Allan-Herndon-Dudley syndrome in Hong Kong: Implication for newborn screening.

BACKGROUND: Allan-Herndon-Dudley syndrome (MCT 8 deficiency) is an X-linked recessive condition caused by hemizygous pathogenic variants in SLC16A2 encoding the monocarboxylate transporter 8 (MCT8). Patients present with global developmental delay and neurological impairment, and abnormal serum thyroid function tests. The drug, 3,3',5 triiodothyroacetic acid (TRIAC), was recently demonstrated to improve the endocrinological profile. Improvement in diagnostic approach is key to earlier start of treatment. PATIENT FINDINGS: We described four Chinese patients with MCT8 deficiency undergoing different diagnostic odysseys. Their initial presentation included global developmental delay and dystonia. Patient 2 also had epilepsy. Patients 1 and 2 presented with two novel variants: (1)hemizygous NM_006517.4(SLC16A2):c.1170 + 2 T > A; p.(?), and (2)hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17) respectively. Patients 3 and 4 were biological brothers harboring hemizygous NM_006517.4(SLC16A2):c.305dupT; p.(Val103GlyfsTer17), which was first reported in 2004. We obtained the measurement of triiodothyronine (T3) and reverse T3 (rT3) from dried blood spot samples collected on Day 1 of life from Patient 1 and studied the biomarkers (rT3 and T3/rT3 ratio) proposed by Iwayama et al. for the detection of MCT8 deficiency at birth. Our data verified the significantly reduced rT3 level in Patient 1, compared with healthy newborns, although low T3 level and comparable T3/rT3 ratio with controls were detected. SUMMARY: Patients with MCT8 deficiency often undergo diagnostic odysseys. An early diagnosis could be missed by a normal newborn thyroid function screening result based on biochemical measurement of TSH and/or T4/fT4. Early detection of rT3 is key to improving current diagnostic approach. CONCLUSION: We recommend that full thyroid function profile (TSH, T4/fT4, T3/fT3, rT3) be considered early for all pediatric patients presenting with unexplained developmental delay and/or dystonia. The potential inclusion of rT3 measurement in newborn screening may prove promising.

A prospective follow-up of thyroid volume and thyroiditis features on ultrasonography among survivors of predominantly mild to moderate COVID-19.

Background: We previously showed that higher SARS-CoV-2 viral load correlated with smaller thyroid volumes among COVID-19 survivors at 2 months after acute COVID-19. Our current follow-up study evaluated the evolution of thyroid volumes and thyroiditis features within the same group of patients 6 months later. Methods: Adult COVID-19 survivors who underwent thyroid ultrasonography 2 months after infection (USG1) were recruited for follow-up USG 6 months later (USG2). The primary outcome was the change in thyroid volume. We also reassessed thyroiditis features on USG, thyroid function and anti-thyroid antibodies. Results: Fifty-four patients were recruited (mean age 48.1 years; 63% men). The mean thyroid volume increased from USG1 to USG2 (11.9 ± 4.8 to 14.5 ± 6.2 mL, p < 0.001). Thirty-two patients (59.3%) had significant increase in thyroid volume by ≥15%, and they had a median increase of +33.3% (IQR: +20.0% to +45.0%). Multivariable logistic regression analysis showed that only higher baseline SARS-CoV-2 viral load independently correlated with significant thyroid volume increase on USG2 (p = 0.022). Among the seven patients with thyroiditis features on USG1, six (85.7%) had the features resolved on USG2. None had new thyroiditis features on USG2. All abnormal thyroid function during acute COVID-19 resolved upon USG1 and USG2. Conclusion: Most COVID-19 survivors had an increase in thyroid volume from early convalescent phase to later convalescent phase. This increase correlated with high initial SARS-CoV-2 viral load. Together with the resolution of thyroiditis features, these may suggest a transient direct atrophic effect of SARS-CoV-2 on the thyroid gland with subsequent recovery of thyroid volume and thyroiditis features.

Mitochondrial diseases in Hong Kong: prevalence, clinical characteristics and genetic landscape.

OBJECTIVE: To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region. METHODS: This study retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators. RESULTS: A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81-1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%. CONCLUSION: This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry.

Case Report: Prenatal Recurrent Microcephaly and Corpus Callosum Abnormalities in a Chinese Family with Novel Biallelic SASS6 Mutations.

INTRODUCTION: Primary microcephaly (MCPH) is not an uncommon disorder with multiple etiologies. There are a growing number of MCPH-related genes discovered due to the extensive application of whole-exome sequencing (WES) in clinical and research settings. Biallelic mutations in the SASS6 gene cause an extremely rare MCPH, type 14. To date, only two families with SASS6 gene-related microcephaly have been reported. CASE DESCRIPTION: We report a case of recurrent congenital microcephaly in a Chinese family. The two affected fetuses presented with microcephaly early in the second trimester with agenesis of the corpus callosum. In the first affected fetus, trio WES detected two compound heterozygous candidate variants c.1139T>C(p.L380P) and c.1223C>G (p.T408S) in the SASS6 gene. Another affected fetus also inherited both variants, while the normal child carried neither variant through Sanger sequencing analysis. Both variants were classified as a variant of uncertain significance according to the current American College of Medical Genetics and Genomics guidelines. CONCLUSION: We reported novel biallelic variants in the SASS6 gene, encoding the SAS6 centriolar assembly protein, associated with prenatal onset of autosomal recessive microcephaly. We postulate that the pathomechanism of the compound heterozygous variants in close proximity could potentiate the overall coiled instability leading to the phenotypic features of our case.

A prospective follow-up on thyroid function, thyroid autoimmunity and long COVID among 250 COVID-19 survivors.

PURPOSE: We evaluated the evolution of thyroid function and autoimmunity among COVID-19 survivors over 6 months in relation to interferon beta-1b treatment and long COVID. METHODS: We included COVID-19 survivors managed in a major COVID-19 centre between July 2020 and May 2021 who were reassessed three and/or six months after acute COVID-19. Thyroid function tests (TFTs) and anti-thyroid antibody titres were measured at acute COVID-19, 3-month and 6-month. RESULTS: 250 COVID-19 survivors were included (mean age 52.7 years, 50.4% men). Persistent thyroid function abnormalities were more likely in those with abnormal TFTs in acute COVID-19 (P < 0.001). Among 51 patients with abnormal TFTs in acute COVID-19, 82.4% resolved upon follow-up. Of 199 patients with normal TFTs in acute COVID-19, only 4.5% had incident abnormal TFTs, more likely in interferon-treated patients (P = 0.044) and none clinically overt. Among 129 patients with complete 6-month follow-up for anti-thyroid antibody titres, there was no significant change overall, except for modest increase in anti-thyroid antibody titres among the 84 interferon-treated patients (P < 0.05 at both 3 months and 6 months). Long COVID occurred in 19.5% and 10.4% at 3 and 6 months respectively, where TFTs and anti-thyroid antibody titres were not predictive of its occurrence. CONCLUSION: Over 6 months, most abnormal TFTs in acute COVID-19 resolved, with no significant incident thyroid dysfunction. SARS-CoV-2 infection did not lead to change in thyroid autoimmunity, while interferon treatment was associated with modest increase in anti-thyroid antibody titres. Thyroid function and anti-thyroid antibodies did not play a significant role in long COVID.

C-terminal truncated SPOP, a Janus-faced variant, causing a mixed type 1 and type 2 Nabais Sa-de Vries syndrome.

Nabais Sa-de Vries syndrome (NSDVS) is an autosomal dominant neurodevelopmental disorder first described in 2020 and is classified into type 1 (NSDVS1) and type 2 (NSDVS2) which encompassed of spectrum of distinct clinical features due to gain-of-function (GOF) and loss-of-function (LOF) variants respectively. So far only 6 cases of 5 different missense pathogenic variants had been reported which impact on the SPOP substrate binding affinity for the downstream ubiquitylation. Here, we report a novel and de novo heterozygous nonsense pathogenic variant, p.Tyr353Term at the BACK domain in a patient with neurodevelopmental delay plus mixed phenotypes of NSDVS type 1 and 2 using trio exome analysis. The BACK domain is functionally critical for the SPOP higher-order oligomerization and is shown to increase substrate binding avidity with enhanced ubiquitylation efficiency in vitro. Experimentally, a missense variant p.Tyr353Glu is proven to attenuate the tandem SPOP oligomer formation and we envisage the current truncated variant at the same residue would attenuate the oligomerization process. This is the first report providing in vivo clue about the clinical significance of SPOP oligomerization in human neurodevelopmental disorders with new understanding on the expanding spectrum of NSDVS. We conclude the p.Tyr353Term is a Janus-faced variant which explains the dual NSDVS type 1 and 2 phenotypes in this case.

Changing pleural fluid triglyceride levels in cirrhotic chylothorax.

Chylothorax is an uncommon disease entity, but it occasionally poses a diagnostic challenge to physicians. Pleural fluid triglyceride level has been advocated as a screening test to diagnose chylothorax. However, its level can be depressed if there is an additional pathology driving the process of pleural fluid production. We report a case of high-volume pleural fluid output due to dual pathologies, cirrhotic hydrothorax and chylothorax, causing an initial failure to diagnose chylothorax due to low pleural fluid triglyceride level. The fluid triglyceride levels were unmasked after the treatment for underlying portal hypertension. These findings were further substantiated by positive lipoprotein electrophoresis for chylomicron. In this patient, lipoprotein electrophoresis of his pleural fluid specimen helps distinguish chylothorax as a second pathology amidst the underlying cirrhotic hydrothorax.

Serum ceruloplasmin monitoring in a case of silver intoxication due to intravenous silver infusion.

INTRODUCTION: Colloidal silver packaged as a dietary supplement is readily available online and is thought to be safe. Literature describing its toxicity in humans is scarce. CASE REPORT: A 47-year-old man presented to us for sensory and gait problems. He had unremarkable past health except dystrophic nails. He further volunteered a history of receiving chronic oral and intravenous administration of colloidal silver. We confirmed his plasma silver was 1200-fold elevated, measuring 11990 nmol/L (normal < 10 nmol/L). He had deranged liver function tests, and liver biopsy showed distorted acinar architecture, bridging fibrosis and lymphocytic infiltrate with silver particles clustering along the vascular endothelium and portal venules. Brain magnetic resonance imagining showed features of mineralization over bilateral globus pallidi. There was biochemical evidence of central adrenal insufficiency, intracellular iron overload and hypoceruloplasminemia (<0.05 g/L). Gradual clinical and biochemical improvement was noted after silver cessation: his plasma silver dropped to 4800 nmol/L (3 months) and 1650 nmol/L (12 months), and serum ceruloplasmin reverted to 0.13 g/L (10 months) and 0.29 g/L (20 months). CONCLUSIONS: The potential effects of silver to liver and copper metabolism were shown in this case. Serum ceruloplasmin also serves as a surrogate marker in monitoring silver intoxication.

The Impact of Interferon Beta-1b Therapy on Thyroid Function and Autoimmunity Among COVID-19 Survivors.

Background: Some studies have indicated that interferon (IFN) may be valuable in COVID-19. We aimed to evaluate the impact of short-term IFN on incident thyroid dysfunction and autoimmunity among COVID-19 survivors. Methods: We included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to January 2021 who had thyroid function tests (TFTs) and anti-thyroid antibodies measured both on admission and at three months. Results: 226 patients were included (median age 55.0 years; 49.6% men): 135 were IFN-treated. There tended to be more abnormal TFTs upon reassessment in IFN-treated patients (8.1% vs 2.2%, p=0.080). 179 patients (65.4% IFN-treated) had a complete reassessment of anti-thyroid antibodies. There were significant increases in titres of both anti-thyroid peroxidase antibodies (anti-TPO: baseline 29.21 units [IQR: 14.97 - 67.14] vs reassessment 34.30 units [IQR: 18.82 - 94.65], p<0.001) and anti-thyroglobulin antibodies (anti-Tg: baseline 8.23 units [IQR: 5.40 - 18.44] vs reassessment 9.14 units [IQR: 6.83 - 17.17], p=0.001) in the IFN-treated group but not IFN-naïve group. IFN treatment (standardised beta 0.245, p=0.001) was independently associated with changes in anti-TPO titre. Of the 143 patients negative for anti-TPO at baseline, 8 became anti-TPO positive upon reassessment (seven IFN-treated; one IFN-naïve). Incident anti-TPO positivity was more likely to be associated with abnormal TFTs upon reassessment (phi 0.188, p=0.025). Conclusion: IFN for COVID-19 was associated with modest increases in anti-thyroid antibody titres, and a trend of more incident anti-TPO positivity and abnormal TFTs during convalescence. Our findings suggest that clinicians monitor the thyroid function and anti-thyroid antibodies among IFN-treated COVID-19 survivors, and call for further follow-up studies regarding the clinical significance of these changes.

Higher SARS-CoV-2 viral loads correlated with smaller thyroid volumes on ultrasound among male COVID-19 survivors.

PURPOSE: Thyroid dysfunction, including thyroiditis, is well recognized in COVID-19 patients. We evaluated thyroid ultrasonographic features among COVID-19 survivors, which are less well known. METHODS: Adult COVID-19 survivors without known thyroid disorders who attended dedicated COVID-19 clinic underwent thyroid ultrasonography and assessment of thyroid function and autoimmunity. Adults admitted for acute non-thyroidal surgical problems and negative for COVID-19 were recruited as control. SARS-CoV-2 viral load (VL) was presented as the inverse of cycle threshold values from the real-time reverse transcription-polymerase chain reaction of the respiratory specimen on admission. RESULTS: In total, 79 COVID-19 patients and 44 non-COVID-19 controls were included. All abnormal thyroid function tests during acute COVID-19 recovered upon follow-up. Thyroid ultrasonography was performed at a median of 67 days after acute COVID-19. The median thyroid volume was 9.73 mL (IQR: 7.87-13.70). In multivariable linear regression, SARS-CoV-2 VL on presentation (standardized beta -0.206, p = 0.042) inversely correlated with thyroid volume, in addition to body mass index at the time of ultrasonography (p < 0.001). Sex-specific analysis revealed similar results among men but not women. Eleven COVID-19 patients (13.9%) had ultrasonographic changes suggestive of thyroiditis, comparable to non-COVID-19 patients (p = 0.375). None of these 11 patients had isolated low thyroid-stimulating hormone levels suggestive of thyroiditis at initial admission or the time of ultrasonography. CONCLUSIONS: Higher SARS-CoV-2 VL on presentation were associated with smaller thyroid volumes, especially in men. Further research is suggested to investigate this possible direct viral effect of SARS-CoV-2 on the thyroid gland. There was no increased rate of ultrasonographic features suggestive of thyroiditis in COVID-19 survivors.

Long COVID in Patients With Mild to Moderate Disease: Do Thyroid Function and Autoimmunity Play a Role?

OBJECTIVE: Post-acute sequelae of coronavirus disease 2019 (COVID-19) or long COVID (LC) is an emerging global health issue. Fatigue is a common feature. Whether thyroid function and autoimmunity play a role is uncertain. We aimed to evaluate the prevalence and predictors of LC and the potential role of thyroid function and autoimmunity in LC. METHODS: We included consecutive adults without a known thyroid disorder who were admitted to a major COVID-19 center for confirmed COVID-19 from July to December 2020. Thyroid function tests and antithyroid antibodies were measured for all patients on admission and at follow-up. LC was defined by the presence or persistence of symptoms upon follow-up. RESULTS: In total, 204 patients (median age, 55.0 years; 95 men [46.6%]) were reassessed at a median of 89 days (interquartile range, 69-99) after acute COVID-19. Of the 204 patients, 41 (20.1%) had LC. Female sex (adjusted odds ratio, 2.48; P = .018) and severe acute respiratory syndrome coronavirus 2 polymerase chain reaction cycle threshold value of <25 on admission (adjusted odds ratio, 2.84; P = .012) independently predicted the occurrence of LC. Upon follow-up, most abnormal thyroid function tests in acute COVID-19 resolved, and incident thyroid dysfunction was rare. Nonetheless, we observed incident antithyroid peroxidase (anti-TPO) positivity. Although baseline or follow-up thyroid function tests were not associated with the occurrence of LC, among 172 patients with symptomatic acute COVID-19, symptom resolution was more likely in those with positive anti-TPO upon follow-up (P = .043). CONCLUSION: LC is common among COVID-19 survivors, with females and those with higher viral load in acute COVID-19 particularly being vulnerable. The observation of incident anti-TPO positivity warrants further follow-up for thyroid dysfunction. Whether anti-TPO plays a protective role in LC remains to be elucidated.

Urine organic acid as the first clue towards aromatic L-amino acid decarboxylase (AADC) deficiency in a high prevalence area.

BACKGROUND: Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disease due to impaired decarboxylation of neurotransmitter precursors to its active form. CASE: We retrospectively reviewed 8 cases from 2008 to 2019 with cerebrospinal fluid neurotransmitter analysis performed at our centre. All cases had an elevated urine vanillactic acid and, in most cases, with N-acetylvanilalanine detected. Cerebrospinal fluid analysis showed low downstream metabolites vanillylmandelic acid, homovanillic acid but high 3-O-methyl-L-DOPA, 5-hydroxytryptophan. Cerebrospinal fluid pterins were normal. Genotyping in DDC confirms the diagnosis. Urine organic acid analysis provided the first clue to diagnosis in four of the cases, which then triggered cerebrospinal fluid neurotransmitter and genetic analysis. We also developed a diagnostic decision support system to assist the interpretation of the mass spectrometry data from urine organic acids. CONCLUSIONS: Urine organic acid could be essential in guiding subsequent investigations for the diagnosis of aromatic L-amino acid decarboxylase deficiency. We propose to screen suspected cases first with urine organic acids, specifically looking for vanillactic acid and N-acetylvanilalanine. Suggestive findings should be followed with target analysis for c.714 + 4A > T in ethnically Chinese patients. The assistive tool allowed expedite interpretation of profile data generated from urine organic acids analysis. It may also reduce interpreter's bias when peaks of interest are minor peaks in the spectrum.

Insights from a Prospective Follow-up of Thyroid Function and Autoimmunity among COVID-19 Survivors.

BACKGROUND: The occurrence of Graves' disease and Hashimoto thyroiditis after coronavirus disease 2019 (COVID-19) raised concerns that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may trigger thyroid autoimmunity. We aimed to address the current uncertainties regarding incident thyroid dysfunction and autoimmunity among COVID-19 survivors. METHODS: We included consecutive adult COVID-19 patients without known thyroid disorders, who were admitted to Queen Mary Hospital from July 21 to September 21, 2020 and had serum levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine (fT3), and anti-thyroid antibodies measured both on admission and at 3 months. RESULTS: In total, 122 patients were included. Among 20 patients with abnormal thyroid function tests (TFTs) on admission (mostly low fT3), 15 recovered. Among 102 patients with initial normal TFTs, two had new-onset abnormalities that could represent different phases of thyroiditis. Among 104 patients whose anti-thyroid antibody titers were reassessed, we observed increases in anti-thyroid peroxidase (TPO) (P<0.001) and anti-thyroglobulin (P<0.001), but not anti-thyroid stimulating hormone receptor titers (P=0.486). Of 82 patients with negative anti-TPO findings at baseline, 16 had a significant interval increase in anti-TPO titer by >12 U, and four became anti-TPO-positive. Worse baseline clinical severity (P=0.018), elevated C-reactive protein during hospitalization (P=0.033), and higher baseline anti-TPO titer (P=0.005) were associated with a significant increase in anti-TPO titer. CONCLUSION: Most patients with thyroid dysfunction on admission recovered during convalescence. Abnormal TFTs suggestive of thyroiditis occurred during convalescence, but infrequently. Importantly, our novel observation of an increase in anti-thyroid antibody titers post-COVID-19 warrants further follow-up for incident thyroid dysfunction among COVID-19 survivors.

Role of non-thyroidal illness syndrome in predicting adverse outcomes in COVID-19 patients predominantly of mild-to-moderate severity.

OBJECTIVE: Existing studies reported the potential prognostic role of non-thyroidal illness syndrome (NTIS), characterized by low triiodothyronine (T3) with normal/low thyroid-stimulating hormone (TSH), mainly in severe COVID-19. None considered the significant impact of SARS-CoV-2 viral load on adverse outcomes. We aimed to clarify the prognostic role of NTIS among predominantly mild-to-moderate COVID-19 patients. DESIGN: A prospective study of COVID-19 patients. PATIENTS AND MEASUREMENTS: Consecutive adults admitted to Queen Mary Hospital for confirmed COVID-19 from July to December 2020 were prospectively recruited. SARS-CoV-2 viral load was represented by cycle threshold (Ct) values from real-time reverse transcription-polymerase chain reaction of the respiratory specimen on admission. Serum TSH, free thyroxine and free T3 were measured on admission. The outcome was deterioration in clinical severity, defined as worsening in ≥1 category of clinical severity according to the Chinese National Health Commission guideline. RESULTS: We recruited 367 patients. At baseline, 75.2% had mild disease, and 27 patients (7.4%) had NTIS. Fifty-three patients (14.4%) had clinical deterioration. Patients with NTIS were older, had more comorbidities, worse symptomatology, higher SARS-CoV-2 viral loads and worse profiles of inflammatory and tissue injury markers. They were more likely to have clinical deterioration (p < .001). In multivariable stepwise logistic regression analysis, NTIS independently predicted clinical deterioration (adjusted odds ratio 3.19, p = .017), in addition to Ct value <25 (p < .001), elevated C-reactive protein (p = .004), age >50 years (p = .011) and elevated creatine kinase (p = .017). CONCLUSIONS: Non-thyroidal illness syndrome was not uncommon even in mild-to-moderate COVID-19 patients. NTIS on admission could predict clinical deterioration in COVID-19, independent of SARS-CoV-2 viral load, age and markers of inflammation and tissue injury.

The Independent Association of TSH and Free Triiodothyronine Levels With Lymphocyte Counts Among COVID-19 Patients.

Background: Both lymphopenia and thyroid dysfunction are commonly observed among COVID-19 patients. Whether thyroid function independently correlates with lymphocyte counts (LYM) remains to be elucidated. Methods: We included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to April 2021 who had thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and LYM measured on admission. Results: A total of 541 patients were included. Median LYM was 1.22 x 109/L, with 36.0% of the cohort lymphopenic. 83 patients (15.4%) had abnormal thyroid function tests (TFTs), mostly non-thyroidal illness syndrome (NTIS). Patients with lymphopenia had lower TSH, fT4 and fT3 levels than those without. Multivariable stepwise linear regression analysis revealed that both TSH (standardized beta 0.160, p<0.001) and fT3 (standardized beta 0.094, p=0.023), but not fT4, remained independently correlated with LYM, in addition to age, SARS-CoV-2 viral load, C-reactive protein levels, coagulation profile, sodium levels and more severe clinical presentations. Among the 40 patients who had reassessment of TFTs and LYM after discharge, at a median of 9 days from admission, there were significant increases in TSH (p=0.031), fT3 (p<0.001) and LYM (p<0.001). Furthermore, patients who had both lymphopenia and NTIS were more likely to deteriorate compared to those who only had either one alone, and those without lymphopenia or NTIS (p for trend <0.001). Conclusion: TSH and fT3 levels showed independent positive correlations with LYM among COVID-19 patients, supporting the interaction between the hypothalamic-pituitary-thyroid axis and immune system in COVID-19.

Novel PPOX exonic mutation inducing aberrant splicing in a patient with homozygous variegate porphyria.

INTRODUCTION: Variegate porphyria (VP; OMIM 176200) is one of the acute hepatic porphyrias, and it is characterized by the partial deficiency of protoporphyrinogen oxidase (PPOX). The unusual homozygous variant with mutations on both alleles of PPOX is distinguished with general heterozygous VP by several typical points such as severe defect in PPOX enzyme activity, early onset of photosensitivity before puberty, and skeletal deformity. MATERIAL AND METHOD: In this study, we describe a very rare case of autosomal recessive form of true homozygous VP found in a Chinese patient with consanguineous parents. Sanger sequencing of the PPOX gene showed a novel homozygous variant located at the first base of exon 8 of the gene, i.e., NM_000309.3c.808G > T. To investigate aberrant splicing induced by the mutant, wild-type exon 8 and mutant exon 8 were expressed in pET01 vector as minigene in cultured-cells and analyzed by RT-PCR. RESULTS: The wildtype PPOX showed an expected band in the gel electrophoresis after RT-PCR. The PPOX c.808G > T only showed a band similar to the band size of the vector only control. This result suggested c.808G > T mutant is an exonic mutation inducing aberrant splicing of pre-mRNA of the PPOX gene. CONCLUSION: This study showed a very rare case of homozygous VP with autosomal recessive homoallelic pattern. In comparison with previous cases of homozygous VP presenting brachydactyly, it is notable that our patient did not have any skeletal deformities.

Thyroid Dysfunction in Relation to Immune Profile, Disease Status, and Outcome in 191 Patients with COVID-19.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related thyroiditis is increasingly recognized. The role of thyroid autoimmunity and SARS-CoV-2 viral load in SARS-CoV-2-related thyroid dysfunction is unclear. We evaluated the thyroid function of a cohort of coronavirus disease 2019 (COVID-19) patients, in relation to their clinical features, and biochemical, immunological, and inflammatory markers. METHODS: Consecutive adult patients, without known thyroid disorders, admitted to Queen Mary Hospital for COVID-19 from July 21 to August 21, 2020, were included. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine, free triiodothyronine (fT3), and antithyroid antibodies were measured on admission. RESULTS: Among 191 patients with COVID-19 (mean age 53.5 ±â€…17.2 years; 51.8% male), 84.3% were mild, 12.6% were moderate, and 3.1% were severe. Abnormal thyroid function was seen in 13.1%. Ten patients had isolated low TSH, suggestive of subclinical thyrotoxicosis due to thyroiditis, although the contribution of autoimmunity was likely in 2 of them. Autoimmune thyroiditis probably also contributed to subclinical hypothyroidism in another patient. Ten patients had isolated low fT3, likely representing nonthyroidal illness syndrome. Lower SARS-Cov-2 polymerase chain reaction cycle threshold values and elevated C-reactive protein were independently associated with occurrence of low TSH (P = .030) and low fT3 (P = .007), respectively. A decreasing trend of fT3 with increasing COVID-19 severity (P = .032) was found. Patients with low fT3 had more adverse COVID-19-related outcomes. CONCLUSION: Around 15% of patients with mild to moderate COVID-19 had thyroid dysfunction. There may be a direct effect of SARS-CoV-2 on thyroid function, potentially leading to exacerbation of pre-existing autoimmune thyroid disease. Low fT3, associated with systemic inflammation, may have a prognostic significance.

Centrosome-associated CDC25B is a novel disease-causing gene for a syndrome with cataracts, dilated cardiomyopathy, and multiple endocrinopathies.

We describe a unique Chinese girl who presented with intrauterine growth retardation, delayed development, bilateral cataracts, hypothyroidism, growth hormone deficiency, and juvenile dilated cardiomyopathy. She was born to consanguineous parents with a history of one fetal and one infantile death in the family. She died from cardiac failure at the age of 12. In the pursuit of a diagnosis, the family was referred to the Clinics for Rare Diseases Referral and the University of Hong Kong Undiagnosed Disease Program. Whole-exome sequencing analysis revealed a homozygous non-sense variant, NM_021873:c.313G > T (p.Glu105*), in the CDC25B gene, a key regulator of the cell cycle. This variant was located in a region of homozygosity of 25 Mb on chromosome 20. Her parents and two asymptomatic sisters were confirmed to be carriers and one brother did not carry the variant. This is the first report of a natural human knockout of the CDC25B gene. Multiple endocrinopathies and fatal juvenile dilated cardiomyopathy suggests the potential for unfavorable complications in oncology patients receiving CDC25B inhibitors as an emerging targeted therapy.

Clinical whole-exome sequencing reveals a common pathogenic variant in patients with CoQ10 deficiency: An underdiagnosed cause of mitochondriopathy.

BACKGROUND: Primary CoQ deficiency occurs because of the defective biosynthesis of coenzyme Q, one of the key components of the mitochondrial electron transport chain. Patients with this disease present with a myriad of non-specific symptoms and signs, posing a diagnostic challenge. Whole-exome sequencing is vital in the diagnosis of these cases. CASE: Three unrelated cases presenting as either encephalopathy or cardiomyopathy have been diagnosed to harbor a common pathogenic variant c.370G > A in COQ4. COQ4 encodes a key structural component for stabilizing the multienzymatic CoQ biosynthesis complex. This variant is detected only among East and South Asian populations. CONCLUSIONS: Based on the population data and our case series, COQ4-related mitochondriopathy is likely an underrecognized condition. We recommend including the COQ4 c.370G > A variant as a part of the screening process for mitochondriopathy in Chinese populations.