Charcot-Marie-Tooth Disease Type 4C and Autosomal Dominant Heterozygous Ichthyosis Vulgaris, with Bilateral Hearing Loss: A Novel Association with Review of Literature

Abstract

A 3-year-old boy, firstborn to nonconsanguineous parents, presented with motor development delay and floppiness of bilateral lower limbs since birth. No significant family history presented at time of check-up. He could stand with support, eat with a spoon without spillage, and speak in two-word sentences. There was no history suggestive of cranial nerve impairment. Examination revealed normal head circumference, dry, scaly skin lesions on the trunk, distal weakness with sluggish deep tendon reflexes in bilateral lower limbs, and a high stepping gait. Nerve conduction studies revealed demyelinating polyneuropathy. Brain stem-evoked response audiometry testing revealed auditory neuropathy. Clinical exome sequencing revealed a known pathogenic variant of 3325C > T in the SH3TC2 gene suggestive of Charcot-Marie-Tooth disease type 4C and ichthyosis vulgaris with a novel variant of 2218C > T in the FLG gene. We have reviewed the available literature for reported associations of Charcot-Marie-Tooth disease type 4C and ichthyosis vulgaris. This is probably the first reported association of Charcot-Marie-Tooth disease type 4C and ichthyosis vulgaris with bilateral hearing loss.

Introduction

Charcot-Marie-Tooth disease (CMT) is a group of inherited motor and sensory neuropathies and is the most common of inherited neuromuscular disorders. CMT was first described by the French neurologists, Jean-Martin Charcot, and Pierre Marie, and a British neurologist, Howard Henry Tooth in 1886. ¹ Recent classification of CMT is based on the mode of Mendelian inheritance and clinical features, with autosomal recessive inheritance under CMT type 4 (CMT4). Charcot-Marie-Tooth disease type 4C (CMT4C) is an early-onset severe demyelinating sensorimotor polyneuropathy due to mutations in the SH3TC2 gene resulting in defective regulation of myelin assembly by Schwann cells. ² CMT4C manifests with distal symmetrical weakness, early-onset spinal and foot deformities, developmental delay predominantly in the motor domain, and cranial nerve abnormalities. Ichthyosis vulgaris (IV) is a genodermatoses due to mutations in the FLG gene (filaggrin), resulting in the deficiency of filaggrin proteins. ³ Due to filaggrin deficiency, the quantity and distribution of lipids in the stratum corneum get affected, thereby resulting in cytoskeletal disorganization. ⁴ This disease is characterized by excessive scaling, hyperkeratosis, xerosis, and hyperlinearities in palms and soles. It has a wide range of genotypic and phenotypic variability and is associated with various disorders including atopic dermatitis, asthma, allergic rhinitis, and hand eczema. ⁵ We report a 3-year-old boy with the genetically proven dual diagnosis of CMT4C with a known pathogenic variant of 3325C > T in the SH3TC2 gene and IV with a novel variant of 2218C > T in the FLG gene. The association in the index child is novel and probably the first reported case of CMT4C and IV with bilateral hearing loss.

Case Presentation

A 3-year-old boy presented to pediatrics outpatient department with motor development delay and floppiness of bilateral lower limbs since birth. He was first born to nonconsanguineous parents. He had an uneventful antenatal and perinatal period. There were no similar complaints in the family. He could stand with support, eat with a spoon without spillage, and speak in two-word sentences. There was no history suggestive of cranial nerve impairment. Examination revealed normal head circumference, dry, scaly skin lesions on the trunk, and no spine or foot deformities. He had hypotonia of bilateral lower limbs, distal weakness with sluggish deep tendon reflexes in bilateral lower limbs, and a high stepping gait. The initial possibility of hereditary motor sensory neuropathy was considered given the absent deep tendon reflexes and high stepping gait. Other differentials considered were spinal muscular atrophy type II and III. A lower-down possibility of Sjogren-Larsson syndrome was also considered due to ichthyosis-like skin lesions and gait difficulty.

Investigations

On investigation, the serum creatine kinase levels were 123 U/L (normal: 34–174 U/L). X-ray spine was normal. Nerve conduction studies revealed prolonged latency and decreased velocity with delayed F-wave latency in all tested motor (medial/ulnar/common peroneal) and sensory (median/ulnar/sural) nerves bilaterally, suggestive of demyelinating polyneuropathy. Brain stem evoked response audiometry testing revealed prolonged absolute I, III, and V latencies and prolonged I to III and I to V latencies bilaterally, suggestive of auditory neuropathy. Fundus examination revealed nonspecific pigmentary changes. Clinical exome sequencing revealed a known pathogenic autosomal recessive homozygous nonsense variant c.3325C > T (p.Arg1109Ter) in exon 14 of the SH3TC2 gene suggestive of CMT4C, and also a novel pathogenic autosomal dominant heterozygous nonsense variant c.2218C > T (p.Arg740Ter) in exon 3 of the FLG gene suggestive of IV ( Table 1 ). Parents of the index child were asymptomatic, and testing for pathogenic variants of CMT4C revealed that both were heterozygous carriers of c.3325C > T variant.

Table 1. Pathogenic variants detected on clinical exome sequencing in index child.

Gene (Transcript) #	Location	Variant	Zygosity	Disease	Inheritance	Classification
SH3TC2 (ENST00000515425.1)	Exon 14	c.3325C > T (p.Arg1109Ter)	Homozygous	CMT4C	AR	Pathogenic
FLG (ENST00000368799.1)	Exon 3	c.2218C > T (p.Arg740Ter)	Heterozygous	IV	AD	Pathogenic

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CMT4C, Charcot-Marie-Tooth disease type 4C; IV, ichthyosis vulgaris.

Discussion

The index child on genetic analysis had two pathogenic variants. An autosomal recessive homozygous nonsense variant c.3325C > T (p.Arg1109Ter) in exon 14 of the SH3TC2 gene (chr5:g.148389835G > A; Depth:50x), resulted in a stop codon and premature truncation at the protein at codon 1109 ( Fig. 1 ), suggestive of CMT4C. This variant p.Arg1109Ter was previously reported by Gooding et al. ⁶ The in silico prediction of the variant was damaging by MutationTaster2 based on build GRCh37/Ensembl69. ⁷ This variant was classified as “pathogenic” based on the guidelines on classification of variations by American College of Medical Genetics (ACMG). ⁸ Another variant detected was an autosomal dominant heterozygous nonsense variant c.2218C > T (p.Arg740Ter) in exon 3 of the FLG gene (chr1:g.152285144G > A; Depth:1524x), resulting in a stop codon and premature truncation of the protein at codon 740 ( Fig. 2 ), suggestive of IV. This variant p.Arg740Ter has not been reported previously. The in silico prediction of the variant was also damaging by MutationTaster2 based on build GRCh37/Ensembl69. ⁷ This variant was also classified as “pathogenic” based on the guidelines on classification of variations by ACMG. ⁸ The concurrence of CMT4C and IV has never been reported in the literature. The association has been considered novel, as both variants were designated as pathogenic variants. The distinctive features that the index child had were bilateral hearing loss, and the presence of co-existing CMT4C and IV.

Fig. 1.

Pathogenic variant c.3325C > T (p.Arg1109Ter) in exon 14 of the SH3TC2 gene (chr5:g.148389835G > A; depth:50x).

Fig. 2.

Novel pathogenic variant c.2218C > T (p.Arg740Ter) in exon 3 of the FLG gene (chr1:g.152285144G > A; depth:1524x).

CMT4C (MIM#601596) is an early-onset, severe demyelinating sensorimotor polyneuropathy due to mutations in the SH3TC2 gene (MIM*608206) on chromosome 5q32. ^{2 9} The SH3TC2 gene encodes a protein with two SH3 domains and ten tetratricopeptide repeats 2 (TC2) motifs, involved in the myelin layer formation by the Schwann cells. ¹⁰ SH3TC2 mutations disrupt the interaction with GTPase (guanosine triphosphatase) Rab11, a key regulator in recycling the endosome functions, resulting in impaired myelination by Schwann cells as this SH3TC2/Rab11 interaction is required for normal myelination. ¹¹ CMT4C has an autosomal recessive mode of Mendelian inheritance. It is characterized by early-onset scoliosis, foot deformities such as pes cavus/planus/valgus, cranial nerve involvement (commonly III, VII, VIII, and XII cranial nerves), symmetrical distal muscle weakness, sensory loss, and respiratory involvement. ² In very young children, delay in motor development may be the initial and only clinical sign observed in these hereditary neuropathies. However, detailed electrophysiological testing can help us in reaching the diagnosis. ¹² The phenotypic variability and associations of CMT4C may be due to the cryptogenic modifiers or the SH3TC2 protein diversity. ¹⁰ In 2015, Kalane et al ¹³ reported the first case of CMT4C in a 10-year-old Indian girl with a homozygous nonsense variation c. 2710C > T in exon 11 of the SH3TC2 gene, with bilateral mild pes cavus foot deformities without any spinal deformity. In 2018, Jerath et al ¹⁰ reported associations of CMT4C with other rare diseases such as Von-Willebrand disease type 2M, short-chain acyl-coenzyme A dehydrogenase deficiency, retinitis pigmentosa, and plasminogen activator inhibitor-1 deficiency. In 2022, Lorenzoni et al ¹⁴ reported the association of CMT4C and myasthenia gravis in a 10-year-old girl ( Table 2 ).

Table 2. Summary of diseases reported to be in association with CMT4C.

Sl. no	Author/year	Associated disease	Age (y)	Sex	Diagnosis confirmation	Mutations ( SH3TC2 gene)
1	Jerath et al 2018 10	Short-chain acyl-coenzyme A dehydrogenase deficiency	12	F	Targeted CMT panel	c.3230C > G, p.Ser1077Ter
2	Jerath et al 2018 10	Von-Willebrand disease type 2M Plasminogen activator inhibitor-1 deficiency	18	F	Targeted CMT panel	c.2860 C > T, p.Arg954Ter (paternal) c.3511C > T p.Arg1171Cys (maternal)
3	Jerath et al 2018 10	Retinitis pigmentosa	29	F	Exome sequencing	Frameshift c.1894_1897 delinsAAA p.E632fs
4	Jerath et al 2018 10	Facioscapulohumeral muscular dystrophy phenotype	40	M	Sanger sequencing	c.2039A > G p.Tyr680Cys
5	Lorenzoni et al 2022 14	Myasthenia gravis	10	F	Next-generation sequencing	p.Arg954*
6	Index study 2022	Ichthyosis vulgaris	3	M	Exome sequencing	c.3325C > T p.Arg1109Ter

Abbreviations: CMT, Charcot-Marie-Tooth disease; F, female; M, male.

IV (MIM#146700) is a cutaneous keratinization disorder presenting with scaling, xerosis of the skin, palmar, and plantar hyperlinearity due to mutations in the FLG (filaggrin) gene (MIM*135940) on chromosome 1q21.3. ¹⁵ The loss-of-function FLG mutations results on the truncation of profilaggrin protein, which cannot be synthesized to functional filaggrin. ^{5 16} The filaggrin deficiency results in cytoskeletal disorganization leading to altered cargo loading and impaired maturation of lamellar bilayers. ^{4 17} Due to filaggrin deficiency, the quantity and distribution of lipids in the stratum corneum get affected. ^{17 18} These changes contribute to the reduced ability of the skin to maintain hydration, increased transepidermal water loss, and elevated skin pH, thereby resulting in manifestations such as xerosis and scaling. ^{16 19} The mode of Mendelian inheritance is either autosomal dominant or autosomal recessive. The clinical features of IV include xerosis, scaling, painful skin fissures of hands, fingers, and heels, palmar and plantar hyperlinearities, and keratosis pilaris. Common disorders associated with FLG mutations frequently include atopic dermatitis, asthma, allergic rhinitis, food allergies, eczema herpeticum, allergic nickel dermatitis, hand eczema, and type II diabetes mellitus. ⁵ The phenotypic variability in IV is based on the zygosity, as there is a complete absence of filaggrin in homozygous FLG mutation carriers with chronic phenotype. In contrast, a milder phenotype is seen in heterozygous FLG mutation carriers. ¹¹ Rare associations of IV reported in the literature ( Table 3 ) include Rickets by Kumar et al ²⁰ in 2012, pycnodysostosis by Kshirsagar et al ²¹ in 2012, acute intermittent porphyria by Varshney et al ²² in 2018, and dystrophic epidermolysis bullous pruriginosa by Gong et el. ²³ in 2018. However, the association of CMT4C and IV with bilateral hearing loss has never been reported.

Table 3. Summary of diseases reported to be in association with ichthyosis vulgaris.

Sl. no.	Author/year	Associated disease	Age (y)	Sex	Diagnosis confirmation	Mutations detected
1	Kumar et al 2012 20	Rickets	12	F	HPE of skin biopsy	–
2	Kshirsagar et al 2012 21	Pycnodysostosis	8	F	HPE of skin biopsy	–
3	Varshney et al 2018 22	Acute intermittent porphyria	9	M	HPE of skin biopsy	–
4	Gong et al 2019 23	Dystrophic epidermolysis bullous pruriginosa	21	M	Next-generation sequencing	FLG gene c.7249C > T p.Q2417X COL7A1 gene c.6698G > A p.G2233D
5	Index Study 2022	CMT4C	3	M	Exome sequencing	FLG gene c.2218C > T p.Arg740Ter SH3TC2 gene c.3325C > T p.Arg1109Ter

Abbreviations: CMT4C, Charcot-Marie-Tooth disease type 4C; F, female; HPE, histopathological examination; M, male.

Genetic testing is required at the earliest to establish the diagnosis in these patients with rare presentations and phenotypic overlap. Based on the genetic testing, the family can be educated, counseled, and provided with options for carrier testing, with implications for future pregnancies. Also, appropriate rehabilitation can be initiated by targeting the improvement of the quality of life in these patients.

Conclusion

“Entities should not be multiplied beyond necessity” is the principle of Occam's razor, advocating to choose the simpler explanations over complex ones. By the same token, dual diagnostic association in a child can be very confusing, and mislead us. Still, in scenarios such as the index case, these associations rather serve as a clue toward the diagnosis. Sensitization of multidisciplinary health care providers on rare associations with atypical presentations helps establish the diagnosis early, improve the quality of life through appropriate patient-centered interventions, and potential consideration for enrolment in new therapeutic trials.