Marsili Syndrome

A number sign (#) is used with this entry because of evidence that Marsili syndrome (MARSIS) is caused by heterozygous mutation in the ZFHX2 gene (617828) on chromosome 14q11. One such family has been reported.

Clinical Features

Habib et al. (2018) reported an Italian family in which 6 individuals spanning 3 generations had a congenital pain insensitivity disorder. The family had previously been reported by Spinsanti et al. (2008), who found an almost 2-fold increased expression of the TRPV1 receptor (602076), which mediates pain and capsaicin perception, in patient lymphocytes compared to controls. The patients had a history of painless injuries from childhood, most notably bone fractures with use of the broken limbs without painful sensation as well as insensitivity to thermal cutaneous burns. They had severe corneal hyporeflexia but without corneal scarring and with normal tear production. Additional features included decreased or absent sweating, and altered sensation of warm and cold temperatures, although some individuals reported episodes of hyperthermia. However, patients did report headaches, visceral pain, and pain during childbirth. Neurologic examination showed that light touch stimuli could be detected normally, but heat and cold pain thresholds were variably affected. There was no pain in the mechanical pain threshold detection test and a sensation of pleasure at deep pressure, such as massage. All individuals also had low sensitivity to capsaicin, manifest by ability to eat large amounts of hot pepper without discomfort. Odor perception was normal. Skin biopsy of 1 patient showed normal intraepidermal nerve fiber density. Cognitive and motor ability were normal. The authors named the disorder 'Marsili syndrome' after the name of the family.

Inheritance

The transmission pattern of MARSIS in the family reported by Habib et al. (2018) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 6 members of a 3-generation Italian family with Marsili syndrome, Habib et al. (2018) identified a heterozygous missense mutation in the ZFHX2 gene (R1913K; 617828.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Transgenic mice bearing the orthologous R1907K mutation had significant behavioral deficits in pain sensitivity to noxious heat, and cultured DRG neurons from these mice showed reduced calcium response to capsaicin compared to controls. There was no difference in the number of small diameter nociceptive neurons. Transgenic mice with 4 to 5 copies of the mutant gene had even higher heat pain thresholds. Gene expression profiles in mice bearing 4 genomic copies of the mutant Zfhx2 gene showed altered expression of genes known to be involved in pain signaling, including SST (182450), GFRA3 (605710), and PTGIR (600022).

Animal Model

Habib et al. (2018) found that Zfhx2-null mice were hyposensitive to noxious mechanical stimuli, but had normal sensitivity to innocuous touch. Dorsal root ganglion neurons isolated from these mice showed a deficit in noxious mechanical coding compared to control, but no differences in response to dynamic low threshold stimuli. Zfhx2-null mice were hypersensitive to noxious heat compared to wildtype, suggesting that Zfhx2 plays a role in both mechanical and thermal acute pain thresholds.

History

Ervin and Sternbach (1960) reported a family in which 6 persons in 2 generations had congenital insensitivity to pain, consistent with autosomal dominant inheritance. Comings and Amromin (1974) described the disorder in a mother and a son and daughter, with a possibility of the disorder having been present in an earlier generation (see 147530).

Landrieu et al. (1990) reported a mother and daughter with possible dominant inheritance of indifference to pain; perception of the other sensory modalities was normal, as was the remainder of the neurologic examination. Electrophysiologic studies and morphometric evaluation of myelinated and unmyelinated fibers from nerve biopsy specimens were normal, and the authors concluded that the disorder was not a variety of HSAN. Because the father of the daughter was unknown, this may have been an instance of pseudodominance, i.e., recessive inheritance.