CLAPO syndrome

CLAPO syndrome (OMIM 613089) was first described in 2008 in six unrelated patients (López-Gutiérrez JC et al. (2008). CLAPO is the acronym for: "Capillary vascular malformation of the lower lip, Lymphatic malformations of the head and neck, Asymmetry and Partial or generalized Overgrowth". CLAPO is a rare capillary, partial or generalized overgrowth syndrome with a diagnostically groundbreaking, usually congenital capillary malformation (CM) of the lower lip.

In a well-documented cohort of patients with CLAPO syndrome, activating PIK3CA mutations were detected in affected tissues in the majority of patients examined. The activating PIK3CA variants were previously described as the cause of the PROS spectrum. It can therefore be assumed that CLAPO belongs to the PROS family of somatic syndromes (Rodriguez-Laguna L et al. 2018).

The characteristic capillary lower lip malformation of CLAPO syndrome (capillary malformation of the lower lip, lymphatic malformations of the face and neck, asymmetry and partial or generalized overgrowth, lymphedema of the extremities) can also occur as an isolated lesion or with only minor abnormalities, supporting the concept that a wide spectrum of malformations exists in CLAPO syndrome.

The CM of the lower lip is always in the midline, with a symmetrical distribution, between 2 and 11 cm, with well-defined borders in several patients, and often affects the part of the skin under the lip or the intraoral mucosa. Tongue involvement is possible. Three different patterns are observed in the changes of the lower lip (Rodriguez-Laguna L et al. (2018):

• Narrow midline CM with reddish color
• Wide CM covering the entire lower lip with a predominant brown/purple color
• Wide involvement of the mucosal area of the lower lip

Surgical correction of lip overgrowth. Preoperative treatment with rapamycin can successfully reduce the size of the vascular malformation.

While midline facial CMs are often correlated with brain lesions in patients with megalencephalic capillary malformation syndrome (MCAP), CLAPO patients show no psychomotor delay or intellectual deficit (Rodriguez-Laguna L et al. 2018).

1. Denorme P et al. (2018) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum: A brief report. Pediatr Dermatol 35:e186-e188.
2. Downey C et al. (2018) Lower lip capillary malformation associated with lymphatic malformation without overgrowth: Part of the spectrum of CLAPO syndrome. Pediatr Dermatol 35:e243-e244.
3. González-Hermosa MR et al. (2019) CLAPO syndrome: Effective response to treatment with oral rapamycin. Dermatol Ther 32:e12991.
4. Ivars M et al. (2020) Clinical overlap between CLAPO syndrome and macrocephaly-capillary malformation syndrome. J Dtsch Dermatol Ges 18:479-482.
5. Krämer D et al. (2016) CLAPO syndrome: case report. Int J Dermatol 55:1149-1150.
6. López-Gutiérrez JC et al. (2008) Capillary malformation of the lower lip, lymphatic malformation of the face and neck, asymmetry and partial/generalized overgrowth (CLAPO): report of six cases of a new syndrome/association. Am J Med Genet A 146A: 2583-2588.
7. Rodriguez-Laguna L et al. (2018) CLAPO syndrome: identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype. Genet Med 20:882-889