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Abstract Background Hypospadias is a congenital displacement of the urethral meatus in male newborns, being either an isolated defect at birth or a sign of sexual development disorders. The aim of this study was to assess the prevalence rate of hypospadias in different Districts of Italy, in order to make a comparison with other countries all over the world. Methods We reviewed all the newborns file records (years 2001–2004) in 15 Italian Hospitals. Results We found an overall hypospadias prevalence rate of 3.066 ± 0.99 per 1000 live births (82.48% mild hypospadias, 17.52% moderate-severe). In newborns Small for Gestational Age (birthweight < 10th percentile) of any gestational age the prevalence rate of hypospadias was 6.25 per 1000 live births. Performing multivariate logistic regression analysis for different degrees of hypospadias according to severity, being born SGA remained the only risk factor for moderate-severe hypospadias (p = 0.00898) but not for mild forms (p > 0.1). Conclusion In our sample the prevalence of hypospadias results as high as reported in previous European and American studies (3–4 per 1000 live births). Pathogenesis of isolated hypospadias is multifactorial (genetic, endocrine and environmental factors): however, the prevalence rate of hypospadias is higher in infants born small for gestational age than in newborns with normal birth weight.

Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder associated with variants in the HUWE1 gene on chromosome Xp11. The condition is characterized by variable phenotypes, including global developmental delay, intellectual disability, and distinctive facial dysmorphisms, with inheritance patterns ranging from X-linked recessive to de novo mutations in females. Here, we describe five probands in two families, highlighting their clinical features and genetic findings. Trio whole-exome sequencing identified a de novo variant in HUWE1 in the proband in one family and a maternally inherited hemizygous variant in three boys in a second family. A comprehensive review of HUWE1-associated cases from the literature assisted genotype-phenotype correlations, revealing consistent features such as intellectual disability, skeletal anomalies, and facial dysmorphisms as well as instances of intrafamilial variability. Our findings confirm the phenotypic variability of MRXST and underscore the significance of the HUWE1 gene product in neurodevelopment. We propose a baseline monitoring protocol to aid in diagnosis and management, contributing to the development of specific guidelines for patient follow-up., (© 2024 Wiley Periodicals LLC.)

Background/Objectives : The pathogenetic role of 15q11.2 Copy Number Variations (CNVs) remains contentious in the scientific community, as microdeletions and microduplications in this region are linked to neurodevelopmental disorders with variable expressivity. This study aims to explore the diagnostic utility of Exome Sequencing (ES) in a cohort of pediatric patients with 15q11.2 CNVs. Methods : We enrolled 35 probands with 15q11.2 microdeletions or microduplications from two genetic centers between January 2021 and January 2023. Chromosomal Microarray Analysis (CMA) and ES were performed with written consent obtained from all parents. Pathogenic variants were classified according to ACMG guidelines. Results : CMA identified additional pathogenic CNVs in 3 of 35 children (9%). Subsequent ES revealed likely pathogenic or pathogenic variants in 11 of 32 children (34%). Notably, a higher percentage of isolated autism spectrum disorder (ASD) diagnoses was observed in patients without other CNVs or point mutations ( p = 0.019). Conclusions : The ES analysis provided a diagnostic yield of 34% in this pediatric cohort with 15q11.2 CNVs. While the study does not dismiss the contribution of the CNV to the clinical phenotype, the findings suggest that ES may uncover the underlying causes of neurodevelopmental disorders. Continuous monitoring and further genetic testing are recommended for all 15q11.2 CNV carriers to optimize clinical management and familial counseling., Competing Interests: The authors declare no conflicts of interest.

Background: Silver-Russell Syndrome (SRS, MIM #180860) is a clinically and genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation; SRS is also accompanied by dysmorphic features such as triangular facial appearance, broad forehead, body asymmetry and significant feeding difficulties. The incidence is unknown but estimated at 1:30,000-100,000 live births. The diagnosis of SRS is guided by specific criteria described in the Netchine-Harbison clinical scoring system (NH-CSS)., Case Presentation: Hereby we describe four patients with syndromic short stature in whom, despite fitting the criteria for SRS genetic analysis (and one on them even meeting the clinical criteria for SRS), molecular analysis actually diagnosed a different syndrome. Some additional features such as hypotonia, microcephaly, developmental delay and/or intellectual disability, and family history of growth failure, were actually discordant with SRS in our cohort., Conclusions: The clinical resemblance of other short stature syndromes with SRS poses a risk of diagnostic failure, in particular when clinical SRS only criteria are met, allowing SRS diagnosis in the absence of a positive result of a genetic test. The presence of additional features atypical for SRS diagnosis becomes a red flag for a more extensive and thorough analysis. The signs relevant to the differential diagnosis should be valued as much as possible since a correct diagnosis of these patients is the only way to provide the appropriate care pathway, a thorough genetic counselling, prognosis definition, follow up setting, appropriate monitoring and care of possible medical problems., (© 2024. The Author(s).)

Background: Some chromatinopathies may present with common clinical findings (intellectual disability, brain and limb malformation, facial dysmorphism). Furthermore, one of their cardinal shared features is growth dysregulation.We aimed to assess and deepen this resemblance in three specific conditions, namely Wiedemann-Steiner (WDSTS), Kleefstra (KLEFS1) and Coffin-Siris syndrome (CSS1), with a particular focus on possible metabolic roots., Methods: Eleven patients were enrolled, three with WDSTS, five with KLEFS1 and three with CSS1, referring to Fondazione IRCCS Ca' Granda Ospedale Maggiore, Milan, Italy. We performed both a physical examination with detailed anthropometric measurements and an evaluation of the patients' REE (rest energy expenditure) by indirect calorimetry, comparing the results with age- and sex-matched healthy controls., Results: We observed new clinical features and overlap between these conditions suggesting that different disturbances of epigenetic machinery genes can converge on a common effect, leading to overlapping clinical phenotypes.
The REE was not distinguishable between the three conditions and healthy controls., Conclusions: Epigenetic machinery plays an essential role both in growth regulation and in neurodevelopment; we recommend evaluating skeletal [craniovertebral junction abnormalities (CVJ) polydactyly], otolaryngological [obstructive sleep apnea syndrome (OSAs), recurrent otitis media], dental [tooth agenesis, talon cusps], and central nervous system (CNS) [olfactory bulbs and cerebellum anomalies] features. These features could be included in monitoring guidelines. Further studies are needed to deepen the knowledge about energy metabolism., (© 2024. The Author(s).)

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes ( CREBBP , EP300 ) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP ; RTS2: EP300 ), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

SATB1 (MIM #602075) is a relatively new gene reported only in recent years in association with neurodevelopmental disorders characterized by variable facial dysmorphisms, global developmental delay, poor or absent speech, altered electroencephalogram (EEG), and brain abnormalities on imaging. To date about thirty variants in forty-four patients/children have been described, with a heterogeneous spectrum of clinical manifestations. In the present study, we describe a new patient affected by mild intellectual disability, speech disorder, and non-specific abnormalities on EEG and neuroimaging. Family studies identified a new de novo frameshift variant c.1818delG (p.(Gln606Hisfs*101)) in SATB1 . To better define genotype-phenotype associations in the different types of reported SATB1 variants, we reviewed clinical data from our patient and from the literature and compared manifestations (epileptic activity, EEG abnormalities and abnormal brain imaging) due to missense variants versus those attributable to loss-of-function/premature termination variants. Our analyses showed that the latter variants are associated with less severe, non-specific clinical features when compared with the more severe phenotypes due to missense variants. These findings provide new insights into SATB1 -related disorders.

We report the case of a 12-year-old girl and her father who both had marked postnatal tall stature, camptodactyly and clinodactyly, scoliosis and juvenile-onset hearing loss. The CATSHL (CAmptodactyly - Tall stature - Scoliosis - Hearing Loss syndrome) syndrome was suspected, and molecular analysis revealed a hitherto unreported, monoallelic variant c.1861C>T (p.Arg621Cys) in FGFR3. This variant affects the same residue, but is different than, the variant p.Arg621His reported in the two families with dominant CATSHL described so far. Interestingly, peg-shaped incisors were observed in the proband, a feature never reported in CATSHL but typical of another FGFR3-related condition, LADD (Lacrimo - Auricolo - Dento - Digital) syndrome. The FGFR3 p.Arg621Cys variant seems to be a newly identified cause of CATSHL syndrome with some phenotypic overlap with the LADD syndrome., (© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Background: The recent guidelines suggest the use of genome-wide analyses, such as whole exome sequencing (WES), at the beginning of the diagnostic approach for cases with suspected genetic conditions. However, in many realities it still provides for the execution of a multi-step pathway, thus requiring several genetic tests to end the so-called 'diagnostic odyssey'., Methods: We reported the results of GENE Project (Genomic analysis Evaluation NEtwork): a multicentre prospective cohort study on 125 paediatric outpatients with a suspected genetic disease in which we performed first-tier trio-WES, including exome-based copy number variation analysis, in parallel to a 'traditional approach' of two/three sequential genetic tests., Results: First-tier trio-WES detected a conclusive diagnosis in 41.6% of patients, way above what was found with routine genetic testing (25%), with a time-to-result of about 50 days. Notably, the study showed that 44% of WES-reached diagnoses would be missed with the traditional approach. The diagnostic rate (DR) of the two approaches varied in relation to the phenotypic class of referral and to the proportion of cases with a defined diagnostic suspect, proving the major difference for neurodevelopmental disorders. Moreover, trio-WES analysis detected variants in candidate genes of unknown significance (EPHA4, DTNA, SYNCRIP, NCOR1, TFDP1, SPRED3, EDA2R, PHF12, PPP1R12A, WDR91, CDC42BPG, CSNK1D, EIF3H, TMEM63B, RIPPLY3) in 19.4% of undiagnosed cases., Conclusion: Our findings represent real-practice evidence of how first-tier genome-wide sequencing tests significantly improve the DR for paediatric outpatients with a suspected underlying genetic aetiology, thereby allowing a time-saving setting of the correct management, follow-up and family planning., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Objective: We describe the prenatal ultrasound findings and autopsy of three fetuses with multiple congenital anomalies (MCA) whose diagnostic workup suggested the same genetic etiology. We conducted a literature review to corroborate the molecular results and find evidence that the identified variants are responsible for the phenotype seen., Methods: Trio-based Exome Sequencing (ES) analysis was performed on chorionic villus samples. We reviewed available reports dealing with prenatal manifestations of genes involved in the Glycosylphosphatidylinositols (GPI) biosynthesis defects (GPIBDs)., Results: Prenatal findings shared by all the three pregnancies included facial dysmorphisms, brain malformations of the posterior fossa, skeletal and genitourinary anomalies. ES analysis identified homozygous variants of uncertain significance in PIGW in the three fetuses. Prenatal findings of the three pregnancies overlapped with those previously described for PIGW variants and with those associated with PIGN, PIGV and PIGA variants., Conclusion: Based on the phenotypic overlap between the prenatal findings in our three cases and other cases with pathogenic variants in other genes involved in GPIBDs, we speculate that the variants identified in the three fetuses are likely causal of their phenotype and that the PIGWclinical spectrum might extend to MCA, mainly involving brain, skeletal and genitourinary systems. Moreover, we suggest that also PIGW could be involved in Fryns/Fryns-like phenotypes., (© 2022 John Wiley & Sons Ltd.)

Objective: To assess autoimmune regulator (AIRE) gene mutations, class II HLA haplotypes, and organ- or non-organ-specific autoantibodies in patients with chronic hypoparathyroidism (CH) without associated Addison's disease (AD) or chronic candidiasis (CC)., Design, Patients and Measurements: Twenty-four patients who had CH without AD or CC were included in the study. AIRE gene mutations in all 14 exons were studied using PCR in 24 patients, 105 healthy controls and 15 first-degree relatives of CH patients with AIRE mutations. Human leucocyte antigens (HLA) were determined for all 24 patients and 105 healthy controls. Autoantibodies to a range of antigens including NACHT leucine-rich-repeat protein-5 (NALP5) and interferon omega (IFNω) were tested in all 24 patients., Results: AIRE gene mutations were found in 6 of 24 (25%) patients, all females, and this was significantly higher (P < 0·001) compared with AIRE mutations found in healthy controls (2/105). Three patients (12·5%) had homozygous AIRE mutations characteristic of Autoimmune-Poly-Endocrinopathy-Candidiasis-Ectodermal-Dystrophy and all three were also positive for IFNω-autoantibodies. Three patients (12·5%) had heterozygous AIRE mutations; two of these were novel mutations. One of the patients with heterozygous AIRE mutations was positive for both NACHT leucine-rich-repeat protein 5 and IFNω autoantibodies. Heterozygous AIRE mutations were found in 10 of 15 first-degree relatives of CH patients with AIRE mutations, although none was affected by CH. Class II HLA haplotypes were not statistically different in patients with CH compared to healthy controls., Conclusions: Analysis of AIRE gene mutations together with serum autoantibody profile should be helpful in the assessment of patients with CH, in particular young women with associated autoimmune diseases., (© 2010 Blackwell Publishing Ltd.)

The potential health consequences of human exposure to environmental estrogen disrupters are not known. Because many chemical compounds are environmentally persistent, toxic and estrogen-active, they can dysregulate the hypothalamic-pituitary-gonadal axis, potentially inducing reproductive disorders such as central precocious puberty (CPP). We performed a multi-center analysis of CPP distribution in northwest Tuscany (NWT), an area of 5990 km2 with 1,280,895 inhabitants. Study criteria consisted of recorded CPP diagnoses and prescriptions of gonadotropin-releasing hormone analogs from January 1, 1998 to December 1, 2003. Although similar CPP prevalences were found in four major cities of NWT (Livorno, Lucca, Massa and Pisa) (mean 30.4 per 100,000 children, standard deviation 18.6; p > 0.05), Viareggio area (< 300 km2) with 19,219 child inhabitants (0-14 years of age) had the highest CPP prevalence: more than 161 CPP cases per 100,000 children. Living in Viareggio area significantly increased the risk of CPP (relative risk (RR) 5.73, 95% confidence interval (CI) 3.5-9.3; rate/risk difference 0.133%, p < 0.05). Annual CPP incidence in the Viareggio area was relatively constant and significantly higher than in other NWT areas (RR 5.04, 95% CI 2.3-11.2; rate/risk difference 0.03%, p < 0.05). Indeed, 47% of total NWT cases were distributed in the countryside (300?km2) surrounding Viareggio. Specifically, three villages - Camaiore, Pietrasanta and Stazzema - in Viareggio presented the highest CPP frequency: 216.1, 393.5 and 274.0 CPP cases per 100,000 children, respectively (RR 9.59, 95% CI 1.71-16.6; rate/risk difference 0.26%, p < 0.05). Owing to the definite geographic distribution of CPP and because increasing distance (km) from Pietrasanta rarefied CPP frequency, we suggest environmental factors (e.g. estrogen disrupter pollution) as major CPP determinants in NWT.

Syncope is a common phenomenon, well-known to all pediatricians: it is defined as a sudden transient loss of consciousness associated with inability to maintain postural tone that is incompatible with a seizure disorder, vertigo, dizziness, coma, shock or other states of altered consciousness. The purpose of this study are to analyse the multiple causes of syncope, to determine the characteristics of pediatric patients with syncope, to define the pathophysiologic mechanisms that result in neurally mediated syncope.

The cysticercosis is an infestation caused from the larva of Taenia solium, which is demoniated Cysticercus cellulosae. Infestation by the encysted forms occur within brain, muscle, cutis, eye and more rarely within kidney, liver, thyroid. The cysties cause inflammation, oedema and residual calcification. In the SNC they are responsible for seizures, usually of focal type, hydrocephalus, meningitis, endocranic hypertension, stroke. One case of neurocysticercosis in a 15 years old boy is described: the clinical pictures, the neuroradiologic images and the treatment are discussed.

Migraine has been recently defined a "central neuronal hyperexcitability state", maybe magnesium-dependent, and magnesium has been occasionally employed in the therapy of adult migraine. The Authors, on the basis of their personal experience (previous electromyographic studies), consider childhood migraine and periodic syndrome as a clinical equivalent of spasmophilia, in which an intracellular deficit of magnesium has been demonstrated, and have employed a magnesium salt in the prophylaxis of childhood migraine and migraine equivalents. 40 children with periodic syndrome (17 M and 23 F, aged 10.4 +/- 2.9 years) have been treated with magnesium pidolate, with doses ranging from 1.5 g/die to 4.5 g/die (corresponding to 122-366 mg Mg++):25 of them presented migraine as the main symptom, 12 recurrent abdominal pain, 3 fever of unknown origin, along with many other periodic symptoms. The first control visits have been done at 1 month, clinical follow-up lasted a mean period of 6.1 months. Therapy was stopped at 1 month visit if ineffective (of some other drug was added); otherwise, magnesium therapy was continued with the same dosage for another month, then gradually reduced. Clinical response was considered good if crises ceased completely or their frequency was reduced to less than 33%; partial if reduced to less than 67% of previous incidence; absent if only slightly or not at all reduced. Clinical response was good in 72.5% of cases at 1 month, in 77.5% later; partial in 12.5% and 10%; absent in 15% and 12.5% respectively. No side effects were observed. The compliance of children and their families was complete.(ABSTRACT TRUNCATED AT 250 WORDS)

The pathogenesis of periodic syndrome (recurrent abdominal pain, cyclic vomiting, headache and other equivalents of childhood migraine) is often related in the literature to a "neuro-vegetative dysfunction", by which occasional stimuli (environmental, metabolic, emotional) should find a particular somatic expression. The homeostatic role of the autonomic nervous system could be deficient in these cases, but systematic research has never been done to explore this hypothesis. We have evaluated the autonomic nervous function in 38 children (12 M, 26 F) with periodic syndrome, by cardiovascular autonomic function tests. They consist of ortho- and parasympathetic parameters obtained by ECG registration and pressure monitoring during deep breathing, Valsalva manoeuvre, lying to standing postural change, sustained handgrip. In the absence of adequate pediatric references values, we have previously standardized these tests in a population of 198 healthy children (94 M, 104 F), aged 8.3-15.7 years. Results have been compared with our standard reference values, matching them by t-test for independent data: in both sexes, significant differences have been found out in only one of 11 parameters (p < 0.05) of the autonomic tests performed. Children affected by periodic syndrome reveal a reduced heart rate variation in transition from the early orthosympathetic phase to the late parasympathetic one after lying to standing passage, showing a smaller fluctuation of autonomic feedback systems. The physiological meaning of this result is unclear. However, in children with periodic syndrome no prevalence of ortho- or parasympathetic systems is evident.

The study of cardiovascular autonomic reflexes is the most physiological and reliable test for the assessment of autonomic function: they consist of the analysis of variation of heart rate and arterial pressure provoked by many physiological stimuli. Up to now normal pediatric reference data were not available: we have standardized these tests in 198 normal children (94 M, 104 F), aged 8.3-15.7 years, without any symptom of possible autonomic dysfunction pathology. A complete auxological evaluation has been performed. Autonomic tests were performed by ECG recording and arterial pressure monitoring during normal and deep breathing, Valsalva manoeuvre, lying to standing postural change, isometric muscular contraction (sustained hand-grip and leg rising). Eleven autonomic parameters were obtained. Many statistical correlation between autonomic parameters and auxological features have been explored, without remarkable results. A significative difference emerged only between sexes. Normal reference values has been calculated. Their utility for the study of autonomic dysfunction is discussed.

Slight, moderate but also high rises in temperature, excluding other causes of fever, can be considered symptoms of periodic syndrome originating by hypothalamic centers as soon as headache, recurrent abdominal pains, growing pains, dizziness, kinetosis. These rises aren't uncommon, but often aren't considered important and this few statistics are available. The Authors present 16 case reports of fever as periodic symptom and discuss how common factors exist in the mechanism of hyperthermia and other clinical signs of periodic syndrome (ex. migraine) but they are generally modulated differently so that disturbance of temperature regulation predominates in the first case, pain in the second.

Two casual clinical observations here reported allow the Authors to discuss the possible relationships between periodic syndrome and spasmophilia. Particularly they stress how these common causes of recurrent symptoms (abdominal pain, headache, growing pains, anxiety, irritability) can be the same clinical entity. This suspicion is confirmed by EMG investigation: 25 children with periodic syndrome (8 males, 17 females; 8-13 years) and 10 normal subjects (6-11 years) participate in this study. Post-ischemic EMG shows signs of neuromuscular hyperexcitability as in spasmophilia in 21 children (84%) of the first group and only in 3 of the second group. Such findings should be regarded as the first step towards a better definition of the relationships between periodic syndrome and spasmophilia.

There has been a great dealt of discussion as to the clinical significance of E.E.G. 14-6 per second positive spikes (14-6 PS), a short burst lasting one second or less which occurs during light sleep in monopolar recordings, mainly in the posterior temporal regions and usually involving the parietal and occipital regions as well, for the most part in unsymmetrical fashion. Early interpretations stress the epileptic nature of vegetative attacks in patients with an inter-critical E.E.G. reading characterized by 14-6 P.S. Subsequently, however, this hypothesis has been refuted, mainly because E.E.G. intra-critical recordings have never shown evidence of any sort of paroxysmal activity. At present time expert think that the presence of 14-6 PS may be merely an indication of an electrical alteration associated with disorders in the neurovegetative area. In order to evaluate the possibility of using them as a diagnostic marker of migraine equivalents and periodic syndromes, we reviewed wake and sleep E.E.G. recordings, carried out consecutively and hence not selectively, in 617 children aged 5-16 years. 14-6 PS were present in 109 children (17.6%), 63 of whom showed evident symptoms of periodic syndrome (headache, recurrent abdominal pain, cyclic vomiting, kinetosis, etc.); hence 46 E.E.G. recording were false positive. 510 children were lacking in 14-6 PS, 91 of these presented symptoms of periodic syndromes (false negative). 14-6 PS are hence a marker 40.9% sensitive, 90.1% specific, with a predictable value of 57.7%. The search for 14-6 PS in children with periodic syndrome is not particularly sensitive as a test, but it is fairly specific: it may well constitute an useful element in diagnosis.

The case history in question refers to 94 high-risk babies, 24 of whom (25%) had neuromotor problems at some time during the first year. Of these, 15 have continued to be supervised up to the present time, i.e. to the age of four. Eight of them have had overall motor treatment and seven have had constant check-ups, advice on posture and active encouragement to move their bodies. All 15 infants developed normal neuromotor behaviour by the age of two (only one was retarded in speech). We therefore feel justified in not encouraging indiscriminate remedial therapy in all cases of abnormal development. It should be used only in those cases in which there are serious, persistent problems in the sphere of feeling and relating.

Many advances characterize the research into the diagnosis of short stature in children. Increasing evidence shows a continuous spectrum of growth hormone (GH) output among GH-deficient patients and short normal children. Although biosynthetic human GH could theoretically offer the chance of treating most slowly growing children, it is not certain that all short normal children with a poor height velocity could benefit from therapy. Indeed, besides auxological findings, the assessment of GH secretion remains essential in selecting candidates for therapy. In this respect the evaluation of GH secretion by means of tests that can explore the physiological pathways involved in the hormone output appears important. Moreover some clinical evidence suggests that pharmacological stimuli cause the pituitary release of stored GH perhaps unavailable in physiological conditions. Among the classical physiological tests, the exercise test, the standardization of which has been debated, is commonly used in clinical practice. The sleep test, i.e. the evaluation of sleep-associated GH secretion, is the most important. It has no side effects and does not require the administration of exogenous stimuli. Several studies have demonstrated its reliability in diagnosing growth disorders in childhood, mainly if performed with EEG monitoring. Among the new physiological diagnostic approaches the most reliable test is the evaluation of 24-hour GH secretion. Knowledge of the integrated hormone concentrations appears particularly important in studying children who may have more subtle disturbances in GH secretion. These cases show normal GH response to provocative stimuli but show a reduced hormone output over 24 h. Indeed they respond well to human GH treatment.