Hereditary autonomic neuropathy of the oral cavity and its management: A case report

Abstract Hereditary sensory and autonomic neuropathies (HSAN) are rare genetic disorders that often manifest during childhood in the form of absence of pain sensation or self-mutilation. Patients often present significant oral self-mutilation manifestations, and biting of the lips, tongue, and cheeks have been frequently reported. This case report describes a case of hereditary sensory and autonomic neuropathy with oral and cutaneous ulcers.Our patient was a 14-month-old girl with the chief complaint of a tongue ulcer, as stated by her parents, who were referred to our private dental clinic. Clinical examination revealed severe ulcers due to biting (Riga-Fede disease) on the ventral surface of the tongue and superficial ulcers on the dorsal surface of the tongue caused by the anterior maxillary teeth, along with some sores on fingers. The parents were healthy, with no congenital disease or familial history of a similar condition. The electrodiagnostic test revealed the absence of sensory nerve action potential response. However, the electromyographic findings and the compound muscle actionpotential of the tibial and ulnar nerves were normal. Oral ulcers such as trauma to the lips and tongue, and self-mutilation trauma to the fingers can be used for early detection of Hereditary sensory and autonomic neuropathies. A multidisciplinary approach involving a professional dental team and a regular treatment protocol are imperative to prevent complications of Hereditary sensory and autonomic neuropathies

Mutations in CNNM4 Cause Jalili Syndrome, Consisting of Autosomal-Recessive Cone-Rod Dystrophy and Amelogenesis Imperfecta

The combination of recessively inherited cone-rod dystrophy (CRD) and amelogenesis imperfecta (AI) was first reported by Jalili and Smith in 1988 in a family subsequently linked to a locus on chromosome 2q11, and it has since been reported in a second small family. We have identified five further ethnically diverse families cosegregating CRD and AI. Phenotypic characterization of teeth and visual function in the published and new families reveals a consistent syndrome in all seven families, and all link or are consistent with linkage to 2q11, confirming the existence of a genetically homogenous condition that we now propose to call Jalili syndrome. Using a positional-candidate approach, we have identified mutations in the CNNM4 gene, encoding a putative metal transporter, accounting for the condition in all seven families. Nine mutations are described in all, three missense, three terminations, two large deletions, and a single base insertion. We confirmed expression of Cnnm4 in the neural retina and in ameloblasts in the developing tooth, suggesting a hitherto unknown connection between tooth biomineralization and retinal function. The identification of CNNM4 as the causative gene for Jalili syndrome, characterized by syndromic CRD with AI, has the potential to provide new insights into the roles of metal transport in visual function and biomineralization

FAM20A mutations can cause enamel-renal syndrome (ERS).

Enamel-renal syndrome (ERS) is an autosomal recessive disorder characterized by severe enamel hypoplasia, failed tooth eruption, intrapulpal calcifications, enlarged gingiva, and nephrocalcinosis. Recently, mutations in FAM20A were reported to cause amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS), which closely resembles ERS except for the renal calcifications. We characterized three families with AIGFS and identified, in each case, recessive FAM20A mutations: family 1 (c.992G>A; g.63853G>A; p.Gly331Asp), family 2 (c.720-2A>G; g.62232A>G; p.Gln241_Arg271del), and family 3 (c.406C>T; g.50213C>T; p.Arg136* and c.1432C>T; g.68284C>T; p.Arg478*). Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to ERS. By characterizing teeth extracted from the family 3 proband, we demonstrated that FAM20A(-/-) molars lacked true enamel, showed extensive crown and root resorption, hypercementosis, and partial replacement of resorbed mineral with bone or coalesced mineral spheres. Supported by the observation of severe ectopic calcifications in the kidneys of Fam20a null mice, we conclude that FAM20A, which has a kinase homology domain and localizes to the Golgi, is a putative Golgi kinase that plays a significant role in the regulation of biomineralization processes, and that mutations in FAM20A cause both AIGFS and ERS

Scanning Electron Micrographs (SEMs) of molar (#18) occlusal surface.

<p><i>A:</i> Low magnification view of occlusal surface after partially cutting and then splitting the tooth sagitally (mesial-distal direction) for SEM analyses (bar: 1 mm). The boxes, from top to bottom, are locations of higher magnification views shown in B–E, respectively. <i>B:</i> Region showing knob-like calcifications (bar: 100 µm). <i>C:</i> Region where dentinal tubules reach the surface (bar: 10 µm); <i>D:</i> Region showing a relatively smooth surface (bar: 10 µm). <i>E:</i> Region from edge of crown (bar: 100 µm); <i>F:</i> Higher magnification of box in panel E showing no true enamel and apparent resorption lacunae (bar: 10 µm).</p

Backscatter Scanning Electron Micrographs (bSEMs) of molar (#32).

<p><i>A:</i> The bSEM of molar after it was cut sagitally (mesial-distally). <i>B:</i> Rough “enamel” (e) covering sclerotic dentin. <i>C:</i> Acellular cementum covering sclerotic root dentin. <i>D–E:</i> Highly mineralized pulp or radicular calcifications (pc) comprised of coalesced spheres above the root furcation and associated with a less mineralized material that contacts dentin (d). <i>F:</i> The radicular area appears to be comprised entirely of acellular cementum (ac) or lamellar bone from the furcation to the highly mineralized coalesced spheres. <i>G:</i> Root dentin covered with a thick layer of acellular cementum (ac) or bone. A thin line of more highly mineralized material, possibly cementum (c), separates these layers. <i>H:</i> The material covering root dentin is deposited in layers and sometimes fills in areas of localized root resorption.</p

Backscatter Scanning Electron Micrographs (bSEMs) of molar (#18) roots.

<p><i>A:</i> The bSEM of molar after it was cut sagitally (mesial-distally). <i>B:</i> Higher magnification of smaller box in A showing the layered build-up resembling cellular cementum. Arrowheads mark the dentin-cementum border. <i>C–D:</i> Higher magnifications of the larger box in A showing the thick layers of “cellular cementum” covering the roots. In panel D a dark line is placed at the dentin surface. <i>E:</i> Higher magnification of the larger box in panel C showing the thick layers of “cellular cementum” covering the roots and how the lamellar pattern suggests that deposition of these layers was punctuated by periods of resorption that sometimes penetrated into the dentin. <i>F–G:</i> Higher magnification of the smaller box in panel C also showing how deposition of the layers of acellular cementum was punctuated by resorption that sometimes penetrated into the dentin.</p

Scanning Electron Micrographs (SEMs) of mineral covering coronal dentin in a molar (#18) split for SEM examination.

<p><i>Left:</i> Enamel layer in normal molar <i>Right:</i> Mineral covering dentin in <i>FAM20</i>^−/− molar. No long thin crystals with rod/interrod organization are observed in the <i>FAM20</i>^−/− molar.</p

Backscatter Scanning Electron Micrographs (bSEMs) of molar (#18) crown.

<p><i>A:</i> The bSEM of molar after it was cut sagitally (mesial-distally). <i>B:</i> Higher magnification of region boxed in A showing regions magnified in C–F. The bowtie-shaped structure in the lower right is the calcified pulp chamber. Most of the coronal dentin has been resorbed, with some of it replaced by well-formed lamellar bone (b). <i>C–E:</i> Region showing dense, rough, crusty mineral in place of enamel (e) covering sclerotic dentin (d) that is fused to lamellar bone (b). There appears to be sites of active resorption of the dentin and bone (arrowheads). <i>F:</i> The pulp calcification (pc) is comprised of coalesced spheres that resemble the crusty “enamel” in mineral density embedded in a second, less mineralized material like dentin or acellular cementum that lacks osteocyte lacunae.</p

Images of <i>FAM20A</i>^−/− tooth #18.

<p><i>A:</i> Photographs of #18 after cutting it sagitally. <i>B:</i> Photographs of a wild-type molar after cutting it sagitally. <i>C:</i> Photograph of #18 before sectioning. <i>D:</i> Occlusal view of #18 by photograph (top) and 3-D μ-CT image. <i>E:</i> 3-D μ-CT image of inside #18. Note the hollow area in the crown and the calcified pulp chamber. <i>F:</i> 3-D μ-CT image of #18. Note the shortness of the crown, which as apparently greatly diminished by resorption.</p

Family 1 from the Caribbean with <i>FAM20A</i> mutation c.992G>A; g.63853G>A; p.G331D.

<p><i>A:</i> Pedigree. A dot marks person who donated samples for DNA sequencing. <i>B: FAM20A</i> exon 7 DNA sequencing chromatograms. The proband's parents (II:1 and II:2) were both heterozygous (R = A or G) at cDNA position 992 (arrowheads). The proband (III-1) had the c.992G>A transition mutation in both alleles of <i>FAM20A</i>. This mutation changed a conserved glycine with an aspartic acid (p.G331D). The proband's affected younger sister (III-4) and her infant niece (IV:1) were also homozygous for this mutation (not shown). II:1 and III:8 were heterozygous for a recognized polymorphism (rs2302234) in exon 7 (K = A or C) unrelated to the phenotype. <i>C:</i> Proband's panoramic radiograph. Note the many unerupted teeth. The mandibular and maxillary unerupted second molars show concave occlusal surfaces without enamel (arrowheads). <i>D:</i> Proband's oral photos. The maxillary central incisors are restored. The clinical crowns were short with hypoplastic enamel. There was a deep anterior overbite, a posterior cross-bite, and retained mandibular primary molars (letters K, L, S, T).</p