Blood pressure: elevated (occult renal disease) Joints: hyperflexibility (usual), restriction of movement (arthropathy similar to juvenile arthritis) Head Size: small (measure and plot on Down syndrome specific growth charts) Shape: brachycephaly, flat occiput; facial profile (flat) Fontanelles: late closure Hair

• Midline hair whorl (parietal area)

• Soft, sparse hair; alopecia

• Excess skin back of neck (infant)

• Webbed neck (occasional finding)

• Low posterior hairline

Eyes Inspection

• Examine any glasses the child wears (myopia common): check vision with child wearing glasses

• Epicanthal folds

• Upward slant of palpebral fissures

• Prominent eyes (coexistent hyperthyroidism)

• Blocked tear duct (infant)

• Ptosis

• Squint

• Nystagmus

Conjunctival pallor (iron deficiency, transient myeloproliferative disorder (infant), acute myeloid leukaemia [AML], acute lymphoblastic leukaemia [ALL]) Scleral jaundice (coexistent liver disease) Iris: Brushfield’s spots (white speckling of the peripheral iris) Cornea

• Large and cloudy (buphthalmos): glaucoma

• Keratoconus

Visual fields: field defect (CVA from cyanotic CHD) Eye movements

• Nystagmus

Ophthalmoscopy: cataracts Nose Small, with flat nasal bridge Mouth and chin Central cyanosis: various forms of CHD Mouth: open (tendency to keep mouth open common) Palate: short hard palate Teeth: hypodontia, irregular placement, periodontal disease, dental caries Tongue: prominent (small pharynx, normal-sized tongue), geographical tongue, fissured tongue Tonsils: presence/size (can contribute to obstructive sleep apnoea [OSA]); absence (previous adenotonsillectomy for OSA) Ears Wearing hearing aid (hearing impairment in two thirds of cases); check aid works and that child will wear it Check hearing (for conductive, sensorineural or mixed loss) Structure: small, overfolded upper helix, small/absent earlobes, low-set Eardrums: ventilation tubes, chronic serous otitis media, permanent perforation, atelectatic eardrum, tympanic membrane scarring from previous infections or tubes, middle-ear cholesteatoma Neck Short, pterygium colli, scoliosis, excess skin back of neck (infant), low posterior hairline, goitre (coexistent thyroid disease) Torticollis (spinal cord compression from atlanto-axial instability) Chest Inspection

• Scars: repairs of congenital heart defects (atrioventricular canal, ventricular septal defect, patent ductus arteriosus, atrial septal defect, tetralogy of Fallot), repair of tracheo-oesophageal fistula, insertion of access port (for chemotherapy for ALL, AML)

• Tanner staging in girls

• Sternal deformity: pectus excavatum or carinatum

Palpate and auscultate praecordium: various forms of CHD, loud second sound with obstructive sleep apnoea, development of mitral valve or tricuspid valve prolapse, or aortic regurgitation Abdomen Inspection

• 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)

Palpation

• Hepatomegaly (congestive cardiac failure [CCF])

• Splenomegaly (subacute bacterial endocarditis)

• Hepatosplenomegaly (ALL, AML)

• Enlarged kidneys (hydronephrosis)

Genitalia Tanner stage genitalia: measure penis length and testes parameters, estimate testes volume Penile anomalies: hypospadias (infant), corrected hypospadias Testicular anomalies: cryptorchidism, enlarged (testicular cancer [seminoma], leukaemic deposits) Gait, back and lower limbs Inspection of lower limbs

• Clubbing of toes (various types of CHD)

• Gap between first and second toes wide, with plantar crease between them

• Hallux valgus

• Hammer toes

• Fungal infection of nails (adolescents)

• Pes planovalgus

Palpation: ankle oedema (CCF with CHD) Gait—standard examination (see the short-case approach) to detect:

• 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)

• Proximal weakness (e.g. developmental dysplasia of hip)

Back

• Look at the back to detect short neck or neck webbing

• Bend over and touch toes to detect scoliosis

Lower limbs neurologically

• Tone (usually decreased), power (usually normal)

• Long tract signs (quadriparesis or quadriplegia—spinal cord compression from atlanto-axial instability); hyperreflexia (spinal cord compression from atlanto-axial instability, CVA or cerebral abscess complicating cyanotic CHD)

Joints: hyperflexibility (usual), restriction of movement (arthropathy similar to juvenile arthritis) Developmental assessment See the short case on developmental assessment—most children with Down syndrome have developmental quotient (DQ) and later intelligence quotient (IQ) in the range 50–70

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).

Hearing loss

Between 50 and 80% of children with DS have hearing problems. This increases to 90% in adults. The hearing loss may be conductive, sensorineural or mixed. The morphology of the head and neck predispose children with DS to hearing problems: the pinnae are small (harder to localise and concentrate sound), the canals are narrow, impacted cerumen is common (and can cause mild losses of 15–25 dB), and they may have conductive losses due to middle-ear fluid or structural abnormalities of the middle ear. Adolescents with DS have hearing losses in the high-frequency range, which are not seen in younger children.

Medical management for conductive loss includes treating otitis media and serous otitis media, surgical intervention with ventilation (pneumoeustachian) tubes, adenoidectomy and tonsillectomy (which also helps OSA). Some studies have questioned the effectiveness of ventilation tubes in DS, suggesting a lower cure rate, more sequelae (atelectatic eardrum, permanent perforation of eardrum, middle-ear cholesteatoma), more frequent episodes of otorrhoea, more antibiotic-resistant bacterial infection, and less hearing improvement after placement of tubes. Hearing aids are underutilised in DS, mainly due to compliance problems. Cochlear implantation may be required in severely hearing-impaired infants. Other management may involve speech therapy, signing and computer-based assisted communication devices.

Ophthalmological disorders

Approximately 50% of children with DS have ocular impairments. These include strabismus, nystagmus, refractive errors (common between 3 and 5 years), accommodation problems (resistant to correction by glasses), congenital (or later-forming) cataracts (present at birth in 3%), blepharitis, hypoplasia of the iris, nasolacrimal duct obstruction with tearing, keratoconus and glaucoma. As well as standard visual screening, all children with DS should be assessed by a paediatric ophthalmologist by 6–12 months of age, and then yearly.

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.

Obesity

The well-known high incidence of obesity (>120% of ideal body weight) in children with DS starts to develop in preschool years. Children with DS are less active, prefer indoor activities and have a lower resting metabolic rate; living at home increases the propensity to obesity compared to a residential setting, and low rates of socialisation also increase the risk. By the time teenage years are reached, the average girl weighs 133% of ideal weight, and boys 124% of ideal weight. Obesity is notoriously difficult to prevent and manage in children with DS. Attempts at prevention should include decreased caloric intake, increased exercise, vitamin supplementation and weight-bearing activities (as bone density in the pelvis and spine is lower in children with DS compared to other children).

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)

Children with DS have an increased risk of developing leukaemia, but a decreased risk of developing solid tumours. Around 10% of newborns with DS develop a pre-leukaemic clone associated with a somatic mutation in the gene encoding for the haematopoietic transcription factor GATA1, which is on the X chromosome; this preleukaemia is called transient leukaemia (TL), or transient myeloproliferative disease (TMD) or transient abnormal myelopoiesis (TAM). TL is a form of self-limited leukaemia that is almost exclusive to neonates with DS, spontaneously regressing by 2–3 months. These infants must be followed up carefully, as some of them later develop myelodysplastic syndrome or, more often, megakaryoblastic leukaemia aged 1–3.

Both ALL and AML occur 10–20 times more frequently in children with DS compared to the general population. ALL and AML (most often acute megakaryoblastic leukaemia) occur with equal frequency (about 1 in 300 children with DS). In DS, AML usually occurs between ages 1 and 5 years (median 2 years). From 20 to 70% of patients with myeloid leukaemia of DS (ML DS) present with myelodysplastic syndrome with thrombocytopenia, followed by anaemia, developing over months. In ML DS, the presenting characteristics of these patients differ from those AML in the general population; patients with ML DS are younger than 5, have a low white cell count and do not show meningeal involvement. These patients have a better outcome than children without DS who have AML. In contrast, children with DS who develop ALL do not have a better outcome compared to their non-DS counterparts.

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).

Lymphomas are more common in DS, as are testicular germ cell tumours (around 50 times the risk of the general population); males with DS usually have hypogonadism and often have cryptorchidism, so orchidopexy is useful to allow early detection of tumours. The risk of other solid tumours is decreased in DS.

Immunological manifestations

Children with DS have increased rates of infections (especially ear and chest infections), autoimmune diseases and certain cancers, which have been attributed to immune dysfunction. The mechanism of dysfunction involves abnormal chemotaxis, deficiencies in cellular immunity, and IgG subclass deficiencies (classes 2 and 4); the latter are responsible for recurrent sinopulmonary infections. It is important to fully immunise all children with DS, and consideration should be given to serial boosters of pneumococcal vaccines.

Seizures

Seizures occur in around 8% of patients with DS. There is a bimodal distribution of age of onset: 40% of seizures commence by 12 months of age, and 40% commence just outside of the paediatric age group, in the third decade of life. Children with DS tend to develop infantile spasms and generalised tonic clonic seizures with myoclonus; about half of those with infantile spasms will go into remission without relapse, and there can be some restoration of development. For further discussion on seizures, see the long-case section on seizures and epilepsy in Chapter 13 (Neurology).

Atlanto-axial instability (AAI)

Atlanto-axial instability (AAI) refers to excessive mobility of the articulation of the atlas (C1) on the axis (C2). The standard method to detect this has been a lateral X-ray of the neck in neutral, flexion and extension. If there is an atlanto-dens space of more than 4.5–5.0 mm, this is considered subluxation, irrespective of the presence or absence of symptoms. Around 13% of DS patients have an increased space but are asymptomatic; a further 2% become symptomatic. The symptoms and signs of spinal cord compression may include altered gait (including limp), neck pain, torticollis, loss of bladder and bowel control, hyperreflexia, hemiparesis or hemiplegia, and quadriparesis or quadriplegia.

Management of symptomatic patients involves immediate referral for stabilisation and surgical consultation. Follow-up of asymptomatic patients shows no progression to becoming symptomatic. Participation in sports does not often trigger spinal cord compromise, and there are discrepancies between guidelines and discordance between X-ray findings, symptoms and risk of spinal cord damage. Sports that are most likely to compress the neck are avoided: this includes gymnastics, boxing, diving, horseback riding, and jumping on a trampoline.

Orthopaedic problems

Apart from AAI, discussed above, there are a number of musculoskeletal problems that are more common in DS, including developmental dysplasia of the hip, acquired hip dislocation (risk related to ligamentous laxity), chronic patellar dislocation, pes planus, ankle pronation, scoliosis and degenerative joint disease (the latter two most likely related to obesity, hypotonia and premature ageing).

Diabetes mellitus

At least 1% of children with DS will develop diabetes. Screening is not indicated, but vigilant observation for any symptoms developing is appropriate.

Constipation

Functional constipation is not uncommon. Standard management for constipation is used. Movicol sachets are very useful. Diet does play a role; parents need to know what a healthy diet entails, and appreciate that cow’s milk protein may be the cause of constipation in up to two thirds of cases, so a diet that decreases cow’s milk intake, and increases fruit juice, dried fruit, unprocessed bran and other forms of fibre, may be useful. An end-point is the MACE procedure, but it can still be very difficult to perform an antegrade colonic washout in these children: some children use a colostomy bag as a missile, so much thought must be given before launching into procedures in this population.

Unproven therapies

Parents of children with DS are vulnerable to claims of remarkable treatment or ‘improvement’ with various unproven therapies. Parents need to be aware of claims of various groups, some of which are promoting a mixture of various substances—for example, gingko, dexmethylphenidate, fluoxetine, phosphatidylcholine and folinic acid—that are entirely without any scientific evidence to support them. Polypharmacy of this type is never good. Alternative therapies are not recommended by the Down’s Syndrome Medical Interest Group, due to lack of data to substantiate any of them. There are also potential dangers; for example, chiropractic manipulation should be avoided, given the risk of AAI.

Breaking the news

The candidate may be asked how they would have informed the parents of the diagnosis initially. Probably, an apprenticeship model is needed. The baby should be held, named and the parents congratulated on the arrival of the baby. When the baby has been examined, then the parents must be spoken to; a useful phrase is ‘I have some news you might not be expecting’.

Turner syndrome

Turner syndrome (TS) is due to haplodeficiency (see below) of some or all genes on the X chromosome. There may be complete absence of one X chromosome or structural anomalies of one X chromosome. The consequent phenotype is variable, relating to the underlying chromosomal pattern. The classic phenotype is 45 X, but the majority of (possibly all) patients with TS demonstrate mosaicism (see below), usually with a second, normal cell line (e.g. 45 X/46 XX or 45 X/46 XY). Other cell lines can include 47 XXX. There can also be structural anomalies of the X chromosome, including rings, deletions, translocations and isochromosomes (equal length chromosome arms, from transverse division of centromere rather than the normal longitudinal division). A Y chromosome is present in about 6% of patients with TS; an additional 3% have a marker chromosome (structurally abnormal chromosome unable to be identified by conventional cytogenetics) derived from the Y or another chromosome.

The physical signs of TS may be very subtle in childhood and adolescence. In the newborn, there may be characteristic features, such as lymphoedema of the hands and feet, nuchal folds, left-sided heart lesions, webbed neck and a low hairline. In childhood, TS should be considered in any girl with declining growth velocity (falling below the 5th centile), even if there are no obvious dysmorphic features. In adolescence, TS may cause short stature, absence of breast development by 13 years of age, or amenorrhoea with elevated follicle-stimulating hormone (FSH) levels. TS can also present with complete phenotypic expression of X-linked recessive conditions in a female, such as haemophilia A, Duchenne muscular dystrophy, or red–green colour-blindness, which suggests X monosomy.

Recently, it has become apparent that the cardiovascular lesions of TS are more widespread than previously recognised; almost 50% of TS patients have an elongated transverse aortic arch. There is a general dilation of major arteries in adult TS patients, including the carotid and brachial arteries. Imaging studies have shown that 11% of TS patients have coarctation of the aorta, 16% have a bicuspid aortic valve (BAV), and each of these is four times more frequent in patients with webbed necks, which are now believed to be residual findings from in utero obstructed jugular lymphatics with nuchal cystic hygromas. The hygromas resolve as lymphatics open later, but the webbing remains and predicts these cardiac lesions: 37% of patients with neck webbing have a BAV, versus 12% in those without webbing.

Definitions

A syndrome is a pattern of multiple structural defects, caused by multiple defects in one or more tissues, due to a known cause. Mosaicism means the presence of two or more chromosomally different cell lines both of which derive from the same zygote.

Haplodeficiency is presence in the cell of one set of genes instead of the usual two sets.

TS is associated with a multiplicity of medical conditions, and this leads to a large number of discussion areas in the long-case format. The relevant conditions are enumerated in the current state of health section of the history below, and in the management section. Much of the management overlaps with several sections in this book; the reader will be directed to these accordingly.

History

Presenting complaint

Reason for current admission.

Diagnosis

When made (antenatal [ultrasound—renal anomalies, coarctation, cystic hygroma, increased nuchal fold thickness], birth [lymphoedema of hands and feet, left-sided heart problems, webbed neck, congenital glaucoma], childhood [decreased growth velocity, nail dysplasia, high-arched palate, strabismus], adolescence [pubertal delay, amenorrhoea, short stature]); where; problems at diagnosis (e.g. cardiovascular (CVS) symptoms/signs [cyanosis, tachypnoea, poor feeding, hypertension], gastrointestinal tract (GIT) symptomatology [diarrhoea, rectal bleeding]; vision and hearing aspects; loss of weight (coeliac disease, Graves’ disease, inflammatory bowel disease [IBD]), weight gain (hypothyroidism from Hashimoto’s disease), growth delay (TS per se, coeliac disease, hypothyroidism, scoliosis); who gave diagnosis; initial reaction to diagnosis; initial investigations carried out (karyotype, full blood examination, chest X-ray, electrocardiography, echocardiography, angiography, abdominal X-ray, ultrasound, brainstem auditory evoked response, ophthalmological assessment), genetic counselling given.

Initial treatment

1. Surgical (e.g. CVS—correction of coarctation, hypoplastic left-heart syndrome [HLHS]; urinary tract—correction of duplex system).

2. Medical (e.g. antihypertensives, growth hormone (GH), oestrogen, progesterone, calcium supplementation, vitamin D, thyroxine for hypothyroidism, gluten-free diet for coexistent coeliac disease).

Past history

Indications for, and number of, any previous hospital admissions. Chronological progression aspects of TS: CVS problems (e.g. when hypertension developed, when and how it was controlled), urinary tract problems (e.g. frequency of urinary tract infections [UTIs], when operative procedures undertaken); ear problems (e.g. recurrent otitis media episodes); eye problems (e.g. strabismus, amblyopia); other complications of disease (e.g. hypothyroidism, coeliac disease, IBD).

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. Frequency of echocardiography or cardiac MRI to screen for aortic root dilatation.

• Growth. When GH started (fell below 5th centile), supervised by whom (paediatric endocrinologist), dosage given (usual commencing dosage 0.05 mg/kg/day [0.1 IU/kg/day]), any combination therapy (e.g. with oxandrolone in girls aged 9–12); when oestrogen replacement therapy commenced (after age 12), when cyclic menstruation achieved.

• Hearing. When impairment detected, level of loss, whether hearing aids prescribed, compliance with hearing aids.

Current state of health

Note any symptoms of the following:

• CVS disease (symptoms suggesting dilation of root of ascending aorta: chest or epigastric pains, or ‘funny feeling’ in chest or epigastrium (preceding aortic dissection and rupture); symptoms of hypertension (headache); other symptoms of CVS involvement (fatigue, shortness of breath, sweating, poor feeding [infants], syncope, alteration of consciousness, dizziness, palpitations).

• Loss of weight (Graves’ disease, inflammatory bowel disease [IBD], coeliac disease, renal disease, malignancy [colon, germ cell tumours]).

• Gain in weight (obesity, non-compliance with diet, exercise, Hashimoto’s thyroiditis causing hypothyroidism).

• Hypothyroidism (dry skin, cold intolerance, lethargy).

• Orthopaedic problems: limp (associated developmental dysplasia of hips, juvenile arthritis, IBD-associated arthritis), back pain (scoliosis, kyphosis, lordosis, juvenile arthritis, IBD-associated arthritis).

• GIT disease: diarrhoea (coeliac, IBD), nausea, abdominal pain, rectal bleeding (IBD).

• Urinary tract problems (infection, haematuria, proteinuria).

• Hearing impairment (recurrent otitis media, recent hearing testing).

• Visual problems (development of strabismus).

• Weight concerns (obesity, non-compliance with diet, exercise, Hashimoto’s thyroiditis causing hypothyroidism).

• Reproductive issues in adolescents (education about advisability or otherwise of pregnancy [increased risk of maternal complications, including risk of dilatation and dissection of aorta], education about donor oocyte pregnancies, sex education, discussion of desire to reproduce).

• Psychosocial/behavioural issues: being bullied, unsatisfactory peer interactions, ADHD-like symptoms (inattention, hyperactivity, impulsivity), immature behaviour, anxiety, depression; any treatment for these.

Social history

• TS impact on child: schooling (type of school, level of support from teachers, therapists, academic performance, teachers’ attitudes, peer attitudes, teasing, amount of school missed and whether it is appropriate).

• TS impact on parents: for example, financial situation, financial burden of disease so far, government allowances 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.

• TS impact on siblings: for example, effect of family’s financial burden, siblings missing out on parental time.

• Social supports: for example, contact with TS parent support groups.

• Coping: contingency plans (e.g. parents’ degree of understanding regarding health supervision issues in TS).

• Access to local doctor, paediatrician, paediatric endocrinologist, neurodevelopmental clinic, various subspecialty clinics attended (where, how often), other clinics attended.

Family history

Any other family members with associated autoimmune conditions.

Immunisations

Any delays, local doctor’s attitudes, parents’ understanding of importance.

Examination

The examination of the child with TS in a long-case setting includes a full cardiological appraisal if the child has any CVS involvement, a documentation of the dysmorphic features of TS occurring in that child, plus an assessment for the development of any of numerous associated problems that may have arisen (e.g. thyroid disease, coeliac disease). The approach given below deals with the physical aspects of the child with TS that are able to be assessed objectively and within the time requirements. This approach can also be used in a short-case setting.

Growth parameters are assessed first: measurements and manoeuvres are given below.

Measurements

Measure height and the lower segment (LS); that is, from the pubic symphysis to the ground. Calculate the upper segment (US) by subtracting the LS from the total height. Work out the US:LS ratio. Normal values (in normal children) are 1.7 at birth, 1.3 at 3 years, 1.0 at 8 years and 0.9 at 18 years. If the US:LS ratio is increased, it suggests short lower limbs (e.g. hypothyroidism). If the US:LS ratio is decreased, it suggests a short trunk (e.g. scoliosis) or a short neck.

Measure the child’s arm span, and compare this to the total height. The normal child’s values (arm span minus height) are: −3 cm from birth to 7 years, 0 cm from 8 to 12 years, +1 cm (girls) and +4 cm (boys) at 14 years. An apparently long arm span can be seen with a short neck, or trunk.

Measure the head circumference and weight.

Plot the available measurements on Turner syndrome (TS) specific percentile charts, and calculate the height velocity. Check the birth parameters and plot these. Plot the parents’ percentiles and ages of puberty. After all these parameters have been evaluated, proceed with the manoeuvres below, or commence a systematic head-to-toe examination and slot in the manoeuvres along the way as relevant.

Manoeuvres

With each manoeuvre, stand opposite the child and demonstrate, so that she will mirror your movements. The skin should be evaluated concurrently with inspecting from front, back and side. Note any pigmented naevi, any scars (keloid common).

1. Inspect from in front

• Screen for carrying angle: have the child hold her arms by her side, with the palms forward. This angle can be increased in TS.

• Screen for short limbs: have the child touch the tips of the thumbs to the tips of the shoulders. If the thumbs do not reach the shoulders, there may be middle-segment (mesomelic) limb-shortening, found in TS and the associated Leri–Weill dyschondrostenosis (caused by abnormalities of the same SHOX gene—the haplodeficiency [loss of one allele] which contributes to the TS stature).

• Screen the hands. Have the child hold the palms up: look for short mid-phalanx of fifth finger, Madelung deformity (congenital subluxation or dislocation of head of ulna with radial deviation of hand). Turn the hands over (palms down) and check the nails (e.g. hyperconvex).

• Screen for short metacarpals by having the child make a fist and look for shortened third, fourth or fifth metacarpal.

2. Inspect from the side

The child should be standing with her arms by her side. Note whether there is micrognathia. Note the shape of the back, for lordosis or kyphosis. Note how far the upper limbs reach. If the limbs are short, the fingers may only reach the proximal thigh; if the trunk is short, the fingers may reach the knees.

3. Inspect from the back

Examine for scoliosis. Have the child bend forward and touch the toes, to determine whether any scoliosis is structural.

Completing the examination

Formal physical examination flows well if commenced at the hands, working up to the head and then downward—essentially a head-to-toe pattern. Table 9.2 gives a selected listing of possible physical findings in children with Turner syndrome. It does not include behavioural aspects (see below).

Table 9.2 The child with Turner syndrome: physical examination

A. Measurements

Height

Lower segment (LS)

Calculate upper segment (US) by subtracting LS from height

Calculate US:LS ratio

Arm span

Head circumference

Record weight

Assess percentile charts

Calculate height velocity

Record birth parameters

Record parents’ percentiles and ages at puberty

B. Manoeuvres

• Arms by side with palms forward (to detect cubitus valgus over 15 degrees between extended supinated forearm to upper arm)

• Thumbs on shoulders, to detect short limbs: can detect middle segment shortening

• Palms up: to detect short mid-phalanx of fifth finger; Madelung deformity (congenital subluxation or dislocation of head of ulna with radial deviation of hand)

• Make a fist (to detect short third, fourth, fifth metacarpal)

• Look at the back to detect short neck or neck webbing

• Low hairline

• Bend over and touch toes (to detect scoliosis)

C. Systematic examination Sitting up is the preferred position for the commencement of the systematic examination—the following is a selected listing of possible physical findings in girls with Turner syndrome General inspection Diagnostic facies Tanner staging

• Delayed

Nutritional status

• Obese (coexisting undertreated hypothyroidism)

• Poor (coexisting inflammatory bowel disease [IBD], cancer)

Skeletal anomalies

• Broad shield-like chest with widely spaced hypoplastic, and/or inverted nipples

• Pectus excavatum

• Scoliosis

• Kyphosis

Skin

• Lymphatic vascular malformations: congenital lymphoedema, residual swelling over hands and feet, dorsal aspect

• Haemangiomata

• Pigmented naevi

Upper limbs Structure

• Short mid-phalanx fifth finger

• Short third, fourth, fifth metacarpal

• Madelung deformity

Nails

• Dysplastic

• Hyperconvex, deep-set

Pulse

• Radiofemoral delay (coarctation of aorta)

Blood pressure: elevated (essential hypertension, coarctation of aorta, renal disease) Joints: swelling, decreased range of movement (coexistent juvenile idiopathic arthritis [JIA]) Eyes Inspection

• Epicanthal folds

• Ptosis

• Squint

Sclerae

• Icterus (coexistent liver disease)

• Blue

Cataracts Fundi

• Hypertensive retinopathy

Mouth and chin Central cyanosis: partial anomalous pulmonary venous return (PAPVR), hypoplastic left heart (neonate) Narrow maxilla/high arched palate Teeth: caries (risk of SBE) Micrognathia Ears Wearing hearing aid (hearing impairment common): check aid works and that child will wear it Check hearing (for conductive, sensorineural or mixed loss) Structure: malformed, rotated Eardrums: ventilation tubes, chronic serous otitis media, permanent perforation, atelectatic eardrum, tympanic membrane scarring from previous infection Neck/hairline Pterygium colli Short Scoliosis Low hairline Chest Inspection

• Shield-like broad chest

• Sternal deformity: pectus excavatum or carinatum

• Scars: repaired left-sided heart lesions (coarctation, aortic stenosis, aortic root dilatation)

• Tanner staging breasts: delay

• Wide-spaced, hypoplastic, inverted nipples

Palpation

• Praecordium (e.g. for CHD)

Auscultation

• Praecordium (e.g. for CHD)

Abdomen Inspection

• Scars: gonadectomy, IBD surgery, removal of tumour (e.g. gonadoblastoma, neuroblastoma)

• Tanner staging pubic hair: delay

Palpation

• Hepatomegaly (e.g. CCF from CHD)

• Splenomegaly (e.g. SBE)

• Hepatosplenomegaly (e.g. coexistent neuroblastoma)

• Enlarged kidneys (e.g. hydronephrosis)

Genitalia Tanner staging: delayed Gait, back and lower limbs Inspection of lower limbs

• Feet: short metatarsals

• Oedema of dorsa of feet

• Clubbing of toes (various types of CHD)

Palpation: ankle oedema (CCF with CHD) Joints: swelling, decreased range of movement (coexistent JIA) Gait—standard examination screening for:

• Limp (e.g. developmental dysplasia of hip [DDH], coexistent JIA)

• Proximal weakness (e.g. DDH)

Back

• Scoliosis

• Kyphosis

• Lordosis

• Decreased range of movement (coexistent JIA)

Specific complications and associations

The mnemonic TURNER ULLRICH’S helps recall most of these:

T. Thyroiditis and other autoimmune disease (JIA, coeliac disease)

Undermineralised bone

R. Root of aorta dilatation risks (bicuspid aortic valve, aortic stenosis, aortic coarctation, hypertension)

Neck short, webbed/Nails hyperconvex/Normal intelligence (but impairments in memory, maths, spatial perception, goal-setting, goal-attainment, attention span)

E. Endocrine deficiency (pubertal failure, short stature)/Eye findings (epicanthic folds, strabismus, ptosis, congenital glaucoma)/Ears (unusual shape, rotation)

R. Reproductive technology assistance (egg donor programs)

Ulcerative colitis/Crohn’s disease

• Left-sided heart problems/Linear growth deficiency

• Lymphoedema/Lymphatic malformations (e.g. cystic hygroma)

R. Renal anomalies (hydronephrosis)

I. Infertility

C. Cancer risks (gonadoblastoma, neuroblastoma, colonic carcinoma)

H. Hearing loss/Hypertension/Hepatic cirrhosis

S. Skeletal (DDH, Madelung)/Spine (scoliosis, kyphosis, lordosis)

Management issues

The following directs you to most areas of management relevant in the long case.

Cardiovascular disease

Up to 60% of TS patients have some form of cardiovascular disease/malformation. Cardiac disorders are the sole source of increased mortality in TS. Patients with TS are at increased risk of aortic root dilation and rupture. Cardiac findings in TS may include left-sided heart defects that can present in infancy, such as bicuspid aortic valve (BAV) (50%), coarctation of the aorta (30%), aortic stenosis (10% of those without BAV) or mitral valve stenosis (under 3%). Systemic hypertension is common in TS and is a risk factor for aortic dilatation (as are BAV, aortic stenosis, aortic regurgitation and obesity).

Aortic root dilatation can occur in up to 9% of patients. Aortic dissection and rupture have been reported rarely: there is one report of a 4-year-old patient dying from aortic rupture. The symptoms for aortic dilation are chest or epigastric pains, often misinterpreted as being of pulmonary or gastrointestinal origin.

Some patients with aortic dilation have had no risk factors. All TS patients must be screened for aortic root dilation. MRI may be more useful than echocardiography in delineating aortic pathology: MRI can detect aortic coarctation or dilation missed by echocardiography. Abnormalities of the aortic valve may not be seen on a neonatal echocardiogram, so that repeated echocardiograms or MRIs every year are essential. If a TS patient later becomes pregnant (through oocyte donation), this significantly increases the risk of aortic dissection or rupture. Patients with TS should have echocardiograms at least every 5 years throughout life.

Around 50% of patients have a particular angulation of the aortic arch termed ‘elongated transverse arch’; of itself, it has no significance clinically, but there is concern that it could represent an abnormal aortic wall, with a tendency to dilation and perhaps dissection. A dissecting aortic aneurysm usually has risk factors (BAV, other aortic valve anomalies, coarctation or dilatation of aorta, hypertension) although a few cases do not have known risk factors; it may be the vasculopathy of TS itself that may predispose to dissection. The International Turner Syndrome Dissection Registry was established to study this problem.

Up to 40% of TS patients have hypertension, usually idiopathic, but cardiac or renal causes must be excluded. Once identified, hypertension must be aggressively treated. Blood pressure should be measured at all routine follow-up visits.

Less commonly seen cardiovascular diagnoses include mitral valve prolapse (5–15%), partial anomalous pulmonary venous drainage (PAPVD), which often involves the left upper pulmonary vein (13%), persistent left superior vena cava (13%), ventricular septal defect (VSD) (<5%) and atrial septal defect (ASD) (>5%).

Hypertension occurs in around 25% of girls, and a higher percentage of adults, with TS; hypertension is a risk factor for aortic dilation and dissection. It has been noted that some babies with TS have an unusual resting tachycardia, that starts in utero, and the occurrence of impaired sympathovagal tone infers that there could be a problem with autonomic regulation of the cardiovascular system in TS. Many patients with TS have nocturnal hypertension, such that 24-hour monitoring may be helpful.

Beta blockers have been used for hypertension, and have been used to reduce the rate of aortic dilation in Marfan syndrome; recently, angiotensin receptor blockers (ARBs) have been used for this in Marfan syndrome and were found to be superior to beta blockers in reducing aortic dilation; but there is insufficient data on the use of ARBs at present to make any recommendations.

Monitoring for aortic dilatation should include measuring the aorta (at the end of systole), at three levels: (a) the annulus, at the hinge point of the valve; (b) at the level of the sinuses of Valsalva perpendicular to the ascending aorta long axis; and (c) at the ascending aorta, 10 mm above the sino-tubular junction. There are tables of aortic diameter as a function of body surface area.

Electrocardiographic findings can include conduction and repolarisation abnormalities, right-axis deviation (especially with PAPVD), T wave anomalies, accelerated AV conduction and QTc prolongation.

Ongoing follow-up should be with one type of imaging, either echocardiography or MRI. Echocardiography is usually sufficient in infants and younger children; but in older adolescents and adults, its use may be limited due to an abnormally shaped chest, or obesity. Pregnancy in TS should be considered only after a full cardiac evaluation. Extreme exercise should be avoided. Patients should have MedicAlert bracelets outlining their aortic disease.

Cardiac anomalies are more common with a 45 X karyotype, and more common in patients with lymphoedema. Prophylaxis for endocarditis is important, particularly as dental malocclusion occurs in TS, and these patients may require dental procedures. Those requiring cardiac surgery may develop keloid, another predisposition in TS. Ankle oedema may occur due to lymphoedema rather than a cardiac cause.

Lymphatic abnormalities

In TS fetuses that do not survive, there are often cardiovascular and lymphatic abnormalities found; fetuses with cardiac failure almost always have obstructed jugular lymphatics with nuchal cystic hygromas. In TS girls who survive, there is often peripheral oedema and webbed neck, which are the residua of fetal lymphoedema and cystic hygromas, respectively. The newborn lymphoedema usually resolves by 2 years, although it may reoccur at any age, particularly when growth hormone or oestrogen are commenced, as these both can cause salt retention. Support stockings and elevation may be required. ‘Decongestive physiotherapy’ has been recommended, comprising skin and nail care, massage for manual lymph drainage, compression bandaging and exercise. These patients should avoid any vascular surgery or diuretics. There is a National Lymphoedema Network in the USA, which provides useful information for families, at www.lymphnet.org.

Growth

From the age of 2 years, growth should be plotted on TS-specific growth charts. GH treatment should be started as soon as the child falls below the 5th centile on the normal female growth charts (or the 95th centile on the TS-specific growth charts). The earlier GH treatment is started, the longer the duration of treatment can be, until oestrogen is commenced, which then leads to growth plate closure. Between the ages of 9 and 12, oxandrolone has been given with GH to improve skeletal maturity, but the drawbacks are potential masculinising effects and potential risk of hepatotoxicity.

GH increases the rate of growth without increasing bone age. Increases in final height of 15 cm have been described if there were at least 6 years of GH therapy, and oestrogen was delayed. The advantages and disadvantages must be covered fully in discussion with the parents. When GH is commenced, it can lead to enlargement of naevi, and recurrence of lymphoedema. The approved doses are 4.7–9.3 mg/m²/week (0.16–0.32 mg/kg/week) in Australia.

Induction of puberty

More than 90% of girls with TS have gonadal failure; however, up to a third may undergo spontaneous puberty and around 3% will have spontaneous menses. Oestrogen therapy is essential for the physical, emotional and psychosexual changes of puberty, and should be commenced around 12 years of age, and no later than age 14; otherwise, adequate uterine size may not be achieved. Pelvic ultrasound can be done before starting oestrogen to check uterine size. The recommended preparation is oestradiol valerate, commencing at 0.5–1 mg on alternate days, increasing the dosage 6–12 monthly until feminisation is complete, which usually takes 2–3 years. Bone density needs to be checked around the time of late puberty to ensure that adequate bone mineralisation has occurred. A progestin such as medroxyprogesterone acetate can be added when vaginal spotting occurs, or after 2 years of treatment with oestrogen, to enable regular withdrawal bleeding to occur. During treatment, height, weight, Tanner staging and blood pressure should be checked, and blood should be taken for serum FSH and oestradiol levels every 3–6 months.

Renal and urinary tract anomalies

Around 30–60% of patients with TS have congenital renal anomalies, particularly horseshoe kidney (10%) and double-collecting systems (20%). Only a small minority develop any renal impairment: there are reports of hypertension, urinary tract infection, hydronephrosis, focal segmental glomerulonephrosis and membranoproliferative glomerulonephritis (MPGN). Follow-up ultrasound examinations of the renal tract are recommended every 5 years.

Hearing loss

This is common, with most girls with TS having recurrent otitis media, which can lead to scarring and conductive hearing loss, even in early childhood. This is related to the morphology of the head and neck in TS: the palate is high-arched and there is Eustachian tube dysfunction. Commonly, these patients have tympanostomy tube placement for recurrent otitis media, and adenoidectomy and tonsillectomy for airway problems, although adenoidectomy can adversely impact on palatal function, and negatively influence quality of speech. Also, there is a progressive sensorineural loss characterised by a sensorineural dip at a frequency of 1–2 kHz and high-frequency loss (above 8 kHz), due to anomalies of the outer hair cells of the lower middle coil of the cochlea; this can present as young as 6 years of age. This is more frequent in patients with 45 X or 45 X/46 Xi (Xq) karyotype. Some children will need hearing aids, but hearing loss is progressive, and eventually at least 25% of adults with TS will require hearing aids because of this sensorineural complication.

Ophthalmological disorders

Approximately 16% of children with TS have ptosis. Other ocular findings include hypertelorism, epicanthal folds, upward-slanting palpebral fissures, strabismus (25–35%), hyperopia (farsightedness) (25–35%), amblyopia (due to the preceding two), blue sclerae and cataracts. Red–green colour-blindness occurs in around 8%. In addition to standard visual screening, all children with TS should be assessed by a paediatric ophthalmologist yearly.

Obesity

There is an increased incidence of obesity (>120% of ideal body weight) in children with TS. Attempts at prevention should include decreased caloric intake, increased exercise, vitamin supplementation and weight-bearing activities (as bone density is lower in children with TS compared to other children).

Thyroid disease and autoimmunity

The incidence of Hashimoto’s thyroiditis (leading to hypothyroidism) is increased in TS after the age of 10 years; the incidence of hypothyroidism is around 10–30% in later childhood, rising to 50% in adults. Patients with structural defects of the X chromosome have increased susceptibility to autoimmune disorders, including Hashimoto’s thyroiditis and Graves’ disease, IBD, myasthenia gravis and MPGN. The recommendation is thyroid screening every year from the age of 10 years (for thyroxine and thyroid-stimulating hormone [TSH], and for anti-thyroid antibodies). The symptoms and signs of hypothyroidism can be subtle. Once identified, hypothyroidism should be treated promptly. For further information about the symptoms of hypothyroidism, see the discussion in the short-case section on thyroid disease in Chapter 7 (Endocrinology).

Craniofacial/dental problems

A narrow maxilla/palate occurs in over 80% of cases. Dental crowding is frequent, as is micrognathia (it occurs in 70%). There is an increased prevalence of distal molar occlusion, early eruption of secondary teeth, thinner enamel, and root resorption that can lead to tooth loss. Growth hormone treatment can alter craniofacial proportions. A high level of dental hygiene should be maintained. All TS 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 other surgical procedure, including the recommended doses of antibiotics. Regular visits to the dentist and routine brushing are important. Orthodontic evaluation is recommended around 8–10 years of age.

Gastrointestinal disease: coeliac disease, IBD and hepatic effects

The frequency of coeliac disease in TS is around 5%. It is sensible to screen all children with TS for coeliac disease, from mid-childhood, regardless of presence or absence of symptoms, repeating the screening every 2 years. See the short case on malabsorption in Chapter 8 (Gastroenterology) for more details on screening tests.

IBD (especially Crohn’s disease) is around two to three times more common in TS than in the general population. Either IBD or coeliac disease can present with poor weight gain or a range of gastrointestinal symptoms, and should be considered in these scenarios.

Elevation of serum hepatic enzyme levels occurs in 40–80% of TS patients, and is associated with up to a five-fold increase in cirrhosis in adult life. The aetiology of this is uncertain.

Osteoporosis

Osteopenia occurs commonly in TS. Peak bone mass attainment is inhibited in adolescents with TS, even with treatment: GH and oestrogen replacement improves, but does not normalise, bone mineralisation. To attempt to optimise bone mineral density, oestrogen should be used with adequate exercise, calcium and vitamin D.

Psychosocial aspects

Adolescents with TS are at increased risk for a number of behavioural abnormalities, including anxiety, depression, significant shyness, social isolation and poor self-esteem. Many of these girls demonstrate social immaturity for their age, and they often need support in becoming independent and in interacting with others socially (particularly with males). Girls with TS may be the subjects of teasing and bullying at school: once identified, this situation must be dealt with promptly and decisively by teachers and parents. Meeting with other girls with TS and their families is very beneficial, and offers valued support for these girls and their parents. Patients with TS are not at any increased risk of significant mental health problems.

Education

Children with TS are known to have problems in four domains: visual–spatial organisation deficits (poor sense of direction); difficulty with socialising (not ‘getting’ subtle social clues); difficulty with problem solving (difficulties with mathematics); and problems with fine motor coordination. Educational and vocational training need to take these specific difficulties into account, as these problems persist into adulthood and throughout life. As a group, despite variable learning difficulties, girls or women with TS often excel at verbal skills, and many adults with TS have university degrees.

Short Case

The dysmorphic child

This case potentially covers more clinical ground than any other and requires a very structured routine, quite similar to that used for the short-stature examination, except that many children with conditions that make them dysmorphic are of normal height, or may be tall (e.g. Sotos, Marfan). A systematic head-to-toe approach gives one or two differential diagnoses for each of the selected signs listed: these are merely examples, not the most frequent or important findings. This approach looks at each anatomical structure in turn (e.g. eyebrow, eyelid, conjunctiva, sclera, iris, pupil, lens, retina) and asks whether it appears normal or abnormal. If any finding appears abnormal, it is noted and may need checking later against reference values (e.g. if you suspect hypertelorism, take the outer canthal, inner canthal and interpupillary measurements and then compare these to standard percentile charts). The three areas in the examination that provide the most clues in the diagnosis of a dysmorphic child are often assessments of the head (concentrating on the face), heart and hands.

Definitions

Patterns of morphological defects include sequences, syndromes and associations. Most often, the term ‘syndrome’ is used in a broader sense than its true meaning. The definitions of relevant terms are as follows:

1. A sequence is a pattern of structural defects caused by a single problem in morphogenesis (e.g. early amnion rupture sequence, Pierre Robin sequence due to hypoplasia of the mandible before 9 weeks’ gestation)

2. A syndrome is a pattern of multiple structural defects, caused by multiple defects in one or more tissues, due to a known cause (e.g. Down syndrome).

3. An association is a pattern of structural defects that are statistically related; that is, a non-random occurrence in at least two people of multiple anomalies not due to a sequence or syndrome. The classic example is the VACTERL association:

V. Vertebral anomalies

A. Anal atresia with/without fistula

C. Cardiac anomalies (e.g. VSD)

T. Tracheo-

E. Esophageal fistula with oesophageal atresia

R. Renal anomalies (urethral atresia with hydronephrosis)

• Limb anomalies (polydactyly, humeral hypoplasia, radial aplasia and proximally placed thumb)

Examination

The lead-in will always be very clear in directing the candidate to what examination is required. One possible lead-in could be ‘This girl looks different to other family members. Please examine her to determine a cause’ or ‘This girl has short stature. Please examine her to find a cause’. The approach outlined here is a blueprint for one method that can work and has proved successful in the examination. While it is true that ‘spot diagnosis’ short cases are best avoided, it is worth having a reproducible approach, as so many unusual-looking children will be encountered by a paediatrician or a general practitioner during his or her working life.

Listen to the child’s age in the lead-in. Introduce yourself to the child and parent. Ask the child which grade he or she is in at school and note whether the response seems age-appropriate (intellectual impairment is a feature of numerous syndromes). Do not overlook the child’s sex when discussing differential diagnoses. It would be embarrassing to talk about Turner syndrome when assessing a boy.

Stand back and look for evidence of an obvious diagnosis (e.g. Down syndrome). Look at the face, noting any dysmorphic features suggesting any of the well-recognised syndromes (e.g. craniofacial syndromes). Note the morphology of the eyes (microphthalmia in Hallermann–Streiff; proptosis in Crouzon, Pfeiffer; hypertelorism in Apert, Crouzon, Pfeiffer, Saethre–Chotzen; iris colobomata in CHARGE). Note if the child has a hearing aid (deafness can occur in Treacher Collins, CHARGE, fetal rubella effects, Waardenburg syndrome), and look at the ears (displaced and malformed in Goldenhar, Treacher Collins) and the jaw. Look for midface hypoplasia (Apert, Crouzon, Pfeiffer, Saethre–Chotzen). Note any facial asymmetry (Beckwith–Wiedemann, Goldenhar). Check the size of the jaw from the side (micrognathia with Robin sequence, Hallermann–Streiff). Look for any neck swelling (e.g. cystic hygroma). Note whether sick or well, and whether there is any stridor, tachypnoea at rest, tracheal tug or use of accessory muscles (e.g. craniofacial syndromes with upper airway obstruction).

Note any particularly unusual body habitus (e.g. Marfanoid in Marfan, homocystinuria; eunuchoid in Klinefelter), obvious disproportion (skeletal dysplasias), obvious asymmetry (e.g. Beckwith–Wiedemann) or abnormal posturing (e.g. hemiplegia in homocystinuria complicated by a cerebrovascular accident due to thrombotic tendency).

Visually assess the pubertal status (hypogonadism can occur in many syndromes; e.g. Down, Prader–Willi, Fanconi pancytopenia, Noonan).

Explain what you are doing as you proceed. Ask for the height and offer to measure the patient yourself: stand the child against a wall, position the head and heels appropriately, and record the height. If the child is short or tall, then the upper segment : lower segment ratio and arm span are worth doing, but in a child of normal stature these additional measurements are not needed, unless there is the impression of disproportion. The lower segment (LS) is the distance from the pubic symphysis to the ground. The upper segment (US) is calculated by subtracting the LS from the total height. Work out the US:LS ratio—normal values are 1.7 at birth, 1.3 at 3 years, 1.0 at 8 years and 0.9 at 18 years.

If the child is short, then proceed as per the short-stature short-case approach (see Chapter 7, Endocrinology). If the child is tall, then proceed as per the tall-stature short-case approach (again, see Chapter 7, Endocrinology). If the child has obvious disproportion, then proceed with manoeuvres as below. If the child seems to have normal proportions, then proceed with a head-to-toe systematic examination, starting with a careful examination of the face.

Further measurements

Measure the head circumference (HC). HC can be increased in syndromes with hydrocephalus (e.g. X-linked hydrocephalus) or macrocephaly (e.g. Sotos). HC is decreased in the many syndromes with microcephaly (e.g. Seckel). The course adopted by the tape measure being placed around the skull can accentuate the abnormal skull shapes in cases of craniosynostosis (e.g. Apert, Crouzon).

Request the weight. Obesity occurs in many syndromes (e.g. Prader–Willi, Bardet–Biedl), while a slim habitus (aesthenia) can occur in others (e.g. Marfan). Request percentile charts and progressive measurements (if not given), and calculate the height velocity. Request birth parameters (for intrauterine and chromosomal causes: numerous chromosomal syndromes have intrauterine growth retardation as a component).

After all these parameters have been evaluated, either: (a) proceed with the manoeuvres below, particularly if the child is very short, or has obvious skeletal anomalies or clearly disproportionate short stature; or (b) commence a systematic head-to-toe examination, and slot in the manoeuvres along the way, should they appear relevant. The order adopted is unimportant; it is the demonstration of a comprehensive approach that is required.

Manoeuvres

Inspect from in front

Note any gross structural anomalies of the upper or lower limbs, such as limb deficiency (e.g. in early amnion rupture sequence, Holt–Oram), or aplasias of any long bones (e.g. radial aplasia in VACTERL association or in thrombocytopenia absent radius [TAR] syndrome), contractures (e.g. distal arthrogryposis syndrome) or pterygia of axilla, antecubital and popliteal areas (e.g. Escobar multiple pterygium syndrome). Next, a set of manoeuvres can be performed that very rapidly screens for a number of syndromes: most of these are relevant for short children. With each manoeuvre, stand opposite the child and demonstrate, so that he or she will mirror your movements.

Screen for asymmetry (irrespective of whether tall or short): have the child put the palms together with the arms out straight, and stand with the legs together. Asymmetry occurs in Russell–Silver syndrome. It may also occur as a result of hemihypertrophy in several syndromes; for example, Beckwith–Wiedemann (B–W), Klippel–Trenauney–Weber (K–T–W), neurofibromatosis type 1 (NF-1) and congenital hemihypertrophy (CH). This manoeuvre may also detect approximation of shoulders (absent clavicles in cleidocranial dysostosis).

Focus on the upper limbs first, then evaluate the lower limbs: look at the knees, for any bowing (e.g. in hypochondroplasia), look at the feet for talipes equinovarus and the toes for their number (e.g. polydactyly in Ellis–van Creveld) and structure (syndactyly, and/or broad malformed distal hallux in Apert).

Screen for carrying angle: have the child hold the arms by his or her side, with the palms forward. This angle can be increased in Turner or Noonan syndromes. Also, restriction of elbow extension may be detected (e.g. hypochondroplasia).

Screen for short limbs: have the child touch the tips of the thumbs to the tips of the shoulders. If the thumbs overshoot, there is proximal segment (rhizomelic) limb shortening. If the thumbs do not reach the shoulders, there might be either middle-segment (mesomelic) or distal-segment (acromelic) limb shortening, or alternatively the limbs may be bent (camptomelic). Thus this manoeuvre should detect proximal segment shortening (e.g. achondroplasia), middle-segment shortening (e.g. Langer mesomelic dysplasia) or distal-segment shortening (e.g. acromesomelic dysplasia).

Screen the hands: have the child hold the palms up. Look for simian crease (Down syndrome) and clinodactyly (Russell–Silver syndrome). Note the structure of the fingers (e.g. short with hypochondroplasia), their number (e.g. polydactyly in Ellis–van Creveld) and any syndactyly (e.g. Apert syndrome). Turn the hands over (palms down), note the structure of the hand (e.g. trident deformity in achondroplasia) and check the nails (e.g. hypoplastic in Ellis–van Creveld, hyperconvex in Turner).

Screen for short metacarpals: have the child make a fist, and look for shortened third, fourth or fifth metacarpal (e.g. Gorlin syndrome), first metacarpal (proximally placed thumb; e.g. in diastrophic dysplasia) or all metacarpals (e.g. in Poland anomaly).

Screen for joint laxity (relevant if short or tall): check the degree of wrist extension and whether the child can appose the thumb to the radius (e.g. hypermobility in Ehlers–Danlos, osteogenesis imperfecta or Marfan). If the child is tall or of normal height, check for arachnodactyly by having the child wrap the fingers of one hand around the other wrist. Check whether there is complete overlap of the distal phalanx of the fifth finger on the distal phalanx of the thumb (the ‘wrist sign’). Then check whether the thumb can project from beyond the ulnar border of the hand when the thumb is apposed to the palm when making a fist (‘the thumb sign’). Arachnodactyly classically occurs in Marfan syndrome.

Inspect from the side

The child should be standing with the arms by his or her side. Note whether there is a prominent forehead (e.g. achondroplasia), flat occiput (Down), proptosis (e.g. syndromes with craniosynostosis, NF-1), micrognathia (e.g. Pierre Robin sequence) or prognathism (e.g. achondroplasia). Note how far the upper limbs reach; if the limbs are short, the fingers may only reach the proximal thigh; if the trunk is short, the fingers may reach the knees. Note the shape of the back, for lordosis (e.g. achondroplasia), thoracolumbar kyphosis (e.g. achondroplasia) or crouched posture (e.g. diastrophic dysplasia).

Inspect from the back

Examine for scoliosis (and any kyphosis, which should have been noted already). Have the child bend forwards and touch the toes to determine whether any scoliosis is structural. Scoliosis can occur in dozens of syndromes, including many skeletal dysplasias, several trisomies and a number of popular examination syndromes (fragile X, Marfan, NF-1, Noonan).

Do explain what you are doing as you proceed, so that the examiners will be aware of the significance of the manoeuvres.

Skin

The skin should be evaluated concurrently with inspecting from the front, back and side. Note any altered pigmentation: café-au-lait spots may occur with NF-1 and Russell–Silver; hypopigmented areas can occur in tuberous sclerosis. Freckling occurs in xeroderma pigmentosum and LEOPARD (multiple lentigines) syndromes. (The acronym stands for Lentigines, ECG changes, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, Deafness.) Small brown to blue–black macules occur in Peutz–Jeghers syndrome. Whorls of pigmentation occur in incontinentia pigmenti. Note any vascular malformations (e.g. Sturge–Weber, Klippel–Trenauney–Weber), telangiectasia (e.g. ataxia-telangiectasia, Osler’s haemorrhagic telangiectasia syndrome), or telangiectatic erythema in butterfly distribution over the malar area (e.g. Bloom, Cockayne). Ichthyotic skin can occur in CHILD syndrome (acronym for Congenital Hemidysplasia, Ichthyosiform erythroderma, Limb Defects). Alopecia or sparse hair may be noted in CHILD and Cockayne syndromes, as well as incontinentia pigmenti. The above are merely a small sample of the vast number of skin disorders within syndromal diagnoses.

Completing the examination

Formal physical examination flows well if commenced at the hands, working up to the head and then downward—essentially a head-to-toe pattern. Table 9.3 lists a small number of sample findings sought at each point.

Table 9.3 Dysmorphic child: measurements, manoeuvres and systematic examination

A. Measurements

Height

(If short, tall, or disproportionate:

Lower segment (LS)

Calculate upper segment (US) by subtracting LS from height

Calculate US: LS ratio

Arm span)

Head circumference

Request weight

Assess percentile charts

Calculate height velocity

Request birth parameters

Request parents’ percentiles and ages at puberty

B. Manoeuvres

• Hands and feet together, to detect asymmetry (e.g. Russell–Silver), hemihypertrophy (e.g. Beckwith–Wiedemann [B–W], McCune–Albright, Proteus) and unilateral growth arrest (e.g. homocystinuria with cerebrovascular accident)—this also detects approximation of shoulders (absent clavicles in cleidocranial dysostosis), genu valgum (e.g. homocystinuria), genu recurvatum (e.g. Marfan), and pes planus (e.g. Marfan)

• Arms by side with palms forward, to detect cubitus valgus (e.g. Turner, Noonan; over 15 degrees in girls; over 10 degrees in boys)

• Thumbs on shoulders, to detect short limbs: can detect if proximal, middle or distal segment shortening

• Palms up, to detect simian crease (e.g. Down, Seckel), clinodactyly (e.g. Russell–Silver, Down, Seckel)

• Make a fist, to detect short fourth metacarpal (e.g. Turner, FAS)

• Check extensibility for hyperextensibility (e.g. Marfan) and for limitation of extension (e.g. homocystinuria)

• Look at the back to detect short neck (e.g. Noonan, Klippel–Feil), or neck webbing (e.g. Turner, Noonan)

• Low hairline (e.g. Noonan, Klippel–Feil)

• Bend over and touch toes, to detect scoliosis (e.g. Noonan, Klippel–Feil)

C. Systematic examination Sitting up is the preferred position for the commencement of the systematic examination—the following is a selected listing of possible physical findings in children with dysmorphic features General inspection Diagnostic facies

• Dysmorphic syndromes (e.g. Russell–Silver, Down, Turner, Noonan, FAS)

Disproportionate stature

• Skeletal dysplasias (e.g. achondroplasia)

• Connective tissue disorders (e.g. osteogenesis imperfecta)

Tanner staging

• Advanced (e.g. McCune–Albright)

• Delayed (e.g. Noonan)

Nutritional status

• Obese (e.g. Prader–Willi, Bardet–Biedl)

• Poor (e.g. Marfan, homocystinuria)

Skeletal anomalies

• Asymmetry (causes of hemihypertrophy: B–W, NF-1)

• Pectus excavatum (e.g. Marfan, Noonan)

• Scoliosis (e.g. Noonan, Klippel–Feil)

Skin

• Vascular malformations (e.g. Klippel–Trenauney–Weber [K–T–W], Sturge–Weber)

• Hypopigmented macules (e.g. tuberous sclerosis)

• Café-au-lait spots (e.g. NF-1, Fanconi anaemia, Russell–Silver)

Upper limbs Structure

• Clinodactyly fifth finger (e.g. Russell–Silver, Shwachman–Diamond)

• Short fourth metacarpal (e.g. Turner, FAS)

• Trident hand (e.g. achondroplasia)

• Polydactyly (e.g. Bardet–Biedl)

• Contractures (e.g. distal arthrogryposis)

Nails

• Short (e.g. cartilage hair hypoplasia)

• Hyperconvex (e.g. Turner)

• Hypoplastic (e.g. FAS)

Palms

• Simian creases (e.g. Down)

Wrists

• Splaying (e.g. X-linked hypophosphataemic rickets)

• Contractures (e.g. ‘classic arthrogryposis’)

Pulse

• Radiofemoral delay (e.g. coarctation of aorta with Turner, NF-1)

Elbows

• Contractures (e.g. ‘classic arthrogryposis’)

Blood pressure: elevated (e.g. coarctation of aorta with NF-1, Turner, renal artery stenosis with NF-1, phaeochromocytoma with NF-1) Head Size

• Small (e.g. TORCH, numerous syndromes)

• Large (e.g. Sotos, X-linked hydrocephalus)

Shape

• Frontal bossing (e.g. achondroplasia)

Consistency: craniotabes (e.g. X-linked hypophosphataemic rickets) Fontanelle

• Large (e.g. Russell–Silver, X-linked hypophosphataemic rickets)

• Bulging (e.g. X-linked hydrocephalus with raised ICP)

Hair

• Sparse (e.g. hypohidrotic ectodermal dysplasia, progeria)

• Greasy (e.g. precocious puberty with NF-1)

Eyes Inspection

• Prominent (e.g. Crouzon)

• Microphthalmos (e.g. CHARGE, fetal rubella effects)

• Hypertelorism (e.g. Noonan, Williams)

• Epicanthal folds (e.g. Noonan, Williams, Turner, Down)

• Ptosis (e.g. Noonan)

• Squint (e.g. Williams, Prader–Willi, septo-optic dysplasia [SOD])

• Nystagmus (e.g. SOD)

Conjunctivae: pallor (e.g. Fanconi pancytopenia) Sclerae

• Icterus (e.g. Alagille)

• Blue (e.g. osteogenesis imperfecta)

Iris

• Aniridia (e.g. Wilms’ tumour, aniridia, genital anomalies, retardation syndrome [WAGR])

• Coloboma (e.g. WAGR, CHARGE)

• Brushfield’s spots (e.g. Down, Zellweger)

• Pale blue (e.g. fragile X, Angelman)

• Heterochromia (e.g. Waardenburg, K–T–W)

• Stellate (e.g. Williams)

Cornea

• Large and cloudy (buphthalmos): glaucoma (e.g. WAGR, fetal rubella effects, Marfan, NF-1)

• Keratoconus (e.g. Noonan)

Visual fields: field defect (e.g. brain tumour with NF-1) Eye movements

• Nystagmus (e.g. SOD, WAGR, Chédiak-Higashi)

• Lateral rectus palsy (e.g. Möbius sequence)

Cataracts (e.g. rubella, WAGR) Lens dislocation: Marfan (goes up), homocystinuria (goes down) Fundi

• Papilloedema (e.g. hydrocephalus with raised ICP)

• Optic nerve hypoplasia (e.g. SOD)

• Chorioretinitis (e.g. TORCH)

Nose Midface hypoplasia (e.g. FAS) Anosmia (e.g. Kallmann) Mouth and chin Central cyanosis: various forms of congenital heart disease (CHD) Midline defects

• Cleft lip (repaired): cleft lip sequence

• Cleft palate (repaired): cleft lip sequence

Teeth

• Hypodontia (e.g. incontinentia pigmenti, Williams)

• Irregularly placed (e.g. Down: Crouzon)

• Late eruption (e.g. incontinentia pigmenti, progeria)

Tongue

• Enlarged (e.g. B–W, Pompe)

• Ptosed (e.g. Pierre Robin sequence)

• Prominent (e.g. Down: small pharynx, normal-sized tongue)

Facial hair or acne (e.g. precocity with NF-1) Micrognathia (e.g. Pierre Robin sequence) Ears Low set (e.g. Turner, Noonan, Treacher Collins) Posteriorly rotated (e.g. Russell–Silver) Malformed (e.g. CHARGE, Treacher Collins, B–W) Hairline Low (e.g. Turner, Noonan) Neck Pterygium colli (e.g. Klippel–Feil, Turner, Noonan) Short (e.g. Klippel–Feil, Noonan, CHARGE) Scoliosis (e.g. Klippel–Feil) Chest Inspection

• Scars: repair of tracheo-oesophageal fistula (e.g. VACTERL, CHARGE), repair of diaphragmatic hernia (e.g. Marfan, DiGeorge [22q11])

• Tanner staging in girls, for precocity (e.g. McCune–Albright) or delay (Turner)

Nipples

• Wide-spaced (e.g. Turner, several trisomies)

• Hypoplastic (e.g. Poland anomaly)

Chest wall

• Sternal deformity: pectus excavatum or carinatum (e.g. Marfan, Noonan)

• Small thoracic cage (e.g. several skeletal dysplasias)

Palpation

• Praecordium (e.g. for CHD)

Auscultation

• Praecordium (e.g. for CHD)

Abdomen Inspection

• Scars: repair of duodenal atresia (e.g. Down), repair of Hirschsprung (e.g. Down, Waardenburg), removal of tumour (e.g. WAGR, adrenal tumour in B–W), repair of inguinal herniae (e.g. Marfan), repair of omphalocoele (e.g. B–W)

• Prune-like appearance (prune belly syndrome)

• Tanner staging pubic hair, for precocity (e.g. McCune–Albright) or delay (Klinefelter, Noonan)

Palpation

• Hepatomegaly (e.g. Shwachman–Diamond, storage diseases)

• Splenomegaly (e.g. storage diseases)

• Hepatosplenomegaly (e.g. various storage diseases)

• Enlarged kidneys (e.g. polycystic kidneys, hydronephrosis)

Auscultation

• Hepatic bruit (e.g. haemangioma, hepatocellular carcinoma associated with B–W)

• Renal artery stenosis (e.g. NF-1)

Posterior aspect

• Midline scar (e.g. spina bifida repair)

Genitalia Tanner staging genitalia

• Measure penis length

• Measure testes parameters; estimate testes volume

• Advanced stage (e.g. NF-1)

• Delayed stage (e.g. Noonan)

Penile anomalies

• Micropenis (e.g. Prader–Willi)

• Hypospadias (e.g. Noonan)

Testicular anomalies: cryptorchidism (e.g. Noonan) Gait, back and lower limbs Inspection of lower limbs

• Lower limb bowing (e.g. X-linked hypophosphataemic rickets)

• Proximal, middle or distal shortening (e.g. bony dysplasias)

• Oedema of dorsa of feet (e.g. Turner)

• Clubbing of toes (various types of CHD)

Palpation: ankle oedema (CCF with CHD) Gait—standard examination screening for:

• Long-tract signs (e.g. X-linked hydrocephalus; brain tumour with NF-1)

• Ataxia (e.g. ataxia-telangiectasia)

• Proximal weakness (e.g. myopathies, developmental dysplasia of hip)

Back

• Scoliosis (e.g. various skeletal dysplasias, NF-1)

• Kyphosis (e.g. achondroplasia)

• Focal spinal shortening (e.g. various skeletal dysplasias)

• Midline scar (spina bifida)

• Spinal tenderness (X-linked hypophosphataemic rickets)

Lower limbs neurologically

• Long-tract signs (e.g. brain tumour with NF-1)

B–W = Beckwith–Wiedemann; CCF = congestive cardiac failure; CHD = congenital heart disease; FAS = fetal alcohol syndrome; ICP = intracranial pressure; K–T–W = Klippel–Trenauney–Weber; LS = lower segment; NF = neurofibromatosis; SOD = septo-optic dysplasia; TORCH = intrauterine infections with toxoplasmosis, other (e.g. syphilis, HIV), rubella, cytomegalovirus, herpes (both simplex and varicella); US = upper segment; VSD = ventricular septal defect; WAGR = Wilms’ tumour, aniridia, genital anomalies, retardation syndrome.

Finally, summarise your findings succinctly, and give a brief differential diagnosis, placing the most likely diagnosis first.