ESPE Abstracts

Baraitser-Winter cerebrofrontofacial syndrome (BWCFF; ORPHACODE 2995) is a multiple congenital anomaly syndrome characterized by distinct craniofacial features and intellectual disability. Affected individuals often present with pachygyria, predominantly in frontal regions, shoulder girdle muscle wasting, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability varies and correlates with the severity of brain malformations. Commonly associated conditions include seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction. Endocrinological manifestations include short stature, hypothyroidism, cryptorchidism, and micropenis. The diagnosis is confirmed through the identification of a heterozygous missense pathogenic variant in either ACTB or ACTG1 genes via molecular genetic testing.

Case description: We present a case of a 16 years-old male, born at 38th weeks via emergency C-section. At birth, his weight was 2320 gr and, lenght 46 cm, occipitofrontal circumference (OFC) 31 cm, categorizing him as a small-for-gestational-age (SGA) newborn with microcephaly. He presented with bilateral cryptorchidism, micropenis, and experienced hypoglycemic seizures. Throughout infancy and childhood, he exhibited moderate psychomotor delay and distinct craniofacial dysmorphism (coarse facies, hypertelorism, bulbous nose, prominent nasal bridge, and prognathism). A neuropsychiatric evaluation conducted to investigate his psychomotor delay revealed mild intellectual disability with autistic features. Genetic analyses showed a normal male karyotype, absence of FMR1 gene mutations, and no segmental aneuploidies in the CGH array. Due to impaired statural growth, an endocrinological evaluation was performed, revealing growth hormone (GH) deficiency. He began recombinant human growth hormone (rhGH) therapy (0.03 mg/kg/die), which is ongoing with positive clinical outcomes. Brain MRI revealed pituitary hypoplasia and a choroidal cyst in the right hemisphere. Concurrently, mild to moderate thrombocytopenia was diagnosed. At 15 years old, due to the absence of pubertal signs, further endocrinological evaluation indicated hypogonadotropic hypogonadism, initially treated with β-HCG and rhFSH for nine months without significant gonadal response. Subsequently, gonadotropin therapy was replaced with testosterone esters, resulting in an increase in external genitalia size. A next-generation sequencing (NGS) panel specific to hypogonadotropic hypogonadism genes did not reveal any pathogenic variants. Ultimately, whole exome sequencing identified a de novo pathogenic variant in the ACTB gene (c.94C>T, p.Pro32Ser), confirming the diagnosis of Baraitser-Winter syndrome.

Conclusion: This case expands the clinical spectrum of Baraitser-Winter syndrome by documenting novel pituitary findings, specifically pituitary hypoplasia and GH deficiency, not previously reported in this condition.