Association of Early Pubertal Onset in Female Rats With Inhalation of Lavender Oil

Background@#Central precocious puberty (CPP) is caused by early activation of the hypothalamic–pituitary–gonadal axis but its major cause remains unclear. Studies have indicated an association between chronic environmental exposure to endocrine-disrupting chemicals and pubertal onset. Essential oil is widely used in homes worldwide for relief of respiratory symptoms, stress, and/or sleep disturbance. @*Methods@#To evaluate this association, we compared the hormone levels and timing of vaginal opening (VO) in female rats exposed to lavender oil (LO) through different routes (study groups: control, LO nasal spray [LS], and indoor exposure to LO [LE]) during the prepubertal period. The body weights of the animals were also compared every 3 days until the day of VO, at which time gonadotropin levels and internal organ weights were assessed. @*Results@#The LS group showed early VO at 33.8 ± 1.8 days compared with the control (38.4 ± 2.9 days) and LE (36.6 ± 1.5 days) groups. Additionally, luteinizing hormone levels were significantly higher in the LE and LS groups than those in the control group. Body weights did not differ significantly among the groups. @*Conclusion@#Inhalation exposure to an exogenic simulant during the prepubertal period might trigger early pubertal onset in female rats. Further evaluation of exposure to other endocrine-disrupting chemicals capable of inducing CPP through the skin, orally, and/or nasally is warranted.

Growth Responses During 3 Years of Growth Hormone Treatment in Children and Adolescents With Growth Hormone Deficiency: Comparison Between Idiopathic, Organic and Isolated Growth Hormone Deficiency, and Multiple Pituitary Hormone Deficiency

Background@#The study aimed to compare the growth responses to 3 years of growth hormone (GH) treatment in children and adolescents with GH deficiency (GHD) according to idiopathic, organic, isolated (IGHD), and multiple pituitary hormone deficiency (MPHD). @*Methods@#Total 163 patients aged 2–18 years (100 males and 63 females; 131 idiopathic and 32 organic GHD; 129 IGHD and 34 MPHD) were included from data obtained from the LG Growth Study. Parameters of growth responses and biochemical results were compared during the 3-year GH treatment. @*Results@#The baseline age, bone age (BA), height (Ht) standard deviation score (SDS), weight SDS, mid-parental Ht SDS, predicted adult Ht (PAH) SDS, and insulin like growth factor-1 (IGF-1) SDS were significantly higher in the organic GHD patients than in the idiopathic GHD patients, but peak GH on the GH-stimulation test, baseline GH dose, and mean 3-year-GH dosage were higher in the idiopathic GHD patients than in the organic GHD patients. The prevalence of MPHD was higher in the organic GHD patients than in the idiopathic GHD patients. Idiopathic MPHD subgroup showed the largest increase for the ΔHt SDS and ΔPAH SDS during GH treatment, and organic MPHD subgroup had the smallest mean increase after GH treatment, depending on ΔIGF-1 SDS and ΔIGF binding protein-3 (IGFBP-3) SDS.The growth velocity and the parental-adjusted Ht gain were greater in the idiopathic GHD patients than the organic GHD patients during the 3-year GH treatment, which may have been related to the different GH dose, ΔIGF-1 SDS, and ΔIGFBP-3 SDS between two groups.Multiple linear regression analysis revealed that baseline IGF-1 SDS, BA, and MPH SDS in idiopathic group and baseline HT SDS in organic group are the most predictable parameters for favorable 3-year-GH treatment. @*Conclusion@#The 3-year-GH treatment was effective in both idiopathic and organic GHD patients regardless of the presence of MPHD or underlying causes, but their growth outcomes were not constant with each other. Close monitoring along with appropriate dosage of GH and annual growth responses, not specific at baseline, are more important in children and adolescents with GHD for long-term treatment.

The first Korean case of 2p15p16.1 microdeletion syndrome, characterized by facial dysmorphism, developmental delay, and congenital hypothyroidism

The microdeletion syndrome of chromosome 2p15p16.1 (MIM: 612513) is an extremely rare contiguous gene deletion syndrome. Microdeletions of varying sizes in the 2p15-16.1 region are associated with developmental delay, intellectual disability, autism spectrum disorder, hypotonia, and craniofacial dysmorphism. Previous studies have identified two critical regions: the proximal 2p15 and distal 2p16.1 regions. BCL11A, PAPOLG, and REL genes play crucial roles in patients with 2p16.1 microdeletion. To our knowledge, only 39 patients have been reported as having 2p15p16.1 microdeletion syndrome. Here, we present another patient with 2p15p16.1 microdeletion syndrome. A nine-month-old boy was referred to our clinic for the psychomotor delay, facial dysmorphism, and congenital hypothyroidism. During his follow-up visits, he was diagnosed with global developmental delay, intellectual disability, abnormal behavior, hypotonia, microcephaly, and abnormal electroencephalography. Using a chromosomal microarray for genetic analysis, a novel, de novo, 622 kb microdeletion of 2p16.1 was identified as one of the critical regions of the 2p15p16.1 microdeletion syndrome. This is the first case of its kind in Korea. We have discussed our case and literature reviews to clarify the relationship between the genes involved and clinical phenotypes in 2p15p16.1 microdeletion syndrome.

Single random measurement of urinary gonadotropin concentration for screening and monitoring girls with central precocious puberty

Purpose@#The gold standard for assessing pubertal activation is the gonadotropinreleasing hormone (GnRH) stimulation test (GnRHST), which is invasive, timeconsuming, and inconvenient. This study evaluated whether a single random measurement of urinary luteinizing hormone (LH) concentration could substitute for the GnRHST in diagnosing and monitoring central precocious puberty (CPP) in girls. @*Methods@#Fifty-five girls with breast buds before 8 years of age were assessed by both the GnRHST and urinary gonadotropin assays. Based on the GnRHST results, 29 girls were assigned to the CPP group (peak LH≥5 IU/L), and 26 were placed in the premature thelarche (PT) group (peak LH<5 IU/L). Auxological data and urine and serum samples were collected at baseline and after treatment with a GnRH agonist for 12 and 24 weeks. @*Results@#Although the auxological data did not differ between the 2 groups, the serum levels of insulin-like growth factor-1, basal LH, follicle-stimulating hormone (FSH), estradiol, and peak LH; urinary LH; and peak serum LH/FSH and urinary LH/FSH ratios were higher in the CPP group than in the PT group. Pearson correlation analysis showed a positive correlation between the urinary and serum LH concentrations (r=0.660, P<0.001). Receiver-operating characteristic curve analyses showed that a urinary LH concentration of 0.725 IU/L was a cutoff that significantly predicted positivity on the GnRHST. Urinary LH and FSH concentrations declined significantly during GnRH agonist treatment. @*Conclusion@#A single, random measurement of urinary gonadotropin concentration could be a reliable tool for initial screening and therapeutic monitoring of CPP in girls.

Single random measurement of urinary gonadotropin concentration for screening and monitoring girls with central precocious puberty

Purpose@#The gold standard for assessing pubertal activation is the gonadotropinreleasing hormone (GnRH) stimulation test (GnRHST), which is invasive, timeconsuming, and inconvenient. This study evaluated whether a single random measurement of urinary luteinizing hormone (LH) concentration could substitute for the GnRHST in diagnosing and monitoring central precocious puberty (CPP) in girls. @*Methods@#Fifty-five girls with breast buds before 8 years of age were assessed by both the GnRHST and urinary gonadotropin assays. Based on the GnRHST results, 29 girls were assigned to the CPP group (peak LH≥5 IU/L), and 26 were placed in the premature thelarche (PT) group (peak LH<5 IU/L). Auxological data and urine and serum samples were collected at baseline and after treatment with a GnRH agonist for 12 and 24 weeks. @*Results@#Although the auxological data did not differ between the 2 groups, the serum levels of insulin-like growth factor-1, basal LH, follicle-stimulating hormone (FSH), estradiol, and peak LH; urinary LH; and peak serum LH/FSH and urinary LH/FSH ratios were higher in the CPP group than in the PT group. Pearson correlation analysis showed a positive correlation between the urinary and serum LH concentrations (r=0.660, P<0.001). Receiver-operating characteristic curve analyses showed that a urinary LH concentration of 0.725 IU/L was a cutoff that significantly predicted positivity on the GnRHST. Urinary LH and FSH concentrations declined significantly during GnRH agonist treatment. @*Conclusion@#A single, random measurement of urinary gonadotropin concentration could be a reliable tool for initial screening and therapeutic monitoring of CPP in girls.

Leri-Weill dyschondrosteosis in a newborn presenting with respiratory failure due to severe micrognathia

Short stature homeobox-containing gene (SHOX) is a well-known causative gene for the short stature in Turner syndrome. The clinical manifestation of SHOX gene related disorders varies from SHOX haploinsufficiency, presenting with idiopathic short stature, disproportionate short stature, or Leri-Weill dyschondrosteosis (LWD) to recessive form of extreme dwarfism and limb deformity in Langer mesomelic dysplasia. LWD is usually diagnosed upon suspicion based on short stature and skeletal abnormalities, and it is rarely accompanied with respiratory failure in the neonatal period. Here, we report the case of a newborn infant with LWD presenting with severe micrognathia that caused respiratory distress, which was diagnosed using microarray testing. Even when the manifestation of Madelung deformity is not yet apparent, LWD should be considered as one of underlying diseases related to congenital micrognathia.

Leri-Weill dyschondrosteosis in a newborn presenting with respiratory failure due to severe micrognathia

Short stature homeobox-containing gene (SHOX) is a well-known causative gene for the short stature in Turner syndrome. The clinical manifestation of SHOX gene related disorders varies from SHOX haploinsufficiency, presenting with idiopathic short stature, disproportionate short stature, or Leri-Weill dyschondrosteosis (LWD) to recessive form of extreme dwarfism and limb deformity in Langer mesomelic dysplasia. LWD is usually diagnosed upon suspicion based on short stature and skeletal abnormalities, and it is rarely accompanied with respiratory failure in the neonatal period. Here, we report the case of a newborn infant with LWD presenting with severe micrognathia that caused respiratory distress, which was diagnosed using microarray testing. Even when the manifestation of Madelung deformity is not yet apparent, LWD should be considered as one of underlying diseases related to congenital micrognathia.

Successful rapid weight reduction and the use of liraglutide for morbid obesity in adolescent Prader-Willi syndrome

Prader-Willi syndrome (PWS), an imprinting disorder, results from the loss of expression of a paternal gene on chromosome 15q11-q13. Progressive obesity and its associated complications lead to increased morbidity and early death in PWS patients. The management techniques available for morbid obesity in adolescents and adults with PWS are limited. Herein, we report successful weight reduction in an adolescent PWS case showing morbid obesity and respiratory failure. An 18-year-old girl with PWS presented with diffuse cellulitis and dyspnea due to severe obesity. Her body weight had increased from 146 to 161 kg despite dietary restriction to 800 kcal/day, and a mechanical ventilator was required for dyspnea. During mechanical ventilation, the patient was managed using diuretics and by restricting fluid intake; her daily calorie intake was reduced to 200 kcal. This aggressive calorie and water restriction continued for 3 weeks and reduced her body weight to 118.6 kg. After transfer to the general ward, the patient was provided with growth hormone therapy and intensive aquatic rehabilitation and was administered liraglutide; as a result, her weight further decreased to 104 kg (body mass index [BMI], 50.8 kg/m2), and she was discharged. Following discharge, she maintained her BMI and adapted to 1,000 kcal/day for 1 year. Aggressive water and calorie restriction were observed as an effective method for rapid weight reduction in PWS patients, and liraglutide appeared useful in maintaining weight reduction in adolescent and adult PWS.

First Case of Peroxisomal D-bifunctional Protein Deficiency with Novel HSD17B4 Mutations and Progressive Neuropathy in Korea

Peroxisomal D-bifunctional protein (DBP), encoded by the HSD17B4 gene, catalyzes β-oxidation of very long chain fatty acids (VLCFAs). The deficiency of this peroxisomal enzyme leads to the accumulation of VLCFAs, causing multisystemic manifestations including the brain, retina, adrenal gland, hearing, and skeletal system. Herein, we report the first Korean neonatal case of peroxisomal DBP deficiency and the clinical prognosis over 2 years. This patient showed craniofacial dysmorphism, club foot, and seizures with cyanosis one day after birth. Elevated VLCFAs levels were indicative of a peroxisomal disorder.Targeted exome sequencing was performed and two missense mutations p.Asp117Val and p.Phe279Ser in the HSD17B4 gene were identified. The patient had type III DBP deficiency;therefore, docosahexaenoic acid and non-soluble vitamins were administered. However, progressive nystagmus, optic nerve atrophy, and bilateral hearing defects were observed and follow-up brain imaging revealed leukodystrophy and brain atrophy. Multiple anti-epileptic drugs were required to control the seizures. Over two years, the patient achieved normal growth with home ventilation and tube feeding. Hereby, the subject's parents had support during the second pregnancy from the proven molecular information. Moreover, targeted exome sequencing is an effective diagnostic approach, considering genetic heterogeneity of Zellweger spectrum disorders.

The Effect of Combined Growth Hormone and a Gonadotropin-Releasing Hormone Agonist Therapy on Height in Korean 3-M Syndrome Siblings

3-M syndrome is a rare autosomal recessive growth disorder characterized by severe growth retardation, low birth weight, characteristic facial features, and skeletal anomalies, for which three causative genes (CUL7, OBSL1, and CCDC8) have been identified. We herein report two Korean siblings with 3-M syndrome caused by two novelOBSL1 mutations, and describe the effect of a combined treatment with growth hormone (GH) and a gonadotropin-releasing hormone (GnRH) agonist. A 7-year-old girl with short stature (-3.37 standard deviation score, SDS) and breast budding presented with subtle dysmorphic features, including macrocephaly, frontal bossing, a triangular face, prominent philtrum, full lips, a short neck, and fifth-finger clinodactyly. GnRH stimulation test revealed a pubertal pattern and advanced bone age of 8 years and 10 months. Her older sister, aged 10 years and 9 months, had experienced an early menarche, and had an advanced bone age (13.5 years) and predicted adult height of 142 cm (-4.04 SDS). Targeted exome sequencing identified that the siblings had two heteroallelic mutations in OBSL1. Both siblings underwent a combination therapy with GH and a GnRH agonist. A height gain was noted in both siblings even after short-term treatment. To fully elucidate the effects of the combined therapy, a larger cohort should be analyzed following a longer treatment period. However, such an analysis would be challenging due to the rarity of this disease.