We identified three unrelated Spanish individuals with an unusual but similar clinical phenotype. They did not have family history of congenital or neurological disorders, and their parents were non-consanguineous. A comprehensive clinical history was gathered and clinical examinations were meticulously performed for each affected individual. Written informed consent was obtained from patients included in this study or their parents.
Patient 1
A 25-year-old female with congenital bilateral hearing loss (Fig. 1A), chronic constipation due to megacolon, gastroesophageal reflux, diabetes and mild language retardation, was referred for asymmetric pain in the lateral aspect of the legs, triggered by exercise and relieved by rest, which was attributed to tenosynovitis.
On examination, bright blue eyes with partial heterochromia iridis, hypopigmentation of hair (white forelock) and skin (café-au-lait spots on the right hand, breasts, right thigh, knees and scalp, Fig. 1B) and pes cavus, were found. Neuromas were present in the left arm, right leg and forehead.
On neurological examination, tendon reflexes were 1/4 in upper limbs and absent in the lower ones. Muscle bulk and power, stance, gait and pain and vibration sense were preserved. Coordination and cranial nerves were normal.
An electrophysiological study revealed decreased sensory (31 m/s) nerve conduction velocity (NCV) in the right median nerve, and absent action potentials in both sural nerves. Motor NCV was decreased in the median, peroneal and tibial nerves, while increased motor latencies were found in the median nerve.
Referred for genetic study by Multiplex Ligation-dependent Probe Amplification (MLPA) of the PMP22 gene and obtaining a negative result, she then went through a massive sequencing study (targeted clinical exome, ExoNIM®, NIMGenetics, Spain) with the aim of identifying variants in 103 selected genes associated with Charcot-Marie Tooth and other HMSN. Four variants of uncertain significance were obtained.
As so, genetic testing was amplified with a massive sequencing of the complete human exome of the patient and his parents (ExoNIM® Trio Approach, NIMGenetics, Spain). The c.395C>G p.(Ala132Gly) variant was identified de novo in the case sample consisting in a single nucleotide substitution in exon 2 of the SOX10 gene (transcript ID: LRG_271). According to the ACMG variant classification guidelines, this missense variant was classified as pathogenic since PS2, PM1, PM2_supporting, PP2, PP3 and PP4 criteria were met.
Patient 2
Infant symptomatic from birth, with dysphagia, a diagnosis of Hirschprung disease and carrier of gastrostomy and ileostomy. Neurologically, abnormal tendon reflexes, rhythmic and horizontal head jerks, limb tremor and rotating eye movements were observed from day 15 of life. The patient died aged 20 months due to complications derived from intestinal obstruction.
A brainstem auditory evoked potential (BAEP) test showed severely prolonged latencies bilaterally.
With these clinical features, we were asked to carry out an array comparative genomic hybridization (aCGH, qChip® Post, qGenomics, Spain), with no relevant findings. Then, we amplified the genetical study by conducting a targeted exome (ExoNIM® Clinical, NIMGenetics, Spain) in order to identify variants in 6102 selected genes that may present an association with our case’s phenotype. The heterozygous c.850G>T p.(Glu284*) variant identified in SOX10 (transcript ID: LRG_271) in the patient’s sample was a nonsense variant classified by ACMG as likely pathogenic (PVS1_strong, PM2_supporting and PP4 criteria).
Patient 3
A 14-year-old boy with congenital bilateral hearing loss, required cochlear implants at one year of age. He had no heterochromia iridis or skin hypopigmentation. The patient was diagnosed with ileocolic Hirschprung disease at 6 months, with ileostomy discharge at 15 months. A colectomy was performed to remove the non-functional segment of the intestine (Duhamel’s technique), but he retains a residual aganglionic colon segment. Later colonoscopic follow-up revealed histopathological lesions and an anastomotic ulcer consistent with moderate-severe active chronic pouchitis.
Nowadays, he experiences frequent episodes of diarrhea, rectal bleeding and dehydration, requiring multiple antibiotic regimens due to bacterial overgrowth. A neurological evaluation was normal: without executive dysfunction or clinical signs of peripheral neuropathy or central neurological involvement.
In this clinical context, a genetic study was carried out by massive sequencing of the complete human exome of the patient and his parents (ExoNIM® Trio Approach, NIMGenetics, Spain) in order to identify variants in potentially causal genes of the patient's phenotype. The c.966dupT p.(Ala323fs) variant identified in SOX10 (transcript ID: LRG_271) in the samples from the patient and his father was catalogued as pathogenic because it met PVS1_strong, PS2, PM2_supporting and PP4 ACMG criteria.