Orofaciodigital syndrome

Oral-facial-digital syndromes (OFDS) are rare genetic disorders characterised by the association of abnormalities of the face (hypertelorism, low-set ears), oral cavity (lingual hamartoma, abnormal frenulae, lobulated tongue) and extremities (brachydactyly, polydactyly). Depending on the OFDS type, additional features like polycystic kidney disease, agenesis of the corpus callosum, tibial dysplasia, vermis hypoplasia, microcephaly, and retinopathy may be present. OFDS type I usually presents at birth with characteristic oral, facial, and digital anomalies. In a few cases, the diagnosis emerges only after polycystic kidney disease is identified in later childhood or adulthood. Because OFDS type 1 is X-linked, it is typically lethal in males before birth, and its severity in females varies widely due to random X-chromosome inactivation. Conversely, the other forms of OFDS (types II–XIII) can fully affect both sexes, often requiring multi-gene panel testing to differentiate their unique recessive mutations.

For OFDS type I, an estimated annual incidence of 1 in 50,000 live births has been reported. Almost all liveborn patients are females. The other OFDS types are considered exceptionally rare with an estimated prevalence of less than 1 in 1,000,000 for each.

OFDS type 1 is caused by germline pathogenic variants in OFD1, which encodes a centriole and centriolar satellite protein required for ciliogenesis and left-right asymmetry determination, with additional roles in microtubule organisation, cell-cycle progression, and protein-quality balance. Most pathogenic variants are truncating and predicted to cause loss of function, although a dominant-negative effect is possible because the OFD1 transcript escapes X-chromosome inactivation. The remaining types II–XIII are caused by biallelic variants in distinct genes that encode critical components of the primary cilium or basal body complex (such as NEK1 for Type II and CPLANE1 for Type VI).

OFDS type I is inherited in an X-linked dominant manner. The condition is observed almost exclusively in females; most affected males are presumed to die in utero, although a few liveborn affected males have been reported. Approximately 75% of affected females represent simplex cases carrying a de novo OFD1 pathogenic variant, while the remaining 25% have an affected mother. The other OFDS types show autosomal recessive inheritance. Prenatal molecular testing is technically possible once the familial pathogenic variant(s) have been identified.

No consensus clinical diagnostic criteria for OFDS type I have been published; the diagnosis is established by identification of a pathogenic variant in OFD1. Kidney ultrasound shows renal cysts in at least 50% of individuals. Brain MRI most commonly demonstrates intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation; hand radiographs often show fine reticular radiolucencies of the phalanges.

Main differential diagnoses include:

• Autosomal dominant : renal cysts develop from tubules only, kidneys are larger and more malformed, and there are no oral, facial, digital, or brain anomalies
• with oral-facial-digital features: brain MRI shows the molar tooth sign and cerebellar vermis hypoplasia; autosomal recessive inheritance

• Establishing the diagnosis through identification of the underlying pathogenic variant
• The molecular diagnosis is the prerequisite for targeted medical care, enabling specific and individualised surveillance and clinical management
• Allowing predictive testing of at-risk family members once the familial pathogenic variant has been identified

• Bruel AL, Franco B, Duffourd Y, et al. Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes. J Med Genet. 2017;54(6):371-80. doi:10.1136/jmedgenet-2016-104436. PMID:; PMCID:PMC5557276.
• Franco B, Bruel AL, Thauvin-Robinet C. Oral-facial-digital syndrome type I. 2023 May 11. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: PMID:20301367.
• Pezzella N, Bove G, Tammaro R, Franco B. OFD1: one gene, several disorders. Am J Med Genet C Semin Med Genet. 2022;190(1):57-71. doi:10.1002/ajmg.c.31962. PMID:; PMCID:PMC9303915.