Russian national consensus. Diagnostics and treatment of hypopituitarism in children and adolescences

2019 ◽  
Vol 64 (6) ◽  
pp. 402-411
Author(s):  
Elena V. Nagaeva ◽  
Tatiana Y. Shiryaeva ◽  
Valentina A. Peterkova ◽  
Olga B. Bezlepkina ◽  
Anatoly N. Tiulpakov ◽  
...  
Keyword(s):  
Short Stature ◽  
Growth Velocity ◽  
Gh Deficiency ◽  
Final Height ◽  
Pituitary Hormone ◽  
Complete Disappearance ◽  
Gh Treatment ◽  
Central Hypothyroidism ◽  
Igf I ◽  
National Consensus

The materials of the National Consensus reflect the modern domestic and international experience on this issue. Before conducting a specialized endocrinological examination of a short child, all other causes of short stature should be excluded: severe somatic diseases in a state of decompensation that can affect growth velocity, congenital systemic skeletal diseases, syndromic short stature (all girls with growth retardation require a mandatory study of karyotype, depending on the presence or absence of phenotypic signs of Turner syndrome), endocrine diseases in decompensation. A specialized examination of the state of GH-IGF-I axis is carried out when the proportionally folded child has pronounced short stature: if the child’s height is < –2.0 SDS, if the difference between the child’s height SDS and child’s midparental height SDS exceeds 1.5 SDS and/or a low growth velocity. The consensus reflects clear criteria for the diagnosis of GH-deficiency, central hypothyroidism, central hypocorticosolism, central hypogonadism, diabetes insipidus, hypoprolactinemia, and also the criteria for their compensation. The dose of somatropin with GH-deficiency in children and adolescents is 0.025–0.033 mg/kg/day. With total somatotropic insufficiency, especially in young children, it is advisable to start therapy with somatropin from lower doses: 25–50% of the substitution, gradually increasing it within 3–6 months to optimal. In children with a growth deficit when entering puberty, the dose may be increased to 0.045–0.05 mg/kg/day. With the development of side effects, the dose of somatropin can be reduced (by 30–50%), or temporarily canceled (depending on the severity of the clinical picture) until the complete disappearance of undesirable symptoms. With swelling of the optic nerve, treatment is temporarily stopped until the picture of the fundus of the eye fully normalizes. If therapy has been temporarily discontinued, treatment is resumed in smaller doses (50% of the initial) with a gradual (within 1–3 months) return to the optimum. GH treatment at pediatric doses not continue beyond attainment of a growth velocity below 2–2.5 cm/year, closure of the epiphyseal growth zones, or earlier, when: the achievement of genetically predicted height, but not more than 170 cm in girls, 180 cm in boys, the patient’s desire and his parents / legal representatives satisfied with the achieved result of the final height. Re-evaluation of the somatotropic axis is carried out after reaching the adult height, after 1–3 months GH therapy will be discontinued. Patients with isolated GH-deficiency or patients with 1 (besides GH) pituitary hormone deficiencies in the presence of a normal IGF-1 level (against the background of somatropin withdrawal) and not having molecular genetic confirmation of the diagnosis need re- evaluation. Patients with two or more (besides GH) pituitary hormone deficiencies, acquired hypothalamic-pituitary lesions due to operations on the pituitary and irradiation of the hypothalamic-pituitary area (if the IGF-1 level is low against somatropin withdrawal), specific pituitary/ hypothalamic structural defect on MRI, gene defects of the GH-IGF-I system do not need re- evaluation. If GH deficiency is confirmed, treatment with somatropin is resumed at metabolic doses of 0.01—0.003 mg/kg/day under the control of the IGF-I level in the blood (measurement 1 time in 6 months), the indicator should not exceed the upper limit of the reference value for the corresponding age and floor.

scholarly journals Transitional care of GH deficiency: when to stop GH therapy

2004 ◽  
pp. S61-S65 ◽  
Author(s):  
MO Savage ◽  
WM Drake ◽  
PV Carroll ◽  
JP Monson
Keyword(s):  
Transitional Care ◽  
Gh Deficiency ◽  
Final Height ◽  
Drop Out ◽  
Smooth Transition ◽  
Pituitary Hormone ◽  
Gh Therapy ◽  
Gh Treatment ◽  
Somatic Development ◽  
Gh Secretion

While the benefits of growth hormone (GH) therapy in adult hypopituitary patients with GH deficiency (GHD) are established, the role of continued GH therapy after final height in adolescent GH-deficient patients remains unclear. Preliminary data suggest that cessation of GH on completion of linear growth may be associated with impairment of somatic development and adverse changes in body composition. For the present time, the decision whether to continue GH treatment in adolescent patients with GHD is best made on an individual basis. For such patients, continuity of care is crucial. Children and adults with GHD are usually managed by physicians in separate departments, who may focus on different aspects of treatment and care. Close collaboration between paediatric and adult physicians is essential to ensure smooth transition and to minimize the drop-out rate from follow-up. Given the previous period of treatment during childhood, paediatric physicians should be best placed to discuss the potential benefits of continuing GH therapy and instigate retesting of GH secretion. Many children with isolated idiopathic GHD will produce normal GH responses if retested at adult height. Patients with multiple pituitary hormone deficits are more likely to have ongoing GHD, as are patients who have received CNS irradiation. Quality of life does not appear to be decreased in adolescents with GHD who stop treatment, so achievement of satisfactory bone mass is a major determinant of the decision whether to continue therapy.

scholarly journals Impact of the underlying etiology of growth hormone deficiency on serum IGF-I SDS levels during GH treatment in children

2017 ◽  
Vol 177 (3) ◽  
pp. 267-276 ◽  
Author(s):  
Juliane Léger ◽  
Damir Mohamed ◽  
Sophie Dos Santos ◽  
Myriam Ben Azoun ◽  
Delphine Zénaty ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Care Center ◽  
Treatment Compliance ◽  
Hormone Deficiency ◽  
Pediatric Care ◽  
Pituitary Hormone ◽  
Gh Treatment ◽  
Pubertal Stage ◽  
Igf I

ContextRegular monitoring of serum IGF-I levels during growth hormone (GH) therapy has been recommended, for assessing treatment compliance and safety.ObjectiveTo investigate serum IGF-I SDS levels during GH treatment in children with GH deficiency, and to identify potential determinants of these levels.Design, patients and methodsThis observational cohort study included all patients (n = 308) with childhood-onset non-acquired or acquired GH deficiency (GHD) included in the database of a single academic pediatric care center over a period of 10 years for whom at least one serum IGF-I SDS determination during GH treatment was available. These determinations had to have been carried out centrally, with the same immunoradiometric assay. Serum IGF-I SDS levels were determined as a function of sex, age and pubertal stage, according to our published normative data.ResultsOver a median of 4.0 (2–5.8) years of GH treatment per patient, 995 serum IGF-I SDS determinations were recorded. In addition to BMI SDS, height SDS and GH dose (P < 0.01), etiological group (P < 0.01) had a significant effect on serum IGF-I SDS levels, with patients suffering from acquired GHD having higher serum IGF-I SDS levels than those with non-acquired GHD, whereas sex, age, pubertal stage, treatment duration, hormonal status (isolated GHD (IGHD) vs multiple pituitary hormone deficiency (MPHD)) and initial severity of GHD, had no effect.ConclusionsThese original findings have important clinical implications for long-term management and highlight the need for careful and appropriate monitoring of serum IGF-I SDS and GH dose, particularly in patients with acquired GHD, to prevent the unnecessary impact of potential comorbid conditions.

scholarly journals Growth and Adult Height in GH-Treated Children with Nonacquired GH Deficiency and Idiopathic Short Stature: The Influence of Pituitary Magnetic Resonance Imaging Findings

2001 ◽  
Vol 86 (10) ◽  
pp. 4649-4654 ◽  
Author(s):  
Régis Coutant ◽  
Stéphanie Rouleau ◽  
François Despert ◽  
Nathalie Magontier ◽  
Didier Loisel ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Short Stature ◽  
Gh Deficiency ◽  
Final Height ◽  
Idiopathic Short Stature ◽  
Imaging Findings ◽  
Resonance Imaging ◽  
Gh Treatment ◽  
Catch Up

We analyzed the final height of 146 short children with either nonacquired GH deficiency or idiopathic short stature. Our purpose was 1) to assess growth according to the pituitary magnetic resonance imaging findings in the 63 GH-treated children with GH deficiency and 2) to compare the growth of the GH-deficient patients with normal magnetic resonance imaging (n = 48) to that of 32 treated and 51 untreated children with idiopathic short stature (GH peak to provocative tests &gt;10 μg/liter). The mean GH dose was 0.44 IU/kg·wk (0.15 mg/kg·wk), given for a mean duration of 4.6 yr. Among the GH-deficient children, 15 had hypothalamic-pituitary abnormalities (stalk agenesis), all with total GH deficiency (GH peak&lt;5 μg/liter). They were significantly shorter and younger at the time of diagnosis than those with normal magnetic resonance imaging, had better catch-up growth (+2.7 ± 0.9 vs.+ 1.3 ± 0.8 sd score; P &lt; 0.01), and reached greater final height (−1.1 ± 1.0 vs.− 1.7 ± 1.0 sd score; P &lt; 0.05). Among patients with normal magnetic resonance imaging, there was no difference in catch-up growth and final height between partial and total GH deficiencies. GH-deficient subjects with normal magnetic resonance imaging and treated and untreated patients with idiopathic short stature had comparable auxological characteristics, age at evaluation, and target height. Although they had different catch-up growth (+1.3 ± 0.8,+ 0.9 ± 0.6, and +0.7 ± 0.9 sd score, respectively; P &lt; 0.01, by ANOVA), these patients reached a similar final height (−1.7 ± 1.0, −2.1 ± 0.8, and −2.1 ± 1.0 sd score, respectively; P = 0.13). Pituitary magnetic resonance imaging findings show the heterogeneity within the group of nonacquired GH deficiency and help to predict the response to GH treatment in these patients. The similarities in growth between the GH-deficient children with normal magnetic resonance imaging and those with idiopathic short stature suggest that the short stature in the former subjects is at least partly due to factors other than GH deficiency.

scholarly journals Resistance to GHRH but Not to PTH in a 15-Year-Old Boy With Pseudohypoparathyroidism 1A

2019 ◽  
Vol 3 (7) ◽  
pp. 1383-1389 ◽  
Author(s):  
Martin Munteanu ◽  
Cordula Kiewert ◽  
Nora Matar ◽  
Berthold P Hauffa ◽  
Nicole Unger ◽  
...  
Keyword(s):  
Short Stature ◽  
Growth Plate ◽  
Gh Deficiency ◽  
Final Height ◽  
Standard Deviation Score ◽  
Clinical Signs ◽  
Bone Age ◽  
Heterozygous Mutation ◽  
Gh Treatment ◽  
Recombinant Growth Hormone

Abstract Pseudohypoparathyroidism 1A (PHP1A) consists of signs of Albright hereditary osteodystrophy (AHO) and multiple, variable hormonal resistances. Elevated PTH levels are the biochemical hallmark of the disease. Short stature in PHP1A may be caused by a form of accelerated chondrocyte differentiation leading to premature growth plate closure, possibly in combination with GH deficiency in some patients. Treatment of short stature with recombinant growth hormone (rhGH) in pediatric patients may improve final height if started during childhood. The 10 11/12-year-old boy with clinical signs of AHO presented for evaluation of short stature [height standard deviation score (SDS) −2.72]. Clinically his mother was affected by AHO as well. A heterozygous mutation c.505G>A (p.E169K) in exon 6 of the GNAS gene confirmed a diagnosis of PHP1A in the boy. However, hormonal assessment was unremarkable except for low serum IGF-1 (SDS −2.67). On follow-up, GH deficiency due to GHRH resistance was suspected and confirmed by clonidine and arginine stimulation tests. Treatment with rhGH (0.035 mg/kg) for 2 years resulted in catch-up growth (height SDS −1.52). At age 15 years the PTH levels and bone age of the patient remain within the normal range. In patients with PHP1A, short stature is caused by the effects of Gs-α deficiency on the growth plate. However, resistance to GHRH and the resulting GH deficiency might also contribute. Recombinant GH treatment increases growth in these patients. Diagnostic workup for GH deficiency as a factor contributing to short stature is recommended even in the absence of other hormonal resistances.

NPR2 Variants Are Frequent among Children with Familiar Short Stature and Respond Well to Growth Hormone Therapy

2020 ◽  
Vol 105 (3) ◽  
pp. e746-e752 ◽  
Author(s):  
Lukas Plachy ◽  
Petra Dusatkova ◽  
Klara Maratova ◽  
Lenka Petruzelkova ◽  
Dana Zemkova ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Standard Deviation ◽  
Short Stature ◽  
Treatment Response ◽  
Growth Velocity ◽  
Final Height ◽  
Standard Deviation Score ◽  
Significant Proportion ◽  
Gene Variants ◽  
Gh Treatment

Abstract Context The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results. Objectives To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response. Design, Settings and Patients Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ –2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated. Results In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment. Conclusions NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.

scholarly journals Adult Height in Patients with Permanent Growth Hormone Deficiency with and without Multiple Pituitary Hormone Deficiencies

2006 ◽  
Vol 91 (8) ◽  
pp. 2900-2905 ◽  
Author(s):  
Mohamad Maghnie ◽  
Linda Ambrosini ◽  
Marco Cappa ◽  
Gabriella Pozzobon ◽  
Lucia Ghizzoni ◽  
...  
Keyword(s):  
Adult Height ◽  
Gh Deficiency ◽  
Final Height ◽  
Tolerance Test ◽  
Term Treatment ◽  
Hormone Deficiency ◽  
Pituitary Hormone ◽  
Gh Treatment ◽  
Long Term Treatment ◽  
Height Gain

Abstract Context: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported. Objectives: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD. Design and Setting: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit. Patients and Methods: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 μg/liter after an insulin tolerance test or peak GH levels less than 5 μg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height sd score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal. Results: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis. Conclusions: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.

Short stature in association with Cornelia de Lange syndrome – it is useful to administrate rhgh?

2016 ◽  
Vol 62 (5) ◽  
pp. 21-22
Author(s):  
Oana Alexandra Petre ◽  
Ivona Gheorghe ◽  
Alice Ioana Albu
Keyword(s):  
Short Stature ◽  
Gh Deficiency ◽  
Genetic Disorder ◽  
Final Height ◽  
Bone Age ◽  
Female Child ◽  
Cornelia De Lange Syndrome ◽  
Gh Treatment ◽  
Stimulation Tests ◽  
Cornelia De Lange

Cornelia de Lange syndrome (CdLS) is a very rare genetic disorder that is apparent at birth (congenital). Since children with CdLS are often compared to a typical child’s grow rate, many are incorrectly diagnosed.In the absence of the genotyping, the diagnosis would be clinical: a range of criteria would be required, such as the facial features and criteria related to at least one of the following : development, behaviour or growth. Short-stature associated with CdLS is usually due to GH deficiency or GH resistance. However the response to GH administration in patients with CdLS was reported in a limited number of cases.We present the case of a female child 4,11 years old reffered for endocrinological evaluation of short stature. From her medical history we mention: language delay and a pulmonary valve regurgitation. At the time of evaluation, she presented short stature (-2,32 SDS) with a -3 SDS growth velocity during the past year, bone age was more than 2 years delayed compared to the chronological age (2,5 years), weight and head circumference below 5th percentile for age, synophrys, oral dystrophy, micrognathism and thin upper lip, down-turned corners of mouth, hypertrichosis, pulmonary systolic murmur, partial elbow extension.Facial findings and criteria met for two major categories confirm the CdLS. The endocrinological evaluation revealed short-stature with GH deficiency based on two GH values below 10 ng/mL during two stimulation tests . The patient began treatment with somatropin 0,04 mg/kg/day and the patient grew 3,5 cm in 6 months (-2,7 SDS for height).This case suggests that adequate evaluation of patients with CdLS and short stature could identify patients that are good candidate for GH treatment in order to improve final height. 

scholarly journals Circulating Irisin Levels in Children With GH Deficiency Before and After 1 Year of GH Treatment

2018 ◽  
Vol 104 (3) ◽  
pp. 801-808 ◽  
Author(s):  
Alessandro Ciresi ◽  
Giuseppe Pizzolanti ◽  
Valentina Guarnotta ◽  
Carla Giordano
Keyword(s):  
Growth Velocity ◽  
Gh Deficiency ◽  
Body Height ◽  
Metabolic Parameters ◽  
Oral Glucose ◽  
Model Assessment ◽  
Gh Treatment ◽  
Lower Growth ◽  
Control Subjects ◽  
Igf I

Abstract Purpose To evaluate circulating irisin levels in children with GH deficiency (GHD) and any relation with clinical and metabolic parameters. Patients Fifty-four prepubertal children (mean age, 7.4 ± 0.8 years) with idiopathic GHD treated with GH for at least 12 months and 31 healthy short children as control subjects. Methods Body height, body mass index (BMI), waist circumference (WC), IGF-I, HbA1c, lipid profile, fasting and after–oral glucose tolerance test glucose and insulin, insulin sensitivity indices, and irisin levels were evaluated at baseline and after 12 months of GH replacement (GHR). Results At baseline, children with GHD, in addition to having lower growth velocity (P &lt; 0.001), GH peak after stimulation tests (both P &lt; 0.001), and IGF-I (P &lt; 0.001), showed significantly lower irisin (P &lt; 0.001) and higher BMI (P &lt; 0.001) and WC (P = 0.001), without any difference in metabolic parameters, than control subjects. After GHR, children with GHD showed a significant increase in height (P &lt; 0.001), growth velocity (P &lt; 0.001), IGF-I (P &lt; 0.001), fasting glucose (P = 0.002) and insulin (P &lt; 0.001), homeostasis model assessment estimate of insulin resistance (P &lt; 0.001), and irisin (P = 0.005), with a concomitant decrease in BMI (P = 0.001) and WC (P = 0.003). In multivariate analysis, the independent variables significantly associated with irisin were BMI (P = 0.002) and GH peak (P = 0.037) at baseline and BMI (P = 0.005), WC (P = 0.018), and IGF-I (P &lt; 0.001) during GHR. Conclusions We report that GHR leads to an increase in irisin levels, strongly related to a decrease in BMI and WC, and to an increase in IGF-I; these changes are among the main goals of GHR. These data confirm the favorable effects of GHR in children.

Efficacy of long-term growth hormone therapy in short non-growth hormone-deficient children

2017 ◽  
Vol 30 (2) ◽  
Author(s):  
Lucia Schena ◽  
Cristina Meazza ◽  
Sara Pagani ◽  
Valeria Paganelli ◽  
Elena Bozzola ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Final Height ◽  
Standard Deviation Score ◽  
Bone Age ◽  
Gh Treatment ◽  
Short Children ◽  
Igf I ◽  
Height Gain ◽  
The Cost

AbstractBackground:In recent years, several studies have been published showing different responses to growth hormone (GH) treatment in idiopathic short stature children. The aim of the present study was to investigate whether non-growth-hormone-deficient (non-GHD) short children could benefit from long-term GH treatment as GHD patients.Methods:We enrolled 22 prepubertal children and 22 age- and sex-matched GHD patients, with comparable height, body mass index (BMI), bone age, and insulin-like growth factor 1 (IGF-I) circulating levels. The patients were treated with recombinant human GH (rhGH) and followed until they reach adult height.Results:During GH treatment, the two groups grew in parallel, reaching the same final height-standard deviation score (SDS) and the same height gain. On the contrary, we found significantly lower IGF-I serum concentrations in non-GHD patients than in GHD ones, at the end of therapy (p=0.0055).Conclusions:In our study, the response to GH treatment in short non-GHD patients proved to be similar to that in GHD ones. However, a careful selection of short non-GHD children to be treated with GH would better justify the cost of long-term GH therapy.

scholarly journals Phenotype and Genetic Analysis of a Syndrome Caused by an Inactivating Mutation in the Growth Hormone-Releasing Hormone Receptor: Dwarfism of Sindh1

1998 ◽  
Vol 83 (11) ◽  
pp. 4065-4074
Author(s):  
Hiralal G. Maheshwari ◽  
Bernard L. Silverman ◽  
Josée Dupuis ◽  
Gerhard Baumann
Keyword(s):  
Gh Deficiency ◽  
Postnatal Growth ◽  
N Gene ◽  
Molecular Characteristics ◽  
Clinical Genetic ◽  
Gh Treatment ◽  
Gh Secretion ◽  
Absolute Requirement ◽  
Igf I ◽  
Igf Binding

We report, in detail, a new form of familial dwarfism, including its phenotypic features, hormonal profile, and molecular basis. Following a newspaper report of severe dwarfism in two villages in the province of Sindh, Pakistan, we organized an expedition to study its clinical, genetic, and molecular characteristics. We identified 18 dwarfs (15 male, 3 female), all members of a consanguineous kindred, ranging in age from newborn to 28 yr. Mean height was 7.2 sd below the norm, with mean adult heights of 130 cm for males and 113.5 cm for females. Body proportions and habitus were normal; but head circumference was 4.1 sd, and blood pressure approximately 3 sd below the norm. There was no dysmorphism, no microphallus, and no history of hypoglycemia. Serum GH did not respond to provocative stimuli (GHRH, l-dopa, or clonidine). Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 were low (5.2 ± 2.0 ng/mL and 0.42 ± 0.13 μg/mL, respectively; mean ± sd) but rose normally with GH treatment. One affected, dwarfed couple had a son, demonstrating fertility in both sexes. Clinical and endocrinological evidence suggested isolated GH deficiency with a recessive inheritance pattern. The GH-N gene was found to be intact. Linkage analysis of microsatellite chromosomal markers near other candidate genes yielded a high LOD score (6.26) for the GHRH receptor (GHRH-R) locus. DNA sequencing revealed a nonsense mutation (Glu50→Stop) in the extracellular domain of the GHRH-R. This mutation predicts a severely truncated GHRH-R; it is identical to that recently reported in four patients from two other families. Inheritance is autosomal recessive (chromosome 7p) with a high degree of penetrance. Relatives heterozygous for the mutation had moderately decreased IGF-I levels and slightly blunted GH responses to GHRH and l-dopa, but they showed only minimal or no height deficit. This syndrome represents the human homologue of the little (lit/lit) mouse and closely resembles its phenotype. It demonstrates the absolute requirement of GHRH signaling for pituitary GH secretion and postnatal growth in humans, and its relatively minor (but discernible) biological importance in extrapituitary sites. The syndrome is distinct from other forms of GH deficiency with respect to microcephaly, asymptomatic hypotension, and absence of features such as facial dysplasia, significant truncal obesity, microphallus, or hypoglycemia. Its discovery raises the possibility of milder mutations in the GHRH-R gene as potential causes for partial GH insufficiency and idiopathic short stature.

Sign in / Sign up

Export Citation Format

Share Document