A Novel CREBBP Gene Mutation in a Patient with a CREBBP-related Neurodevelopmental Disorder
Joshua Siebeneicher1, Muhammad Khalid1, Vijayakumar Javalkar1, Sheila Asghar1, Ammar Husan1
1LSU shreveport
Objective:
To describe a case of a novel pathogenic CREBBP variant c.4283G>T (p.Arg1428Leu) with CREBBP-related neurodevelopmental disorder, distinct from Rubinstein-Taybi syndrome (RSTS) and Menke–Hennekam syndrome (MHS).
Background:
The CREBBP gene encodes CRB-binding protein, a coactivator that is involved in the transcription process. CREBBP gene mutations are classically known to cause RSTS and MHS. However, emerging evidence suggests a broader phenotypic spectrum, collectively referred to as CREBBP-related disorders, that are genetically and clinically distinct from RSTS and MHS. We present a case of CREBBP-related neurodevelopmental disorder with a novel pathogenic mutation.
Results:
An 8-year-old boy with a past medical history of global neurodevelopmental delay, epilepsy, dysmorphic facial features, and failure to thrive was presented to our clinic. He had no family history of genetic disorder. His exam was remarkable for an elongated face, long curly eyelashes, sparse eyebrows, low-set ears, microcephaly, bulbous nose tip, 6 cafe-au-lait spots, axillary freckling, and 2-3 toes with syndactyly. He had increased muscle tone and hyperreflexia in patellar and ankle reflexes. His MRI brain was unremarkable for any structural abnormality. Genetic panel testing identified a pathogenic CREBBP mutation (p.Arg1428Leu) (CGT>CTT): c.4283 G>T in axon 26 of the CREBBP gene (NM-004380.2) and a variant of undetermined significance in NF1 c.6999 G>A; p.K2333=. He was diagnosed with "CREBBP-related disorder". He did not meet the diagnostic criteria for either RSTS or MHS. He was referred to speech and physical therapy. Over time, he made developmental progress and was noted to be achieving milestones.
Conclusions:
The CREBBP-related disorders present with multiple abnormalities, not specifically attributed to RSTS and MHS. The CREBBP mutation in our patient was outside the known MHS-associated hotspot (exons 30-31). Additionally, he lacked several extremely common features of RSTS, such as broad thumbs, beaked nose, and cryptorchidism. Therefore, he was labelled as CREBBP- related disorder rather than RSTS or MHS.
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