirds of DS patients, language comprehension is equal to the mental age, but expressive language is more delayed. Gross and fine motor skills are delayed. Academic attainment is higher in mainstream schools rather than specialist schools, and is influenced also by IQ, gender (females tend to do better) and the father’s role in the child’s life. Self-sufficiency is determined by IQ, excitability, extent of behaviour problems (see below) and whether the mother uses practical means to cope with things, showing the child what, when and why, with more showing and less talking; the level of social activity in which the child is engaged also affects self-sufficiency.
Behavioural and psychiatric issues
The most common behavioural issues include problems associated with ADHD-like behaviour, autism (appears in around 7% of children with DS), conduct/oppositional defiant disorder and aggressive behaviour. See the discussion in the long cases in Chapter 5 (Behavioural paediatrics) on each of these topics for relevant clinical aspects and their management. The diagnosis of autism is usually much later than in non-DS children, and parents often are reassured by various people that it is due to DS; there appear to be two groups, one where atypical behaviours appear in infancy, and the second when children have autistic regression at 3–7 years (this is a loss, or plateauing, of social and language skills). Depression is the other common psychiatric issue in DS, but tends to present beyond the paediatric age group. In those who appear depressed, thyroid function should be checked, as hypothyroidism can present in this way. Both the intellectual impairment and speech problems in DS complicate the prompt recognition of mental illness. Excluding sensory impairment in either vision or hearing, or both, should always occur before attributing new unusual behaviours to mental illness or Alzheimer’s syndrome. In the adult population, 25% of those with DS have major depression or aggressive behaviour.
Dental problems
A high level of dental hygiene should be maintained. The immunological deficiency of DS results in periodontal disease in almost all children with DS, probably due to aberrations of mouth flora. Any carious teeth should be dealt with promptly, with appropriate antibiotic cover. All DS children with congenital heart disease should be given a letter or card to show to any dentist or doctor, explaining the need for antibiotic prophylaxis for any dental or similar procedure (e.g. tonsillectomy), including the recommended doses of antibiotics. Regular visits to the dentist and routine brushing can prevent periodontal disease. Orthodontic problems occur in almost all patients with DS, but compliance with orthodontic procedures and braces can be problematic.
Thyroid disease
The rate of congenital hypothyroidism in DS is around 1 in 140, versus 1 in 4000 for the general population. The recommendation is thyroid screening (for thyroxine and thyroid-stimulating hormone [TSH]) at birth, 6 months and then every year thereafter. The frequency of thyroid disease increases with age, such that it eventually affects 15% of people with DS. The symptoms and signs of hypothyroidism can be difficult to differentiate from those of DS itself. Children with DS who have a normal thyroxine level, but a TSH concentration above 10 mU/L, are considered to have compensated hypothyroidism and should be treated. Treatment with thyroxine in this group often results in increased growth velocity. For further discussion of the symptoms of hypothyroidism, see the discussion in the short-case section on thyroid disease (Chapter 7).
Coeliac disease
The average time between the first symptoms of coeliac disease and definitive diagnosis approaches 4 years in patients with DS. The frequency of coeliac disease in DS is around 5–7%. It is sensible to screen all children with DS for coeliac disease: the Down Syndrome Medical Interest Group recommends this be done at 24 months of age, but there is yet to be consensus as to whether screening should be repeated later in life. See the short case on malabsorption for more details on screening tests (Chapter 8).
Obstructive sleep apnoea (OSA)
OSA is increasingly recognised in DS, and in children previously incorrectly labelled as having ADHD. OSA has also been a major contributor to pulmonary hypertension and the development of Eisenmenger’s syndrome in children with DS and cyanotic CHD historically. As soon as OSA is identified, referral to an ear, nose and throat surgeon for tonsillectomy and adenoidectomy is appropriate in most cases. See the further discussion of clinical and management aspects in the long case on OSA in Chapter 15.
Haematological disorders (including leukaemia)
Chemotherapy in children with DS is associated with a higher morbidity and mortality. Anthracycline dosages are reduced in children with DS because of the increased long-term risk of cardiotoxicity in a population that may have compromised cardiac function due to congenital heart disease. For further discussion of leukaemia, see the long-case section on oncology (Chapter 14). The other haematological aberrations seen in DS are neonatal polycythaemia (occurs in two thirds of babies with DS) and macrocytosis (also in two thirds).
