Case Report and Literature Review: Homozygous DNAJC3 Mutation in a Saudi Family Causing Maturity Onset Diabetes of the Young (MODY), Hypothyroidism, Short Stature, Neurodegeneration, and Hearing Loss
Authors: Alwatban Saud Mohammed , Alfaraidi Haifa , Alfadhel Majid , Almutair Angham N 
Published: May 2021

Abstract
Introduction: Monogenic diabetes results from a mutation in single gene, predominantly inherited and typically affects the young. DNAJC3 acts in attenuating endoplasmic reticulum stress and is found in abundance in pancreatic tissue. Clinical Case: We report a homozygous DNAJC3 mutation in two siblings of a consanguineous Saudi family. A 3-year boy presented with short stature and thyroid nodule; lab findings confirmed hypothyroidism, with TSH 27.8 and FT4 6.7 (n: TSH:0.35-4.94 mIU/L, FT4:9.0-19 pmol/L). Subsequently, L-thyroxine was started. GH stimulation test was normal. He was severely short; 80.5 cm (&lt; 1 percentile, -3.79 SD). The patient developed sensorineural hearing loss (SNHL) at 6 years. He had low intellectual function and weak school performance. GH treatment was postponed to age 9 due to strong family history of DM. At that point, the patient developed progressive ataxic gait, for which he had muscle biopsy that excluded mitochondrial disease and workup for multiple sclerosis, which was excluded. Brain and spine MRI showed prominent neurodegeneration in subcortical white matter. At age 11, the patient developed DM, 4 years after GH treatment initiation. DM autoimmune markers were negative on multiple occasions. Lifestyle modification was initiated but soon required basal and bolus insulin therapy. Whole exome sequencing revealed homozygous DNAJC3 mutation, which explained his clinical presentation. At age of 17, adult height was 141 cm (Z-score: -5.87). His older brother had similar history discovered retrospectively but did not develop neurodegeneration or ataxia from the same DNAJC3 mutation. Literature Review: Literature review revealed six individuals with homozygous DNAJC3 mutation. All patients developed DM, with onset ranging from 11 to 19 years, highly suggestive of MODY. Other endocrine manifestations included short stature, and hypothyroidism due to primary etiology; in view of elevated TSH levels, vs. being secondary, as suggested by the authors. All patients had mitochondrial disease workups and was excluded. Variable neurodegeneration degrees are described; SNHL, progressive ataxia, sensorimotor neuropathy, and cognitive deficits. MRI findings showed atrophy of cerebellum, brainstem, cervical spinal cord, and hyperintense T2 lesions typical of neurodegeneration. Conclusion: Homozygous DNAJC3 gene mutation fits MODY criteria, we propose recognizing it as one of the known MODY gene mutations. Hypothyroidism is due to primary etiology, evident by TSH spikes. Physicians evaluating mitochondrial disease in patients with a constellation of SNHL, DM, hypothyroidism, neurodegeneration, and short stature should suspect DNAJC3 as one differential diagnosis. GH treatment must be initiated cautiously, with close monitoring due to its known diabetogenic effect, especially in DNAJC3 mutations, defective endoplasmic stress attenuation mechanism.