ABSTRACT
Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development. Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed. Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay. Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment. .
Subject(s)
Hypogonadism , Puberty, Delayed , Adolescent , Humans , Male , Adult , Female , Puberty, Delayed/diagnosis , Retrospective Studies , Testosterone , Hypogonadism/diagnosisABSTRACT
CONTEXT: Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. OBJECTIVE: To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients. DESIGN: Retrospective study. METHODS: Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. RESULTS: Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. CONCLUSION: This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.
Subject(s)
Puberty, Delayed/diagnosis , Puberty, Delayed/genetics , Adolescent , Cohort Studies , Computational Biology , Computer Simulation , Diagnosis, Differential , Exome/genetics , Female , Genetic Testing , Genetic Variation , Genome-Wide Association Study , Genotype , Humans , Hypogonadism/genetics , Male , Predictive Value of Tests , Reproducibility of Results , Retrospective Studies , Exome SequencingABSTRACT
Asiatic lions (Panthera leo persica) are an icon of conservation success, yet their status is inferred from total counts that cannot account for detection bias and double counts. With an effort of 4,797 km in 725 km2 of western Gir Protected Area, India, we used polygon search based spatially explicit capture recapture framework to estimate lion density. Using vibrissae patterns and permanent body marks we identified 67 lions from 368 lion sightings. We conducted distance sampling on 35 transects with an effort of 101.5 km to estimate spatial prey density using generalized additive modeling (GAM). Subsequently, we modeled lion spatial density with prey, habitat characteristics, anthropogenic factors and distance to baiting sites. Lion density (>1-year-old lions) was estimated at 8.53 (SE 1.05) /100 km2 with lionesses having smaller movement parameter (σ = 2.55 km; SE 0.12) compared to males (σ = 5.32 km; SE 0.33). Detection corrected sex ratio (female:male lions) was 1.14 (SE 0.02). Chital (Axis axis) was the most abundant ungulate with a density of 63.29 (SE 10.14) as determined by conventional distance sampling (CDS) and 58.17 (SE 22.17)/km2 with density surface modeling (DSM), followed by sambar (Rusa unicolor) at 3.84 (SE 1.07) and 4.73 (SE 1.48)/km2 estimated by CDS and DSM respectively. Spatial lion density was best explained by proximity to baiting sites and flat valley habitat but not as much by prey density. We demonstrate a scientifically robust approach to estimate lion abundance, that due to its spatial context, can be useful for management of habitat and human-lion interface. We recommend this method for lion population assessment across their range. High lion densities in western Gir were correlated with baiting. The management practice of attracting lions for tourism can perturb natural lion densities, disrupt behavior, lion social dynamics and have detrimental effects on local prey densities.
Subject(s)
Conservation of Natural Resources , Demography/statistics & numerical data , Ecosystem , Lions/physiology , Population Dynamics , Animals , Feeding Behavior , Female , Forests , India , Male , Predatory Behavior , Sex RatioABSTRACT
Rarely human communities coexist in harmony with large predators. Most often communities suffer due to predation on their stock while large carnivores suffer losses and at times extirpation due to retaliation. We examine the mechanisms permitting the coexistence of Asiatic lions (Panthera leo persica) and pastoral communities (Maldharis) in the Gir forests, India. We monitored six Maldhari settlements between 2005 and 2007 to quantify seasonal livestock holding, density and losses due to predation and other causes. Lion density, estimated by mark recapture, was 15±0.1 SE/100 km(2). Livestock density, estimated by total counts, ranged between 25/km(2)-31/km(2) with buffaloes being most abundant. Average livestock holding of Maldhari families was 33±3 SE. Lions predated mostly on unproductive cattle (30%). Scat analysis (n = 165), predation events (n = 180) and seven continuous monitoring sessions of 1,798 hours on four radio-collared lions estimated livestock to contribute between 25 to 42% of lions' biomass consumptions, of which only 16% was predated; rest scavenged. With free grazing rights within Gir forests, Maldharis offset 58±0.2 SE% of annual livestock rearing cost in comparison to non-forest dwelling pastoralists. With government compensation scheme for livestock predation, this profit margin augmented to 76±0.05 SE%. Lion density was higher in areas with Maldhari livestock in comparison to areas without livestock. Thus, the current lifestyles and livestock holdings of Maldharis seem to be beneficial to both lions and local pastoralists. We conclude that a combination of strict protection regime for lions, Maldharis' traditional reverence towards lions and the livelihood economics permit the delicate balance of lion-Maldhari coexistence. Indefinite increase in human and livestock population within Gir might upset this equilibrium undermining the conservation objectives. We see no end to compensation programs worldwide as they constitute a crucial element needed for human-carnivore coexistence.
Subject(s)
Lions/physiology , Symbiosis/physiology , Trees/physiology , Animals , Conservation of Natural Resources/economics , Ethnicity , Feeding Behavior , Geography , Humans , India , Livestock , Models, Biological , Population Dynamics , Predatory Behavior/physiology , SeasonsABSTRACT
CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.
Subject(s)
Genetic Testing , Human Growth Hormone/deficiency , Human Growth Hormone/genetics , Mutation , Receptors, Neuropeptide/genetics , Receptors, Pituitary Hormone-Regulating Hormone/genetics , Adolescent , Child , Child, Preschool , Cohort Studies , Homeodomain Proteins/genetics , Humans , Infant , Locus Control Region , Pedigree , SOXB1 Transcription Factors/geneticsABSTRACT
Type 1 diabetes mellitus is characterized by dysregulation of the immune system leading to inflammation and selective destruction of pancreatic beta cells. Mild to moderate pancreatic exocrine insufficiency is found in patients with type 1 diabetes. Diabetes mellitus may also be part of a syndrome occasionally involving hair and skin abnormalities. We report our observations on two siblings with insulin-dependent diabetes, severe exocrine pancreatic deficiency, pigmented hypertrichotic skin patches with induration and chronic inflammation. The first sibling presented at the age of 9 months with hypertrichosis and hyperpigmentation, particularly on her back and legs and then developed diabetes mellitus at the age of 4 yr. The second sibling presented with exactly the same clinical features but at a later age of 12 yr. Both siblings had severe pancreatic exocrine deficiency with chronic persistent inflammation. Some of the clinical features in these siblings resemble those described by Prendiville et al. although our patients had additional features. The chronic inflammatory response in both siblings is highly suggestive of some form of immune dysregulation. The presence of consanguinity in the parents and similarity of clinical features in the siblings are suggestive of a novel autoimmune disorder, possibly secondary to autosomal recessive inheritance.
Subject(s)
Diabetes Mellitus, Type 1/complications , Exocrine Pancreatic Insufficiency/complications , Hyperpigmentation/complications , Hypertrichosis/complications , Inflammation/complications , Siblings , Child , Chronic Disease , Consanguinity , Diabetes Mellitus, Type 1/genetics , Enzyme Therapy , Exocrine Pancreatic Insufficiency/genetics , Female , Humans , Hyperpigmentation/genetics , Hypertrichosis/genetics , Infant , Inflammation/genetics , Male , Pancreas/enzymology , Parents , Skin Diseases/complications , SyndromeABSTRACT
OBJECTIVE: To investigate the characteristics of spontaneous GH secretion in four male children with short stature due to partial GH insensitivity. Their molecular defect consists of inclusion of a mutant intronic pseudoexon in the region of the GH receptor involved in homodimerization. SUBJECTS: The subjects were two pairs of brothers who were first cousins, aged 10.4-14.2 years, heights -3.3 to -5.6 SDS, from a consanguineous Pakistani family. Basal serum IGF-I levels were extremely low (20-29 mg/l; NR > 50), with absent or minimal response to human recombinant GH (hGH) stimulation. Serum IGFBP-3 SDS levels were also low (-2.9 to -8.9). GH binding protein (GHBP) levels were normal (28.1-51.7%). METHODS: Spontaneous GH secretion was studied by intermittent (20 min) venous sampling from 2000 to 0800 h. The secretion profiles were analysed using the Pulsar programme and compared to data from a reference population of 76 prepubertal Swedish children [median age 10.7 years, median height -1.1 SDS (-2.0 to 1.4)] according to Swedish growth standards. RESULTS: Median (range) Pulsar-derived values in the four patients and controls were, respectively: GHmax (mU/l) 276.6 (178.7-325.8) and 27.2 (13.1-94.9), mean GH (mU/l) 64.5 (41.9-77.8) and 5.8 (3.2-20.6), baseline (mU/l) 12.3 (11.7-20.1) and 1.1 (0.2-6.1), AUCb (mU/l x 24 h) 1210 (684-1555) and 112.5 (60.6-316.4), i.e. all parameters of GH secretion in the four patients were markedly elevated compared with the control population. CONCLUSIONS: Spontaneous GH secretion is elevated in partial GH insensitivity. This investigation could be of diagnostic value in children with short stature.