Neuroimaging appearance of hypothalamic hamartomas in monozygotic twins with Pallister-Hall syndrome: case report and review of the literature.

BACKGROUND: Pallister-Hall syndrome (OMIM #146510) is a rare autosomal dominant condition caused by a mutation in the GLI3 gene. The cardinal feature of Pallister-Hall syndrome is the presence of hypothalamic hamartomas, which may manifest with seizures, panhypopituitarism and visual impairment. In Pallister-Hall syndrome, dysplastic histogenetic processes responsible for hypothalamic hamartomas are thought to disrupt early craniofacial development. The clinical presentation of Pallister-Hall syndrome may include: characteristic facies (low-set and posteriorly angulated ears, short nose with flat nasal bridge), cleft palate and uvula, bifid epiglottis and laryngotracheal cleft, limb anomalies (e.g., polysyndactyly, short limbs and nail dysplasia), anal atresia, genitourinary abnormalities and congenital heart defects. CASE PRESENTATION: We report the case of two monochorionic diamniotic twins diagnosed with Pallister-Hall syndrome during the neonatal period, after the identification of a hypothalamic hamartoma on day 1 by cerebral ultrasound scan, later confirmed by brain magnetic resonance imaging. Cerebral ultrasound and magnetic resonance imaging presentations were identical in both twins. DISCUSSION AND CONCLUSIONS: We review previously published cases (four reports) of hypothalamic hamartomas identified via cerebral ultrasound and compare reported ultrasonographic features. Main differential diagnoses based on cerebral ultrasound findings are discussed. Full description of typical magnetic resonance imaging appearance is also provided. This is the first case reported in the literature of monochorionic diamniotic twins affected by genetically confirmed Pallister-Hall syndrome with identical hypothalamic hamartomas at cerebral ultrasound and magnetic resonance imaging. Moreover, this paper adds to the existing literature on the sonographic appearance of hypothalamic hamartomas. Considering the consistency in hypothalamic hamartomas' sonographic appearance, we support the use of cerebral ultrasound as a first-line neuroimaging modality in case of clinical suspicion of Pallister-Hall syndrome.

A GLI3 variant leading to polydactyly in heterozygotes and Pallister-Hall-like syndrome in a homozygote.

Variants in transcriptional activator Gli Kruppel Family Member 3 (GLI3) have been reported to be associated with several phenotypes including Greig cephalopolysyndactyly syndrome (MIM #175700), Pallister-Hall syndrome (PHS) (MIM #146510), postaxial polydactyly types A1 (PAPA1) and B (PAPB) (MIM #174200), and preaxial polydactyly type 4 (MIM #174700). All these disorders follow an autosomal dominant pattern of inheritance. Hypothalamic hamartomas (MIM 241800) is associated with somatic variants in GLI3. We report a related couple with parents having PAPA1 and PAPB, who had a fetus with a phenotype most compatible with PHS. Molecular analyses demonstrated homozygosity for a pathogenic GLI3 variant (c.1927C > T; p. Arg643*) in the fetus and heterozygosity in the parents. The genetic analysis in this family demonstrates that heterozygosity and homozygosity for the same GLI3 variant can cause a different phenotype. Furthermore, the occurrence of Pallister-Hall-like syndrome in a homozygous patient should be taken into account in genetic counseling of families with PAPA1/PAPB.

Positron emission tomography with glucose hypermetabolism of a hypothalamic hamartoma in infantile spasms associated with Pallister-Hall syndrome.

Although hypothalamic hamartomas (HHs) have been shown to be intrinsically epileptogenic and to participate in the generation of gelastic seizures, no evidence has been reported regarding its contribution to the pathogenesis of infantile spasms. We describe a male infant with Pallister-Hall syndrome who had a large HH presenting with infantile spasms without hypsarrhythmia. [(18)F]fluoro-deoxyglucose positron emission tomography scan performed during the period of epileptic spasms demonstrated glucose hypermetabolism of the HH, which resolved after cessation of the spasms with adrenocorticotropin hormone treatment. No concurrent increased metabolic activity in the lenticular nuclei or brainstem was observed in the ictal or interictal states. The present case suggests that HHs may be involved in the pathogenesis of infantile spasms, possibly with propagation of epileptic discharges from the hamartoma to the descending spinal pathway.