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Silver Russell syndrome (SRS) is a congenital disorder characterised by intrauterine growth retardation (IUGR), feeding difficulties and postnatal growth retardation. In a small number of cases PLAG1 variants have been described (OMIM #618907). PLAG1 haploinsufficiency decreases IGF2 expression and produces a Silver Russell syndrome like phenotype. Here, we describe the phenotype and molecular features of a 26 months girl with clinical features of SRS and a de novo 2.1 Mb deletion encompassing PLAG1 is reported in association with clinical features suggestive of SRS. This manuscript has been published in "Clinical Dysmorphology". https://journals.lww.com/clindysmorphol/Abstract/2021/10000/Silver_Russell_syndrome_in_a_preterm_girl_with.7.aspxMust be cited as follows: Fernandez-Fructuoso JR, De la Torre-Sandoval C, Harbison MD, Chantot-Bastaraud S, Temple K, Lloreda-Garcia JM, Olmo-Sanchez M, Netchine I. Silver Russell syndrome in a preterm girl with 8q12.1 deletion encompassing PLAG1. Clin Dysmorphol. 2021 Oct 1;30(4):194-196. doi: 10.1097/MCD.0000000000000375. PMID: 34480472.

Introduction Russell-Silver syndrome (RSS) is a unique cause of syndromic, and often severe, limb length discrepancy (LLD). RSS causes growth retardation both in utero and postnatally, with asymmetry in limb length more noticeable as growth progresses throughout childhood and adolescent. We aim to present the largest cohort in the literature on limb lengthening in patients with RSS and to validate previous literature supporting faster bony consolidation in these patients with more robust data. We further aim to establish differences in healing within this cohort based on age, sex, segment lengthened, or type of lengthening procedure performed, to help refine patient expectations and guide practitioners in treating this population. Methods This was a retrospective study of patients with a diagnosis of RSS who underwent a limb lengthening procedure for the purpose of limb equalization. They were compared with a historic control group of patients who underwent limb lengthening for LLD of a non-RSS etiology. The primary outcome measure was bone healing index (BHI). Results The RSS group consisted of 24 patients with 29 segments lengthened, and was compared with a historic control group consisting of 20 patients with 22 segments lengthened (Goldman). Patients with RSS had a significantly lower BHI, and therefore faster healing of their lengthening site, than their non-RSS peers (P=0.02). Within the RSS cohort, we did not detect a difference in BHI based on intervention type or sex, but we did find a trend toward faster healing in femurs over tibiae (P=0.08), and established that younger patients tended toward lower BHIs (P Conclusions Our results confirmed with more robust data the prior finding that patients with RSS may undergo limb lengthening procedures at least as safely as their non-RSS counterparts, and with even faster bony consolidation, especially in younger patients. We hypothesize that concurrent treatment with growth hormone supplementation may contribute to this finding, although further study is necessary. This is the largest cohort of RSS patients treated with limb lengthening for LLD reported in the literature, and these findings will help to guide surgeon decision-making when treating this unique population. Level of evidence Level III-retrospective comparative study.

Here we describe phenotype and molecular features of a preterm girl diagnosed of Silver-Russell syndrome (SRS), resulting of a de novo heterozygous 8q12.1 deletion encompassing PLAG1 gene. The proband was a 32 weeks preterm girl born asymmetric small for gestational age, after a pregnancy complicated by severe intrauterine growth restriction (IUGR). SRS was clinically diagnosed, but molecular genetic testing for methylation analysis of 11p15.5 and maternal UPD7 yielded normal results. A 60k microarray CGH was also performed simultaneously, showing a 2.1 Mb de novo deletion of 8q12.1 involving PLAG1 gene. To our knowledge, this is the first time a deletion involving PLAG1 is reported as causative of SRS. This finding could further support the previously reported dominant expression of PLAG1 mutations associated to SRS and could contribute to more accurate diagnosis of affected patients.

International audience; Purpose: Fetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver–Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.Methods: Whole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.Results: We report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.Conclusion: Genetic defects of the HMGA2–PLAG1–IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.

The 11p15 region harbors the IGF2/H19 imprinted domain, implicated in fetal and postnatal growth. Silver-Russell syndrome (SRS) is characterized by fetal and postnatal growth failure, and is caused principally by hypomethylation of the 11p15 imprinting control region 1 (ICR1). However, the mechanisms leading to ICR1 hypomethylation remain unknown. Maternally inherited genetic defects affecting the ICR1 domain have been associated with ICR1 hypermethylation and Beckwith-Wiedemann syndrome (an overgrowth syndrome, the clinical and molecular mirror of SRS), and paternal deletions of IGF2 enhancers have been detected in four SRS patients. However, no paternal deletions of ICR1 have ever been associated with hypomethylation of the IGF2/H19 domain in SRS. We screened for new genetic defects within the ICR1 in a cohort of 234 SRS patients with hypomethylated IGF2/H19 domain. We report deletions close to the boundaries of ICR1 on the paternal allele in one familial and two sporadic cases of SRS with ICR1 hypomethylation. These deletions are associated with hypomethylation of the remaining CBS, and decreased IGF2 expression. These results suggest that these regions are most likely required to maintain methylation after fertilization. We estimate these anomalies to occur in about 1% of SRS cases with ICR1 hypomethylation.

International audience; Context - Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective - To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients - We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results - Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions - Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.

BackgroundThe 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex.ObjectivesTo report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations.MethodsFrom a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain.ResultsLarge duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C.ConclusionsThe phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is caused by the autosomal recessive inheritance of mutations in the gene CYP21A2. CYP21A2 mutations lead to variable impairment of the 21-hydroxylase enzyme, which, in turn, is associated with three clinical phenotypes, namely, salt wasting, simple virilizing, and nonclassical CAH. However, it is known that a given mutation can associate with different clinical phenotypes, resulting in a high rate of genotype-phenotype nonconcordance. We aimed to study the genotype-phenotype nonconcordance in a family with three siblings affected with nonclassical CAH. All had hormonal evidence of nonclassical CAH, but this phenotype could not be explained by the genotype obtained from commercial CYP21A2 genetic testing, which revealed heterozygosity for the maternal 30 kb deletion mutation. We performed Sanger sequencing of the entire CYP21A2 gene in this family to search for a rare mutation that was not covered by commercial testing and found in the three siblings a second, rare c.1097G>A (p.R366H) mutation in exon 8. Computational modeling confirmed that this was a mild mutation consistent with nonclassical CAH. We recommend that sequencing of entire genes for rare mutations should be carried out when genotype-phenotype nonconcordance is observed in patients with autosomal recessive monogenic disorders, including CAH.

Patient-support organizations can facilitate a significant change in the way rare disorders are approached. Besides connecting families with each other and directing patients to experienced medical specialists, these groups, by collaborating with government initiatives like COST, can effect the direction and funding of rare disease research. By concentrating the rare disease patient population and funneling them to specific centers of excellence, these organizations help build specialists' experience and their study populations. It requires a basic spirit of collaboration, driven parent leaders, a well-organized support platform, sources of funding, supportive clinical and research professionals and finally an effective method of collecting and disseminating information. Silver-Russell Syndrome is an excellent example of a rare disorder that has become better recognized, understood and treated because patient-support organizations, using the internet as a critical tool, have worked together with clinical care/research specialists and public funding agencies to build collaboration.

Nutritional management of children with Silver-Russell syndrome (SRS) is crucial, especially before initiating growth hormone therapy. Since cyproheptadine (CYP) has been reported to be orexigenic, we retrospectively investigated the effects of CYP on changes in weight and height in patients with SRS.Anthropometric parameters (weight [W], length or height [H], weight on expected weight for height [W/H], and body mass index) were recorded for 34 children with SRS receiving CYP. We specifically analyzed the anthropometric parameters (expressed in median) in a group of 23 patients treated with CYP at baseline (M0-CYP) and every 3 months (M3 to M12-CYP) after the initiation of CYP treatment.The 23 children with SRS treated by CYP only had weight stagnation during the months preceding the start of treatment. Anthropometric parameters, especially the weight, differed significantly between M0-CYP and all other times (M3, M6, M9, M12-CYP). After 1 year of treatment, a gain in overall length/height and weight was observed (W: +1.1 standard deviations from the mean [SDS]; H: +0.5 SDS). At M3, significant improvements in W/H (74.9% vs 79.3% [P = 0.01]) and body mass index (-3.4 vs -2.4 SDS [P = 0.001]) were also observed. Twenty-one patients (91%) improved their weight by at least +0.5 SDS, and 12 (52%) by at least +1 SDS.Our results show that CYP can be effective in patients with SRS with significant improvements in growth velocity and nutritional status before initiation of growth hormone therapy. Further prospective studies are required to confirm these results.

International audience; This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.

Russell-Silver Syndrome (RSS) is a prenatal and postnatal growth retardation syndrome caused mainly by 11p15 ICR1 hypomethylation. Clinical presentation is heterogeneous in RSS patients with 11p15 ICR1 hypomethylation. We previously identified a subset of RSS patients with 11p15 ICR1 and multilocus hypomethylation. Here, we examine the relationships between IGF2 expression, 11p15 ICR1 methylation, and multilocus imprinting defects in various cell types from 39 RSS patients with 11p15 ICR1 hypomethylation in leukocyte DNA. 11p15 ICR1 hypomethylation was more pronounced in leukocytes than in buccal mucosa cells. Skin fibroblast IGF2 expression was correlated with the degree of ICR1 hypomethylation. Different tissue-specific multilocus methylation defects coexisted in 38% of cases, with some loci hypomethylated and others hypermethylated within the same cell type in some cases. Our new results suggest that tissue-specific epigenotypes may lead to clinical heterogeneity in RSS.

To the Editor: Iatrogenic Creutzfeldt-Jakob disease (iCJD) is an acquired form of prion disease that has been declining in incidence since the mid-1990s (1). Worldwide, at least 226 cases of iCJD, including 29 US cases, have been associated with administration of contaminated human growth hormone (hGH) from cadavers. Reported incubation periods ranged from 5 to 42 years (mean 17 years) (2). Commercially produced cadaveric hGH has been associated with only 1 previously reported case of iCJD: CJD developed in a 39-year-old Austrian man ≈22 years after he received commercial cadaveric hGH (Crescormon, Kabivitrum, Stockholm, Sweden) during 1984–1985 (3). We report a second case of probable iCJD acquired through treatment with commercial cadaveric hGH. The patient was born at 32 weeks’ gestation with subsequent developmental delay, agenesis of the corpus callosum, and panhypopituitarism. He demonstrated clinical and laboratory signs of growth hormone deficiency but was denied treatment with hGH through the US government–supported National Hormone and Pituitary Program (NHPP) because he did not meet the height requirement. Treatment with commercial cadaveric hGH began when he was 5.8 years of age and continued for 23 months (1983–1985). He received 1.5 units intramuscularly 3× per week and was primarily treated with Asellacrin (Ares-Serono, Geneva, Switzerland). In early 1984, for an unspecified duration, he received Crescormon (Kabivitrum) because of an Asellacrin shortage. Treatment was halted in 1985 because of iCJD concerns and resumed 2 years later with recombinant hGH. At age 33, 26.5 years (range 25.5–28 years) after the midpoint of commercial cadaveric hGH treatment, dizziness and gait imbalance developed, causing a fall. The patient’s mental status also began declining, and he never returned to his baseline status. Six months after illness onset, he experienced hallucinations, weakness of lower extremities, and limb ataxia. Seven months after the fall, he entered a state of akinetic mutism; he died 9 months after symptom onset. A lumbar puncture, performed 8 months after illness onset, demonstrated 14-3-3 proteins and an elevated cerebrospinal fluid (CSF) τ level of 14,111 pg/mL (decision point 1,150 pg/mL) (4), although the specimen was contaminated with blood (39,375 erythrocytes/μL). Electroencephalogram demonstrated severe diffuse encephalopathy. Two brain magnetic resonance imaging studies performed 8 months after illness onset indicated probable CJD, given lack of prior metabolic and anoxic insults (Figure). The patient was discharged from a referral hospital with this diagnosis; no postmortem analysis was conducted. Figure Maps showing axial fluid attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) at the level of the basal nuclei (top row) and dorsal frontoparietal cortex (bottom row) of the brain of a 33.8-year-old ... On the basis of World Health Organization criteria, we conclude that this patient had probable iCJD as a result of hGH treatment (5). The patient’s condition was treated with 2 different formulations of commercial cadaveric hGH, including one of the same brands in the same year as that of the first reported patient with iCJD associated with commercial cadaveric hGH (3). The patient’s incubation period (25.5–28 years) is well within expectations (1). Despite an ongoing active surveillance program that identified ≈3,500 of ≈4,500 post-1977 cadaveric hGH recipients in the US NHPP, all 29 CJD infections in NHPP recipients occurred among the estimated ≈2,700 pre-1977 recipients (1,2). This significant reduction in iCJD was attributed to the 1977 introduction of a highly selective, column chromatography step in the hormone purification protocol that can markedly reduce prion infectivity (1,2). As shown by the many iCJD cases linked to hGH in France, the efficacy of column chromatography purification steps may vary (1). Commercially derived cadaveric hGH was produced in different laboratories from those that produced NHPP-distributed hGH, and sufficient details regarding sourcing and production methods of the commercial products are lacking. Approximately 10,000 persons, mostly outside the United States, received commercial cadaveric hGH produced by Kabivitrum, and substantially fewer persons received product from Ares-Serono (A.F. Parlow, pers. comm.). Identification through passive surveillance of 2 CJD cases among recipients of such hGH further supports a causal, rather than chance, association between commercial hormone and CJD. It also suggests a difference in iCJD risk between post-1977 NHPP-distributed hGH and commercial cadaveric hGH. Limitations of this report include the lack of neuropathologic confirmation and insufficient information to strongly implicate a single commercial cadaveric hGH product as infection source. The report of another iCJD case-patient who received Crescormon during the same period provides some evidence that the product was the source of prion contamination. Although the patient may have had sporadic CJD, his young age at disease onset (33 years) makes this unlikely (6). This report suggests that a potential risk for iCJD in persons who received commercial cadaveric hGH should be considered. Also, clinicians should not assume that all cadaveric hGH administered after 1977 carries the same risk for infectivity. In addition, when CJD is being considered as a clinical diagnosis, a history of exposure to cadaveric hGH should always be sought, even when patients have normal or tall stature. Finally, we recommend that when a clinical diagnosis of CJD is suspected, but before the patient’s death, the local caregivers, with the family, should initiate arrangements for a postmortem examination to confirm diagnosis (e.g., www.cjdsurveillance.com).

International audience; Background Multiple clinical scoring systems have been proposed for Silver-Russell syndrome (SRS). Here we aimed to test a clinical scoring system for SRS and to analyse the correlation between (epi)genotype and phenotype. Subjects and methods Sixty-nine patients were examined by two physicians. Clinical scores were generated for all patients, with a new, six-item scoring system: (1) small for gestational age, birth length and/or weight ≤−2SDS, (2) postnatal growth retardation (height ≤−2SDS), (3) relative macrocephaly at birth, (4) body asymmetry, (5) feeding difficulties and/or body mass index (BMI) ≤−2SDS in toddlers; (6) protruding forehead at the age of 1–3 years. Subjects were considered to have likely SRS if they met at least four of these six criteria. Molecular investigations were performed blind to the clinical data. Results The 69 patients were classified into two groups (Likely-SRS (n=60), Unlikely-SRS (n=9)). Forty-six Likely-SRS patients (76.7%) displayed either 11p15 ICR1 hypomethylation (n=35; 58.3%) or maternal UPD of chromosome 7 (mUPD7) (n=11; 18.3%). Eight Unlikely-SRS patients had neither ICR1 hypomethylation nor mUPD7, whereas one patient had mUPD7. The clinical score and molecular results yielded four groups that differed significantly overall and for individual scoring system factors. Further molecular screening led identifying chromosomal abnormalities in Likely-SRS-double-negative and Unlikely-SRS groups. Four Likely-SRS-double negative patients carried a DLK1/GTL2 IG-DMR hypomethylation, a mUPD16; a mUPD20 and a de novo 1q21 microdeletion. Conclusions This new scoring system is very sensitive (98%) for the detection of patients with SRS with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum.

Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency typically reach a final adult height well below their mid-parental target height.The objective of this study was to examine whether GH alone or in combination with an LHRH analog (LHRHa) improved the final adult height in patients with CAH.The study was a nonrandomized prospective study.The study was conducted at two university hospitals in New York City, NY.Thirty-four patients with CAH treated with GH participated in this study. Nineteen males and 15 females who were predicted to be more than 2 SD below their mid-parental target height or more than 2 SD below the population mean received GH until reaching final adult height. In addition to GH, 27 patients (16 males, 11 females) were also treated with an LHRHa.The mean duration of GH treatment was 5.6 ± 1.8 yr in males and 4.5 ± 1.6 yr in females. The mean duration of LHRHa therapy was 3.7 ± 1.7 yr for both sexes.The primary endpoint variables were final adult height, final height discrepancy, and gain in height.Males reached a significantly higher final adult height (172.0 ± 4.8 cm) than their initial predicted height (162.8 ± 7.7 cm) (P0.00001). Females also reached a significantly higher final adult height (162.2 ± 5.3 cm) than initially predicted (151.7 ± 5.2 cm) (P0.0000001). Mean gain in height was 9.2 ± 6.7 cm in males and 10.5 ± 3.7 cm in females.Our results indicate that GH alone or in combination with LHRHa improves final adult height in patients with CAH.

Short stature in the adult patient with congenital adrenal hyperplasia (CAH) is commonly seen, even among patients in excellent adrenal control during childhood and puberty. In this study we examine the effect of GH therapy on height prediction in children with both CAH and compromised height prediction. Leuprolide acetate, a GnRH analog (GnRHa), was given to patients with evidence of early puberty. GH (n = 12) or the combination of GH and GnRHa (n = 8) was administered to 20 patients with CAH while they continued therapy with glucocorticoids. Each patient in the treatment group was matched according to age, sex, bone age, puberty, and type of CAH with another CAH patient treated only with glucocorticoid replacement. The match was made at the start of GH treatment. Of the 20 patients, 12 have completed 2 yr of therapy. After 1 yr of GH or combination GH and GnRHa therapy, the mean growth rate increased from 5 ± 1.9 to 7.8 ± 1.6 cm/yr vs. 5.4 ± 1.7 to 5 ± 2 cm/yr in the group not receiving GH (P < 0.0001)....

Apparent mineralocorticoid excess (AME) is a genetic disorder causing pre- and postnatal growth failure, juvenile hypertension, hypokalemic metabolic alkalosis, and hyporeninemic hypoaldosteronism due to a deficiency of 11β-hydroxysteroid dehydrogenase type 2 enzyme activity (11βHSD2). The 11βHSD2 enzyme is responsible for the conversion of cortisol to the inactive metabolite cortisone and therefore protects the mineralocorticoid receptors from cortisol intoxication. Several homozygous mutations are associated with this potentially fatal disease. We have examined the phenotype, biochemical features, and genotype of 14 patients with AME. All of the patients had characteristic signs of a severe 11βHSD2 defect. Birth weights were significantly lower than those of their unaffected sibs. The patients were short, underweight, and hypertensive for age. Variable damage of one or more organs (kidneys, retina, heart, and central nervous system) was found in all of the patients except one. The follow-up studies of e...

Four deleterious mutations are described in the gene for HSD11B2, which encodes the type 2 isoenzyme of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD2). In seven families with one or more members affected by apparent mineralocorticoid excess, this disorder is shown to be the result of a deficiency in 11 beta HSD2. Surprisingly, the patients are all homozygous for their mutation. This results from consanguinity in two families and possibly from endogamy or a founder effect in four of the other five families. The absence of compound heterozygotes remains to be investigated.

Final adult height is often compromised in children with congenital adrenal hyperplasia (CAH). This report examines the impact of growth hormone (GH) with or without LHRH analogue (LHRHa) on final adult height in patients with CAH due to 21-hydroxylase deficiency. Boys and girls with CAH who had a predicted final height of more than 2 SD below their mid-parental target height or more than 2 SD below the population mean were eligible for treatment with GH. Other inclusion criteria included open epiphyses (bone age

BackgroundAortic dilation and dissection is reported in patients with Turner’s syndrome, both with and without cardiovascular risk factors. The bicuspid aortic valve is closely associated with dilated aortic root, although expression of aortic dilation is variable. The determinants for variable expression of aortic dilation in individuals with Turner’s syndrome, however, are unknown.HypothesisA primary mesenchymal defect is prevalent in individuals with Turner’s syndrome, suggested by having abnormalities in bone matrix, and lymphatic and peripheral blood vessels. We hypothesize that an abnormal intrinsic elastic property of aorta is a forerunner of aortic dilation in Turner’s syndrome.ObjectiveAssess utility of aortic distensibility as a measure of aortic elasticity for the stratification of the risk for aortic dilation, and its relationship with age, karyotype, and hormonal therapy.DesignProspective cross-sectional study.Patients and methodWe performed cross-sectional M-mode and Doppler echocardiography in 24 individuals with Turner’s syndrome. Dimensions of the aortic root, and its distensibility, were calculated using standard techniques. We also examined a control group of 24 age matched normotensive patients with structurally normal hearts, who had been referred for evaluation of cardiac murmurs or chest pain.ResultsAortic dilation was the most common cardiac anomaly, seen in 11 of 24 (46%) individuals with Turner’s syndrome, and none in control group. Of these individuals, 5 without cardiovascular risk factors had aortic dilation. In 2 young girls, aortic dimensions were normal, albeit with reduced distensibility. Aortic dilation correlated inversely with aortic distensibility, but not with age, karyotype or hormonal therapy.ConclusionIndividuals with Turner’s syndrome, even without cardiovascular risk factors, do develop aortic dilation accompanied by decreased aortic distensibility, suggestive of an intrinsic abnormality in elastic property of the ascending aorta.

Background Previous studies of varied populations of non-uniformly defined children born small for gestational age (SGA) receiving different growth hormone (GH) regimens have found that GH treatment increased growth velocity and adult height and was safe. The GH dose was the major predictor of first year growth response. Aim To identify pre- and within-treatment predictors of growth in well defined children born SGA treated with a fixed dose of GH. Methods 139 short, prepubertal children born SGA (i.e. birth weight and/or length > or =2 standard deviations below the mean) received Genotropin (rhGH) at 0.24 mg/kg/wk for 1 month then an additional 11 months at a dose of 0.48 mg/kg/wk, the FDA-approved dose of GH for children born SGA. Results Height improved significantly by month 3, with progressive improvement over the entire 12 months (median height SDS change of 0.78). Pretreatment predictors of growth included baseline bone age, IGFBP-3, total cholesterol, WBC and height SDS minus mid-parental height SDS. Within-treatment predictors of the change (Delta) height SDS at month 12 were the A height SDS at months 3 and 6 and growth velocity SDS at months 3 and 6. Conclusion GH at 0.48 mg/kg/wk was well tolerated and improved growth in children born SGA; the Delta IGF-I was not predictive of the 12 month height SDS gain, while the Delta height SDS at 3 and 6 months were predictive. Underweight children grew as well as normal weight children, and both groups showed improved body composition following GH treatment.

Final adult height is often compromised in children with congenital adrenal hyperplasia (CAH). This study examines the impact of GH and LHRH analog (LHRHa) on final adult height in patients with CAH due to 21-hydroxylase deficiency. Fourteen patients with CAH (eight males, six females) predicted to be more than 1.0 sd below their midparental target height received GH and LHRHa until final height. Each patient was matched at the start of GH therapy to a CAH patient treated only with glucocorticoids according to type of CAH, sex, and chronological age. Mean age, bone age, height, height prediction, and target height were the same in both groups at the beginning of GH therapy. Mean duration of GH treatment was 4.4 +/- 1.5 yr. Mean duration of LHRHa therapy was 4.2 +/- 2.0 yr. In the treatment group, final height sd score of -0.4 + 0.8 was significantly greater than both the initial prediction of -1.5 +/- 0.9 (P < 0.0001) and the final height sd score of the untreated group of -1.4 +/- 1.1 (P = 0.01). Our results indicate that the combination of GH and LHRHa improves final adult height in patients with CAH.

Congenital fusion of the fourth and fifth metacarpals is described in a male infant and his maternal grandfather. Primary gonadal failure, which is present in the infant, has not been noted in previously, reported cases. The pedigree in this family is compatible with X-linked recessive or autosomal dominant inheritance with incomplete penetrance.

The growth hormone releasing hormone receptor (GHRHR) plays a critical role in growth. We identified three nominally unrelated kindreds harboring the identical mutation (E72X) in GHRHR, the gene that encodes GHRHR; all three families originated in the Indian subcontinent. Because of the relative geographic proximity of these populations, we employed haplotype analysis in the region of GHRHR to determine the likelihood that this mutation occurred in a common ancestor rather than having occurred on separate occasions in different individuals. Members of all three kindreds segregating the E72X mutation were genotyped for highly polymorphic dinucleotide repeat microsatellites in a 15.5 centimorgan (cM) region around GHRHR on chromosome 7p15. We conclude that the affected individuals share a common ancestor, and we use the association with linked markers to estimate the age of this unique mutation.

Pituitary growth hormone release is under dual hypothalamic control, stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. Childhood growth hormone deficiency (GHD), leading to dwarfism and metabolic dysfunction1, can result from a failure of hypothalamic GHRH production or release, from maldevel-opment of the pituitary somatotrophes, and from genetic disorders of growth hormone synthesis. Some familial cases of isolated GHD have been attributed to mutations in the growth hormone gene itself2 but in other families GHD is not linked to this locus2. The mouse dwarfism trait, little, is due to a recessively inherited missense mutation (lit) in the extracellular domain of the GHRH receptor (Ghrhr)3–6: Pituitary glands of the little mouse are deficient in growth hormone and are unresponsive to GHRH in vivo and in vitro7. Somatic growth is increased by systemic administration of human growth hormone8. Human GHPHR shows strong sequence homology to the murine gene. The cDNA contains an open reading frame of 1,269 base pairs (bp) coding for a 423-amino acid protein10. Having mapped the human homologue (GHRHR) to chromosome 7p15 (ref. 9), we undertook to look for mutations in GHRHR in familial GHD. We now report a nonsense mutation in the human GHRHR gene that results in profound GH deficiency in at least two members of a consanguineous family. Mutations of GHRHR may account for other instances of GH deficiency in which the growth hormone gene is normal

A mutation in the HSD11B2 gene has been discovered in a consanguineous Iranian family with three sibs suffering from Apparent Mineralocorticoid Excess (AME). Sequence data demonstrate a C to T transition resulting in an R337C mutation.

The persistent Mullerian duct syndrome (PMDS) is a rare form of male pseudohermaphroditism, characterized by the persistence of Mullerian derivatives in otherwise normal males. Two mutations, present in the homozygous state, have been previously described in such patients. The present observation is the first example of compound heterozygosity in this condition. DNA was obtained from a 3-month-old patient with PMDS, in whom no serum anti-Mullerian hormone (AMH) could be detected by enzyme-linked immunosorbent assay. Sequencing of cloned polymerase chain reaction amplified fragments of the AMH gene revealed a 14-bp deletion in the second exon of the maternal allele; this deletion disrupted the open reading frame. It occurred at a site containing two 8-bp direct repeats flanking a 6-bp sequence and removed one whole repeat plus all of the intervening sequence. It may be the result of a slipped mispairing at the DNA replication fork. The paternal allele contains a stop mutation in the third exon. These two mutations, impairing both AMH alleles, are consistent with the occurrence of PMDS, and are shared with a phenotypically normal younger sister. In this family, various other mutations, devoid of physiological significance, suggest that the AMH gene is highly polymorphic.

To minimize subjective bias and to shorten control and trial-treatment periods, especially when using hazardous or scarce medications, we applied statistical methods to evaluate the influence of treatment upon the growth rates of children with growth disturbances. Utilization was encouraged by programming techniques for a desk-top calculator and demonstrating uses with six questions. The program assumes linearity of data and requires groups of paired variables, i.e. age and height. Section 1 describes growth statistically: 1. By my measurements, what is the child's growth rate? (linear regression and correlation) 2. What is my average error when measuring this child? (standard error of measurement) 3. How can I know when I have sufficient measurements to permit a therapeutic change? (F-test for regression) 4. What do I use to compare this child's growth to “normal” growth? (t test for confidence limits of slope). Section 2 compares growth periods statistically: 1. Are growth periods 1 and 2 different? (linear covariance for comparison of slopes).2. If different, how do they differ? (linear covariance discriminates change in rate from parallelism due to difference in measurement techniques or non-consecutive periods). The program can also be used to facilitate evaluation, retrospective or prospective, of a wide variety of influences on linear functions ranging from pharmacokinetics to applications in behavioral science, e.g. comparison of teaching techniques on rates of learning.