PRDM12 – Congenital Insensitivity to Pain-Hypohidrosis Syndrome

PRDM12 is causally implicated in congenital insensitivity to pain-hypohidrosis syndrome (HSAN-VIII), a rare autosomal recessive disorder characterized by loss of pain and temperature sensation, hypohidrosis, self-mutilation behaviors, and orofacial complications. The first patient described was an 8-month-old boy homozygous for a PRDM12 missense variant, detailed in Chen et al. (PMID:28807049). Early recognition of oral manifestations—in particular premature tooth loss and mandibular osteomyelitis—can expedite diagnosis and multidisciplinary management.

Genetic evidence is currently limited. Only a single unrelated proband has been reported with a homozygous c.503G>A (p.Arg168His) PRDM12 variant, consistent with autosomal recessive inheritance and absent in controls (PMID:28807049). No additional affected relatives with confirmed segregation have been documented. Other PRDM12 variants reported in hereditary sensory and autonomic neuropathy include c.91G>T (p.Asp31Tyr), c.516G>C (p.Glu172Asp), and c.303del (p.Ile102fs) in unrelated cases of CIP (PMID:25891934).

Functional studies substantiate a key developmental role for PRDM12 in nociceptor neurogenesis. Knockdown and overexpression assays in Xenopus and Drosophila demonstrate that PRDM12 (and its fly homolog Hamlet) regulates sensory neuron specification and nociceptive behavior, with mutant alleles failing to induce sensory markers (PMID:25891934). Zebrafish prdm12b germline mutants lack eng1b expression in the p1 neural tube domain and exhibit defective touch-evoked escape responses, confirming a transcriptional repressor function in vivo (PMID:30813944).

Mammalian models further reinforce PRDM12’s mechanism of pathogenicity. Constitutive Prdm12 knockout mice display profound deficits in nociceptor proliferation during embryogenesis, leading to congenital insensitivity to pain, whereas conditional deletion in mature dorsal root ganglia has minimal impact on nociception, highlighting a critical developmental window (PMID:33789102).

No conflicting evidence has been reported. Although clinical reports remain sparse, convergent data from multiple model systems establish loss-of-function as the primary mechanism underlying HSAN-VIII. Identification of additional families and systematic segregation analysis will be essential to elevate the genetic evidence strength.

Key Take-Home: PRDM12 LoF variants cause autosomal recessive congenital insensitivity to pain-hypohidrosis syndrome; early genetic testing can guide preventive dental and multisystem management.

References

• Journal of medical case reports • 2017 • Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature. PMID:28807049
• Cell reports • 2021 • Loss of Prdm12 during development, but not in mature nociceptors, causes defects in pain sensation. PMID:33789102
• Neural development • 2019 • Zebrafish prdm12b acts independently of nkx6.1 repression to promote eng1b expression in the neural tube p1 domain. PMID:30813944
• Cell cycle (Georgetown, Tex.) • 2015 • The evolutionarily conserved transcription factor PRDM12 controls sensory neuron development and pain perception. PMID:25891934

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