Genetic Characteristics Of Patients Research Articles

Clinical and genetic features of patients with glutaric aciduria type I (GA1)

Clinical and genetic features of patients with glutaric aciduria type I (GA1)

Clinicopathologic, Immunophenotypic, Cytogenetic, and Molecular Features of γδ T-Cell Large Granular Lymphocytic Leukemia: An Analysis of 14 Patients Suggests Biologic Differences With αβ T-Cell Large Granular Lymphocytic Leukemia. [corrected

T-cell large granular lymphocytic (T-LGL) leukemia is a rare disorder in which the neoplastic cells usually express the αβ T-cell receptor (TCR). To determine the significance of γδ TCR expression in this leukemia, we compared the clinicopathologic, immunophenotypic, and genetic features of patients with T-LGL leukemia expressing γδ TCR or αβ TCR. We used the World Health Organization classification criteria to confirm the diagnosis. All patients were diagnosed and treated at our institution. We identified 14 patients with γδ T-LGL leukemia, 11 men and three women; six (43%) patients had a history of rheumatoid arthritis, 10 (71%) had neutropenia, four (29%) had thrombocytopenia, and three (21%) had anemia. Eight (67%) of 12 patients had a CD4-/CD8- phenotype, and four (33%) had a CD4-/CD8+ phenotype. The median overall survival was 62 months. Patients with γδ T-LGL leukemia were more likely to have rheumatoid arthritis (P = .04), lower absolute neutrophil count (P = .04), lower platelet count (P = .004), and a higher frequency of the CD4-/CD8- phenotype (P < .0001). However, there was no significant difference in overall survival between the two groups (P = .64). Although patients with γδ and αβ T-LGL leukemia show some different clinical or phenotypic features, overall survival is similar, suggesting that γδ TCR expression does not carry prognostic significance.

Undifferentiated spondyloarthritis is more frequently seen in women than in men

Spondyloarthritis (SpA) are a group of inflammatory rheumatic diseases that share some common clinical and genetic features such as inflammatory back pain, peripheral arthritis, enthesitis, anterior uveitis, sacroiliitis, and HLA-B27 positivity. The aim of the present study was to describe the clinical, radiologic, and genetic features of patients with undifferentiated spondyloarthritis (uSpA) and ankylosing spondylitis (AS). This study included 225 SpA patients (134 uSpA and 91 AS) attending our Rheumatology Outpatient Clinic consecutively. Patients underwent peripheral and axial joint and enthesitis assessment, erythrocyte sedimentation rate or C-reactive protein determination, HLA-B27 tissue typing, radiographic evaluation, and sacroiliac MRI. In total, 26 of 91 AS patients and 115 of 134 uSpA patients were women (28.6 vs. 85.8%) and 65 of AS and 19 of uSpA were men (71.4 vs. 14.2%). The time for diagnosis was 15.82 ± 20.7 months for AS patients and 5.91 ± 3.63 months for uSpA patients. Diagnostic delay was 102.46 ± 88.99 (median 83, range 8–377) months for AS and 74.23 ± 60.7 (median 55.5, range 0–238) months for uSpA patients. HLA-B27 positivity was present in 51.6% of AS and 14.9% of uSpA patients. The mean BASDAI level of patients with AS was 6.4 ± 1.1 and that of uSpA patients was 4.8 ± 2.1. SpA are frequent diseases and physicians other than rheumatologists should also be aware of them. uSpA is more frequent in women than men. Early diagnosis of SpA is important because early treatment with new biological therapies may lead to much better results than applying them in the advanced stages.

Kabuki syndrome: clinical and molecular characteristics.

Kabuki syndrome (KS) is a rare syndrome characterized by multiple congenital anomalies and mental retardation. Other characteristics include a peculiar facial gestalt, short stature, skeletal and visceral abnormalities, cardiac anomalies, and immunological defects. Whole exome sequencing has uncovered the genetic basis of KS. Prior to 2013, there was no molecular genetic information about KS in Korean patients. More recently, direct Sanger sequencing and exome sequencing revealed KMT2D variants in 11 Korean patients and a KDM6A variant in one Korean patient. The high detection rate of KMT2D and KDM6A mutations (92.3%) is expected owing to the strict criteria used to establish a clinical diagnosis. Increased awareness and understanding of KS among clinicians is important for diagnosis and management of KS and for primary care of KS patients. Because mutation detection rates rely on the accuracy of the clinical diagnosis and the inclusion or exclusion of atypical cases, recognition of KS will facilitate the identification of novel mutations. A brief review of KS is provided, highlighting the clinical and genetic characteristics of patients with KS.

Genetic features of patients with influenza A / H1N1 / 09 complicated by pneumonia

The aim of this study was to investigate polymorphisms of cytokine genes (TNF G308A, IL 10 C592A, IL 10 C819T, IL 10 G1082A), and molecular regulation of inflammation (CD14 C159T) and vascular tone (еNOS C786T) in patients with A / H1N1 flu complicated by pneumonia. Methods. Patients hospitalized for pneumonia complicating influenza A / H1N1 / 09 were involved in the study: 37 patients with severe pneumonia, 74 patients with non severe pneumonia and 115 healthy subjects as controls. Polymerase chain reaction (PCR) was used for molecular investigations. Results. Patients with influenza A / H1N1 complicated by pneumonia carried the homozygous G allele of TNF gene polymorphism (308 G/A) and the homozygous G allele of IL 10 gene polymorphism (1082 G/A) more often compared with controls. Patients with pneumonia more often carried IL 10 gene 592 C/A allele and largely as homozygous variant. Frequencies of homozygous IL 10 gene polymorphism (819 C/T) T/T and CD14 gene polymorphism (159 C/T) T/T were significantly lower compared with healthy subjects. On contrary, the homozygous T/T polymorphism (786 C/T) of еNOS gene was more common in patients with pneumonia. Prognostic risk factors for occurrence of pneumonia in patients with influenza А / H1N1 were IL 10 gene polymorphisms 592 CC, 819 CC, and 1082 GG. TNF (308 GG); IL 10 (819 CC) and (1082 GG) haplotypes had the highest prognostic value for severe pneumonia in patients with influenza A / H1N1. TNF (308 GG); IL 10 (819 CC); (1082 GG) and TNF (308 GG); IL 10 (819 CC); (1082 GG) and CD14 (159 CC) haplotypes predicted ARDS and death in patients with influenza A / H1N1 / 09, respectively. Conclusion . Identifying genetic status in a patient with influenza A / H1N1 could predict severity and complications of the disease.

Demographic, clinical, and genetic characteristics of patients with medullary thyroid cancer in the past 16 years in Castilla-La Mancha

Objective Medullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. Patients and methods Data were collected through a review of patients' medical records. Results The medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (iii or iv) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. Conclusions In Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population.

The clinical and genetic features of patients with hyper-immunoglobulin D syndrome (HIDS)

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive disorder causing 1 of 2 phenotypes, hyper-immunoglobulin D syndrome and mevalonic aciduria, presenting with recurrent fever episodes, often starting in infancy, and sometimes evoked by stress or vaccinations. This autoinflammatory disease is caused by mutations encoding the mevalonate kinase (MVK) gene and is classified in the group of periodic fever syndromes. HIDS is characterized by recurrent fever attacks of 3-7 days that begin in infancy and recur every 4-6 weeks. The febrile period is accompanied by lymphadenopathy, arthralgia, abdominal pain, diarrhea, aphthous ulcers, and varying degree of skin involvement. The course and severity of the disease may be quite different. There is no effective or proven therapy for HIDS.

THU0367 Familial Mediterranean Fever (FMF): A Single Center Clinical-Genetic Study

BackgroundFMF is the prototype of autoinflammatory disorder characterized by recurrent self-limited inflammatory episodes.1FMF is an autosomal recessive disease that is prevalent among eastern Mediterranean populations. The responsible gene (MEFV) encodes...

Demografía, características clínicas y genéticas de pacientes con carcinoma medular de tiroides en los últimos 16 años en Castilla-La Mancha

ObjectiveMedullary thyroid cancer is a rare tumor that is more aggressive and has a worse prognosis than differentiated thyroid cancer. The purpose of this study was to report the demographic, clinical, and genetic characteristics of patients seen in the health care system of the community of Castilla-La Mancha over a 16-year period. Patients and methodsData were collected through a review of patients’ medical records. ResultsThe medical records of 58 patients (mean age at diagnosis, 51 years; range, 6-82 years; 63.8% women) were reviewed. Prevalence rate was 2.84 cases per 100,000 inhabitants, with a high variability between areas (range, 0-5.4 cases per 100,000 inhabitants). Familial cases accounted for 34.5% of all medullary thyroid cancers, and the most common mutation was C634Y. The condition was most commonly diagnosed following palpation of a cervical lump (70.6%). At diagnosis, 56 of 58 patients underwent ultrasound and 8 of 58 patients were tested for serum calcitonin. Tumor multicentricity was reported in 59 and 50% of patients with multiple endocrine neoplasia syndrome type 2A and 2B, respectively, and in no sporadic cases. Fifty-two percent of patients had an advanced stage (iii or iv) at diagnosis. Median follow-up was 36 months (interquartile range, 14-210); 11 patients were lost to follow-up. ConclusionsIn Castilla-La Mancha, medullary thyroid cancer is diagnosed by cervical ultrasound, rather than calcitonin assay. There is a high prevalence of both familial and sporadic medullary thyroid cancer, and a significant variability in the type of proto-oncogen rearranged during transfection mutation as compared to the rest of the Spanish population.

The Quality of Quality

Over the past 2 decades, hydroxymethylglutaryl-CoA reductase inhibitors (statins) have taken center stage in the secondary prevention after myocardial infarction (MI) as evidence of their efficacy emerged from clinical trials.1–4 Practice guidelines then incorporated the results of clinical trials, and, because guideline-based care processes were shown to be associated with outcomes,5 performance measures became an indicator of the quality of care.6 Performance measures track whether or not evidence-based medications are administered after MI. However, they do not assess whether or not the dose is optimal. The dose is an important issue for statins, because their efficacy to prevent recurrent MI and death after the initial event has been shown to be greater at higher doses.2,7 Article see p 1303 The article by Arnold et al8 in this issue of Circulation adds more depth to the conversation on quality of care after MI by examining the dose of statins that patients received after acute MI in an observational study. The authors report on data from the Translational Research Investigating Underlying disparities in acute Myocardial infarction Patients’ Health status (TRIUMPH) study. TRIUMPH is an National Heart, Lung, and Blood Institute–funded prospective registry designed to study the outcomes after MI with a distinct focus on health status outcomes in black and white patients. TRIUMPH collected detailed data on the socioeconomic, clinical, treatment, health status, metabolic, and genetic characteristics of patients with acute MI enrolled in 24 centers across the United States between 2005 and 2008.9 The design of the TRIUMPH study included an extensive (5 hours) data collection process, and, on study completion, 4340 patients were eligible for analysis. The depth of the data collected in …

How have advances in our understanding of the molecular genetics of paediatric leukaemia led to improved targeted therapies for these diseases?

The term "leukaemia" refers to a large and heterogenous group of diseases, with treatment response and outcome dependent on the specific type of malignancy. New molecular methods allow us to specifically evaluate the type of disorder, and provide treatment of necessary intensity. The aim of this review is to provide insight into the progress in leukaemia treatment that had been possible due to advances in molecular genetics over the last few decades. Those new sophisticated diagnostic methods have allowed us not only to predict patients' prognosis but also to provide a specific therapy depending on the molecular and genetic characteristics of patients. Our review is based on 25 articles regarding novel diagnostic and therapeutic methods as well as prognostic factors, released between 1992 and 2011. Those articles focus mostly on molecular and cytogenetic testing allowing revolutionary methods of patient classification and individual therapy for this highly heterogeneous group of disorders. Implementation of molecular genetic testing to evaluate the type of leukaemia allowed paediatric oncologists and haematologists to adjust the intensity of treatment, improve outcome, minimize toxicity of therapies and considerably lower the risk of side effects. In the last few decades there has been a great improvement in survival among children suffering from haematopoietic malignancies. Progress made in molecular genetics allowed the creation of new treatment protocols that are designed to maintain a high cure rate for children with leukaemia while reducing toxicity.

Histopathological and genetic features of patients with limb girdle muscular dystrophy type 2c

In this study, it was aimed to describe the clinical, histopathological and genetic features of 20 patients with gamma sarcoglycanopathy confirmed by muscle biopsies and genetic analysis. We retrospectively reviewed 20 patients from whom muscle biopsy specimens were obtained between 2007 and 2012. All patients were clinically diagnosed as muscular dystrophy and biopsy materials were collected from five different centers of neurological disorders. All DNAs were extracted from muscle tissues or blood samples of patients and genetic tests (mutation analyses for gamma sarcoglycan gene and deletion-duplication analyses for all 4 sarcoglycan genes) were performed. The mean age of the patients was 7.6 years (2 -21 years). Only one case (5%) was older than 14 years. The mean CPK level was 10311 U/L (1311 - 35000 U∕L). There were 4 siblings in these series. Expression defects of gamma sarcoglycan staining were determined in (15 males, and 5 females) all patients with muscle biopsy specimens. But only in 9 of them, disease-causing defects could be determined with genetic analyses. The present study has demonstrated that both examination of muscle biopsy specimens and DNA analysis remain important methods in the differential diagnosis of muscular dystrophies. Because dystrophinopathies and sarcoglycanopathies have similar clinical manifestation.

Clinical and genetic characteristics of patients with multiple polyposis of the large bowel negative for APC and MYH gene mutations using conventional methods

A genealogical analysis and molecular and clinical investigations were carried out in 19 probands with multiple colorectal adenomas (numbering near 100 or more). Twelve of these patients (63.1%) were negative for the APC and MYH gene mutations using conventional methods. A hereditary form of the disorder was confirmed in three (25%) probands. The median age of the disease onset in APC-negative patients was somewhere between the mean age of the disease onset in APC- and MYH-positive polyposis. Extraintestinal signs of the disorder were less frequent in APC-negative than in APC-positive probands. Half of APC- and MYH-negative probands with multiple polyposis developed colon cancer. APC- and MYH-negative patients formed a genetically heterogeneous group.

Clinical and genetic features of Huntington disease in Sri Lanka

BackgroundHuntington disease was one of the first neurological hereditary diseases for which genetic testing was made possible as early as 1993. The study describes the clinical and genetic characteristics of patients with Huntington disease in Sri Lanka.MethodsData of 35 consecutive patients tested from 2007 to 2012 at the Human Genetics Unit, Faculty of Medicine, University of Colombo was analyzed retrospectively. Clinical data and genetic diagnostic results were reviewed. Statistical analysis was performed using descriptive statistics.ResultsThirty patients had fully penetrant (FP) CAG repeat mutations and 5 had reduced penetrant (RP) CAG repeat mutations. In the FP group mean ages of onset and diagnosis were 37.5 and 40.4 years, while in the RP group it was 63.0 and 64.8 years respectively. The age of diagnosis ranged from 15 to 72 years, with 2 patients with Juvenile onset (<20 years) and 3 with late onset (>60 years) Huntington disease. The symptoms at diagnosis were predominantly motor (32/35 -91%). Three patients had psychiatric and behavioral disorders. The age difference between onset and genetic diagnosis showed significant delay in females compared to males (p < 0.05). Twenty two (62.8%) had a positive family history, with 13/22 (59.1%) showing a paternal inheritance of the disease. In both groups, those with a family history had a significantly lower age of presentation (p < 0.05). The mean CAG repeat length in patients with FP alleles was 44.6 ± 5 and RP alleles was 37.2 ± 1.1. Age of onset and CAG repeat length of the HTT gene showed significant inverse correlation (p < 0.0005, R2 = 0.727).ConclusionsThe clinical and genetic features seen in patients with Huntington disease in the Sri Lankan study population were similar to that previously reported in literature.

Multiple primary melanomas: do they look the same?

A series of studies has investigated epidemiological, clinical and genetic characteristics of patients with multiple primary melanoma (MPM). However, comparison of the clinical and dermoscopic features of MPM within a given individual has been described only in case reports. To describe the dermoscopic features of MPM for each given patient, and to evaluate the characteristics eventually associated with similar or dissimilar appearance. From the databases of three skin-lesion clinics in the U.S.A., Italy and Spain we collected the dermoscopic images of melanomas in patients diagnosed with MPM. Among 58 patients with MPM, we found that 53% of patients had dermoscopically similar melanomas and 47% of patients had dermoscopically different melanomas. In older patients 59% of melanomas were dermoscopically similar vs. 47% in younger patients (P=0·377). Similar thickness was associated with the occurrence of dermoscopically similar melanomas (19/30 cases, 63%; P=0·039). Most (65%) of the synchronous lesions were similar, compared with 36% of nonsynchronous lesions (P=0·029), and most (69%) of the melanomas on sun-damaged skin were similar, vs. 37% of melanomas on nonsun-damaged skin (P=0·015; odds ratio 3·88, 95% confidence interval 1·11-13·98). The percentage of dermoscopically different melanomas was higher in patients with a family history of melanoma (67% vs. 48%). MPMs in a given patient have almost the same chance of looking dermoscopically similar or different. However, a subset of elderly patients with sun-damaged skin may present multiple, similar, thin melanomas characterized by pigment-network and regression structures.

Analysis of clinical and genetic characteristics of 20 cases of children with Silver Russell syndrome

To improve the accuracy of the diagnosis of the disease on the basis of the clinical features and genetic characteristics of patients with Silver Russell syndrome (SRS). Patients diagnosed with SRS by Price criteria in 2006 to 2011 were reviewed for their clinical manifestations, physical signs, laboratory examinations and treatments. Twenty cases with SRS were 0.08-12.17 yr old. Fifteen were male and 5 were female. The clinical characteristics included more than 80% of cases had postnatal growth retardation 100% (20/20), craniofacial dysmorphism 100% (20/20), small for gestation age 95% (19/20), asymmetry and thinning of the face and/or limbs 90% (18/20), fifth finger clinodactyly 80% (16/20), BMI < -2 SDS 80% (16/20). Their height was obviously lagging behind in the bone age. HD SDS/average of bone retardation was 3.08. The two patients with the chief complaint of external genital abnormalities would have aggressive surgical treatment and they did not use the growth hormone (GH) treatment. Only six patients had used the GH treatment. GH treatment at a dose of 0.1 IU/(kg·d) used in 2 cases achieved a growth velocity (GV) 8 - 11 cm/yr but in another 2 cases < 5 cm/yr. In genetic study, 6 patients were found to have 11p15 low methylation, 1 had low and high methylation, 1 had duplication, no relation between clinical and methylation of 11p15 was found. There were great variations of clinical features in SRS characterized by small for gestation age and/or postnatal growth retardation, craniofacial dysmorphism, asymmetry of the face and/or limbs or ultrafine limbs, fifth finger clinodactyly. Severely low BMI was seen and height was obviously lagging behind in the bone age. The findings of laboratory tests and imaging of SRS were not specific. Some of SRS had 11p15 imprinting defects. The treatment of SRS is mainly symptomatic.

Frequent delay of coeliac disease diagnosis in symptomatic patients with type 1 diabetes mellitus: Clinical and genetic characteristics

BackgroundPatients with type 1 diabetes mellitus (T1DM) are more prone to develop other auto-immune diseases, including coeliac disease (CD). Paediatric patients with T1DM are screened for CD, whereas in adult T1DM patients screening programs for CD are not standardised. The aim of this study was to investigate clinical and genetic characteristics of patients with both diagnoses so as to lead to better detection of CD in adult patients with T1DM. MethodsWe studied 118 patients with both T1DM and CD identified in The Netherlands. We retrospectively collected data on sex distribution, age of onset of T1DM, age of CD diagnosis, CD complaints, duration of CD complaints before CD diagnosis, family history of CD or T1DM, comorbidity and HLA-DQ type. ResultsThirty-three percent of T1DM+CD patients reported CD related complaints for at least 5years before CD diagnosis. Two peaks in the age of CD diagnosis in T1DM patients were observed: around 10 and 45years of age. Women were diagnosed with CD at a younger age than men (median 25years (IQR 9–38) versus 39 (12–55) years, respectively, P<0.05). ConclusionA delay of CD diagnosis is frequently found in adult T1DM patients and two peaks in the age of CD diagnosis are present in T1DM patients. This observational study emphasises that more frequent screening for CD in particularly adult T1DM patients is required, preferably by a 5years interval.

Spectrum of RB1 Mutations in Argentine Patients: 20-years Experience in the Molecular Diagnosis of Retinoblastoma

ABSTRACTBackground: Retinoblastoma is a hereditary cancer of childhood caused by mutations in the RB1 tumor suppressor gene. An early diagnosis is critical for survival and eye preservation, thus identification of RB1 mutations is important for unequivocal diagnosis of hereditary retinoblastoma and risk assessment in relatives.Methods: We studied 144 families for 20 years, performing methodological changes to improve detection of mutation. Segregation analysis of polymorphisms, MLPA, FISH and cytogenetic assays were used for detection of “at risk haplotypes” and large deletions. Small mutations were identified by heteroduplex/DNA sequencing.Results: At risk haplotypes were identified in 11 familial and 26 sporadic cases, being useful for detection of asymptomatic carriers, risk exclusion from relatives and uncovering RB1 recombinations. Ten large deletions (eight whole gene deletions) were identified in six bilateral/familial and four unilateral retinoblastoma cases. Small mutations were identified in 29 cases (four unilateral retinoblastoma patients), being the majority nonsense/frameshift mutations. Genotype-phenotype correlations confirm that the retinoblastoma presentation is related to the type of mutation, but some exceptions may occur and it is crucial to be considered for genetic counseling. Three families included second cousins with retinoblastoma carrying different haplotypes, which suggest independent mutation events.Conclusion: This study enabled us to obtain information about molecular and genetic features of patients with retinoblastoma in Argentina and correlate them to their phenotype.

Autosomal Recessive Bestrophinopathy: Differential Diagnosis and Treatment Options

To describe the clinical and genetic characteristics of patients with autosomal recessive bestrophinopathy (ARB).Retrospective case series.Ten patients with ARB from 7 different families.All patients underwent a complete ophthalmic examination, including dilated fundus examination, fundus photography, and fluorescein angiography (FA). In all probands, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (OCT), full-field electroretinography (ERG), electro-oculography (EOG), and Goldmann perimetry were performed. In selected patients, multifocal ERG was performed. Blood samples were obtained to analyze the BEST1 gene for biallelic mutations that confirmed the diagnosis of ARB.Age at onset; visual acuity; fundus appearance; characteristics on FA, FAF, OCT, full-field ERG, and EOG; BEST1 gene mutations; and genotype-phenotype correlation.The age at onset varied widely, from 2 to 54 years. A spectrum of fundus abnormalities was observed, such as multifocal yellowish subretinal deposits, subretinal fibrous scars, and cystoid intraretinal fluid collections in the macula. All ARB patients were hyperopic, and some had shallow anterior chamber angles that predisposed them to angle-closure glaucoma. The EOG results were abnormal in all patients. The full-field ERG results were abnormal in 8 ARB patients, whereas 2 patients demonstrated normal cone and rod responses on full-field ERG. Nine ARB patients carried biallelic mutations in the BEST1 gene, and in 1 patient with a characteristic ARB phenotype, only 1 mutation could be identified. Seven different mutations were detected, including 4 novel mutations.Autosomal recessive bestrophinopathy is a recognizable phenotype caused by autosomal recessively inherited mutations in the BEST1 gene. A differential diagnosis with other conditions can be made on the basis of marked autofluorescence changes in combination with an absent light rise on the EOG that outweighs the full-field ERG abnormalities, which point to the BEST1-related hereditary nature of the disease. A number of currently available therapeutic options should be considered in ARB, a disease that seems to be a suitable candidate for future gene therapy.

Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System

A subset of patients diagnosed with idiopathic hypogonadotropic hypogonadism (IHH) later achieves activation of their hypothalamic-pituitary-gonadal axis with normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. The objective of this study was to determine the natural history of reversal and to identify associated phenotypes and genotypes. This was a retrospective review of clinical, biochemical, and genetic features of patients with IHH evaluated at an academic medical center. History of spontaneous fertility, regular menses, testicular growth, or normalization of serum sex steroids, LH secretory profiles, brain imaging findings, and sequences of 14 genes associated with IHH were reviewed. Of 308 patients with IHH, 44 underwent reversal. Time-to-event analysis estimated a lifetime incidence of reversal of 22%. There were no differences in the rates of cryptorchidism, micropenis, or partial pubertal development in patients with reversal vs IHH patients without reversal. Fifteen patients with reversal (30%) had Kallmann syndrome (IHH and anosmia); one had undetectable olfactory bulbs on a brain magnetic resonance imaging scan. Subjects with reversal were enriched for mutations affecting neurokinin B signaling compared with a cohort of IHH patients without reversal (10% vs 3%, P = .044), had comparable frequencies of mutations in FGFR1, PROKR2, and GNRHR, and had no mutations in KAL1. Five men did not sustain their reversal and again developed hypogonadotropism. Reversal of IHH may be more widespread than previously appreciated and occurs across a broad range of genotypes and phenotypes. Enrichment for mutations that disrupt neurokinin B signaling in patients who reversed indicates that, despite the importance of this signaling pathway for normal pubertal timing, its function is dispensable later in life. The occurrence of reversal in a patient with no olfactory bulbs demonstrates that these structures are not essential for normal reproductive function. Patients with IHH require lifelong monitoring for reversal and, if reversal occurs, subsequent relapse also may occur.