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Monitoring for Permanent Consequences

Author(s): Euro Histio Net Work Group for LCH Guidelines (see introduction page), Created: 2011/05/20, last update: 2014/02/09

General Considerations; Diabetes insipidus; Hormone Deficiency; Orthopaedic Sequelae; Problems with Ears, Oral Tissue and Jaw; Neurological Sequelae; Damage of Lung and Liver

General Considerations

Although LCH is a mostly benign and treatable disease, it can result in sequelae affecting various tissues involved. Some may be present or even precede diagnosis, while other may become manifest later. It is thus important to keep monitoring these patients at least until growth is completed and possibly into adult life. The most common long-term consequences are endocrine and growth, auditory, and orthopedic. Neurocognitive, pulmonary and liver sequelae are rare but cause major morbidity. The frequency of investigations and tests that are recommended are shown in Tests and Frequency, Table 7.

A scoring system for sequelae has been developed in order to observe the evolution [Nanduri et al 2006].

Diabetes Insipidus

Diabetes insipidus (DI) is the most frequent endocrinopathy associated to LCH with incidence ranging between 15 to 50% of cases. It is due to involvement of posterior pituitary gland and may become manifest either before, concurrently or after LCH diagnosis. It is thus important to always investigate thirst and polyuria in LCH patients, even many years after diagnosis. In case of symptoms investigate according to Scenarios - Additional Testing.

Hormone Deficiency

Growth hormone deficiency is the most frequent anterior pituitary hormone loss and is seen in up to 10% of patients. Other problems include delayed puberty and rarely panhypopituitarism. Measurement of height and weight and assessment of puberty is therefore recommended every 6 months or 1 year until growth is completed.

Growth

Ideally, standardized equipment, such as a Harpenden stadiometer or other similar stadiometer should be used, and by the same operator. Measurements must be plotted onto appropriate growth charts (National growth charts if available, or WHO charts) and assessed in relation to parents’ heights.
Serial measurements should be plotted. Standard deviation (SD) scores for age, sex and country should be calculated where possible and plan for investigations as below.

Indications for investigation of growth:

Criteria for investigation are taken from the Consensus guidelines of the GH Research Society [GHRS 2000].

If SD scores are available:

  • Any child with severe short stature defined as a height more than 3SD below the mean
  • Height more than 1.5 SD below mid-parental height
  • Height more than 2 SD below the mean and a height velocity > 1SD below mean for age
  • In the absence of short stature, a height velocity more than 2SD below the mean over 1 year or 1.5 SD over 2 years

If SD scores are not available:

  • Any child between the ages of 2 and 10 years who is growing at less than 5 cms per year (this child has a low height velocity, and will drop below the expected percentile with time)
  • Any child whose height is well below the expected percentile for parents’ heights
  • Children with excessive weight gain in relation to height
  • Any child who does not have an adequate pubertal growth spurt despite onset of puberty

Puberty

Assess puberty according to Tanner stages starting from age 8 years in girls and 9 years in boys.

Indications for investigation of puberty:

  • Delayed onset of puberty (B2 > 13 years in girls, P2, T2 > 14 years in boys)
  • Delayed onset of periods (menarche) in girls (> 14 years)
  • Precocious puberty (B2 < 8 years in girls, P2, T2 < 9 years in boys)
  • Arrest or regression of pubertal development (a child who starts pubertal development at correct time, but then does not progress or has loss of secondary sexual characteristics)

Suggested Investigations for Delayed Growth/Puberty

  • Bone age assessed on X ray
  • Anterior pituitary function tests (in those with poor growth / delayed puberty depending on the suspected deficit)
  • MRI scan of head (details see here) if there is any hormone deficiency
  • Bone mineral density (DEXA) scan needs to be monitored in patients with GH deficiency, delayed puberty, panhypopituitarism
  • Consider karyotype analysis in girls with delayed puberty and short stature as they might have Turner syndrome

Anterior pituitary function test must include:

  • Stimulation of GH secretion using Insulin, Glucagon or Arginine stimulation test
  • Gonadotropin releasing hormone/luteinizing hormone releasing hormone (GnRH, LHRH) test to assess LH and FSH secretion in case of suspicion of hypogonadotropic hypogonadism
  • Thyroid function test
  • Cortisol levels

Orthopaedic

Lesions of the vault of the skull and the long bones of the limbs usually heal without major problems. However, when vertebrae are affected scoliosis may become manifest later in life, in particular during periods of rapid growth such as puberty. Children should be assessed clinically at least annually in particular during puberty in order to identify any early signs of scoliosis. They should be referred to the orthopaedic surgeon in order to start preventative physical therapies (e.g. orthopaedic corset/ brace, or neck collar) in order to manage this proactively.

If facial bones are affected by the disease, facial asymmetry may become manifest as the child grows and reconstructive surgery may be required.

Ears

Subjects with disease involvement of the middle or inner ear and the temporal bone should be monitored with audiometry at diagnosis and at end of treatment and reassessed at start of school and if any new symptoms develop. Early diagnosis and interventional strategies such as hearing aids can avoid deterioration of school performance and significantly improve outcome.

Oral Tissue and Jaw

Subjects with LCH involvement of gums and jaw should be monitored for dental development and growth of the jaw, as they might need orthodontic surgery.

Neurological

Children with multisystem LCH are at risk of developing late neuropsychological sequelae, in particular cerebellar ataxia and learning difficulty. All children with multisystem LCH should be regularly followed up clinically. In those children where there is a significant history or clinical neurological abnormality further investigations should be performed as below.

  1. Neuropsychological tests – IQ, memory and attainment
  2. Cerebellar function assessment according to the Ataxia rating scales [Schmahmann et al 2009; Trouillas et al 1997].
  3. MRI of the head (details see here)

Lungs

In those children with a history of lung involvement spirometry should be performed regularly and if abnormal may need X ray and HR-CT of chest.

The dangers of smoking should be explained and smoking avoided.

Liver

Liver involvement is rare, but can have serious morbidity. Only those with abnormal liver function might need further investigation including ultrasound scan of liver or cholangiography.

References

[Nanduri et al 2006] Nanduri VR, Pritchard J, Levitt G, Glaser AW: Long term morbidity and health related quality of life after multi-system Langerhans cell histiocytosis. European journal of cancer (Oxford, England : 1990) 2006, 42: 2563 [PMID: 16959486]

[GHRS 2000] Growth Hormone Research Society: Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J clin endocrinol Metab. 85:3990-3

[Schmahmann et al 2009] Schmahmann JD, Gardner R, MacMore J, Vangel MG: Development of a brief ataxia rating scale (BARS) based on a modified form of the ICARS. Movement disorders : official journal of the Movement Disorder Society 2009 Sep 15; 24: 1820 [PMID: 19562773]

[Trouillas et al 1997] Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timann D, Honnorat J, Nighoghossian N, Manyam B: International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. Journal of the neurological sciences 1997 Feb 12; 145: 205 [PMID: 9094050]