Clinical and molecular heterogeneity of syndromic hypothalamic hamartoma

Abstract

Two children are presented who have a distinct syndrome of multiple buccolingual frenula, a stiff and short fifth finger with small nails, a hypothalamic hamartoma, mild to moderate neurological impairment, and mild endocrinological symptoms. No variant assessed to be pathogenic or likely pathogenic was detected in the GLI3 gene in either child. This syndrome appears to be distinct from the inherited Pallister-Hall syndrome associated with GLI3 variants, which is characterized by hypothalamic hamartoma, mesoaxial polydactyly, and other anomalies. In the individuals described here, manifestations outside of the central nervous system were milder and the mesoaxial polydactyly, which is common in individuals with Pallister-Hall syndrome, was absent. Instead, these children had multiple buccolingual frenula together with the unusual appearance of the fifth digit. It remains unclear whether these two individuals represent a separate nosologic entity or if they represent a milder manifestation of one of the more severe syndromes associated with a hypothalamic hamartoma.

Keywords: GLI3 gene; Pallister-Hall Syndrome; buccolingual frenulum; hypothalmic hamartoma; mesoaxial polydactyly.

Figure 1:

Multiple frenula from the lips to the alveolar ridge in individuals 1 (A) and 2 (B). Note additional lip pits especially in individual 2 (B). Fifth fingers of the left hand in individual 1 (C) and 2 (D). Note the pronounced shortness, small nails, and stiff interphalangeal joints.

Figure 2:

Sagittal T1-weighted MRI of the brain in individual 1 (A) at the age of 2 weeks and in individual 2 (B) at the age of 7 months. Note the interpeduncular mass in continuity with the hypothalamus (arrows). The masses are isointense to grey matter. X-rays of the left hands of individual 1 (C) at the age of 2 years and of individual 2 (D) at the age of 7 months. Note the pronounced shortness of especially the middle and distal phalanx of the fifth finger. The middle and distal phalanx in individual 2 appear to show symphalangism.