DeCure for Orofaciodigital syndrome 19

Orofaciodigital syndrome type I is an X-linked dominant condition with lethality in the vast majority of affected males, and the other types show autosomal recessive inheritance. In a 2007 report of twin girls, buccal exploration, cephalometric examination, and genetic analysis identified a previously unreported causative mutation in the OFD1 gene: a nucleotide change 243C>G leading to the missense mutation H81Q in exon 3. A 2013 case of a seven-year-old Indian girl with OFDS type I had most of the typical features and also nephrocalcinosis. A 2020 report described a young Indian child with sparse hairs, milia over the face, absence of the corpus callosum, and a frameshift pathogenic variant in exon 13 of the OFD1 gene, consistent with OFD1.

Cystic kidney disease was reported in an infant with orofaciodigital syndrome type I in a 1992 case, which the authors noted had not previously been described in an infant with the syndrome. That same girl also had unilateral tibial pseudarthrosis, which the authors stated had only rarely been reported in orofaciodigital syndromes and in type II only. A 2022 report described a male patient with OFD syndrome type XVI, caused by a homozygous variant of TMEM107 (p.Phe106del), who additionally had tibial dysplasia, a finding the authors called pivotal for OFD syndrome type IV. His family history included two fetuses with anencephaly with or without cleft lip/palate and polydactyly, but no genetic information was available for them.

The 1992 authors emphasised that an exact diagnosis among the orofaciodigital syndromes is important for genetic counselling because the inheritance patterns differ. The 2007 authors noted that their patients were diagnosed as having Orofaciodigital I syndrome. The 2013 authors reported that their patient had nephrocalcinosis. The 2020 authors stated that OFD1 presents in females with mutations in CXorf5 or OFD1 gene. The 2022 authors advised careful attention in interpreting this rare pattern.

What is still missing is any systematic clinical trial or prospective cohort that tests a treatment for any orofaciodigital syndrome subtype. No drug has been studied in these patients in the available literature. The evidence consists entirely of case reports and small case series describing genetic findings and clinical features. There is no data on disease progression, no validated outcome measures, and no patient stratification beyond genetic subtype. Funding for natural history studies and for developing any intervention is absent.