Long-Term Efficacy of T3 Analogue Triac in Children and Adults With MCT8 Deficiency: A Real-Life Retrospective Cohort Study.

CONTEXT: Patients with mutations in thyroid hormone transporter MCT8 have developmental delay and chronic thyrotoxicosis associated with being underweight and having cardiovascular dysfunction. OBJECTIVE: Our previous trial showed improvement of key clinical and biochemical features during 1-year treatment with the T3 analogue Triac, but long-term follow-up data are needed. METHODS: In this real-life retrospective cohort study, we investigated the efficacy of Triac in MCT8-deficient patients in 33 sites. The primary endpoint was change in serum T3 concentrations from baseline to last available measurement. Secondary endpoints were changes in other thyroid parameters, anthropometric parameters, heart rate, and biochemical markers of thyroid hormone action. RESULTS: From October 15, 2014 to January 1, 2021, 67 patients (median baseline age 4.6 years; range, 0.5-66) were treated up to 6 years (median 2.2 years; range, 0.2-6.2). Mean T3 concentrations decreased from 4.58 (SD 1.11) to 1.66 (0.69) nmol/L (mean decrease 2.92 nmol/L; 95% CI, 2.61-3.23; P < 0.0001; target 1.4-2.5 nmol/L). Body-weight-for-age exceeded that of untreated historical controls (mean difference 0.72 SD; 95% CI, 0.36-1.09; P = 0.0002). Heart-rate-for-age decreased (mean difference 0.64 SD; 95% CI, 0.29-0.98; P = 0.0005). SHBG concentrations decreased from 245 (99) to 209 (92) nmol/L (mean decrease 36 nmol/L; 95% CI, 16-57; P = 0.0008). Mean creatinine concentrations increased from 32 (11) to 39 (13) µmol/L (mean increase 7 µmol/L; 95% CI, 6-9; P < 0.0001). Mean creatine kinase concentrations did not significantly change. No drug-related severe adverse events were reported. CONCLUSIONS: Key features were sustainably alleviated in patients with MCT8 deficiency across all ages, highlighting the real-life potential of Triac for MCT8 deficiency.

Uterine leiomyoma with fumarate hydratase deficiency: A case report.

RATIONALE: Hereditary leiomyomatosis and renal cell carcinoma is an uncommon autosomal dominant disease caused by mutations in the fumarate hydratase (FH) gene. They usually demonstrated multiple uterine myomas and preformed surgical procedures for myomectomy and/or hysterectomy 10 years earlier than sporadic myomas due to early development. This case report describes a woman with multiple uterine leiomyomas diagnosed with FH deficiency. PATIENT CONCERNS: A 37-year-old woman visited a gynecological clinic for the discovery of uterine leiomyoma for more than 1 year. The size of the largest grew from 42 × 27 × 46 to 98 × 85 × 113 mm in 1 year. She had a history of surgery for breast cancer and thyroid cancer but denied a history of uterine leiomyoma in her family. DIAGNOSIS AND INTERVENTIONS: The patient underwent successful transabdominal hysterectomy. The pathological results showed multiple uterine leiomyomas (partly cellular leiomyomas) with scattered large bizarre giant cells. Immunohistochemistry results demonstrated FH deficiency. OUTCOMES: On follow-up, the patient did not have any complications. She was finally referred to the oncologists and urologists for follow-up. LESSONS: Gynecologists should be aware that early onset uterine leiomyoma presenting as large, multiple, and symptomatic lesion, may be associated with FH deficiency.

Measurement of Reverse Triiodothyronine Level and the Triiodothyronine to Reverse Triiodothyronine Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Detection of Monocarboxylate Transporter 8 Deficiency.

Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transport across the cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as the inability of standard biomarkers of neonatal screening to provide early detection. In this study, we report, for the first time, the ability to detect MCT8 deficiency at birth using dried blood spot (DBS) samples. Methods: We retrospectively measured triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3) levels in DBS samples obtained at 4-5 days of life from 6 infants with genetically confirmed MCT8 deficiency and from 110 controls. The latter consisted of 58 healthy term neonates obtained at the same time, 16 were stored for more than 1 year before measurement to match samples from the MCT8-deficient infants. Ten DBS samples were collected at day 1 of life and 42 samples were from prematurely born neonates. Measurements were carried out in extract from eight millimeters diameter DBS using liquid chromatography-tandem mass spectrometry. Results: Contrary to characteristic iodothyronine abnormalities of MCT8 deficiency during later life, T3 and T4 values were not discriminatory from those of other study groups. In contrast, rT3 was significantly lower. The T3/rT3 ratio was higher in the DBS samples from the MCT8-deficient infants compared with all other groups with no overlap (p < 0.0001). Conclusions: rT3 and T3/rT3 ratio in DBS samples obtained from neonates can serve as biomarkers to detect MCT8 deficiency at birth.

Microcephaly, Hypotonia, and Intracranial Calcifications in an 11-Week-Old Boy.

An 11-week-old unvaccinated, term Amish boy initially presented with poor feeding, microcephaly, failure to thrive, and developmental delays. His physical examination was significant for both weight and head circumference being less than the third percentile, and he was noted to have micrognathia, truncal hypotonia, and head lag. He was admitted to the pediatric hospital medicine service for further diagnostic evaluation. Laboratory studies assessing for endocrinological and metabolic etiologies yielded negative results, and imaging studies (including a chest radiograph, echocardiogram, and abdominal ultrasound) were normal. However, intracranial calcifications were noted on a head ultrasound. The etiology of his constellation of symptoms was initially thought to be infectious, but the ultimate diagnosis was not made until after discharge from the pediatric hospital medicine service.

A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome.

Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with edema, Hypsarrhythmia and Optic atrophy). The proband presented with severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly conserved amino acid and a frameshift variant with consequent degradation of the transcript resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO syndrome patients. The study highlights the challenges in clinical diagnosis of patients with neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI findings.

Sorting Variants of Unknown Significance Identified by Whole Exome Sequencing: Genetic and Laboratory Investigations of Two Novel MCT8 Variants.

Mutations in the cell membrane thyroid hormone (TH) transporter monocarboxylate transporter (MCT) 8 produce severe neuropsychomotor defects and characteristic thyroid function test (TFT) abnormalities. Two children with mild neurological phenotypes and normal TFTs were found to harbor MCT8 gene variants of unknown significance (VUS), MCT8-R388Q that occurred de novo, and MCT8-Q212E. Normal TH transport and action in fibroblasts of MCT8-R388Q was demonstrated in a novel nonradioactive functional assay measuring the intracellular TH availability after L-T3 treatment. No genotype-phenotype correlation was found in additional family members carrying MCT8-Q212E. For the field of MCT8 deficiency, it is important to assess the significance of MCT8 gene VUS.

Expanding the phenotypic spectrum of Allan-Herndon-Dudley syndrome in patients with SLC16A2 mutations.

The aim of the study was to redefine the phenotype of Allan-Herndon-Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty-four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro-orthopaedic, pulmonary, and epileptic complications. WHAT THIS PAPER ADDS: Mild intellectual disability is associated with SLC16A2 mutations. A thyroid hormone profile with a free T3 /T4 ratio higher than 0.75 can help diagnose patients. Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders. Axial hypotonia is a consistent feature of Allan-Herndon-Dudley syndrome and leads to specific complications.

Mild hypotonia and recurrent seizures in an 8-month-old boy: Questions.

Hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder which manifests in early infancy with generalized seizures, other symptoms of neuromuscular irritability, and growth disturbances. Homozygous mutations in the magnesium transporter gene, transient receptor potential melastatin 6 (TRPM6), cause the disease. Here, we present an 8-month-old Turkish boy with a novel mutation of TRPM6. The patient, son of first-degree cousins, was hospitalized because of recurrent seizures and mild hypotonia. He had seizures since the newborn period and he had been treated with phenobarbital but there was no favorable response to therapy. His past history also revealed hypocalcemia detected on the newborn period but serum magnesium levels were not studied at that time. During hospitalization, we detected hypocalcemia, hypomagnesemia, and normal parathormone levels. Abdominal ultrasound was normal. Magnesium excretion was slightly increased. Considering the consanguinity of the parents and clinical features of the patients, genetic testing of the TRPM6 gene was performed and a novel homozygous mutation was detected as c.3178A>T. He was started on magnesium and calcium supplementation and he is symptom-free for 1 year. We would like to call attention to the measurement of serum magnesium levels in children with hypocalcemic convulsions. Early and appropriate treatment with magnesium supplementation is crucial.

Pityriasis Rosea during Pregnancy: Major and Minor Alarming Signs.

BACKGROUND: Pityriasis rosea (PR) is a self-limiting exanthematous disease associated with human herpesvirus (HHV)-6 and/or HHV-7 reactivation. In pregnant women, PR may be associated with pregnancy complications. OBJECTIVE: To determine relevant risk factors in the development of negative pregnancy outcome in PR. METHODS: Between 2005 and 2017 at the Department of Dermatology, University of Genoa, we recruited 76 women who developed PR during pregnancy. In 60 patients without known risk factors for intrauterine fetal death (30 with pregnancy complications and 30 without) we analyzed the pregnancy week of PR onset, presence of enanthem and of constitutional symptoms, PR body surface area involvement, age, and in 50 patients (20 with pregnancy complications and 30 without), the viral load of HHV-6 and HHV-7 (copies/mL). RESULTS: In logistic regression analysis, early onset of PR (p = 0.0017) and enanthem (p = 0.0392) proved to be significantly associated with pregnancy complications. HHV-6 viral load (copies/mL) (p < 0.0001), constitutional symptoms (p < 0.001), and PR body surface area involvement (p < 0.004) were also significantly associated with pregnancy complications. CONCLUSION: The onset of PR before week 15 and enanthem may be considered major risk factors that should alarm the dermatologist. Constitutional symptoms and involvement of > 50% of the body area may be considered minor risk factors.

Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome.

BACKGROUND: Nonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties and autism spectrum disorder. Prader-Willi syndrome (PWS) is a genetic disorder characterised by severe infantile hypotonia, hypogonadotrophic hypogonadism, early childhood onset obesity/hyperphagia, developmental delay/intellectual disability and short stature. Scoliosis and growth hormone insufficiency are also prevalent in PWS.There is extensive documentation of the endocrine and metabolic phenotypes for PWS, but not for SYS. This study served to investigate the hormonal, metabolic and body composition phenotype of SYS and its potential overlap with PWS. METHODS: In nine individuals with SYS (5 female/4 male; aged 5-17 years), we measured serum ghrelin, glucose, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3, follicle-stimulating hormone, luteinising hormone, thyroid-stimulating hormone, free T4, uric acid and testosterone, and performed a comprehensive lipid panel. Patients also underwent X-ray and dual-energy X-ray absorptiometry analyses to assess for scoliosis and bone mineral density. RESULTS: Low IGF-1 levels despite normal weight/adequate nutrition were observed in six patients, suggesting growth hormone deficiency similar to PWS. Fasting ghrelin levels were elevated, as seen in individuals with PWS. X-rays revealed scoliosis >10° in three patients, and abnormal bone mineral density in six patients, indicated by Z-scores of below -2 SDs. CONCLUSION: This is the first analysis of the hormonal, metabolic and body composition phenotype of SYS. Our findings suggest that there is marked, but not complete overlap between PWS and SYS.

The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency.

Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

A 7-month-old male with Allan-Herndon-Dudley syndrome and the power of T3.

Allan-Herndon-Dudley syndrome (AHDS, MIM 300523) is an X-linked neurodegenerative disorder characterized by intellectual disability, severe hypotonia, diminished muscle mass, and progressive spastic paraplegia. All affected males have pathognomonic thyroid profiles with an elevated T3 , low-normal free T4 , and normal TSH. Mutations in the monocarboxylate transporter 8 (MCT8) gene, SLC16A2, have been found to be causative. Here, we describe a proband whose extensive evaluation and ultimate diagnosis of AHDS unmasked three previously undiagnosed generations of affected individuals in one family. This case illustrates the need for clinicians to consider obtaining full thyroid studies on individuals with the non-specific findings of severe hypotonia, failure to thrive, and gross motor delay.

MAOA/B deletion syndrome in male siblings with severe developmental delay and sudden loss of muscle tonus.

Deletion of the monoamine oxidase (MAO)-A and MAO-B was detected in two male siblings and in their mother. The approximately 800-kb deletion, extending from about 43.0MB to 43.8MB, was detected by array comparative genomic hybridization analysis. The MAOA and MAOB genes were included in the deletion, but the adjacent Norrie disease gene, NDP, was not deleted. The boys had short stature, hypotonia, severe developmental delays, episodes of sudden loss of muscle tone, exiting behavior, lip-smacking and autistic features. The serotonin levels in their cerebrospinal fluid were extremely elevated. Another set of siblings with this deletion was reported previously. We propose recognition of MAOA/B deletion syndrome as a distinct disorder.

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling.

3-M syndrome is a primordial growth disorder caused by mutations in CUL7, OBSL1 or CCDC8. 3-M patients typically have a modest response to GH treatment, but the mechanism is unknown. Our aim was to screen 13 clinically identified 3-M families for mutations, define the status of the GH-IGF axis in 3-M children and using fibroblast cell lines assess signalling responses to GH or IGF1. Eleven CUL7, three OBSL1 and one CCDC8 mutations in nine, three and one families respectively were identified, those with CUL7 mutations being significantly shorter than those with OBSL1 or CCDC8 mutations. The majority of 3-M patients tested had normal peak serum GH and normal/low IGF1. While the generation of IGF binding proteins by 3-M cells was dysregulated, activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls. Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells. The prevalence of 3-M mutations was 69% CUL7, 23% OBSL1 and 8% CCDC8. The GH-IGF axis evaluation could reflect a degree of GH resistance and/or IGF1 resistance. This is consistent with the signalling data in which the CUL7(-/-) cells showed impaired IGF1 signalling, CCDC8(-/-) cells showed impaired GH signalling and the OBSL1(-/-) cells showed impairment in both pathways. Dysregulation of the GH-IGF-IGF binding protein axis is a feature of 3-M syndrome.

Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency.

CONTEXT: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific cell membrane transporter. MCT8 deficiency causes severe psychomotor retardation and abnormal thyroid tests. The great majority of affected children cannot walk or talk, and all have elevated serum T(3) levels, causing peripheral tissue hypermetabolism and inability to maintain weight. Treatment with thyroid hormone is ineffective. In Mct8-deficient mice, the thyroid hormone analog, diiodothyropropionic acid (DITPA), does not require MCT8 to enter tissues and could be an effective alternative to thyroid hormone treatment in humans. OBJECTIVE: The objective of the study was to evaluate the effect and efficacy of DITPA in children with MCT8 deficiency. METHODS: This was a multicenter report of four affected children given DITPA on compassionate grounds for 26-40 months. Treatment was initiated at ages 8.5-25 months, beginning with a small dose of 1.8 mg, increasing to a maximal 30 mg/d (2.1-2.4 mg/kg · d), given in three divided doses. RESULTS: DITPA normalized the elevated serum T(3) and TSH when the dose reached 1 mg/kg · d and T(4) and rT(3) increased to the lower normal range. The following significant changes were also observed: decline in SHBG (in all subjects), heart rate (in three of four), and ferritin (in one of four). Cholesterol increased in two subjects. There was no weight loss and weight gain occurred in two. None of the treated children required a gastric feeding tube or developed seizures. No adverse effects were observed. CONCLUSION: DITPA (1-2 mg/kg · d) almost completely normalizes thyroid tests and reduces the hypermetabolism and the tendency for weight loss. The effects of earlier commencement and long-term therapy remain to be determined.

Euthyroid submedian free T4 and subclinical hypothyroidism may have a detrimental clinical effect in Down syndrome.

BACKGROUND: Aberrant thyroid function is highly prevalent in Down syndrome (DS). We aimed to find whether subclinical hypothyroidism (SCH) or low-normal free T4 (FT4) are associated with a detrimental clinical outcome in untreated DS patients. METHODS: 157 patients assessed at Hadassah Down Syndrome Center between 2004 and 2010 by comprehensive clinical evaluation and tests for hemoglobin, FT4 and thyroid-stimulating hormone (TSH) were subdivided into subgroups including: clinical hypothyroidism, SCH, euthyroid submedian or supramedian FT4, and alternatively for euthyroidism and TSH levels (submedian or supramedian TSH). RESULTS: Hypothyroidism was found in 21.7% and SCH in another 14.9% of the patients. Moderate/severe hypotonia were more frequent among SCH patients compared to euthyroid patients (52.6 vs. 16.4%, p = 0.002). Patient's hemoglobin levels were lower in the euthyroid submedian FT4 group compared to the euthyroid supramedian FT4 group (10.9 vs. 0% below the normal range, p = 0.001). Interestingly, FT4 levels correlated negatively with increasing age among euthyroid DS patients (Pearson's correlation coefficient = -0.324, p = 0.009). CONCLUSION: SCH and euthyroid submedian FT4 may have significant clinical sequelae, such as hypotonia and anemia. Interventional studies with L-thyroxine replacement may be indicated in these subpopulations. Our finding that FT4 levels decrease with age in DS (contrasting the general population trend) may indicate redefining the normal FT4 levels range in DS.

Small nuclear ribonucleoprotein polypeptide N quantitative methylation analysis in infants with central hypotonia.

Central hypotonic is one of the most difficult issues in neurology, ruling out neurogenetic syndromic causes is critical, Prader-Willi syndrome (PWS) it is the most frequent genetic syndrome, it is caused by the loss of expression of the paternal allele in a group of imprinted genes within 15q11-q13, and is characterized by severe prenatal and postnatal hypotonia. SNURF-SNRPN gene methylation detects 99% of the cases but fluorescent in situ hybridization (FISH) analysis is necessary to confirm chromosome microdeletions. The advantage of SNRP-quantitative strategy of methylated alleles is that it makes it possible to make the diagnosis and identify deletions and mosaicism in one reaction. In infants clinical diagnosis is difficult. It has been proposed that around 40% of hypotonic patients have PWS but an accurate percentage has not been established. Twenty-four central hypotonic infants were studied by this molecular strategy, showing 41.5% with the disease. This molecular approach also permitted calculation of gene dosage and detection of those cases with microdeletion.