Respiratory papillomatosis, juvenile recurrent, congenital J38.1

Congenital juvenile respiratory recurrent papillomatosis is an autosomal recessive inherited disorder (homozygous missense mutation in the NLRP1 gene/606636) characterized by recurrent growth of papillomas in the mucosal region of the upper respiratory tract, particularly the larynx.

Drutman et al (2019) identified a homozygous missense mutation in the NLRP1 gene (T755N; 606636.0008). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient-derived keratinocytes and HEK293 cells transfected with the mutation showed expression of the mutant protein, which underwent spontaneous oligomerization. The cultured immortalized keratinocytes, showed increased production of IL1B (147720), consistent with increased activation of the inflammasome and a gain-of-function effect.

Patients present in early childhood with hoarse voice and, in severe cases, respiratory stridor due to airway obstruction. Affected individuals may also present with dermatologic abnormalities (palmo plantar warts, keratosis pilaris syndrome, facial atrophoderma vermiculata).

While JRRP is a genetic disorder due to abnormal activation of the immune system, respiratory recurrent papillomatosis (RRP) is generally associated with acquired HPV infection, usually HPV types 6 and 11 (abstract by Drutman et al.2019). Within HPV subtypes, they are considered ''low risk'' or generally not associated with malignancy. Less commonly, RRP is caused by HPV types 16, 18, 31, and 33. In neonates, vertical transmission from an infected mother with prominent genital warts at the time of delivery has been documented.

Drutman et al (2019) reported 2 brothers with JRRP born to consanguineous Belgian parents. The older patient presented at 5 years of age with hoarseness and recurrent laryngitis associated with papillomas in the glottis and supraglottis, requiring 8 surgical ablations within 1 year. The younger brother presented with hoarseness shortly after birth and was diagnosed with laryngeal papillomatosis at 20 months of age. Both patients also had dermatologic abnormalities: palmo plantar warts, keratosis pilaris syndrome, atrophoderma vermiculata of the face.

1. Drutman SB et al (2019) Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis. Proc Nat Acad Sci 116: 19055-19063.