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Fifteen-minute consultation: Assessment, surveillance and management of hemihypertrophy
  1. Catherine Mark1,
  2. Caroline Hart2,
  3. Anthony McCarthy3,
  4. Andrew Thompson3,4
  1. 1 MRC centre for medical mycology, Aberdeen Royal Infirmary (Foresterhill Hospital), Aberdeen, Scotland, UK
  2. 2 Department of Paediatrics, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland, UK
  3. 3 Children’s Haematology Unit, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland, UK
  4. 4 General Paediatrics, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland, UK
  1. Correspondence to Catherine Mark, MRC centre for medical mycology, Aberdeen Royal Informary (Foresterhill), Aberdeen AB25 2ZN, UK; catherinemark{at}hotmail.co.uk

Abstract

This article aims to provide a structured and concise guide for the general paediatrician managing a child with hemihypertrophy. Hemihypertrophy is a relatively uncommon condition. The significance is that a proportion of those affected are at risk of developing malignancies in childhood. For these children regular surveillance is required. We have outlined how one might assess and investigate a child presenting with hemihypertrophy. We have also formulated a practicable surveillance strategy which is in line with the current Royal College of Paediatrics and Child Health (RCPCH) guideline ‘Wilms’ tumour surveillance in at-risk children’.

  • hemihypertrophy
  • childhood
  • paediatric practice
  • malignancy

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Introduction

Hemihypertrophy is defined as overgrowth of one side of the body relative to the other leading to asymmetry. The overgrowth process can involve soft tissue, bony structures or both. The resulting asymmetry may be limited to a limb, the face or may involve one side of the body in its entirety. Associated hypertrophy of internal organs can occur.1

Hemihypertrophy is  a feature of syndromes such as Beckwith-Wiedemann and Klippel-Trenaunay-Weber but also  occurs as an isolated finding termed ‘isolated hemihypertrophy’. The terms hemihypertrophy and hemihyperplasia are used interchangeably in the literature. The latter is more physiologically correct; the underlying pathology being an increase in cell proliferation rate, in the affected body part, rather than an increase in cell size.1–4

Incidence has been reported in the range of 1 in 13 000 to 1 in 86 000 live births.5 6 Hemihypertrophy is more prevalent in girls and more often affects the right side of the body.2

There is an established association between hemihypertrophy and increased risk of cancer, most commonly Wilms’ tumour and hepatoblastoma. Other tumours can be found such as neuroblastoma, adrenocortical tumours and sarcoma.1 2 4 7 For children with isolated hemihypertrophy, the risk of Wilms’ tumour is between 3% and 6% but tends to be somewhat higher in children with a combination of both hemihypertrophy and Beckwith-Wiedemann syndrome.8

The Royal College of Paediatrics and Child Health (RCPCH) guideline ‘Wilms’ tumour surveillance in at-risk children’ advises on the management of children with isolated hemihypertrophy and overgrowth syndromes.9 It is extrapolated from a 2006 peer-reviewed paper in which the authors propose that all ‘at-risk’ children should undergo genetic testing.10 Thereafter, only those with specific genetic abnormalities and an associated risk of malignancy >5%, should be enrolled in a tumour surveillance programme.10

There are challenges and limitations with currently available genetic testing.11 Our ability to accurately differentiate between subtypes of individuals with hemihypertrophy continues to evolve.

An international review regarding the management of Beckwith-Wiedemann syndrome and hemihypertrophy is under way, the results of which may alter the existing RCPCH guideline. In view of this rapidly evolving area, we would recommend that all patients referred to paediatrics with hemihypertrophy be enrolled on a tumour surveillance pathway pending results of genetic testing.

Case report

A 10-month-old girl is referred to the paediatric outpatient clinic. Her General Practitioner  is concerned that her lower limbs appear ‘asymmetrical’. The referral letter states that the infant was delivered at term via caesarean section due to breech presentation. She had a normal follow-up ultrasound scan of her hips. She is noted to be meeting her developmental milestones appropriately.

The infant’s mother reports that from 3 months of age she has felt the girl’s right leg to be larger than her left.

On examination, the infant is thriving, following the 50th centile for all growth parameters. The right leg does indeed have a larger circumference than the left when measured. Otherwise the infant examines normally. How should one approach and manage this case?

Clinical approach

The general paediatrician will be the first point of referral for many patients presenting with hemihypertrophy. They should be able to assess the child, coordinate necessary investigations and plan surveillance.7

The asymmetry may be

  1. within normal variation (i.e. not true hemihypertrophy)

  2. secondary to an isolated anatomical variant

  3. associated with a recognised syndrome

  4. isolated hemihypertrophy

A detailed history, particularly focusing on perinatal events and early development, must be taken. A neonatal history detailing hypoglycaemia and umbilical hernia would raise suspicion of Beckwith-Wiedemann syndrome. A history of evolving skin lesions could point to neurofibromatosis or McCune-Albright syndrome.1 Remember, none of these syndromes, nor indeed isolated hemihypertrophy, may be evident at birth and parents may state that asymmetry was not apparent until the child was a few months of age.12 Enquiring about other family members with asymmetry is essential; Beckwith-Wiedemann in particular can, with variable phenotypical manifestations, affect numerous family members.

A thorough systemic examination is required to determine the nature of hemihypertrophy and direct investigation and follow-up. There are no defined measurements which would differentiate a diagnosis of hemihypertrophy from normal growth variation. A pragmatic approach to examination should be taken; ask yourself, is the asymmetry apparent ‘from the end of the bed’? If so, then a diagnosis of hemihypertrophy should be considered.4

When examining patients with hemihypertrophy, there are several key elements that the clinician should consider (see figure 1).

Figure 1

Key questions to consider when examining the child with hemihypertrophy

Figure 2 lists the more common differential diagnoses the clinician may reach following assessment. This list is far from exhaustive but acts as a useful and succinct starting point.2

Figure 2

Classifying hemihypertrophy

Investigation and confirmation of the diagnosis

The diagnosis may be obvious based on the history and clinical examination. Conversely, the underlying aetiology may be less clear. Regardless, one must always seek input and review of the child by a clinical geneticist at the time of initial assessment. This allows for genetic testing, assessment of tumour risk following review of test results and counselling as required. Referring all children ensures that those with soft phenotypic features of a genetic syndrome are not missed by the general paediatrician and inappropriately discharged from follow-up.13

The specifics of genetic testing should be directed by the clinical geneticist. The genetic basis of certain overgrowth syndromes, such as Klippel-Trenaunay-Weber, is unknown. Beckwith-Wiedemann syndrome is complex but all known molecular anomalies, identifiable in up to 80% of patients, affect chromosomal locus 11p15.5.7

Genetic testing has shown that a significant number of patients with isolated hemihypertrophy, despite having an absence of other syndromic features, have one of three epigenotypes associated with Beckwith-Wiedemann syndrome. This impacts on their predisposition to tumour growth. Certain molecular defects in isolated hemihypertrophy are strongly associated with tumour risk. For example, patients with paternal uniparental disomy (pUPD) for chromosome 11p15 are at higher risk (>5%).14

Complications and surveillance guideline

Surveillance is essential, initially for all patients with hemihypertrophy pending evaluation by a clinical geneticist and, thereafter, on a continuing basis until age 5–7 years for those stratified as genetically high risk. Parents may decide that they wish to continue with surveillance regardless of their child’s low-risk status.

For the most commonly occurring tumours, prognosis is good particularly if disease is localised. Wilms’ tumour has a >90% cure rate for localised disease and hepatoblastoma has a 5-year event-free survival rate of >80%.15 Surveillance aims to identify early-stage and localised disease.

Abdominal ultrasound scan (USS) is a cheap and widely accessible imaging modality. This is the surveillance tool of choice for all children with molecular abnormalities associated with tumour development. Abdominal USS screening leads to reduced late-stage presentation of Wilms’ tumour.16 The interval between scans has been debated, though advice sits somewhere between 3 and 6 months.9 16 Ultrasonography should be undertaken by an experienced radiologist trained in scanning paediatric patients.

We recommend that scans should be undertaken every three months and no less frequently than three times a year. The recommendations from the Children’s Cancer & Leukaemia Group and the RCPCH are that it is reasonable to stop ultrasound surveillance at age 5–7 years (7 years for those with conditions such as Beckwith-Weidemann syndrome or certain genetic mutations associated with familial Wilms' tumour).9 17

Serum alpha fetoprotein (AFP), a tumour marker for hepatoblastoma, can detect hepatoblastoma before it is visible on USS. Many children with overgrowth syndromes have baseline elevated levels of AFP, therefore, serial measurement and plotting of the trend is required.18

Due to the challenges surrounding interpretation of raised AFP and the invasive nature of this test, it is currently proposed that AFP screening be considered for those with paternal uniparental disomy of chromosome 11p15 or loss of methylation at IC2 genetic defects only.19 For these patients, AFP should be checked on a 3-monthly basis, coordinated with abdominal USS.20A single elevated AFP with a normal abdominal USS can be repeated at 1 month. As 90% of hepatoblastomas occur before age 4, after this age serial measurement of AFP can be discontinued.7

Provided the clinician is following the surveillance guideline outlined in table 1, abdominal examination need only be carried out during routine clinic review (6–12 monthly). The benefits of teaching parents’ abdominal palpation are largely anecdotal,that being said, there is no evidence that teaching has an adverse effect.4

Table 1

A recommendation for tumour surveillance in patients with hemihypertrophy: 

Case study conclusion

Our patient attended clinical genetics and was determined to have idiopathic hemihypertrophy. On genetic testing she had a molecular abnormality associated with a >5% risk of tumour development She continued on a tumour surveillance regimen. At 3 years of age, a small mass arising from the right kidney was found on abdominal USS. She was diagnosed with early-stage Wilms’ tumour and successfully treated with chemotherapy.

References

Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.