ESPE Abstracts

Introduction: NS is a relative frequent cause of short stature (ST) in pediatrics and its diagnosis is based on a combination of typical facial features, ST, chest wall defects, cardiac defects, developmental delay, cryptorchidism, lymphatic dysplasia, and family history (“Van Der Burgt Criteria”, revised 2007). Around 50% of NS patients presents a pathogenic variant in the PTPN11 gene. The overlap with other conditions, phenotypic changes with age and clinical variability expression leads to underdiagnosis of mildly affected patients. We present three ST patients (P1, P2, P3): with molecular diagnosis of NS that did not fulfill clinical criteria for diagnosis.

Case Reports: P1: 3.6y female with history of Intrauterine Growth Restriction (IUGR), ST (-2.93 sd), microcephaly, mild short limbs, prominent forehead, facial hypoplasia, and synophrys. Her mother had similar phenotype, with normal karyotype and normal SHOX gene study. P2: 1y female with history of IUGR, severed postnatal growth failure and significant feeding disorders. She had ST (-4.54 sd), relative macrocephaly, wide forehead, micrognathia, thin and sparse hair, joint hyperlaxity, and a small vascular forehead malformation. P3: 0.6y male with history of pre and postnatal growth failure, ST (-3.28 sd), microcephaly, mild developmental delay, pyramidal signs, and asymptomatic interatrial communication. He had prominent eyes, short nasal bridge, and protruding heels. He had normal karyotype. GH-IGF-1 axis evaluation suggested partial GH resistance in all patients, with normal/high peak of serum GH at the GH stimulation test. Serum IGF-1 levels were undetectable in P2 and normal/high in P2 and P3. P1 and P2 had good response to prolonged rhGH treatment. No variants were detected at GHR gene in all patients, IGF1R gene in P1 and P3, and G H1 gene in P2. Whole exome sequencing revealed a heterozygous pathogenic or probably pathogenic variant in the PTPN11 gene in the 3 patients (P1: p.(Thr73Pro); P2: p.(Ile221Met); P3: p.(Gly503Arg))

Discussion: None of our 3 patients met the combination of the clinical criteria proposed for NS. Patients with a biochemical pattern of GH resistance and indetermined phenotype may be NS, representing a challenge for diagnosis.

Concluding Remarks: Being aware of mildly phenotype of NS in pediatric ST patient will allow an earlier diagnosis andadequate multidisciplinary long-term follow-up.