GNRH1 Variants in Congenital Hypogonadotropic Hypogonadism: Single-Center Experience and Systematic Literature Review.

OBJECTIVE: As GNRH1 genotype-phenotype correlation in CHH is not well studied, we aim to describe the GNRH1 variants in our CHH cohort and present a systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in the world literature. DESIGN: This is a retrospective study of GNRH1 mutation-positive patients from a western Indian center. PRISMA guidelines-based PubMed search of the published literature of all GNRH1 mutation-positive patients was conducted. SETTING: This study was conducted in an academic medical center. PATIENT(S): This study included 2 probands from our cohort and 19 probands from the world literature. MAIN OUTCOME MEASURE(S): Demographic details, clinical presentation, biochemistry, imaging, treatment details, and genotypic data were recorded. RESULT(S): Two probands in our cohort carried two novel pathogenic biallelic GNRH1 variants (p.Glu24Leu, c.238-2A>G). Both had a severe reproductive phenotype. We report successful gonadotropin therapy and fertility in 1 proband. We included 19 probands from 12 studies after the literature review. Ten CHH probands (inclusive 2 from this study) with biallelic GNRH1 variants had severe reproductive phenotype, low gonadotropin levels, low/normal prolactin, normal pituitary imaging, and no extra-reproductive phenotype. Of seven biallelic variants reported, three were frameshift, two were splice-site, and two were missense mutations. All of them were pathogenic/likely pathogenic without oligogenicity. Of seven monoallelic GNRH1 variants reported in 11 probands, 4 had nonreproductive phenotype, 3 were benign/likely benign, and 4 were oligogenic. CONCLUSION(S): GNRH1 biallelic variants lead to severe reproductive phenotype, with low gonadotropin levels without nonreproductive features or oligogenicity. However, the role of GNRH1 monoallelic variants in CHH pathophysiology for reported variants remains questionable.

Regional genotypic variations in normosmic congenital hypogonadotropic hypogonadism: our experience and systematic review.

PURPOSE: To describe phenotype-genotype data of Asian-Indian normosmic congenital hypogonadotropic hypogonadism (nCHH) from our centre and perform a systematic review of genetic studies using next-generation sequencing (NGS) in nCHH. METHODS: Sixty-eight nCHH probands from our center, and 370 nCHH probands from published studies were included. Per-patient genetic variants were analyzed as per ACMG guidelines. Molecular diagnosis was defined as presence of a pathogenic or likely pathogenic variant in a known CHH gene following zygosity status as per known mode of genetic inheritance. RESULT: At our centre molecular diagnosis was observed in 35.3% of probands {GNRHR:16.2%, FGFR1:7.3%, KISS1R:4.4%, GNRH1:2.9%, TACR3:2.9%, CHD7:1.4%}. Molecular diagnosis was observed more often (44.7% vs 14.3%, p = 0.026) with severe than partial reproductive-phenotype. The study adds 12 novel variants and suggests GNRHR p.Thr32Ala variant may have a founder effect. In per-patient systematic review (including our cohort), the molecular diagnosis was reached in 23.2%, ranging from 3.5 to 46.7% at different centers. The affected genes were FGFR1:6.4%, GNRHR:4.3%, PROKR2:3.6%, TACR3:1.8%, CHD7:1.6%, KISS1R:1.4%, GNRH1:1.4% and others (PROK2, SOX3, SOX10, SOX11, IL17RD, IGSF10, TAC3, ANOS1, oligogenic): < 1% each. FGFR1 was the most commonly affected gene in most cohorts except Asia, whereas PROKR2 (in China and Japan) and GNRHR (in India) were the commonest. CONCLUSION: (s): The global molecular diagnosis rate was 23.2% in nCHH cohorts whereas that in our cohort was 35% with a higher rate (44.7%) in those with severe reproductive-phenotype. The most commonly affected gene in nCHH patients was FGFR1 globally while it was PROKR2 in East Asia and GNRHR in India.

Expanding the phenome and variome of skeletal dysplasia.

PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized. METHODS: Detailed phenotyping and next-generation sequencing (panel and exome). RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average. CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

Serum Oxytocin Concentration in Patients Receiving Electroconvulsive Therapy: An Exploratory Study and Review of Literature.

BACKGROUND: Neuroendocrine biomarkers have long been studied in the context of electroconvulsive therapy (ECT). We prospectively assessed serum oxytocin change and moderators thereof in an exploratory study of patients receiving ECT. METHODS: Serum oxytocin concentrations were assessed immediately before and 1 to 3 minutes after the first ECT in 33 patients with schizophrenia (n = 14), other nonaffective psychosis (n = 6), mania (n = 10), and depression (n = 3) who received 6 to 7 bitemporal, brief-pulse ECTs. Change in serum oxytocin was assessed in the sample as a whole, and as a function of age, sex, diagnosis, and treatment response. The primary outcome was change in serum oxytocin in the overall sample. RESULTS: There was much variation across patients; oxytocin concentrations increased marginally by a mean (standard deviation) (M [SD]) of 6.4 (82.7) pg/mL (P = 0.43). The M (SD) change was -8.2 (85.0) pg/mL in patients with schizophrenia and other nonaffective psychoses (P = 0.84). There was no significant correlation between change in Brief Psychiatric Rating Scale scores and change in oxytocin concentrations in patients with schizophrenia, other nonaffective psychoses, and mania (ρ = 0.10, P = 0.61). Serum oxytocin rose in men, after ECT, and fell in women (P = 0.01). CONCLUSIONS: Change in serum oxytocin immediately after the first ECT in a course may not be a useful biomarker of ECT action. This is the first report on the subject in a sample comprising mostly patients with nonaffective psychosis and mania rather than depression. We discuss our findings in the light of previous research and offer general conclusions about the field.

The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care.

PURPOSE: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established. METHODS: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians. RESULTS AND CONCLUSION: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses.Genet Med 18 5, 483-493.

Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy.

​Multicentric osteolysis nodulosis and arthropathy (MONA) is an infrequently described autosomal recessive skeletal dysplasia characterized by progressive osteolysis and arthropathy. Inactivating mutations in MMP2, encoding matrix metalloproteinase-2, are known to cause this disorder. Fifteen families with mutations in MMP2 have been reported in literature. In this study we screened thirteen individuals from eleven families for MMP2 mutations and identified eight mutations (five novel and three known variants). We characterize the clinical, radiographic and molecular findings in all individuals with molecularly proven MONA from the present cohort and previous reports, and provide a comprehensive review of the MMP2 related disorders.

The Dual Innervation of the Gluteus Maximus Associated with Other Anatomical Variations of the Gluteal Region.

The gluteus maximus (GM) is a big quadrilateral musculature that lines the rear portion of the pelvis. It is innervated by the inferior gluteal nerve. The sciatic nerve, inferior gluteal nerve, and posterior cutaneous nerve of the thigh are branches of the sacral plexus. The superior and inferior gluteal arteries are the chief arterial supply to the gluteal region. In the present case, there was a dual innervation of the GM. The superior gluteal artery and the superior gluteal nerve was piercing the piriformis and the inferior gluteal artery was running between the posterior cutaneous nerve of the thigh and the inferior gluteal nerve. According to our literature review, anatomical studies in which this cadaveric procedure has been performed have not been previously reported. The anatomical variations of the gluteal region are important to surgeons, physicians, anatomists, and nurses.

A Rare Variation of High Division of the Sciatic Nerve and Associated Neuromuscular Variations in the Gluteal Region.

Variations in the anatomical division of the sciatic nerve are not uncommon. In this case report, we are presenting a rare variation of the sciatic nerve in relation to the superior gemellus and the presence of anomalous muscle. To the best of our knowledge, the anomalous communicating branches of the posterior cutaneous femoral nerve with tibial and common peroneal nerve and the presence of an anomalous muscle originating from the greater sciatic notch and inserting at ischial tuberosity have not been reported yet in the literature. This anomalous muscle found can be named as 'Sciaticotuberosus' after its origin and insertion. Such variations hold clinical significance as they may contribute to piriformis syndrome, coccydynia, non-discogenic sciatica, and popliteal fossa block failure leading to local anesthesia toxicity and blood vessel traumatization. The current classifications of division of the sciatic nerve are based on its relation to the piriformis muscle. In our case report, the variation of the sciatic nerve in relation to the superior gemellus suggests the need for the revision of current classification systems. Category-like division of the sciatic nerve in relation to the superior gemellus muscle can be added.

Biological, pathological, and multifaceted therapeutic functions of exosomes to target cancer.

Exosomes, small tiny vesicle contains a large number of intracellular particles that employ to cause various diseases and prevent several pathological events as well in the human body. It is considered a "double-edged sword", and depending on its biological source, the action of exosomes varies under physiological conditions. Also, the isolation and characterization of the exosomes should be performed accurately and the methodology also will vary depending on the exosome source. Moreover, the uptake of exosomes from the recipients' cells is a vital and initial step for all the physiological actions. There are different mechanisms present in the exosomes' cellular uptake to deliver their cargo to acceptor cells. Once the exosomal uptake takes place, it releases the intracellular particles that leads to activate the physiological response. Even though exosomes have lavish functions, there are some challenges associated with every step of their preparation to bring potential therapeutic efficacy. So, overcoming the pitfalls would give a desired quantity of exosomes with high purity.

Engendering connection: The embodied emotional labor of U.S. cosmetic surgeons.

Emotional labor has typically been analyzed as a gendered phenomenon in managed workers like nurses. Broadening this frame, this study analyzes how a different strata of workers perform emotional labor: surgeons. Drawing on 42 in-depth interviews with U.S. cosmetic surgeons and a content analysis of online reviews by patients, we argue that cosmetic surgeons perform both intimate and professionalized strategies of emotional labor to build long-term relationships with patients. We highlight how some surgeons strategically use their gender and bodies to forge emotional connections with patients, combining physician authority and their own embodied experiences. We identify two intimate, embodied strategies of emotional labor used by cosmetic surgeons (Paternalistic and Empathic) which are highly gendered and two additional strategies that more closely resemble professional norms (Egalitarian and Technical). Cosmetic surgeons can and do switch between strategies, subject to the constraints of gender norms and expectations; embodied strategies have different payoffs for men and women. Women surgeons, in particular, may sometimes adopt professionalized strategies of emotional labor to assert their physician authority and status and resist expectations of feminized emotional labor. In commercialized medicine, emotional labor enables elite healthcare providers to negotiate power dynamics with dependent patients. In addition to making patients feel better, embodied labor can confer meaning on surgeons' work.

Odor-specific habituation arises from interaction of afferent synaptic adaptation and intrinsic synaptic potentiation in olfactory cortex.

Segmentation of target odorants from background odorants is a fundamental computational requirement for the olfactory system and is thought to be behaviorally mediated by olfactory habituation memory. Data from our laboratory have shown that odor-specific adaptation in piriform neurons, mediated at least partially by synaptic adaptation between the olfactory bulb outputs and piriform cortex pyramidal cells, is highly odor specific, while that observed at the synaptic level is specific only to certain odor features. Behavioral data show that odor habituation memory at short time constants corresponding to synaptic adaptation is also highly odor specific and is blocked by the same pharmacological agents as synaptic adaptation. Using previously developed computational models of the olfactory system we show here how synaptic adaptation and potentiation interact to create the observed specificity of response adaptation. The model analyzes the mechanisms underlying the odor specificity of habituation, the dependence on functioning cholinergic modulation, and makes predictions about connectivity to and within the piriform neural network. Predictions made by the model for the role of cholinergic modulation are supported by behavioral results.

Patient Perspectives on the Use of Artificial Intelligence for Skin Cancer Screening: A Qualitative Study.

Importance: The use of artificial intelligence (AI) is expanding throughout the field of medicine. In dermatology, researchers are evaluating the potential for direct-to-patient and clinician decision-support AI tools to classify skin lesions. Although AI is poised to change how patients engage in health care, patient perspectives remain poorly understood. Objective: To explore how patients conceptualize AI and perceive the use of AI for skin cancer screening. Design, Setting, and Participants: A qualitative study using a grounded theory approach to semistructured interview analysis was conducted in general dermatology clinics at the Brigham and Women's Hospital and melanoma clinics at the Dana-Farber Cancer Institute. Forty-eight patients were enrolled. Each interview was independently coded by 2 researchers with interrater reliability measurement; reconciled codes were used to assess code frequency. The study was conducted from May 6 to July 8, 2019. Main Outcomes and Measures: Artificial intelligence concept, perceived benefits and risks of AI, strengths and weaknesses of AI, AI implementation, response to conflict between human and AI clinical decision-making, and recommendation for or against AI. Results: Of 48 patients enrolled, 26 participants (54%) were women; mean (SD) age was 53.3 (21.7) years. Sixteen patients (33%) had a history of melanoma, 16 patients (33%) had a history of nonmelanoma skin cancer only, and 16 patients (33%) had no history of skin cancer. Twenty-four patients were interviewed about a direct-to-patient AI tool and 24 patients were interviewed about a clinician decision-support AI tool. Interrater reliability ratings for the 2 coding teams were κ = 0.94 and κ = 0.89. Patients primarily conceptualized AI in terms of cognition. Increased diagnostic speed (29 participants [60%]) and health care access (29 [60%]) were the most commonly perceived benefits of AI for skin cancer screening; increased patient anxiety was the most commonly perceived risk (19 [40%]). Patients perceived both more accurate diagnosis (33 [69%]) and less accurate diagnosis (41 [85%]) to be the greatest strength and weakness of AI, respectively. The dominant theme that emerged was the importance of symbiosis between humans and AI (45 [94%]). Seeking biopsy was the most common response to conflict between human and AI clinical decision-making (32 [67%]). Overall, 36 patients (75%) would recommend AI to family members and friends. Conclusions and Relevance: In this qualitative study, patients appeared to be receptive to the use of AI for skin cancer screening if implemented in a manner that preserves the integrity of the human physician-patient relationship.

Do online reviews diminish physician authority? The case of cosmetic surgery in the U.S.

This article analyzes the substance and perception of online physician reviews, which are qualitative and quantitative assessments of physicians written and shared by patients, in the case of U.S. cosmetic surgery. Like other cash-pay medical specialties, cosmetic surgery is elective and paid for largely out of pocket, with patients having latitude in their choice of surgeon. Drawing on qualitative data from interviews, observations of an American Society of Aesthetic Plastic Surgery professional meeting, and online reviews from the platforms RealSelf and Yelp, I identify two interdependent contributors to physician authority: reputation and expertise. I argue that surgeons see reviews overwhelmingly as a threat to their reputation, even as actual review content often positively reinforces physician expertise and enhances physician reputation. I show that most online reviews linked to interview participants are positive, according considerable deference to surgeons. Reviews add patients' embodied and consumer expertise as a circumscribed supplement to surgeons' technical expertise. Moreover, reviews change the doctor-patient relationship by putting it on display for a larger audience of prospective patients, enabling patients and review platforms to affect physician reputation. Surgeons report changing how they practice to establish and maintain their reputations. This research demonstrates how physician authority in medical consumerist contexts is a product of reputation as well as expertise. Consumerism changes the doctor-patient relationship and makes surgeons feel diminished authority by dint of their reputational vulnerability to online reviews.

Isoleucine Deficiency in a Neonate Treated for Maple Syrup Urine Disease Masquerading as Acrodermatitis Enteropathica.

BACKGROUND: Special diet with restricted branched-chain-amino-acids used for treating maple syrup urine disease can lead to specific amino acid deficiencies. CASE CHARACTERISTICS: We report a neonate who developed skin lesions due to isoleucine deficiency while using specialised formula. INTERVENTION/OUTCOME: Feeds were supplemented with expressed breast milk. This caused biochemical and clinical improvement with resolution of skin lesions. MESSAGE: Breast milk is a valuable and necessary adjunct to specialized formula in maple syrup urine disease to prevent specific amino acid deficiency in the neonatal period.

Neuroblastoma-like schwannoma in a case of schwannomatosis: Report of a rare case.

Schwannomatosis is a term used to describe patients with multiple nonvestibular schwannomas with no other stigmata of neurofibromatosis type-2 (NF2). Neuroblastoma-like schwannoma is a rare subtype of schwannoma, with histological features resembling a neuroblastoma. This case is probabaly the second case of very uncommon neuroblastoma-like schwannoma, in a patient of schwannomatosis.

Recurrent and novel GLB1 mutations in India.

GM1 gangliosidosis is a lysosomal storage disorder caused by mutations in the GLB1 gene, leading to the deficiency of the enzyme ß-d-galactosidase. In this study, we report molecular findings in 50 Asian Indian families with GM1 gangliosidosis. We sequenced all the exons and flanking intronic sequences of GLB1 gene. We identified 33 different mutations (20 novel and 13 previously reported). The novel mutations include 12 missense (p.M1?, p.E129Q, p.G134R, p.L236P, p.G262E, p.L297F, p.Y331C, p.G414V, p.K493N, p.L514P, p.P597L, p.T600I), four splicing (c.246-2A>G, c.397-2A>G, c.552+1G>T, c.956-2A>G), three indels (p.R22Qfs*8, p.L24Cfs*47, p.I489Qfs*4) and one nonsense mutation (p.Q452*). Most common mutations identified in this study were c.75+2InsT (14%) and p.L337P (10%). Known mutations accounted for 67% of allele frequency in our cohort of patients, suggesting that these mutations in GLB1 are recurrent across different populations. Twenty three mutations were localized in the TIM barrel domain, ß-domain 1 and ß-domain 2. In silico sequence and structure analysis of GLB1 reveal that all the novel mutations affect the function and structure of the protein. We hereby report on the largest series of patients with GM1 gangliosidosis and the first from India.

MURCS association with situs inversus totalis: Expanding the spectrum or a novel disorder.

We are reporting a female patient with a MURCS association (Müllerian duct aplasia, unilateral renal agenesis, cervico-thoracic somite fusion defects), situs inversus totalis, short stature with normal development and intelligence. We are presenting the comparison with two other patients published with similar finding. Our patient is distinct in having all the characteristic features and represents the severe spectrum of this disorder. We present our argument favoring this to be a monogenic syndrome distinct from the other two entities and probably a ciliopathy.

Patient with mutation in the matrix metalloproteinase 2 (MMP2) gene - a case report and review of the literature.

Torg and Winchester syndromes and patients reported by Al-AqeelSawairi as well as nodulosis-arthropathy-osteolysis (NAO) patients, patients with multicentric NAO share autosomal recessive inheritance. The common presenting symptomatology includes progressive osteolysis chiefly affecting the carpal, tarsal and interphalangeal joints. Here, we report a patient with Torg syndrome. Torg syndrome is caused by homozygous or compound heterozygous mutations in the matrix metalloproteinase 2 (MMP2) gene. MMP2 codes for a gelatinase that cleaves type IV collagen, a major component of basement membrane. The clinical presentation of our patient included moderate osteolysis of the small joints of the hands and knees, hirsutism, nodulosis sparing the palms and soles, corneal opacities and mild facial dysmorphism without gum hypertrophy. Genetic analysis showed that the patient was homozygous for a novel base variant c538 G>A (p.D180N) in the MMP2 gene. Both parents were carriers of the same mutated variant. Our patient had some previously unreported endocrine manifestations such as premature thelarche and elevated follicle-stimulating hormone levels.

A descriptive analysis of 14 cases of progressive-psuedorheumatoid-arthropathy of childhood from south India: review of literature in comparison with juvenile idiopathic arthritis.

BACKGROUND: Progressive-psuedorheumatoid-arthropathy of childhood (PPAC) is an autosomal recessive single gene skeletal dysplasia involving joints. The gene attributed to its cause is WNT1-inducible-signaling pathway protein3 (WISP3). OBJECTIVE: To study the clinical and radiographic presentation of PPAC in Indian patients and to compare with described features of PPAC and Juvenile Idiopathic Arthritis (JIA) from published literature. METHODS: All cases (n = 14) of PPAC seen in the Rheumatology and Clinical Genetics outpatient clinic between 2008 and 2011 with classical, clinical, and radiological features were studied. The demographic and clinical data were obtained from medical records of the outpatient visits. RESULTS: Slight female preponderance (57%) and history of consanguinity in parents (43%) was observed in this group. The median age at onset was 4.5 years (range from birth to 9 years of age). Early presentation below the age of 3 years was seen in 3/14 patients (21%) in this group. The growth of all the patients fell below the 3rd percentile for the age. Historically, hip joint involvement was the most common presenting feature; however, elbow, wrist, knees, feet, spine, shoulder joints and small joints, namely proximal interphalangeal (PIP), distal interphalangeal (DIP), metacarpophalangeal (MCP), metatarsophalangeal joints (MTP), and interphalangeal joints (IP) of the feet, were also involved, either clinically or radiologically in varying proportions. Platyspondyly was noted in all. Molecular analysis of the WISP3 gene identified mutations in all the 5 individuals in whom it was done. CONCLUSION: This descriptive case series of PPAC from India reports distinctly differentiating clinical, radiological, and molecular markers in contrast with classically described features of JIA, its mimic. Early presentation (age of onset below 3 years) with involvement of interphalangeal joints seen in three patients (21%) was a unique finding, with missense WISP3 gene mutations in all of them. Timely diagnosis of this entity can spare the patient from unnecessary investigations and toxic medications.