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1.  Liver Disease and Other Comorbidities in Wolcott-Rallison Syndrome: Different Phenotype and Variable Associations in a Large Cohort 
Hormone Research in Pædiatrics  2015;83(3):190-197.
Background
Wolcott-Rallison syndrome (WRS) is caused by recessive EIF2AK3 mutations and characterized by early-onset diabetes and skeletal dysplasia. Hepatic dysfunction has been reported in 60% of patients.
Aims
To describe a cohort of WRS patients and discuss the pattern and management of their liver disease.
Methods
Detailed phenotyping and direct sequencing of EIF2AK3 gene were conducted in all patients.
Results
Twenty-eight genetically confirmed patients (67% male; mean age 4.6 years) were identified. 17 different EIF2AK3 mutations were detected, of which 2 were novel. The p.S991N mutation was associated with prolonged survival and p.I650T with delayed onset. All patients presented before 25 months with diabetes with variation in the frequency and severity of 10 other features. Liver disease, first manifested as non-autoimmune hepatitis, was the commonest extra-pancreatic feature identified in 85.7% (24/28). 22/24 had at least one episode of acute hepatic failure which was the cause of death in all deceased patients (13/28). One child was treated by liver transplantation and had no liver disease and better diabetes control for the following 6 years.
Conclusions
Liver disease in WRS is more frequent than previously described and carries high mortality. The first experience with liver transplantation in WRS is encouraging.
doi:10.1159/000369804
PMCID: PMC4464042  PMID: 25659842
EIF2AK3 mutations; Hepatitis; Childhood diabetes; Liver transplantation; Skeletal dysplasia
2.  Diabetes Mellitus in Neonates and Infants: Genetic Heterogeneity, Clinical Approach to Diagnosis, and Therapeutic Options 
Hormone Research in Pædiatrics  2013;80(3):137-146.
Over the last decade, we have witnessed major advances in the understanding of the molecular basis of neonatal and infancy-onset diabetes. It is now widely accepted that diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes. The vast majority of such patients will have a monogenic disorder responsible for the disease and, in some of them, also for a number of other associated extrapancreatic clinical features. Reaching a molecular diagnosis will have immediate clinical consequences for about half of affected patients, as identification of a mutation in either of the two genes encoding the ATP-sensitive potassium channel allows switching from insulin injections to oral sulphonylureas. It also facilitates genetic counselling within the affected families and predicts clinical prognosis. Importantly, monogenic diabetes seems not to be limited to the first 6 months but extends to some extent into the second half of the first year of life, when type 1 diabetes is the more common cause of diabetes. From a scientific perspective, the identification of novel genetic aetiologies has provided important new knowledge regarding the development and function of the human pancreas.
doi:10.1159/000354219
PMCID: PMC3884170  PMID: 24051999
Neonatal diabetes; Monogenic diabetes of infancy ; Permanent neonatal diabetes; Transient neonatal diabetes ; Type 1 diabetes

3.  A Recessive Mutation Resulting in a Disabling Amino Acid Substitution (T194R) in the LHX3 Homeodomain Causes Combined Pituitary Hormone Deficiency 
Background/Aims
Recessive mutations in the LHX3 ho-meodomain transcription factor gene are associated with developmental disorders affecting the pituitary and nervous system. We describe pediatric patients with combined pituitary hormone deficiency (CPHD) who harbor a novel mutation in LHX3.
Methods
Two female siblings from related parents were examined. Both patients had neonatal complications. The index patient had CPHD featuring deficiencies of GH, LH, FSH, PRL, and TSH, with later onset of ACTH deficiency. She also had a hypoplastic anterior pituitary, respiratory distress, hearing impairment, and limited neck rotation. The LHX3 gene was sequenced and the biochemical properties of the predicted altered proteins were characterized.
Results
A novel homozygous mutation predicted to change amino acid 194 from threonine to arginine (T194R) was detected in both patients. This amino acid is conserved in the DNA-binding homeodomain. Computer modeling predicted that the T194R change would alter the homeodomain structure. The T194R protein did not bind tested LHX3 DNA recognition sites and did not activate the α-glycoprotein and PRL target genes.
Conclusion
The T194R mutation affects a critical residue in the LHX3 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in the LHX3 gene.
doi:10.1159/000335929
PMCID: PMC3355643  PMID: 22286346
Growth; Transcription; LIM; Development; Pediatric patients
4.  Cross-Sectional Association between Blood Pressure, in vivo Insulin Sensitivity and Adiponectin in Overweight Adolescents 
Hormone Research in Pædiatrics  2011;76(6):379-385.
Aims:
To examine the cross-sectional relationship between blood pressure (BP) and (1) in vivo insulin sensitivity (IS) and (2) circulating adiponectin levels in overweight adolescents, and to determine if these relationships are driven by adiposity.
Methods
Sixty-five white pubertal overweight adolescents underwent a hyperinsulinemic-euglycemic clamp to measure IS. Body composition and abdominal adiposity were determined by dual energy X-ray absorptiometry and computed tomography scan. BP was measured by an automated sphygmomanometer every 10 min over 1 h, between 06:00 and 07:00 a.m.
Results
In vivo IS was not associated with BP after adjustment for adiposity measurements (body mass index, percentage body fat or abdominal adiposity). However, adiponectin was inversely related to systolic BP independent of adiposity.
Conclusion
Our findings demonstrate that in overweight adolescents the relationship between in vivo IS and systolic BP is mediated through adiposity. However, the association between adiponectin and BP is independent of adiposity suggestive of a potential modulatory role of adiponectin in BP regulation.
doi:10.1159/000331462
PMCID: PMC3696355  PMID: 21968570
Blood pressure; Insulin sensitivity; Adiponectin; Obesity; Adolescents; Adipose tissue
5.  Factors Associated with Insulin Resistance among Children and Adolescents Perinatally Infected with HIV-1 in the Pediatric HIV/AIDS Cohort Study 
Hormone Research in Pædiatrics  2011;76(6):386-391.
Background/Aims:
Because of prior inconsistent findings, we studied a large cohort of HIV-infected children to determine: (1) prevalence of insulin resistance (IR); (2) anthropometric and clinical correlates of IR, and (3) concomitant abnormalities of glucose tolerance.
Methods
The study population consisted of 451 children from the Pediatric HIV/AIDS Cohort Study. The outcome of interest was HOMA-IR. Covariates included demographic, metabolic, growth, body composition, HIV laboratory tests, and treatment characteristics. Children meeting triggers for IR underwent oral glucose tolerance tests and hemoglobin A1c (HbA1c) measurements.
Results
Among 402 children with glucose and insulin measurements, 15.2% had IR of whom 79% were pubertal. IR was associated with higher alanine aminotransferase, body mass index, and nadir CD4%, Tanner stage 5, and ever having received amprenavir. Of those with IR, three had impaired fasting glucose (IFG), three impaired glucose tolerance (IGT), one IFG and IGT, none diabetic glucose tolerance, and three HbA1c between 6.1 and 6.5%.
Conclusion
In our cohort of HIV-infected adolescents, we observed a 15.2% prevalence of IR more closely linked to obesity than any other variable. This finding mirrors the high prevalence of obesity-mediated IR in American youth. However, associations with CD4 count and use of protease inhibitors may indicate some effect of HIV and/or its treatment.
doi:10.1159/000332957
PMCID: PMC3697231  PMID: 22042056
Insulin resistance; HIV; Highly active antiretroviral therapy; Homeostatic model assessment of insulin resistance
6.  Endothelial Function as Measured by Peripheral Arterial Tonometry Increases during Pubertal Advancement 
Hormone Research in Pædiatrics  2011;76(4):226-233.
Background/Aims: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). Methods: 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 (E1), estradiol (E2), DHEAS and E1-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. Results: 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 E2, DHEAS and age. Conclusion: Enhancement of the PAT index was associated with an increment in Tanner stages. The changes in E2 and DHEAS levels may contribute to increasing endothelial response to shear stress or arterial blood flow.
doi:10.1159/000328455
PMCID: PMC3224510  PMID: 21778688
Peripheral arterial tonometry; Puberty; Endothelial function; Estradiol; DHEAS; Nitric oxide
7.  Relationship between Cardiovascular Risk Factors and Adipokines in Adolescents 
Hormone Research in Pædiatrics  2011;76(2):123-129.
This study evaluated the associations of adipokines with cardiovascular risk factors.
Subjects/Methods
60 normal weight (BMI ≤75th percentile) and 60 overweight (BMI ≥95th percentile) adolescents aged 10–14 years. Resting systolic and diastolic blood pressures (SBP, DBP) and waist circumference were obtained in duplicate. Circulating adiponectin, resistin, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), total cholesterol (TC), high-density lipoprotein (HDL), and triglycerides (TG) were measured from fasting plasma samples.
Results
Simple correlations showed that SBP was significantly related (p < 0.05) to adiponectin (r = –0.185), resistin (r = 0.207), and IL-6 (r = 0.238); HDL was significantly related to adiponectin (r = 0.398) and TNF-α (r = –0.227). TG was only related to adiponectin (r = –0.292, p < 0.05). Multiple regression models controlling for puberty and ethnicity indicated that adiponectin (R2 = 0.152, p < 0.05), resistin (R2 = 0.152, p < 0.05), and IL-6 (R2 = 0.170, p < 0.05) were associated with SBP. The association between adiponectin and HDL was stronger in normal weight versus overweight adolescents (R2 = 0.336, p < 0.05). None of the other models showed differences in the associations by weight status.
Conclusions
In adolescents, SBP but not DBP was associated with most adipokines. HDL, but not TC, was also associated with some adipokines. TG were only associated with adiponectin. Associations were mostly related to adiposity.
doi:10.1159/000327852
PMCID: PMC3182039  PMID: 21701142
Blood pressure; Cytokines; Lipids; Obesity; Adolescents
8.  Treatment Approaches for Diabetes and Dyslipidemia 
Hormone Research in Pædiatrics  2011;76(Suppl 1):76-80.
Background
Dyslipidemia is an important risk factor for cardiovascular complications in persons with diabetes. Low-density lipoprotein-cholesterol (LDL-C) is the ‘cornerstone’ for assessment of lipoprotein-associated risk. However, LDL-C levels do not reflect the classic ‘diabetic dyslipidemia’ of hypertriglyceridemia and low high-density lipoprotein-cholesterol (HDL-C). Measurements of plasma apolipoprotein B100 concentrations and non-HDL-C may improve the definition of dyslipidemia. Statins, nicotinic acid and fibrates have roles in treating dyslipidemia in diabetes. Residual risk (i.e. risk that persists after correction of ‘conventional’ plasma lipoprotein abnormalities) is a new concept in the role of dyslipidemia in the pathogenesis of diabetic vascular complications. For example, regardless of plasma levels, lipoprotein extravasation through a leaking retinal blood barrier and subsequent modification may be crucial in the development of diabetic retinopathy. The current approach to the management of dyslipidemia in diabetes is briefly summarized, followed by a discussion of new concepts of residual risk and emerging lipoprotein-related mechanisms for vascular disease in diabetes.
Conclusions
Effective treatments must correct adverse quantitative plasma lipoprotein levels and a spectrum of qualitative abnormalities in plasma and tissue, as well as the processes by which lipoproteins and cells interact at the sites of disease.
doi:10.1159/000329180
PMCID: PMC3202950  PMID: 21778754
Diabetes; Dyslipidemia; Nuclear magnetic resonance spectroscopy; Residual risk
9.  Coexistent Autoimmunity in Familial Type 1 Diabetes: Increased Susceptibility in Sib-Pairs? 
Hormone Research in Pædiatrics  2011;75(4):284-290.
Background
Type 1 diabetes (T1D) patients are at risk for additional autoimmune diseases (AID).
Objective
To compare the characteristics of associated autoimmunity among familial (parent-offspring and sib-pair) subgroups and sporadic T1D patients.
Patients and Methods
Data regarding AID in T1D patients and their nuclear family members were extracted from medical files of 121 multiplex T1D families (58 parent-offspring, 63 sib-pairs) and 226 sporadic controls followed between 1979 and 2008.
Results
The prevalence of associated autoimmunity was similar in familial and sporadic cases (33.6 vs. 32.7%). The frequency of additional AID and percentage of patients with two or more coexistent AID were significantly higher among sib-pairs than parent-offspring (p = 0.05 and p = 0.04, respectively). The median time elapsed between diagnosis of T1D and occurrence of additional autoimmunity tended to be shorter in the sib-pairs. Only in familial cases did a positive autoimmune family background predict the development of coexistent autoimmunity (OR = 2.11, CI [1.0, 4.49] p = 0.05).
Conclusions
Among sib-pairs with T1D, the higher prevalence of additional AID, the increased number of diseases per person, and the relatively earlier appearance of associated AID suggest an increased susceptibility for coexistent autoimmunity in this subgroup. Positive family history for autoimmunity in multiplex T1D families increased their risk for co-occurrence of AID.
doi:10.1159/000322936
PMCID: PMC3078238  PMID: 21242668
Type 1 diabetes; Familial type 1 diabetes; Coexistent autoimmunity
10.  Effects of Prenatal Ethanol Exposure on Postnatal Growth and the Insulin-Like Growth Factor Axis 
Hormone Research in Pædiatrics  2010;75(3):166-173.
Aims
To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation.
Methods
We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (≥48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age.
Results
IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects.
Conclusion
Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure.
doi:10.1159/000319706
PMCID: PMC3068754  PMID: 20847545
Fetal alcohol syndrome; Pregnancy; Alcohol abuse; Insulin-like growth factor I; Insulin-like growth factor II
11.  Comparison of Multiple Steroid Concentrations in Serum and Dried Blood Spots throughout the Day of Patients with Congenital Adrenal Hyperplasia 
Background/Aim
Periodic measurement of plasma concentrations of cortisol precursors on a clinic visit may be of limited value in patients with congenital adrenal hyperplasia because it does not reflect a patient's circadian patterns of adrenal steroid secretion. Steroid profiling in dried blood spots (DBS) may allow for more frequent and sensitive monitoring.
Methods
We compared the agreement between 17α-hydroxyprogesterone (17-OHP) and androstenedione (D4A) levels determined from DBS samples and concurrently collected serum samples. Blood was drawn from 9 congenital adrenal hyperplasia patients every 4 h over a 24-hour period. Serum and DBS steroid levels were measured by liquid chromatography tandem mass spectrometry.
Results
DBS determinations of 17-OHP overestimated corresponding serum levels (mean difference 1.67 ng/ml), and underestimated D4A serum levels (mean difference 0.84 ng/ml). However, the DBS assay yielded excellent agreement (97%) with serum 17-OHP, but did considerably poorer for D4A (31%).
Conclusions
Our results indicate an excellent agreement between DBS and serum 17-OHP measurements to identify the peaks and troughs associated with an individual's circadian pattern. Larger-scale studies are required to evaluate the utility of DBS for home monitoring and to determine if more frequent monitoring leads to improved clinical outcomes.
doi:10.1159/000315910
PMCID: PMC3202930  PMID: 20798478
Congenital adrenal hyperplasia; 17α-hydroxyprogesterone; Tandem mass spectrometry; Circadian rhythms of hormones; Glucocorticoid therapy
12.  Associations of Progesterone Receptor Polymorphisms with Age at Menarche and Menstrual Cycle Length 
Hormone Research in Pædiatrics  2010;74(6):421-427.
Background
Age at menarche and menstrual cycle characteristics are indicators of endocrine function and may be risk factors for diseases such as reproductive cancers. The progesterone receptor gene (PGR) has been identified as a candidate gene for age at menarche and menstrual function.
Methods
Women office workers ages 19–41 self-reported age at menarche and participated in a prospective study of menstrual function and fertility. First-morning urine was used as the DNA source. 444 women were genotyped for a functional variant in PGR, rs1042838 (Val660Leu), and 264 women were also genotyped for 29 other SNPs across the extended gene region.
Results
Genetic variation across PGR was associated with age at menarche using a global score statistic (p = 0.03 among non-Hispanic whites). Women carrying two copies of the Val660Leu variant experienced menarche 1 year later than women carrying one or no copies of the variant (13.6 ± 0.5 vs. 12.6 ± 0.1; p = 0.03). The Val660Leu variant was also associated with decreased odds of short menstrual cycles (17–24 days) (OR, 95% CI: 0.54 [0.36, 0.80]; p = 0.002).
Conclusion
Genetic variation in PGR was associated with age at menarche and menstrual cycle length in this population. Further investigation of these associations in a replication dataset is warranted.
doi:10.1159/000316961
PMCID: PMC3021500  PMID: 20814185
Age at menarche; Menstrual cycles; Polymorphism; Progesterone receptor; Reproductive cancers
13.  Growth Hormone Treatment Does Not Affect Incidences of Middle Ear Disease or Hearing Loss in Infants and Toddlers with Turner Syndrome 
Context
No randomized, controlled, prospective study has evaluated the effect of growth hormone (GH) on the rates of middle ear (ME) disease and hearing loss in girls with Turner syndrome (TS).
Design
A 2-year, prospective, randomized, controlled, open-label, multicenter, clinical trial (‘Toddler Turner Study’; August 1999 to August 2003) was carried out.
Setting
The study was conducted at 11 US pediatric endocrine centers.
Subjects
Eighty-eight girls with TS, aged 9 months to 4 years, were enrolled.
Intervention
The interventions comprised recombinant GH (50 μg/kg/day, n = 45) or no treatment (n = 43) for 2 years.
Main Outcome Measures
The outcome measures included occurrence rates of ear-related problems, otitis media (OM) and associated antibiotic treatments, tympanometric assessment of ME function and hearing assessment by audiology.
Results
At baseline, 57% of the girls (mean age = 1.98 ± 1.00 years) had a history of recurrent OM, 33% had undergone tympanostomy tube (t-tube) insertion and 27% had abnormal hearing. There was no significant difference between the treatment groups for annual incidence of OM episodes (untreated control: 1.9 ± 1.4; GH-treated: 1.5 ± 1.6, p = 0.17). A quarter of the subjects underwent ear surgeries (mainly t-tube insertions) during the study. Recurrent or persistent abnormality of ME function on tympanometry was present in 28–45% of the girls without t-tubes at the 6 postbaseline visits. Hearing deficits were found in 19–32% of the girls at the annual postbaseline visits. Most of these were conductive deficits, however, 2 girls had findings consistent with sensorineural hearing loss, which was evident before 3 years of age.
Conclusions
Ear and hearing problems are common in infants and toddlers with TS and are not significantly influenced by GH treatment. Girls with TS need early, regular and thorough ME monitoring by their primary care provider and/or otolaryngologist, and at least annual hearing evaluations by a pediatric audiologist.
doi:10.1159/000313964
PMCID: PMC2914351  PMID: 20424424
Turner syndrome; Somatropin; Conductive hearing loss; Sensorineural hearing loss; Tympanostomy tube; Otitis media, child; Preschool
14.  Preeclampsia and Adiponectin in Cord Blood 
Aims
To compare cord blood concentrations of total adiponectin in the offspring of pregnancies with and without preeclampsia.
Methods
Using a Luminex analyzer, cord blood adiponectin was measured in 182 singleton pregnancies with preeclampsia and compared to adiponectin measured in 511 singleton pregnancies without preeclampsia.
Results
Adiponectin levels in cord blood increased with increasing gestational age, but overall, crude levels were similar in pregnancies with and without preeclampsia. However, in pregnancies with early delivery (weeks 32–36), and in pregnancies with delivery after spontaneous contractions, adiponectin levels were higher in the preeclampsia group.
Conclusion
In preterm pregnancies and in pregnancies with spontaneous contractions, adiponectin levels in cord blood were higher in the preeclampsia group than in pregnancies without preeclampsia, maybe reflecting the need to optimize energy in preeclampsia.
doi:10.1159/000313376
PMCID: PMC2919428  PMID: 20395665
Preeclampsia; Cord blood; Adiponectin; Infant development
15.  New Insights into Endocrine Pancreatic Development: The Role of Environmental Factors 
The pancreas is a mixed gland that contains endocrine and exocrine components. Within the pancreatic islets, β cells produce insulin and control the glycemia. Their deficiency leads to diabetes and several potential complications. In the last decade, numerous studies have focused on pancreas development. The objective was to characterize the cellular and molecular factors that control the differentiation of endocrine and exocrine cell types. Investigation of the role of transcription factors by using genetic approaches led to the discovery of key molecules that are expressed both in rodents and humans. Some of them are ubiquitous, and some others are specifically involved in endocrine or exocrine specification. In addition to these intrinsic factors, recent studies have focused on the role of environmental factors. In the present review, we describe the roles of nutrients and oxygen in the embryonic pancreas. Interestingly, these extrinsic parameters can interfere with β-cell differentiation and function. Altogether, these data should help to generate β cells in vitro and define strategies for a cell-based therapy of type 1 diabetes.
doi:10.1159/000314894
PMCID: PMC3202916  PMID: 20551619
Pancreas; β-Cell; Development; Hypoxia; Hypoxia-inducible factor; Nutrients; Transcription factors
16.  Central Precocious Puberty due to Hypothalamic Hamartomas Correlates with Anatomic Features but Not with Expression of GnRH, TGFα, or KISS1 
Hormone Research in Pædiatrics  2010;73(5):312-319.
Background/Aims
Hypothalamic hamartomas are the most common identifiable cause of central precocious puberty (CPP). Hamartoma characteristics proposed to be associated with CPP include specific anatomic features and expression of molecules such as gonadotropin-releasing hormone (GnRH), transforming growth factor α (TGFα), and GRM1A, which encodes the type 1 metabotropic glutamate receptor α isoform. We sought to determine whether hamartomas that cause CPP could be distinguished by anatomic features, expression of these molecules, or expression of KISS1, whose products signal through the receptor GPR54 to stimulate GnRH release.
Methods
Clinical records and radiologic images were reviewed for 18 patients who underwent hamartoma resection for intractable seizures; 7 had precocious puberty. Resected tissue was examined for expression of GnRH, GnRH receptor (GnRHR), TGFα, KISS1, GPR54, and GRM1A.
Results
Hypothalamic hamartomas associated with CPP were more likely to contact the infundibulum or tuber cinereum and were larger than hamartomas not associated with CPP. GnRH, TGFα, and GnRHR were expressed by all hamartomas studied. Expression of KISS1, GPR54, and GRM1A did not differ significantly between hamartomas associated and not associated with CPP.
Conclusion
Anatomic features rather than expression patterns of candidate molecules distinguish hypothalamic hamartomas that are associated with CPP from those that are not.
doi:10.1159/000308162
PMCID: PMC2868525  PMID: 20389100
Kisspeptin; KISS1R; GPR54; Reproduction; LHRH; Hypothalamic hamartoma
17.  Acid-Labile Subunit Deficiency and Growth Failure: Description of Two Novel Cases 
Hormone Research in Pædiatrics  2010;73(5):328-334.
Background/Aims
Mutations in the acid-labile subunit (ALS) gene (IGFALS) have been associated with circulating insulin-like growth factor I (IGF-I) deficiency and short stature. Whether severe pubertal delay is also part of the phenotype remains controversial due to the small number of cases reported. We report 2 children with a history of growth failure due to novel IGFALS mutations.
Methods
The growth hormone receptor gene (GHR) and IGFALS were analyzed by direct sequencing. Ternary complex formation was studied by size exclusion chromatography.
Results
Two boys of 13.3 and 10.6 years, with pubertal stages 2 and 1, had mild short stature (−3.2 and −2.8 SDS, respectively) and a biochemical profile suggestive of growth hormone resistance. No defects were identified in the GHR. Patient 1 was homozygous for the IGFALS missense mutation P73L. Patient 2 was a compound heterozygote for the missense mutation L134Q and a novel GGC to AG substitution at position 546–548 (546–548delGGCinsAG). The latter causes a frameshift and the appearance of a premature stop codon. Size exclusion chromatography showed no peaks corresponding to ternary and binary complexes in either patient.
Conclusion
Screening of the IGFALS is important in children with short stature associated with low serum IGF-I, IGFBP-3 and ALS.
doi:10.1159/000308164
PMCID: PMC2868526  PMID: 20389102
Acid-labile subunit; Short stature; Insulin-like growth factor I deficiency; Mutations, acid-labile subunit; Linear growth

Results 1-17 (17)