A number sign (#) is used with this entry because of evidence that polydactyly-macrocephaly syndrome (PDMCS) is caused by heterozygous mutation in the MAX gene (154950) on chromosome 14q23.

Polydactyly-macrocephaly syndrome (PDMCS) is characterized by postaxial polydactyly and progressive macrocephaly. Variable ocular anomalies have been observed, including microphthalmia and coloboma as well as delayed visual maturation. Neurodevelopmental anomalies are also present, including global developmental delay and autism or autistic traits, with prominent perivascular spaces on brain imaging (Harris et al., 2024).

Harris et al. (2024) reported 2 boys from the Deciphering Developmental Disorders dataset (P1, DDD:304967; and P2, DDD:303133) with progressive macrocephaly and postaxial polydactyly and mutation in the MAX gene. P1 also had bilateral microphthalmia and large chorioretinal colobomas; he developed retinal exudation requiring cryotherapy and also a cataract in his right eye. In addition, P1 exhibited autistic traits, but intellectual development was appropriate for the level of visual impairment. P2 was autistic and had developmental delay; he also displayed delayed visual maturation with visual inattention that normalized by 44 months of age. Brain scans of the patients showed marked similarities, including prominent perivascular spaces in the basal ganglia/pericaudate region; P2 also had prominent perivascular spaces more posteriorly, adjacent to the trigone of the right lateral ventricle. The authors also ascertained a third male infant (P3) from a cohort in the Netherlands, who had 4-limb polydactyly and mutation in the MAX gene. P3 had multiple additional complications, including atrial septal defect, single umbilical artery, hypospadias, and he died 1 hour after birth due to bilateral renal agenesis. He had a normal head circumference, but postmortem MRI showed a swollen brain with decreased gray-white matter differentiation and decreased demarcation of the cortex.

The heterozygous mutation in the MAX gene that was identified in patients with polydactyly-macrocephaly syndrome by Harris et al. (2024) occurred de novo.

By interrogation of 2 large exome datasets, Harris et al. (2024) identified 3 unrelated children with polydactyly, 2 of whom also exhibited progressive macrocephaly, who were heterozygous for the same de novo missense mutation in the MAX gene (R60Q; 154950.0006). The variant was not found in the gnomAD database, but had been identified 56 times as a somatic mutation in tumor tissue in the COSMIC database. Functional analysis demonstrated that the R60Q mutant forms an activating DNA complex with c-Myc (MYC; 190080) more readily than wildtype MAX, likely increasing transcriptional activity. The authors suggested that the variable phenotypes observed in the patients might be due to misregulation of additional genes downstream of c-Myc, and noted that RNA sequencing analysis showed broad transcriptional dysregulation in the presence of the R60Q mutant.