Congenital Central Hypothyroidism Caused by Novel Variants in IGSF1 Gene : Case Series of three patients.

INTRODUCTION: Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Loss of function mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene causes X-linked central hypothyroidism and represent the most common genetic cause of central hypothyroidism. In addition to central hypothyroidism, some patients with IGSF1 deficiency have hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Here, we describe a case-series of three patients with central hypothyroidism caused by two novel IGSF1mutations. CASE PRESENTATION: Three males (including two siblings) were diagnosed with central hypothyroidism between 0.06 - 1.5 years of age. Additional features included hypoprolactinemia, normal cortisol and growth hormone - insulin like growth factor 1 axis, high body mass index, birth weight greater than 0 SDS and isolated speech delay. Genetic testing identified two novel IGSF1 mutations [(c.1829G>A, p.W610* and c.3692G>A, p.(Cys123Tyr)]. Both variants have not been reported in the gnoMAD database (~90,000 individuals) and are predicted deleterious. CONCLUSIONS: Loss of function mutations in IGSF1 represent the most common genetic cause of central hypothyroidism Detailed phenotyping of IGSF1 deficiency from extensive case series have led to formulation of recommendations for clinical management of these patients. We have highlighted the potential adverse consequences of delayed treatment of CCH (speech delay).

A well child with prolonged oral thrush: an unexpected diagnostic journey.

Oral thrush is a familiar presentation in both general practice and paediatrics, and is usually responsive to treatment in the community. Here, we present the diagnostic journey of a previously well boy aged 3 years who presented with treatment-resistant thrush and describe how 'unexpected' results led to eventual diagnosis and management. This intriguing case was managed jointly by district hospital general paediatric team and tertiary hospital specialist teams.

A Single-Center, Observational Study of 607 Children and Young People Presenting With Differences of Sex Development (DSD).

Context: Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important. Objective: We aimed to better understand the presentation and prevalence of pediatric DSD. Methods: A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results: Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood. Conclusion: DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care.

Pathogen-sugar interactions revealed by universal saturation transfer analysis.

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an "end-on" manner. uSTA-guided modeling and a high-resolution cryo-electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.

Pituitary apoplexy in an adolescent male with macroprolactinoma presenting as middle cerebral artery territory infarction.

Pituitary apoplexy typically presents with acute headache, vomiting, visual disturbance, and confusion. Herein, we report a rare presentation of ischemic stroke due to pituitary apoplexy. A 16.5-year-old male presented with reduced Glasgow Coma Scale (GCS) score, slurred speech, right-sided hemiparesis, and bitemporal hemianopia. Magnetic resonance imaging of the brain showed a large hemorrhagic sellar/suprasellar mass and an area of cortical T2/FLAIR hyperintensity with corresponding diffusion restriction in the middle cerebral artery territory. Computed tomography (CT) intracranial angiogram showed luminal occlusion of the clinoid and ophthalmic segments of both internal carotid arteries (ICAs, left>right) due to mass pressure effect. Biochemical investigations confirmed hyperprolactinemia and multiple pituitary hormone deficiencies. Stress-dose hydrocortisone was commenced with cabergoline, followed by urgent endoscopic transsphenoidal debulking of the tumor (subsequent histology showing prolactinoma). Postoperative CT angiogram showed improved caliber of ICAs. Intensive neurorehabilitation was implemented and resulted in complete recovery of motor and cognitive deficits. At the last assessment (18.8 years), the patient remained on complete anterior pituitary hormone replacement without cabergoline. Pituitary apoplexy is a medical emergency requiring prompt recognition and treatment and should be suspected in patients presenting with sudden, severe headache; nausea; or visual disturbance and meningism. Ischemic stroke is a rare manifestation of pituitary apoplexy in the pediatric population.

Reductive site-selective atypical C,Z-type/N2-C2 cleavage allows C-terminal protein amidation.

Biomolecule environments can enhance chemistries with the potential to mediate and modulate self-modification (e.g., self-cleavage). While these enhanced modes are found in certain biomolecules (e.g., RNA ribozymes), it is more rare in proteins. Targeted proteolytic cleavage is vital to physiology, biotechnology, and even emerging therapy. Yet, purely chemically induced methods for the site-selective cleavage of proteins remain scarce. Here, as a proof of principle, we designed and tested a system intended to combine protein-enhanced chemistry with tag modification to enable synthetic reductive protein chemistries promoted by diboron. This reductively driven, single-electron chemistry now enables an operationally simple, site-selective cleavage protocol for proteins directed to readily accessible dehydroalanine (Dha) residues as tags under aqueous conditions and in cell lysates. In this way, a mild, efficient, enzyme-free method now allows not only precise chemical proteolysis but also simultaneous use in the removal of affinity tags and/or protein-terminus editing to create altered N- and C-termini such as protein amidation (─CONH2).

Central Diabetes Insipidus in Children and Adolescents: Twenty-Six Year Experience from a Single Centre.

Introduction: Paediatric cohorts of central diabetes insipidus (CDI) have shown varying prevalence for different causes of CDI. The objective of this study was to determine the causes of CDI and long-term outcome in children and adolescents from a Tertiary Paediatric Endocrinology unit. Methods: The clinic database was searched to identify patients with CDI managed between 1993 and 2019. Relevant clinical information was collected from patient records. Results: A total of 138 CDI patients, median age 6 years (range <1-18) at presentation, were identified. Principal CDI aetiologies were craniopharyngioma (n = 44), acute central nervous system (CNS) insult (n = 33), germinoma (n = 15), postneurosurgery (indication other than craniopharyngioma and germinoma, n = 20), midline CNS malformation (n = 14), Langerhans cell histiocytosis (n = 5), and familial (n = 2). Idiopathic CDI in this cohort was infrequent (n = 5). Patients with CNS malformations/infections presented with CDI at a younger age compared to patients with CNS tumours (p < 0.0001). Five patients, initially presenting as idiopathic CDI, were subsequently diagnosed with germinoma after a median interval of 3.3 years. All patients with CDI related to craniopharyngioma and nearly all (87%) patients with CDI related to germinoma had concomitant GH, ACTH, and TSH deficiency. The majority of patients who manifested CDI due to acute CNS insult either deceased (30%) or had transient CDI (33.3%). Conclusion: Surgery for craniopharyngioma was the most common underlying aetiology of CDI with ubiquitous occurrence of panhypopituitarism in these patients. Manifestation of CDI in patients with acute CNS insult carries poor prognosis. We affirm that neuroimaging assessment in idiopathic CDI should be continued beyond 3 years from diagnosis as a significant number of patients exhibited progression of infundibular thickening 3 years post-CDI diagnosis.

Post-translational insertion of boron in proteins to probe and modulate function.

Boron is absent in proteins, yet is a micronutrient. It possesses unique bonding that could expand biological function including modes of Lewis acidity not available to typical elements of life. Here we show that post-translational Cß-Bγ bond formation provides mild, direct, site-selective access to the minimally sized residue boronoalanine (Bal) in proteins. Precise anchoring of boron within complex biomolecular systems allows dative bond-mediated, site-dependent protein Lewis acid-base-pairing (LABP) by Bal. Dynamic protein-LABP creates tunable inter- and intramolecular ligand-host interactions, while reactive protein-LABP reveals reactively accessible sites through migratory boron-to-oxygen Cß-Oγ covalent bond formation. These modes of dative bonding can also generate de novo function, such as control of thermo- and proteolytic stability in a target protein, or observation of transient structural features via chemical exchange. These results indicate that controlled insertion of boron facilitates stability modulation, structure determination, de novo binding activities and redox-responsive 'mutation'.

Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years' Experience in the UK.

CONTEXT: Although primary adrenal insufficiency (PAI) in children and young people is often due to congenital adrenal hyperplasia (CAH) or autoimmunity, other genetic causes occur. The relative prevalence of these conditions is poorly understood. OBJECTIVE: We investigated genetic causes of PAI in children and young people over a 25 year period. DESIGN SETTING AND PARTICIPANTS: Unpublished and published data were reviewed for 155 young people in the United Kingdom who underwent genetic analysis for PAI of unknown etiology in three major research centers between 1993 and 2018. We pre-excluded those with CAH, autoimmune, or metabolic causes. We obtained additional data from NR0B1 (DAX-1) clinical testing centers. INTERVENTION AND OUTCOME MEASUREMENTS: Genetic analysis involved a candidate gene approach (1993 onward) or next generation sequencing (NGS; targeted panels, exomes) (2013-2018). RESULTS: A genetic diagnosis was reached in 103/155 (66.5%) individuals. In 5 children the adrenal insufficiency resolved and no genetic cause was found. Pathogenic variants occurred in 11 genes: MC2R (adrenocorticotropin receptor; 30/155, 19.4%), NR0B1 (DAX-1; 7.7%), CYP11A1 (7.7%), AAAS (7.1%), NNT (6.5%), MRAP (4.5%), TXNRD2 (4.5%), STAR (3.9%), SAMD9 (3.2%), CDKN1C (1.3%), and NR5A1/steroidogenic factor-1 (SF-1; 0.6%). Additionally, 51 boys had NR0B1 variants identified through clinical testing. Although age at presentation, treatment, ancestral background, and birthweight can provide diagnostic clues, genetic testing was often needed to define the cause. CONCLUSIONS: PAI in children and young people often has a genetic basis. Establishing the specific etiology can influence management of this lifelong condition. NGS approaches improve the diagnostic yield when many potential candidate genes are involved.

Longitudinal Curricular Assessment of Knowledge and Awareness of Intimate Partner Violence among First-Year Dental Students.

BACKGROUND: Intimate partner violence (IPV) has previously been recognized as a major public health issue. Oral healthcare providers, such as dentists, are crucial to the screening and identifying of individuals experiencing IPV, since most injuries occur in the head and neck region. A lack of knowledge and awareness regarding teaching and learning about IPV in dental school curricula has been identified. Based upon the overall lack of knowledge, the objective of this study was to conduct a longitudinal assessment of knowledge, awareness, and beliefs regarding IPV among dental students in their first year of education. METHODS: All students (n = 245) from three consecutive, first-year dental student cohorts (n = 81, n = 82, n = 82) were provided a brief and voluntary in-class survey in conjunction with an instructional workshop. The survey included questions designed to ascertain knowledge, awareness, and beliefs regarding IPV as a healthcare and dental issue before and after the instructional session. Differences in responses to the questions before and after the IPV educational workshop were measured using paired t-tests. RESULTS: A total of n = 232 completed pre- and post-responses were received from all three first-year dental student cohorts (n = 76, n = 80, n = 76), representing an overall 94.6% response rate. Analysis of these data showed that the student population was predominantly male and white (non-minority), aged in their mid- to late twenties, with most students reporting no previous IPV education. The few students reporting previous IPV education were mainly younger (<25 years), which may represent more recent endeavors to increase awareness of IPV among students currently attending colleges and universities. CONCLUSIONS: The results of this study may suggest that information-specific seminars within the curriculum might be adequate to provide dental students with awareness and knowledge of IPV and specific information regarding local resources and referrals for any patients experiencing IPV.

IgG4-related hypophysitis in adolescence.

OBJECTIVES: IgG4-related hypophysitis is a novel clinical disease entity, which is typically seen in the sixth decade of life and is typically complicated by hypopituitarism. We describe an adolescent female with IgG4-related hypophysitis with normal pituitary function and summarize the relevant literature. CASE PRESENTATION: A 11.8-year-old girl presented with headache and left VI cranial nerve palsy. MRI brain identified an enlarged pituitary gland. Endocrine investigations revealed normal pituitary function. She underwent a transsphenoidal biopsy of the pituitary gland, and histological examination confirmed the diagnosis of IgG4-related hypophysitis. Serum IgG4 concentrations were normal and no evidence of other organ involvement was found. Although the patient tested strongly positive for TB on an interferon gamma release assay, pituitary biopsy was negative for granuloma formation and acid-fast bacilli (Ziehl-Neelson staining). IgG4-related hypophysitis was treated with oral prednisolone and mycophenolate-mofetil with a good response. CONCLUSIONS: We describe to the best of our knowledge, the youngest patient in the published literature with IgG4-related hypophysitis presenting without pituitary insufficiency. A literature review identified only five cases of IgG4-related hypophysitis in adolescence. Serum IgG4 concentrations were normal in all, except one of the adolescent patients reported so far, and appear unhelpful in diagnosis in this age group.

Prolactinoma in childhood and adolescence-Tumour size at presentation predicts management strategy: Single centre series and a systematic review and meta-analysis.

OBJECTIVE: To report the clinical presentation, management and outcomes of young patients with prolactinomas (<20 years) and conduct a systematic review and meta-analysis. PATIENTS AND DESIGN: Clinical, biochemical and radiological data (1996-2018) were collected from our centre. A systematic review and meta-analysis of published literature (1994-2019) on prolactinoma (age <20 years) were conducted. Both random and fixed effects meta-analysis were used to pool outcomes across studies. RESULTS 1 CASE SERIES: Twenty-two patients (14 females) were identified; median age at diagnosis 15.7 years (range 13-19); 12 patients (6 females) had a macroprolactinoma. Seven patients (macroprolactinoma-6) had associated pituitary hormone deficiencies at presentation. Five patients (4 males) underwent surgical resection due to poor response to cabergoline or apoplexy. Patients undergoing surgery had larger tumours (p < .02) and higher serum prolactin concentration (p < .005). All patients with macroprolactinoma >20 mm required surgical intervention. RESULTS 2 SYSTEMATIC REVIEW AND META-ANALYSIS: We selected 11 studies according to strict inclusion criteria describing 275 patients. Macroprolactinoma was more common in girls (78.7% [95% CI 70.5-85.9]) than boys and was more frequent than microprolactinoma (56.6% [95% CI 48.4-64.5]). In males, only 6/57 (10.5%) of tumours were microprolactinoma as compared to 102/198 (51.5%) microprolactinoma in females (risk difference -0.460; [95% CI -0.563 to -0.357]; p < .001). Surgery was first-line therapy in 18.9% patients, with another 15.4% requiring it as a second line (overall 31.3%). CONCLUSIONS: Macroprolactinoma, particularly if >20 mm, usually requires multimodal therapy including surgical intervention. While overall prolactinomas in <20 years age group are more common in females, the proportion of macroprolactinoma vs microprolactinoma is greater in males, particularly for large invasive tumours. Microprolactinoma is a rare diagnosis in adolescent males.

Regioselectively substituted cellulose benzoate propionates for compensation film in optical displays.

Cellulose benzoate propionates (CBzP) were prepared via a staged addition of Pr2O followed by Bz2O to cellulose dissolved in tributylmethylammonium dimethyl phosphate (TBMADMP) providing regioselectively substituted cellulose esters in which the benzoate was preferentially installed at C2 and C3. By systematically varying the DSPr, DSBz, and DSOH (DS = degree of substitution), we synthesized CBzP that could potentially be utilized as a unique compensation film in optical displays.

Acromesomelic Dysplasia, Type Maroteaux: Impact of Long-Term (8 Years) High-Dose Growth Hormone Treatment on Growth Velocity and Final Height in 2 Siblings.

INTRODUCTION: Acromesomelic dysplasia, type Maroteaux (AMDM) is a rare autosomal recessive skeletal dysplasia, characterized by severe dwarfism and disproportionate limb shortening. It results from loss-of-function NPR2 mutations affecting the C-type natriuretic peptide receptor. Resistance to growth hormone (GH) action has previously been suggested. We describe outcomes of 2 siblings with AMDM after prolonged high-dose GH treatment. PATIENTS/METHODS: Two siblings (Pt-A and Pt-B; consanguineous parents) presented in early childhood with severe disproportionate short stature and radiological features of AMDM. Subsequent genetic testing identified a novel homozygous NPR2 mutation. GH provocation testing showed relatively high GH levels. Serum insulin-like growth factor 1 (IGF-1) was ∼2 SD below age/sex-specific mean. High-dose GH (0.075 mg/kg/day) was started. Pre-GH height velocities were 3.7 (Pt-A) and 4.5 (Pt-B) cm/year. GH dose was adjusted to sustain serum IGF-1 towards +3 SDS for age/sex. Annualized height velocities for first 3 years on GH were 7.0, 5.4, and 4.7 cm/year for patient A and 9.4, 8.0, and 5.9 cm/year for patient B. Height gain during puberty was 10.6 (Pt-A) and 5.9 (Pt-B) cm. Final heights after 8.5 years of GH treatment were 130.5 cm (-6.57 SDS, Pt-A) and 134 cm (-4.58 SDS, Pt-B). CONCLUSIONS: To the best of our knowledge, this is the first report of final height in patients with AMDM after long-term GH treatment. Our results confirm the finding of relative GH resistance in AMDM, which when overcome with high-dose GH treatment resulted in improved height SDS during childhood and adolescence and associated quality of life. The final height of our patients was significantly higher than average reported final height (120 cm) of AMDM patients.

A novel heterozygous mutation in the insulin receptor gene presenting with type A severe insulin resistance syndrome.

Background Inherited severe insulin resistance syndromes (SIRS) are rare and can be caused by mutations in the insulin receptor gene (INSR). Case presentation A 12-year-old Jamaican girl with a BMI of 24.4 kg/m2 presented with polyuria and polydipsia. A diagnosis of T1DM was made in view of hyperglycaemia (18 mmol/l), and elevated Hba1C (9.9%), and insulin therapy was initiated. Over the next 2 years, she developed hirsutism and acanthosis nigricans, and had minimal insulin requirements with frequent post-prandial hypoglycaemia. In view of this, and her strong family history suggestive of a dominantly inherited type of diabetes, the diagnosis was revisited. Targeted next-generation sequencing (NGS) of the patient's monogenic diabetes genes was performed. What is new? NGS revealed a novel heterozygous missense INSR variant, NM_000208.3:c.3471T>G, p.(His1157Gln), confirming a diagnosis of Type A SIRS. Conclusions Type A SIRS can be difficult to differentially diagnose due to the variable phenotype. Features of insulin resistance may be absent at initial presentation and may develop later during pubertal progress. Awareness of the clinical features and comprehensive genetic testing are essential to identify the condition.

A mysterious cause of chronic cough.

This case alerts professionals to take a broad approach when considering childhood chronic cough in sickle cell disease. Certain respiratory conditions are difficult to recognise in childhood, with many children suffering from delayed diagnosis. https://bit.ly/2GZAgmE.

Xq27.1 Duplication Encompassing SOX3: Variable Phenotype and Smallest Duplication Associated with Hypopituitarism to Date - A Large Case Series of Unrelated Patients and a Literature Review.

BACKGROUND: Xq27.1 duplication encompassing SOX3 has been implicated in the aetiology of X-linked hypopituitarism associated with intellectual disability and neural tube defects. We describe the largest case series to date of 5 unrelated patients with SOX3 duplication with a variable clinical phenotype, including the smallest reported SOX3 duplication. CASE REPORTS: Five male patients who presented with congenital hypopituitarism (CH) were identified to have Xq27.1 duplication encompassing SOX3. The size of the duplication ranged from 323.8 kb to 11 Mb. The duplication was maternally inherited or de novo in 2 patients each (and of unknown inheritance in 1 patient). The age at presentation was variable. Three patients had multiple pituitary hormone deficiencies, whereas 2 patients had isolated growth hormone deficiency. All patients had micropenis and/or small undescended testes. Structural pituitary and/or other midline cranial abnormalities (callosal hypogenesis/absence of the septum pellucidum) were present in all patients. Two patients had a neural tube defect in addition to CH. CONCLUSIONS: This is the largest series reported to date of unrelated patients with CH in association with Xq27.1 duplication encompassing SOX3. The clinical phenotype is variable, which may be due to genetic redundancy or other unknown aetiological factors. We have expanded the phenotypic spectrum through description of the smallest Xq27.1 duplication (323.8 kb) with CH reported to date, as well as a second family with CH and a neural tube defect.

Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients.

BACKGROUND: The thyroid hormone receptor α gene (THRA) transcript is alternatively spliced to generate either thyroid hormone receptor (TR)α1 or a non-hormone-binding variant protein, TRα2, the function of which is unknown. Here, we describe the first patients identified with a mutation in THRA that affects both TRα1 and TRα2, and compare them with patients who have resistance to thyroid hormone owing to a mutation affecting only TRα1, to delineate the relative roles of TRα1 and TRα2. METHODS: We did clinical, biochemical, and genetic analyses of an index case and her two sons. We assessed physical and radiological features, thyroid function, physiological and biochemical markers of thyroid hormone action, and THRA sequence. FINDINGS: The patients presented in childhood with growth failure, developmental delay, and constipation, which improved after treatment with thyroxine, despite normal concentrations of circulating thyroid hormones. They had similar clinical (macrocephaly, broad faces, skin tags, motor dyspraxia, slow speech), biochemical (subnormal ratio of free thyroxine:free tri-iodothyronine [T3], low concentration of total reverse T3, high concentration of creatine kinase, mild anaemia), and radiological (thickened calvarium) features to patients with TRα1-mediated resistance to thyroid hormone, although our patients had a heterozygous mis-sense mutation (Ala263Val) in both TRα1 and TRα2 proteins. The Ala263Val mutant TRα1 inhibited the transcriptional function of normal receptor in a dominant-negative fashion. By contrast, function of Ala263Val mutant TRα2 matched its normal counterpart. In vitro, high concentrations of T3 restored transcriptional activity of Ala263Val mutant TRα1, and reversed the dominant-negative inhibition of its normal counterpart. High concentrations of T3 restored expression of thyroid hormone-responsive target genes in patient-derived blood cells. INTERPRETATION: TRα1 seems to be the principal functional product of the THRA gene. Thyroxine treatment alleviates hormone resistance in patients with mutations affecting this gene, possibly ameliorating the phenotype. These findings will help the diagnosis and treatment of other patients with resistance to thyroid hormone resulting from mutations in THRA. FUNDING: Wellcome Trust, NIHR Cambridge Biomedical Research Centre, Marie Curie Actions, Foundation for Development of Internal Medicine in Europe.