FIBP – Thauvin-Robinet-Faivre Syndrome

Thauvin-Robinet-Faivre syndrome (TROFAS) is a rare autosomal recessive overgrowth disorder characterized by generalized overgrowth, dysmorphic facial features, intellectual disability, and variable congenital malformations. Causative biallelic variants in the intracellular binding protein gene FIBP underlie the syndrome, which to date has been reported in only a handful of families. The typical presentation includes prenatal and postnatal overgrowth, macrocephaly, facial dysmorphism, renal anomalies, and neurodevelopmental delay.

Genetic evidence stems from three affected individuals across two families: a 4-year-old male with global developmental delay, recurrent pneumonia, chronic lung disease, drooling, hypoplastic nipples, unilateral cryptorchidism and overgrowth harboring a homozygous c.415_416insCAGTTTG (p.Asp139AlafsTer3) variant ([PMID:37218527]), and two siblings with intellectual disability, macrocephaly and facial dysmorphism carrying the same homozygous variant ([PMID:37876348]). Segregation of the variant with disease was observed in one additional affected sibling, supporting autosomal recessive inheritance.

The c.415_416insCAGTTTG (p.Asp139AlafsTer3) frameshift is predicted to cause loss of the C-terminal FIBP domain, consistent with a loss-of-function mechanism. While no direct functional assays have yet been reported, the variant’s truncating nature and concordance with clinical phenotype across multiple individuals support pathogenicity.

No conflicting evidence to date has been reported challenging the FIBP–TROFAS association. Additional functional studies and wider population screening could further clarify the gene’s role in overgrowth and tumor susceptibility.

In summary, limited but concordant genetic evidence from three probands and segregation in one relative establishes a limited-level association between FIBP and Thauvin-Robinet-Faivre syndrome. Key take-home: Biallelic truncating variants in FIBP cause AR overgrowth syndrome with macrocephaly, intellectual disability and variable pulmonary and renal anomalies, informing diagnostic genetic testing and counselling.

References

• American journal of medical genetics. Part A | 2023 | Expanding the phenotype and genotype in Thauvin-Robinet-Faivre syndrome: A new patient with a novel variant and additional clinical findings. PMID:37218527
• American journal of medical genetics. Part A | 2024 | New cases of recently described Thauvin-Robinet-Faivre syndrome with a novel homozygous FIBP gene variant. PMID:37876348

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