medwireNews: The genetic causes of short stature are highly heterogenous and a new classification system for these children is needed, delegates were told at the 58th Annual ESPE Meeting in Vienna, Austria.

Jesús Argente (Hospital Infantil Universitario Niño Jesús, Madrid, Spain) proposed a system with six categories for children with genetic short stature.” These were:

  • Hypothalamic-pituitary alterations (isolated growth hormone [GH] deficiency, combined pituitary hormone deficiency).
  • Peripheral axis abnormalities (GH resistance, insulin-like growth factor [IGF]-1 resistance, IGF-2 resistance, IGF2 deficiency, acid-labile subunit deficiency, pregnancy-associated plasma protein [PAPP]-A2 deficiency).
  • Skeletal dysplasias with minor stigmata (Leri-Weill dyschondrosteosis, Langer dysplasia and others).
  • Syndromes with microcephaly (Seckel syndrome spectrum disorders, microcephalic osteodysplatic primordial dwarfism, 3M syndrome, Meier-Gorlin syndromes).
  • Syndromes and imprinting disorders (Silver-Russell Syndrome, Prader-Willi Syndrome, Temple Syndrome, Kagami-Ogata Syndrome).
  • Other syndromes (RASopathies).

He then talked about more recently discovered genetic mutations associated with short stature with mild skeletal findings, such as ACAN, NPPC, NPR2 and FBN1, or microcephaly and syndromic short stature, ie, DONSON, PLK4 and TOP3A, and asked whether the conditions associated with these mutations are being adequately diagnosed and treated.

Argente suggested that serum markers, auxology and bone age play an important role in the diagnosis of genetic short stature. For example, a patient with elevated IGF-1 levels should be further investigated for mutations in IGF1R or PAPP-A2 genes, while a patient with elevated serum IGF-1, IGF-2, BP-3 and ALS levels should be investigated for PAPP-A2 mutations.

He added that auxology is becoming “more and more relevant” because it “tells us a lot” about these patients”.

Argente also presented a flow-chart to help physicians decide which patients with short stature should undergo genetic testing. These included, among others, children with disproportionate short stature, patients with proportional short stature of prenatal origin and those with proportional short stature of postnatal origin with data suggesting a probable pathological origin.

Argente concluded that “new generation sequencing techniques will continue to discover genes implicated in the regulation of human growth, which will benefit patients by allowing management and counselling specific for the disorder and may reveal novel treatment approaches.”

By Laura Cowen

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