Hypothalamic Hamartomas

In a case of hypothalamic hamartoma, Marcuse et al. (1953) reported that 1 sib had internal hydrocephalus and died at age 6 months, within a day after operation. Another sib had a similar clinical course and died at age 2 months; autopsy was not performed. A double first cousin of the proband likewise had a similar clinical course; postmortem at age 5 months showed 'mature glioma of the brain stem.' See 146510.

Encha-Razavi et al. (1992) described 3 unrelated fetuses (one was actually a term neonate who had died a few minutes after birth) in whom, at autopsy, congenital hypothalamic hamartomas were found. Two were associated with skeletal dysplasia. A third was associated with malformations suggestive of Meckel syndrome (249000): heart defect, pulmonary hypoplasia, renal dysplasia, and posterior encephalocele. The first family reported by Encha-Razavi et al. (1992) had, in addition to the fully studied female newborn, an apparently identically affected brother who also died in the newborn period but was not studied neuropathologically. That boy showed micropenis, suggesting hypopituitarism, and had micromelia, short ribs, midline cleft of the upper lip, short nose, alveolar frenula, and macrocephaly. The parents were young, healthy, and unrelated. Neither child had postaxial polydactyly. Encha-Razavi et al. (1992) suggested the designation congenital hypothalamic hamartoma syndrome (CHHS) for a possibly familial disorder that combines orofacial abnormalities and skeletal dysplasia with hypothalamic hamartomas.

The familial case reported by Graham et al. (1983) has some similarities. The infant showed abnormal auricles, short nose with flattened bridge, microglossia, micrognathia, cleft palate, short limbs, dislocated hips, and 4-limb postaxial polydactyly. The infant died at 2 hours of age and autopsy showed hypothalamic hamartoblastoma. A sister of the mother died at 17 hours of age and showed 4-limb polydactyly, recessed mandible, and small tongue; autopsy was not done.

Because approximately 5% of cases of hypothalamic hamartomas are associated with Pallister-Hall syndrome (PHS; 146510), which is caused by haploinsufficiency of GLI3, Craig et al. (2008) investigated the possibility that HH pathogenesis in sporadic cases is due to a somatic mutation in GLI3. They isolated genomic DNA from peripheral blood and surgically resected HH tissue in 55 patients with sporadic HH and intractable epilepsy. A genomewide screen for loss of heterozygosity (LOH) and chromosomal abnormalities was performed with parallel analysis of blood and HH tissue with Affymetrix 10K SNP microarrays. Additionally, resequencing and fine mapping with SNP genotyping were completed for the GLI3 gene with comparisons between peripheral blood and HH tissue pairs. By analyzing chromosomal copy number data for paired samples on the array, Craig et al. (2008) identified a somatic chromosomal abnormality on chromosome 7p in one HH tissue sample. Resequencing of GLI3 did not identify causative germline mutations but did identify LOH within the GLI3 gene in the HH tissue samples of 3 patients. Further genotyping of 28 SNPs within and surrounding GLI3 identified 5 additional patients exhibiting LOH. Together, these data provided evidence that the development of chromosomal abnormalities within GLI3 is associated with the pathogenesis of HH lesions in sporadic, nonsyndromic patients with HH and intractable epilepsy. Chromosomal abnormalities including the GLI3 locus were seen in 8 of 55 (15%) of the resected HH tissue samples.