Context: LHX3 encodes LIM homeodomain class transcription factors with important roles in pituitary and nervous system development. The only previous report of LHX3 mutations described patients with ...two types of recessive mutations displaying combined pituitary hormone deficiency coupled with neck rigidity.
Objective: We report a patient presenting a unique phenotype associated with a novel mutation in the LHX3 gene.
Patient: We report a 6-yr, 9-month-old boy born from a consanguineous relationship who presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T4, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency were consistent with hypopituitarism. A rigid cervical spine leading to limited head rotation was noticed on follow-up examination. Magnetic resonance imaging revealed an apparently structurally normal cervical spine and a postcontrast hypointense lesion in the anterior pituitary.
Results: Analysis of the LHX3 gene revealed homozygosity for a novel single-base-pair deletion in exon 2. This mutation leads to a frame shift predicted to result in the production of short, inactive LHX3 proteins. The results of in vitro translation experiments are consistent with this prediction. The parents of the patients are heterozygotes, indicating a recessive mode of action for the deletion allele.
Conclusions: The presence of a hypointense pituitary lesion and other clinical findings broadens the phenotype associated with LHX3 gene mutation.
Noonan, Turner, and Prader-Willi syndromes are classical genetic disorders that are marked by short stature. Each disorder has been recognized for several decades and is backed by extensive published ...literature describing its features, genetic origins, and optimal treatment strategies. These disorders are accompanied by a multitude of comorbidities, including cardiovascular issues, endocrinopathies, and infertility. Diagnostic delays, syndrome-associated comorbidities, and inefficient communication among the members of a patient’s health care team can affect a patient’s well-being from birth through adulthood. Insufficient information is available to help patients and their multidisciplinary team of providers transition from pediatric to adult health care systems. The aim of this review is to summarize the clinical features and genetics associated with each syndrome, describe best practices for diagnosis and treatment, and emphasize the importance of multidisciplinary teams and appropriate care plans for the pediatric to adult health care transition.
The LHX3 and LHX4 LIM-homeodomain transcription factors play essential roles in pituitary gland and nervous system development. Mutations in the genes encoding these regulatory proteins are ...associated with combined hormone deficiency diseases in humans and animal models. Patients with these diseases have complex syndromes involving short stature, and reproductive and metabolic disorders. Analyses of the features of these diseases and the biochemical properties of the LHX3 and LHX4 proteins will facilitate a better understanding of the molecular pathways that regulate the development of the specialized hormone-secreting cells of the mammalian anterior pituitary gland.
The known markers of insulin resistance in obese children are well studied. However, they require serial measurements and complicated calculations. The objective is to study IGFBP-1 and its relation ...with other known risk measures.
The study included 98 New York City school students of diverse ethnic/racial backgrounds (57 males and 41 females), 11-15 years of age. Subjects were enrolled in a cross-sectional study, and anthropometric measures were collected. They underwent fasting intravenous glucose tolerance tests (IVGTT), and glucose, insulin, lipids, IGFBP-1, adiponectin and inflammatory markers were collected.
The subjects were stratified into 3 groups based upon the BMI Z-score. Out of all the subjects, 65.3% were in the group with a BMI Z-score <1 SDS, 16.3% subjects were in the group with a BMI Z-score of 1 to 2 SDS, and 18.4% of the subjects were in the group with a BMI Z-score of more than 2 SDS. The group with a BMI Z-score of more than 2 SDS had increased waist circumference (WC), body fat, increased fasting insulin, and triglycerides (TG). This group had decreased levels of adiponectin and HDL and low IGFBP-1 as compared to the group with BMI <1 SDS. The group with a BMI Z-score of 1 to 2 SDS had a decreased level of IGFBP-1 as compared to the group with a BMI Z-score less than 1 SDS. IGFBP-1 inversely correlated with age, WC, BMI, body fat, TG, and insulin levels. IGFBP-1 positively correlated with adiponectin and HDL levels.
IGFBP-1 in children can identify the presence of insulin resistance in the group with BMI 1 to 2 SDS, even before the known markers of insulin resistance such as elevated triglycerides and even before decreased HDL and adiponectin levels are identified.
Sex steroids, such as estrogens, are known to influence endothelial function by their vasodilator action. The aim of this study was to study the relation of puberty and sex steroids with endothelial ...function using peripheral arterial tonometry (PAT).
In 89 healthy school boys and girls, we determined height, weight, waist circumference, percent body fat, BMI, BMI z-score, blood pressure (BP), BP percentiles, lipid profile, insulin, and glucose levels after overnight fast. Estrone (E(1)), estradiol (E(2)), DHEAS and E(1)-sulfate were measured using ultrasensitive assays. Participants were divided into 3 pubertal groups on the basis of their estrogen levels: group 1 (Tanner stage I), group 2 (Tanner stages II-III), and group 3 (Tanner stages IV-V). Endothelial function was measured by Endo-PAT 2000® and expressed as PAT index. A higher PAT index represents a higher reactive hyperemia response.
The PAT index was lowest at 1.42 ± 0.44 (mean ± SD) in group 1 and significantly increased in group 2 at 1.71 ± 0.35 (p = 0.02) and group 3 at 1.92 ± 0.38 (p < 0.001). The PAT index correlated positively with E(2), DHEAS and age.
Enhancement of the PAT index was associated with an increment in Tanner stages. The changes in E(2) and DHEAS levels may contribute to increasing endothelial response to shear stress or arterial blood flow.
Summary In this case report, we present a novel mutation in Lim-homeodomain (LIM-HD) transcription factor, LHX3, manifesting as combined pituitary hormone deficiency (CPHD). This female patient was ...originally diagnosed in Egypt during infancy with Diamond Blackfan Anemia (DBA) requiring several blood transfusions. Around 10 months of age, she was diagnosed and treated for central hypothyroidism. It was not until she came to the United States around two-and-a-half years of age that she was diagnosed and treated for growth hormone deficiency. Her response to growth hormone replacement on linear growth and muscle tone were impressive. She still suffers from severe global development delay likely due to delay in treatment of congenital central hypothyroidism followed by poor access to reliable thyroid medications. Her diagnosis of DBA was not confirmed after genetic testing in the United States and her hemoglobin normalized with hormone replacement therapies. We will review the patient’s clinical course as well as a review of LHX3 mutations and the associated phenotype. Learning points: Describe an unusual presentation of undertreated pituitary hormone deficiencies in early life Combined pituitary hormone deficiency due to a novel mutation in pituitary transcription factor, LHX3 Describe the clinical phenotype of combined pituitary hormone deficiency due to LHX3 mutations
Partial androgen insensitivity syndrome (PAIS) is the milder variant of androgen receptor (AR) defects. The subtle effects of AR mutations present in a patient with micropenis, peno-scrotal ...hypospadias, infertility, clitoromegaly and posterior labial fusion. We studied the association of isolated micropenis with the genetic defects resulting in androgen resistance, that is, AR gene defects and 5-α reductase type 2 (SRD5A2) deficiency. We describe two cases of isolated micropenis: one in a 14-year-old boy and the other in a 3-year-old boy who was followed until he was 10 years old. There were no findings of hypospadias, cryptorchidism or gynecomastia in either of these patients. Serum gonadotrophin and androgen levels were obtained and karyotyping was done. Human chorionic gonadotropin (hCG) stimulation testing assessed the functional capacity of the testes. DNA was extracted from peripheral leukocytes, and all exons of the SRD5A2 and AR genes were amplified by polymerase chain reaction and sequenced. In both patients, baseline testosterone (T) level was low and the values were elevated after hCG testing. The sequence of the SRD5A2 gene was normal in patient 1, and a heterozygous polymorphism, V89L, was found in patient 2. Two known mutations, P390S and A870V, were identified in patients 1 and 2, respectively. Mutations in the AR gene can be associated with isolated micropenis without other features of PAIS, such as hypospadias or gynecomastia. This underlines the importance of including AR gene analysis in the evaluation of isolated micropenis with normal plasma T to ensure proper management of the patient and appropriate genetic counseling for the family.
Background. Underlying insulin resistance and/or obesity has clearly been implicated in the development of metabolic syndrome in adolescents and young adults with polycystic ovarian syndrome (PCOS). ...It is not clear however what role hyperandrogenism has on the development of metabolic syndrome or its role on those metabolic parameters associated with metabolic syndrome. Methods. We studied 107 adolescent girls; 54 had PCOS according to NIH criteria. Data was obtained for systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), total testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, fasting lipid profile, and glucose. The PCOS group was divided initially into subgroups according to BMI (kg/m2), then based on T (ng/dL) levels as follows: High Testosterone PCOS (HT), Intermediate Testosterone PCOS (IT), Obese and Normal Testosterone (ONT), and lean and normal T (Control, C). t-test analysis was performed in between all the groups. Results. There was no statistical difference between HT and IT, HT and ONT, or IT and ONT in SBP, DBP, fasting blood glucose, lipid panel, LH, FSH, and prolactin levels. The control group had lower SBP and BMI comparing with ONT, IT, and HT groups. There were no statistical differences found in DBP, fasting blood glucose, lipid panel, LH, FSH, or Prolactin. Conclusion. Metabolic profile in adolescent girls with PCOS is not affected by either the presence of hyperandrogenism or the degree of hyperandrogenism.