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Título

Autossomal Dominant IFIH1-Disorder associated with sensorimotor polyneuropathy

RESUMO

The IFIH1 gene encodes a cytoplasmic receptor for viral double-stranded RNA, that activates type I interferon signaling and antiviral response. Gain-of-function mutations in IFIH1 are related to increased and inappropriate exposure to type I interferon resulting in a distinct set of inborn errors of immunity, Aicardi-Goutieres, and Singleton-Merten syndromes (SMS).
SMS is a rare genetic disease characterized by calcifications in the aorta and cardiac valves, delayed primary tooth eruption, dysregulated mineralization, teeth loss, osteoporosis, dysmorphisms, muscle weakness, psoriasis, and recurrent infections.
This is the first description of polyneuropathy in an autosomal dominant IFIH1-Disorder presenting with incomplete Singleton-Merten syndrome.
Case report: A male patient by the age of 2 started presenting joint retractions, hypodontia, fatigue, exercise intolerance, and large joint pain. He had severe bone fractures following minor traumas. At the age of 12, he was diagnosed with psoriasis.
Clinical examination revealed hypodontia, broad forehead, anteverted ears, malformation of helix and goblin, and trophic alteration of skin. We observed distal weakness and retractions. Lower limb deep tendon reflexes were absent and upper limb reflexes were hypoactive. There was hypoesthesia in the lower limbs up to the knee and in fingertips in the upper limbs, associated with reduced vibration sense. Cognition was normal.
Brain MRI showed foci of calcification in the left frontal radiated crown. Echocardiogram, EKG, and CSF analysis were normal. Bone densitometry revealed severe osteoporosis. Nerve conduction studies showed a length-dependent sensorimotor polyneuropathy. The nerve ultrasound was normal. Muscle ultrasound showed neurogenic changes in lower limbs sparing the rectus femoris, and tibialis anterior. Upper limb muscles were normal, as were paraspinal and respiratory muscles.
Whole exome sequencing revealed a heterozygous mutation in the IFIH1 gene that was not previously described and is absent from population databases. We classified the variant presented here as likely pathogenic according to the ACMG criteria.
This case confirms that IFIH1 gain-of-function mutations cause a spectrum of diseases. The sparing of the tibialis anterior muscle is of particular interest, as it is a commonly affected muscle in other hereditary polyneuropathies and this pattern may help in the differential diagnosis. Finally, polyneuropathy could play a role in patients’ phenotype.

Palavras Chave

IFIH1, polyneuropathy, Singleton-Merten, muscle ultrasound