Respiratory system involvement in Costello syndrome

Abstract

Costello syndrome (CS) is a multisystem disorder caused by heterozygous germline mutations in the HRAS proto-oncogene. Respiratory system complications have been reported in individuals with CS, but a comprehensive description of the full spectrum and incidence of respiratory symptoms in these patients is not available. Here we report the clinical course of four CS patients with respiratory complications as a major cause of morbidity. Review of the literature identified 56 CS patients with descriptions of their neonatal course and 17 patients in childhood/adulthood. We found that in the neonatal period respiratory complications are seen in approximately 78% of patients with transient respiratory distress reported in 45% of neonates. Other more specific respiratory diagnoses were reported in 62% of patients, the majority of which comprised disorders of the upper and lower respiratory tract. Symptoms of upper airway obstruction were reported in CS neonates but were more commonly diagnosed in childhood/adulthood (71%). Analysis of HRAS mutations and their respiratory phenotype revealed that the common p.Gly12Ser mutation is more often associated with transient respiratory distress and other respiratory diagnoses. Respiratory failure and dependence on mechanical ventilation occurs almost exclusively with rare mutations. In cases of prenatally diagnosed CS, the high incidence of respiratory complications in the neonatal period should prompt anticipatory guidance and development of a postnatal management plan. This may be important in cases involving rarer mutations. Furthermore, the high frequency of airway obstruction in CS patients suggests that otorhinolaryngological evaluation and sleep studies should be considered.

Costello syndrome: Clinical phenotype, genotype, and management guidelines

“…Complex pulmonary and airway co‐morbidities are present in a significant proportion of neonates and infants with CS (Gomez‐Ospina et al, ; Myers et al, ), and are more common and severe than in the general population, even accounting for prematurity. Upper and lower airway abnormalities as well as abnormalities of the lung parenchyma such as chronic lung disease occur.…”

“…Nasal papillomata are common in older individuals and may require removal. Obstructive or central sleep apnea (Della Marca et al, ), ongoing parenchymal lung injury, or the evolution of cardiopulmonary disease require early recognition and treatment (Gomez‐Ospina et al, ).…”

RASopathies: A significant cause of polyhydramnios?

“…These ultrasound features, either in isolation or combination, are considered an indication for follow‐up genetic testing 18,19 . The ability to identify pregnancies at risk for a RASopathy can help provide anticipatory guidance for associated adverse perinatal complications including respiratory complications, cardiac problems, and lymphatic abnormalities which can be difficult to detect solely by second trimester ultrasound or fetal echocardiogram 12,20 . For instance, Myers et al 12 reported congenital heart defects in 68% of newborns with Noonan syndrome, but a prenatal detection rate of only 21%.…”

A novel HRAS c.466C>T p.(Phe156Leu) variant in two patients with attenuated features of Costello syndrome

“…Respiratory and otolaryngologic findings as well as cardiovascular abnormalities have also been described in patients with CS (Table 1) [1]. Notably, airway problems requiring tracheostomy has been reported as rare complication in patients with CS and different HRAS variants; [1,14,17] thus, this finding is not related to specific (rare common) variants. On the other hand, individuals showed milder facial features than patients with HRAS p.Gly12Ser; this is more in keeping with findings seen in individuals with rare HRAS variants affecting residues Thr 58 , Gly 60 , Lys 117 or Ala 146 (Table 1) [1-3, 5, 7, 9-11, 18].…”