Syndromes for Monday, June 1st, 2026

History

A term neonate with unremarkable antenatal and perinatal history, presented with left lower limb swelling with overlying hyperpigmentation upon birth. Physical examination showed increased temperature, with preserved perfusion and pulse over left lower limb. Cardiovascular and neurological examinations were normal. Patient remained active, stable and afebrile. Blood tests were unremarkable with normal platelet count and clotting profile. Magnetic resonance imaging (MRI) of bilateral lower limbs was later performed.

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Question

What is the most likely diagnosis? (choose one)

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Correct answer

Capillary malformation-arteriovenous malformation syndrome/Parkes Weber syndrome

Discussion

Capillary malformation-arteriovenous malformation syndrome is an autosomal dominant genetic disease first described in 2003, characterized by multifocal capillary malformations, often in association with fast-flow vascular malformations, including arteriovenous malformations (AVMs) and arteriovenous fistulas, and Parkes Weber syndrome. The AVMs can occur in the brain, face or extremities. Parkes Weber syndrome is a specific type of CMAVM that is characterized by overgrowth, capillary malformations/port-wine stains, with soft-tissue and skeletal hypertrophy of the affected limb. In severe cases, patient can complicate with cardiovascular events or high-output heart failure.

Clinical history is essential in narrowing the differential diagnosis for a neonate presenting with enlargement of a limb. Limb swelling due to acute acquired cause such as trauma/birth injury, infection or ischemia should be excluded and seldom face diagnostic challenge. Other key differential diagnoses include Klippel-Trénaunay syndrome, Parkes Weber syndrome, vascular tumour and other syndromal cause such as Proteus syndrome, Beckwith-Wiedemann syndrome, etc.

Klippel-Trénaunay syndrome and Parkes Weber syndrome are both vascular malformation syndromes that share similar clinical manifestations. The key distinction lies in the presence of significant arteriovenous fistulas in Parkes Weber syndrome, which are typically absent or minimal in Klippel-Trénaunay syndrome, characterized by a low-flow state.

Upon further history taking, patient’s father revealed history of mild left lower limb hypertrophy since birth with similar skin lesions, and remained otherwise asymptomatic.

Whole exome sequencing detected a paternally-inherited RASA1 nonsense variant, confirming the diagnosis of RASA1-related capillary malformation-arteriovenous malformation syndrome for the proband and father. MRI brain screening showed no intracranial vascular malformation. Management plan was discussed with multidisciplinary meeting with hematology, oncology, cardiac, neonatal team, surgeons, orthopaedics.

References

• Online Mendelian Inheritance in Man (OMIM) Coccia E, Valeri L, Zuntini R, Caraffi SG, Peluso F, Pagliai L, Vezzani A, Pietrangiolillo Z, Leo F, Melli N, Fiorini V, Greco A, Lepri FR, Pisaneschi E, Marozza A, Carli D, Mussa A, Radio FC, Conti B, Iascone M, Gargano G, Novelli A, Tartaglia M, Zuffardi O, Bedeschi MF, Garavelli L. Prenatal Clinical Findings in RASA1-Related Capillary Malformation-Arteriovenous Malformation Syndrome. Genes (Basel). 2023 Feb 22;14(3):549. doi: 10.3390/genes14030549. PMID: 36980822; PMCID: PMC10048332.