Our objective was to further expand the spectrum of clinical characteristics of the
deficiency syndrome in affected males. These characteristic include almost universal congenital central ...hypothyroidism (CeH) with disharmonious pubertal development (normally timed testicular growth, but delayed rise of serum testosterone), macroorchidism, increased body mass index (BMI), and decreased attentional control. In addition, a subset of patients show prolactin deficiency, transient partial growth hormone deficiency in childhood and increased growth hormone secretion in adulthood. We present a family in which the proband was diagnosed with CeH and low serum prolactin. Severe weight gain started at two years old, with a BMI of 42.3 at 13.9 years. Testicular enlargement (5-6 mL, 3.8-4.3 standard deviation score) started aged three years. A pathogenic variant was found in the
gene: c.3411_3412del, p.(Tyr1137*). His brother was referred for short stature at age 13 years and was diagnosed with CeH, normal serum prolactin and IGF-1, and disharmonious puberty. In four male relatives (the proband’s brother and three cousins) with the variant (one adult), free thyroxine (fT4) was below the lower limit of the reference range in two, and just above this limit in the other two. Three were overweight or obese, adolescents had disharmonious pubertal development and the adult had profound macroorchidism. In conclusion, male hemizygous carriers of a pathogenic
variant can present with fT4 concentration above the lower limit of the reference range while severe early onset obesity or premature testicular growth are part of the phenotypic spectrum.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Context:
Autosomal-recessive mutations in the growth hormone receptor (GHR) are the most common causes for primary growth hormone insensitivity (GHI) syndrome with classical GHI ...phenotypically characterized by severe short stature and marked insulin-like growth factor (IGF)-I deficiency. We report three families with dominant-negative heterozygous mutations in the intracellular domain of the GHR causing a nonclassical GHI phenotype.
Objective:
To determine if the identified GHR heterozygous variants exert potential dominant-negative effects and are the cause for the GHI phenotype in our patients.
Results:
All three mutations (c.964dupG, c.920_921insTCTCAAAGATTACA, and c.945+2T>C) are predicted to result in frameshift and early protein termination. In vitro functional analysis of variants c.964dupG and c.920_921insTCTCAAAGATTACA (c.920_921ins14) suggests that these variants are expressed as truncated proteins and, when coexpressed with wild-type GHR, mimicking the heterozygous state in our patients, exert dominant-negative effects. Additionally, we provide evidence that a combination therapy of recombinant human growth hormone (rhGH) and rhIGF-I improved linear growth to within normal range for one of our previously reported patients with a characterized, dominant-negative GHR (c.899dupC) mutation.
Conclusion:
Dominant-negative GHR mutations are causal of the mild GHI with substantial growth failure observed in our patients. Heterozygous defects in the intracellular domain of GHR should, therefore, be considered in cases of idiopathic short stature and IGF-I deficiency. Combination therapy of rhGH and rhIGF-I improved growth in one of our patients.
In patients with mild GHI, heterozygous, truncating GHR mutations exerted dominant-negative effects. A combined therapy of rhGH plus rhIGF-I is an effective treatment option.
GH insensitivity and IGF deficiency may result from aberrations of the GH receptor (GHR). We describe a 4-year-old child with modest growth failure and normal serum concentrations of GH-binding ...protein (GHBP), but clinical evidence of GH insensitivity.
Serum and DNA samples from the proband and his parents were analyzed.
The child had a height of -4 SD, elevated serum GH concentrations, abnormally low serum IGF-I and IGFBP-3 concentrations and normal GHBP concentrations. DNA analysis revealed compound heterozygosity for mutations of GHR, including a previously reported R211H mutation and a novel duplication of a nucleotide in exon 9 (899dupC), the latter resulting in a frameshift and a premature stop codon. Treatment with recombinant DNA-derived IGF-I resulted in growth acceleration.
Mutations affecting the intracellular domain of the GHR can result in GH insensitivity and IGF deficiency, despite normal serum concentrations of GHBP. The presence of clinical and biochemical evidence of GH resistance is sufficient to consider the possibility of aberrations of the GHR, even in the presence of normal serum GHBP concentrations.
Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid ...production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Childhood cancer and its treatment can affect normal bone accretion. In this study, bone mineral density (BMD) in young adult survivors of childhood cancer is assessed to determine what ...cancer-related factors, patient characteristics, or treatment-related complications correlate with reductions in BMD.
The study population consisted of 40 (24 women) long-term survivors of childhood cancer treated at the Memorial Sloan-Kettering Cancer Center for a solid tumor (n = 16), lymphoma (n = 14), or acute leukemia (n = 10) at a mean age of 12.7 +/- 0.96 years and evaluated at a mean age of 25.8 +/- 0.7 years. Dual energy X-ray absorptiometry was used to determine BMD of the lumbar spine, femoral neck, and total body and single photon absorptiometry was used to determine BMD of the distal radius.
The mean BMD standard deviation score (SDS) for the patients was significantly reduced compared to controls at the distal radius (-1.57 +/- 0.18, p = 0.0001), femoral neck (-0.68 +/- 0.20, p = 0.00014), and total body (-0.33 +/- 0.15, p = 0.03) but not at the lumbar spine (-0.22 +/- 0.22, p = 0.33). Univariate analysis revealed that gonadal dysfunction (i.e., estrogen or testosterone insufficiency) (p = 0.018) was the only variable that correlated with a reduced BMD.
Young adult survivors of childhood cancer have reduced BMD. Because age at study coincides with the normal age of attainment of peak bone mass and peak bone mass is a major determinant of BMD later in life, many of these patients are at increased risk for osteoporosis and fractures.
Triptorelin is an established treatment for central precocious puberty (CPP) as 1- and 3-month formulations. The current triptorelin 22.5 mg 6-month formulation is approved for prostate cancer ...therapy. This is the first study in patients with CPP.
The efficacy and safety of the triptorelin 6-month formulation in CPP were investigated. The primary objective was to evaluate the efficacy in achieving luteinizing hormone (LH) suppression to pre-pubertal levels at month 6. This was an international, non-comparative phase III study over 48 weeks. Eighteen medical centers in the US, Chile and Mexico participated. Forty-four treatment naïve patients (39 girls and five boys) aged at treatment start 2-8 years for girls and 2-9 years for boys with an advancement of bone age over chronological age ≥1 year were to be included. Triptorelin was administered im twice at an interval of 24 weeks. LH, follicle stimulating hormone (FSH) (basal and stimulated), estradiol (girls), testosterone (boys), auxological parameters, clinical signs of puberty and safety were assessed.
Forty-one patients (93.2%) showed pre-pubertal LH levels (stimulated LH ≤5 IU/L) at month 6 and maintained LH suppression through month 12. The percentage of patients with LH suppression exceeded 93% at each time point and reached 97.7% at month 12. No unexpected drug-related adverse events were reported.
The triptorelin 6-month formulation was safe and effective in suppressing the pituitary-gonadal axis in children with CPP. The extended injection interval may improve compliance and increase comfort in the management of CPP.
Context:
GH insensitivity (GHI) is a condition characterized by pronounced IGF-I deficiency and severe short stature. We previously identified a novel compound heterozygous GH receptor (GHR) ...mutation, GHR:p.R229H/c.899dupC, in a patient presenting with GHI. The heterozygous p.R229H (prepeptide) variant was previously associated with GHI despite a lack of adequate functional studies. The novel heterozygous GHR:c.899dupC variant affects the critical JAK2-binding Box 1 region of the GHR intracellular domain; the duplication predicted a frameshift and early protein termination.
Objective:
The individual and synergistic effect(s) of the p.R229H and c.899dupC mutations on GHR function(s) were evaluated in reconstitution studies.
Results:
The recombinant human GHR (hGHR):p.R229H variant was readily expressed, and unexpectedly, GH-induced signal transducer and activator of transcription 5b (STAT5b) phosphorylation was comparable to that induced by wild-type hGHR. The truncated, immunodetected hGHR:c.899dupC variant, in contrast, was unresponsive to GH. To mimic a compound heterozygous state, the two variants were coexpressed, and strikingly, the presence of the hGHR:c.899dupC effectively abolished the GH-induced STAT5b activities that were observed with hGHR:p.R229H alone. Furthermore, hGHR:c.899dupC dose-dependently reduced the GH-induced STAT5b activities associated with hGHR:p.R229H. This dominant negative effect was also observed when hGHR:c.899dupC was coexpressed with wild-type hGHR.
Conclusion:
The p.R229H variant, contrary to an earlier report, appeared to function like wild-type GHR and, therefore, is unlikely to cause GHI. The c.899dupC variant is a novel dominant negative mutation that disrupted normal GHR signaling and is the cause for the GHI phenotype of the reported patient.
Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid ...production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The purpose of this study was to assess the performance and acceptability of a blood glucose meter coupled with a gaming system for children, adolescents, and young adults with type 1 diabetes. ...During an in‐clinic visit, duplicate blood samples were tested by subjects (N = 147; aged 5–24 yr) and health care providers (HCPs) to evaluate the accuracy and precision of the Didget® system. Subjects' meter results were compared against Yellow Springs Instruments (YSI) reference results and HCP results using least squares regression and error grid analyses. Precision was measured by average within‐subject and within‐HCP coefficient of variation (CV). During the home‐use component of this study, subjects (n = 58) tested their blood glucose at least two to three times daily for 3–5 d to evaluate routine use of the system. Subjects' meter results showed significant correlations with both YSI (r2 = 0.94; p < 0.001 for regression slope) and HCP results (r2 = 0.96; p < 0.001). Average within‐subject and within‐HCP CVs were 5.9 and 7.2%, respectively. Overall satisfaction was assessed by subjects, their parents or guardians, and HCP surveys. Subject satisfaction with the Didget® system was good to excellent; most subjects found the system easy to use, motivating, and helpful for building good blood glucose monitoring habits. Most HCPs agreed that the system fulfilled a need in diabetes management. In conclusion, the Didget® system was precise and clinically accurate in the hands of children, adolescents, and young adults with type 1 diabetes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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