ESPE Abstracts

Introduction: Mutations in PTPN11 gene accounts for 50-60% of genetically identified patients with Noonan syndrome (NS). This report is of three siblings with familial NS due to mutation in PTPN11. Among the three, two of them have an additional mutation in PLOD1 gene and have normal height. The sibling who is shorter compared to the other two does not have this additional mutation. PLOD1 -related kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is an autosomal recessive disorder characterized by hypotonia, early-onset kyphoscoliosis, joint hypermobility, skin fragility, and ocular abnormality. The existence of such a double pathogenic mutation has not been reported in literature previously.

Case presentation: This is a report of 3 siblings, 14 year old boy, 12 year old girl and 10 year old girl, three of whom were confirmed to have Noonan syndrome in early childhood secondary to distinctive facial characteristics, hypotonia, motor and speech delay. They are being followed up at our center to monitor growth velocity. The boy has a growth rate of 6cm/yr and testicular volume of 5ml. The third sibling has a growth rate of 7cm/yr and Tanner stage B2. The middle sibling has a growth rate of 4.5cm/yr and absence of signs of puberty. The current height of the first and the third siblings are on the 97% centile on Noonan growth chart for boys (corresponds to above 50^th centile in normal population for age) and above the 97% centile on Noonan chart for girls (corresponds to above 50^th centile in normal population for age) respectively. The middle sibling’s current height is on 90^th centile on Noonan growth chart for girls (corresponds to above 3^rd centile for normal population for age). The three siblings were found to be heterozygous for Thr468Met variant in PTPN11 gene inherited from father. In addition to the PTPN11 mutation first and third siblings were found to be heterozygous for the R718H variant inherited from mother and T624M variant inherited from father in PLOD1 gene (both the variants are predicted to be likely pathogenic). The middle sister was negative for mutations in PLOD1 gene which could explain the shorter height compared to the other siblings.

Conclusion: PLOD1 mutations coexisting with PTPN11 could explain the presence of normal height in the first and third siblings as kEDS is generally associated with marfanoid habitus. Further studies are required to understand the role of PLOD1 in patients with Noonan syndrome due to PTPN11.