A number sign (#) is used with this entry because of evidence that Pallister-Hall-like syndrome (PHLS) is caused by homozygous or compound heterozygous mutation in the SMO gene (601500) on chromosome 7q32.

Pallister-Hall-like syndrome (PHLS) is a pleiotropic autosomal recessive disorder characterized by phenotypic variability. Patients exhibit postaxial polydactyly as well as hypothalamic hamartoma, cardiac and skeletal anomalies, and craniofacial dysmorphisms. Hirschsprung disease has also been observed (Rubino et al., 2018; Le et al., 2020).

Pallister-Hall syndrome (146510) is an autosomal dominant disorder with features overlapping those of PHLS, caused by mutation in the GLI3 gene (165240).

Marcuse et al. (1953) reported a male infant (DMH) with failure to thrive and cyanotic episodes, who also had partial cleft palate and was described as 'obviously mentally defective.' He died at age 6 months; autopsy revealed a large hypothalamic hamartoma. Two older brothers also died in infancy. One had hydrocephalus and died at age 7 months after a surgical procedure; the other had a clinical course similar to that of the proband and died at age 2 months. A double first cousin of the proband likewise had a similar clinical course; she died at age 5 months, and necropsy showed 'mature glioma of the brain stem.' The authors also described an unrelated girl with recurrent attacks of cyanosis and unconsciousness since birth, who died at age 5 years after another such episode. Autopsy revealed a large hypothalamic hamartoma as well as enlarged heart with tetralogy of Fallot.

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.

Rubino et al. (2018) described 2 brothers, aged 6 and 3 years, who displayed hypothalamic hamartomas and polydactyly/syndactyly as well as various other features, and had mutations in the SMO gene. The older brother presented with microcephaly, short stature, spatulate mandible with mandibular epulis, and polydactyly/syndactyly of the toes. MRI showed a suprasellar mass, pituitary cyst, and type I Chiari malformation. At 3 years of age, the patient developed gelastic seizures which were well controlled with medication; brain imaging remained stable over the next 3 years, and psychomotor development was age-appropriate and unaffected. The younger brother was born with right hand and bilateral foot polydactyly. At age 2.5 years, he developed dacrystic seizures and began experiencing speech delays. MRI showed an exophytic nonenhancing suprasellar mass with compression and displacement of the optic nerves and chiasm. He underwent debulking of the mass, and histopathology showed disorganized hypothalamic tissue with several foci of vague nodularity, compatible with a benign hypothalamic hamartoma. The authors noted that apart from hypothalamic hamartomas and polydactyly, the brothers exhibited different phenotypes, indicating a syndrome with variable expressivity.

Le et al. (2020) reported 7 patients from 5 families, including the 2 brothers previously reported by Rubino et al. (2018) (patients 2 and 3), who had mutations in the SMO gene and exhibited a wide spectrum of developmental anomalies involving the brain, heart, skeleton, and enteric nervous system. All 7 patients had postaxial polydactyly; additional skeletal features observed in 2 patients included narrow chest, trident acetabulum, and shortening of the long bones. Hypothalamic hamartoma and gelastic or dacrystic epilepsy was present in 3 patients, 1 of whom (patient 2) also exhibited microcephaly, pituitary cyst, and type I Chiari malformation. Congenital heart defects were present in 3 patients, who all had atrioventricular septal defect; 2 of the patients showed additional cardiovascular anomalies including atrioventricular valvular defects, monoatrium, and coarctation of the aorta. One patient had short-segment Hirschsprung disease, with rectosigmoid aganglionosis, as well as micropenis and bilateral cryptorchidism, and another had glandular hypospadias. Variable craniofacial dysmorphisms were present in 5 of the patients, including large fontanel, choanal stenosis, cleft palate, microstomia, microglossia, ankyloglossia, gingival frenulum, sublingual appendages, retrognathia, micrognathia, short nose, and overfolded helices.

The transmission pattern of PHLS in the family reported by Rubino et al. (2018) was consistent with autosomal recessive inheritance.

In 2 brothers with hypothalamic hamartomas and polydactyly as well as various other skeletal and brain anomalies, Rubino et al. (2018) performed exome sequencing and identified compound heterozygosity for a 2-bp deletion in the SMO gene (601500.0004) and a deletion at chromosome 7q32.1 involving part of the SMO gene. The authors stated that this was the first report of a familial syndrome involving germline mutations in the SMO gene, and noted the variable expressivity between the 2 brothers.

In 7 patients from 5 families with Pallister-Hall-like syndrome, including the 2 brothers originally reported by Rubino et al. (2018), Le et al. (2020) identified homozygous or compound heterozygous mutations in the SMO gene (601500.0005-601500.0009). Le et al. (2020) noted that the patients displayed a broad spectrum of developmental anomalies.

Exclusion Studies

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.