ESPE Yearbook of Paediatric Endocrinology

Horm Res Paediatr. 2021;94(11-12):456-466. PMID: 35086092

Brief Summary: This study reports 2 girls with a complex phenotype associated with severe short stature and IUGR who were diagnosed with a de novo 17p13. 3 deletion by array-CGH. The deletion involved the CRK gene that transcribes for Crk protein, a component of GH and IGF-I receptor signaling pathways. In vitro assay confirmed defective CRK expression and GH/IGF1 signaling in the patients’ peripheral blood mononuclear cells. The 2 children were treated with rhGH with a partial response in patient 1 and catch-up growth in patient 2, encouraging the use of rhGH to improve adult height in this condition.

This study reports two girls with a de novo 17p13.3 deletion and sharing a common phenotype characterized by intrauterine growth retardation, post-natal severe short stature, facial dysmorphisms and brain MRI abnormalities. The microdeletion harbors the CRK gene, which encodes for Crk, an intracellular adaptor downstream both GH and IGF-1 receptors (1, 2). In vitro assay analysis performed on PBMCs showed that reduced expression of CRK was associated with impaired GH/IGF-1 signaling, likely accounting for the pre- and post-natal growth failure of the two patients. rhGH treatment was effective in reducing growth deficit in one patient and inducing sustained catch-up growth in the other one.

Multiple pathogenic CNVs have been described in short children with history of intrauterine growth retardation (3). In particular, 17p13.3 anomalies are detected with a relative high frequency in short SGA children, suggesting that genes located in this region could play a key role in pre- and post-natal growth. This region is characterized by genomic instability and has been associated with isolated lissencephaly sequence (ILS) and Miller Dieker syndrome (MDS), characterized by facial dysmorphisms, microcephaly, short stature, seizures, cardiac malformations and different severity grades of cerebral agyria (4).

These findings show that CRK haploinsufficiency may represent the first example of a genetic disorder affecting both GH and IGF signaling, ultimately leading to pre- and post-natal growth failure.

Furthermore, the efficacy of rhGH therapy either in reducing growth deficit or stimulating catch-up growth, indicates that rhGH may be a therapeutic option in short children with 17p13.3 deletion and CRK haploinsufficiency.

References: 1. Feller SM. Crk family adaptors-signalling complex formation and biological roles. Oncogene. 2001;20:6348–71. 2. Goh EL, Zhu T, Yakar S, LeRoith D, Lobie PE. CrkII participation in the cellular effects of growth hormone and insulin-like growth fac- tor-1. Phosphatidylinositol-3 kinase dependent and independent effects. J Biol Chem. 2000 Jun 9;275(23):17683–92. 3. Inzaghi E, Deodati A, Loddo S, Mucciolo M, Verdecchia F, Sallicandro E, et al. Prevalence of copy number variants (CNVs) and rhGH treatment efficacy in an Italian cohort of children born small for gestational age (SGA) with persistent short stature associated with a complex clinical phenotype. J Endocrinol Invest. 2022;45(1):79–87. 4. Barros Fontes MI, Dos Santos AP, Rossi Tor- res F, Lopes-Cendes I, Cendes F, Appenzeller S, et al. 17p13.3 Microdeletion: insights on genotype-phenotype correlation. Mol Syndromol. 2017;8:36–41.