Genetic architecture of congenital hypogonadotropic hypogonadism: insights from analysis of a Portuguese cohort.

STUDY QUESTION: What is the contribution of genetic defects in Portuguese patients with congenital hypogonadotropic hypogonadism (CHH)? SUMMARY ANSWER: Approximately one-third of patients with CHH were found to have a genetic cause for their disorder, with causal pathogenic and likely pathogenic germline variants distributed among 10 different genes; cases of oligogenic inheritance were also included. WHAT IS KNOWN ALREADY: CHH is a rare and genetically heterogeneous disorder characterized by deficient production, secretion, or action of GnRH, LH, and FSH, resulting in delayed or absent puberty, and infertility. STUDY DESIGN SIZE DURATION: Genetic screening was performed on a cohort of 81 Portuguese patients with CHH (36 with Kallmann syndrome and 45 with normosmic hypogonadotropic hypogonadism) and 263 unaffected controls. PARTICIPANTS/MATERIALS SETTING METHODS: The genetic analysis was performed by whole-exome sequencing followed by the analysis of a virtual panel of 169 CHH-associated genes. The main outcome measures were non-synonymous rare sequence variants (population allele frequency <0.01) classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS). MAIN RESULTS AND THE ROLE OF CHANCE: A genetic cause was identified in 29.6% of patients. Causal pathogenic and likely pathogenic variants were distributed among 10 of the analysed genes. The most frequently implicated genes were GNRHR, FGFR1, ANOS1, and CHD7. Oligogenicity for pathogenic and likely pathogenic variants was observed in 6.2% of patients. VUS and oligogenicity for VUS variants were observed in 85.2% and 54.3% of patients, respectively, but were not significantly different from that observed in controls. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The identification of a large number of VUS presents challenges in interpretation and these may require reclassification as more evidence becomes available. Non-coding and copy number variants were not studied. Functional studies of the variants were not undertaken. WIDER IMPLICATIONS OF THE FINDINGS: This study highlights the genetic heterogeneity of CHH and identified several novel variants that expand the mutational spectrum of the disorder. A significant proportion of patients remained without a genetic diagnosis, suggesting the involvement of additional genetic, epigenetic, or environmental factors. The high frequency of VUS underscores the importance of cautious variant interpretation. These findings contribute to the understanding of the genetic architecture of CHH and emphasize the need for further studies to elucidate the underlying mechanisms and identify additional causes of CHH. STUDY FUNDING/COMPETING INTERESTS: This research was funded by the Portuguese Foundation for Science and Technology (grant numbers PTDC/SAU-GMG/098419/2008, UIDB/00709/2020, CEECINST/00016/2021/CP2828/CT0002, and 2020.04924.BD) and by Sidra Medicine-a member of the Qatar Foundation (grant number SDR400038). The authors declare no competing interests.

Carotid Intima-Media Thickness and Cardiometabolic Profile in Turner Syndrome: A Cross-Sectional Study.

INTRODUCTION: Turner syndrome (TS), one of the most common chromosomal abnormalities in females, often results in adult cardiovascular and metabolic complications. Information on pediatric age is scarce. This study aimed to compare the presence of cardiometabolic risk factors in children with TS and healthy controls. METHODS: This is a cross-sectional study comparing patients with TS to age-matched healthy controls, regarding cardiometabolic risk factors including lipid profile, fasting glucose, insulin resistance, body composition, body mass index, blood pressure, and carotid intima-media thickness (cIMT). RESULTS: We included nine TS patients and nine controls with a median age of 13 years (9-14 years). Three TS patients and three controls were prepubertal. All TS patients received growth hormone treatment (GHT), median treatment of six years (3-10 years); four patients underwent treatment with estradiol. No statistically significant differences were detected between TS patients and controls regarding body mass index (BMI), cholesterol levels, and insulin resistance. cIMT indexed to body surface area showed no significant differences between TS patients and controls (0.37 vs 0.35 mm/m2, respectively, p=0.605). TS patients had lower body fat levels (7.2% vs 34.9%, p=0.004). On the other hand, TS patients had higher levels of systolic (z-score 1.04 vs -0.08, p=0.001) and diastolic (z-score 1.08 vs 0.33, p=0.031) blood pressure (BP) and aspartate (AST) and alanine (ALT) aminotransferase levels (26 vs 20 U/L, p=0.008 and 19 vs 14 U/L, p=0.004, respectively). CONCLUSION: Patients with TS, all submitted to GHT, had lower body fat levels compared with controls, despite similar BMI. Although we found no differences in cIMT between the two groups, young girls with TS had higher BP and transaminase levels. Early anthropometric, cardiovascular, and analytical monitoring of patients with TS is essential to detect abnormalities and prevent further complications.

Treatment modalities and outcomes in pediatric Cushing's disease - report of three cases and literature review.

OBJECTIVES: Cushing's disease (CD) is a diagnostic and therapeutic challenge, especially in pediatric patients. CD, primarily caused by adrenocorticotropic hormone-secreting pituitary adenomas, manifests typically with growth retardation and weight gain. There are no published guidelines for pediatric patients. CASE PRESENTATION: We report three pediatric patients diagnosed with CD in a Portuguese tertiary hospital. All patients presented with hypercortisolism features. All patients underwent transsphenoidal pituitary surgery (TSS) as a first-choice treatment; however, it was unsuccessful in one patient and the other patients experienced recurrence. Patients were submitted to different approaches so basal serum cortisol levels could be achieved. Two of three patients achieved remission. CONCLUSIONS: TSS remains the first-line treatment yet challenging due to microadenomas and technical complexities. Medical therapy with agents like metyrapone or ketoconazole, pituitary radiotherapy, or bilateral adrenalectomy are, usually, second-line interventions, unless there is a contraindication to surgery. Our findings support the finding that a shorter hypothalamic-pituitary-adrenal axis recovery time increases the risk of recurrence of CD. Our cases illustrate the intricate management and variable outcomes of pediatric CD, underscoring the importance of multidisciplinary care and continuous surveillance.

Quality of Life and Hormonal Impairment in Pediatric Patients With Craniopharyngiomas.

INTRODUCTION: Craniopharyngiomas (CP) are tumors in the sellar region that, despite a high survival rate, are associated with significant morbidity, including hypothalamic, hormonal, and visual dysfunction. This study aimed to assess the quality of life (QoL) in pediatric patients with CP and to evaluate its relationship with various factors, with a focus on the impact of endocrine dysfunction. METHODS: In this observational cross-sectional study, patients with CP aged between 0 and 18 years, currently followed up in a tertiary hospital by a multidisciplinary team, were included. QoL was assessed using the validated PEDS-QL4.0 questionnaire, which was administered to parents. This tool estimates Global QoL (QoL-G), further divided into Physical (QoL-P) and Psychosocial (QoL-PS) dimensions, including Emotional (QoL-Em), Social (QoL-S), and School (QoL-Sc) aspects. In Portugal, the estimated average QoL-G is 79.8, QoL-P is 83.5, and QoL-PS is 78.2. Variables studied included gender, current and diagnostic age, follow-up time, presence of hydrocephalus, hypothalamic involvement, type of resection (total or subtotal), radiotherapy, visual impairment, hormonal deficits, and therapy. RESULTS: The study included 11 patients with a median age of 15.2 years (interquartile ratio (IQR), 9.7-17.9 years) and a mean age at diagnosis of 9.3±4.1 years. Of these patients, 54.5% were male, and 36.4% were obese. Subtotal resection was performed in 72.7% of cases. Hydrocephalus was present in 54.5% of the patients, hypothalamic involvement in 63.7%, radiotherapy was received by 81.8%, and visual impairment was noted in 54.5%. All patients presented with at least one hormonal deficit. The average QoL-G was 69.9±22.5, with QoL-P at 66.9±30.0 and QoL-PS at 70.9±21.4. A worse QoL-S was associated with female gender (p=0.030) and subtotal resection (p=0.048). Worse QoL-G, QoL-P, QoL-Em, and QoL-PS were linked to hypothalamic involvement (p values 0.008, 0.025, 0.015, and 0.009, respectively). Irradiated patients had worse QoL-G (p=0.006). Treatment with sexual hormones enhanced QoL-Global (p=0.035) and QoL-Emotional (p=0.020), while treatment for adrenal insufficiency and diabetes insipidus improved QoL-Emotional (p=0.021 and p=0.013). No significant associations with visual deficit or obesity were found. CONCLUSIONS: Pediatric patients with CP appear to have poorer QoL-G, QoL-P, and QoL-PS compared to the healthy Portuguese population. However, the small sample size limits statistically significant associations with many of these variables. Predictors of worse QoL include female gender, hypothalamic involvement, subtotal resection, and radiotherapy. The results may be biased due to the small sample size, questionnaire administration to parents, and possible inadequacy of the questionnaire for the studied population. There is a need for a more suitable tool to enable a more precise assessment of QoL in these patients.

Glycemic Control and Metabolic Parameters in Children and Adolescents With Type 1 Diabetes.

AIM: The association between glycemic control and metabolic status is poorly defined in children and adolescents with T1D, besides being biologically plausible. We aimed to evaluate the association between glycemic control and body mass index (BMI), blood pressure (BP), and lipid profile in children and adolescents with T1D. METHODS: Observational cross-sectional study including children and adolescents (5-18 years old) followed in our outpatient clinic with the diagnosis of T1D for at least a year. We used linear regression models (unadjusted and adjusted to sex and age) to evaluate the association between glycated hemoglobin (A1c) and time in range (TIR), several prespecified metabolic parameters, and prespecified demographic and clinical characteristics. We considered a p-value of <0.05 to be statistically significant. RESULTS: A total of 144 patients were included, 51% of whom were female. The population had a mean age of 12.7±3.4 years old. We report a positive association between A1c and BMI, systolic and diastolic BP, total- and LDL-cholesterol and triglycerides. Females and patients diagnosed at a younger age presented with higher A1c values. There is a tendency for a negative association between TIR and the former parameters. Higher A1c levels and lower TIR were associated with higher glycemic variability and were treated with a higher basal insulin per Kg dose. CONCLUSION: Our results support an important association between worse glycemic control and an unhealthier metabolic profile in children and adolescents with T1D. We can hypothesize that a good glycemic profile is needed to achieve good metabolic control at a young age.

Adrenal carcinoma as the first manifestation of a Li­Fraumeni syndrome in three paediatric patients.

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Quality of Life of Children and Adolescents with Short Stature: The Twofold Contribution of Physical Growth and Adaptive Height-Related Cognitive Beliefs.

This study aimed to examine the health-related quality of life (HrQoL), coping, height-related beliefs, and social support of children/adolescents with short stature, the sociodemographic, clinical, and psychosocial variables associated with HrQoL, and the moderating role of sociodemographic and clinical variables on the associations between psychosocial variables and HrQoL. 114 Portuguese children/adolescents with short stature, aged 8-18 years old, completed the Quality of Life in Short Stature Youth questionnaire and the Satisfaction with Social Support Scale. Regression analyses explained 54% of the variance of HrQoL, with significant main effects of current height deviation and height-related beliefs, and a significant interaction effect between beliefs and diagnosis. Results suggest that a multidisciplinary therapeutic approach, not only focused on hormone treatment to boost physical growth, but also including psychosocial interventions focused on the modification of height-related beliefs, may contribute to improve the HrQoL of pediatric patients with short stature.

Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia

ABSTRACT Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Subjects and methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Treatment of Isolated Idiopathic Growth Hormone Deficiency in Children and Thyroid Function: Is the Need for LT4 Supplementation a Concern in Long-Term Therapy?

Introduction Recombinant human growth hormone (rhGH) replacement therapy might be able to induce hypothyroidism, but this is a controversial issue. Previous studies evaluated the effects of rhGH replacement therapy on thyroid function, but little information is available in the subset of children with isolated idiopathic growth hormone deficiency (GHD). Our aim was to assess the effects of rhGH replacement therapy on thyroid function in children with isolated idiopathic GHD. Methods Retrospective analysis of the medical files of 64 children with confirmed GHD treated with rhGH. After review, 56 children with isolated idiopathic GHD and treated with rhGH for at least one year were included. Auxological (weight standard deviation score [SDS], height SDS, growth velocity [GV] SDS) and biochemical (free thyroxine [FT4], thyroid-stimulating hormone [TSH], and insulin-like growth factor 1 [IGF-1]) parameters were recorded before, during, and after treatment with rhGH. Results FT4 and TSH levels decreased significantly during rhGH therapy in children with isolated idiopathic GHD. Twenty-one percent (n=12) of the children developed hypothyroidism, on average 47 months after initiation of rhGH. Higher baseline FT4 levels were protective against the need for levothyroxine (LT4) (OR=0.8, CI 0.592-0.983; p=0.036). Hypothyroidism was reversed after interruption of rhGH, except in one patient; FT4 levels returned to baseline in the first year after completing the treatment. Final height SDS of the children who developed hypothyroidism was not different from their counterparts without hypothyroidism (-1.24 [-1.52 to -1.10] vs -1.13 [-1.78 to -0.74], p=1.000). Predicted adult height (PAH) SDS in patients who completed rhGH treatment was similar in both LT4 supplemented (n=7; final Ht SDS -1.16 [-1.31 to -1.10] vs PAH -1.00 [-1.42 to -0.48]; p=0.398) and not supplemented patients (n=25; final Ht SDS -1.46 [-1.83 to -0.78] vs PAH SDS -0.88 [-1.35 to -0.56]; p=0.074). Conclusions Our results show that patients with isolated idiopathic GHD may transiently need LT4 during GH treatment. Properly supplemented patients achieved PAH.

Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia.

Objective: CYP21A2 mutation heterozygote carriers seem to have an increased risk of hyperandrogenism. However, the clinical relevance of the heterozygote carrier status and the reliability of hormonal testing in discriminating a carrier from a non-carrier are puzzling questions. We aimed to characterize a population of Portuguese females suspected of having non-classic congenital adrenal hyperplasia (NC-CAH) due to clinical and biochemical criteria and who have undergone CYP21A2 molecular analysis. Methods: Retrospectively, we have analyzed the clinical records of 131 females (32 girls aged 3-9 and 99 adolescents and premenopausal women aged 13-49) who underwent complete CYP21A2 molecular analysis due to suspicion of NC-CAH. We divided included participants into three groups according to the CYP21A2 molecular analysis: NC-CAH females (46), heterozygous carriers (49), and wild type (36). We then compared clinical signs and symptoms as well as biochemical and molecular data between carriers and NC-CAH individuals and between carriers and wild type females. We measured 17OHP by electrochemiluminescence immunoassay. Results: Clinical features were similar between groups. Heterozygous carriers presented higher basal and post-cosyntropin 17-hydroxyprogesterone (17OHP) than wild type individuals (p < 0.05) and lower basal and stimulated 17OHP levels than NC-CAH patients (p < 0.05). We discovered a considerable overlap between 17OHP levels among groups. The most common pathogenic variant we identified was p.Val282Leu. Conclusion: In this population of hyperandrogenic women and children, heterozygous carriers showed higher basal and stimulated 17OHP than non-carriers although normal basal and stimulated 17OHP responses do not exclude heterozygosity for CYP21A2 pathogenic variants. In this study, only the molecular analysis presented good sensitivity in identifying heterozygotes.

Quality of Life in Children Diagnosed With Non-classic Congenital Adrenal Hyperplasia.

Background Non-classical congenital adrenal hyperplasia (NC-CAH) is a chronic disease characterised by excessive androgen production that may negatively affect the quality of life (QoL) of affected patients. Pediatric Quality of Life Inventory 4.0 (PedsQL™) is a validated tool to assess health-related QoL (HRQoL). Methods A cross-sectional study including 19 patients with NC-CAH was carried out in the pediatric endocrinology department. NC-CAH patients who agreed to participate were included. Anthropometric data was collected. PedsQL™ was applied to the patients and their parents. Patients were divided into four groups according to age: 2-4, 5-7, 8-12, and 13-18 years old. The control group consisted of healthy individuals from the instrument's validation studies for the Portuguese population and the standard control population used in the PedsQL™ validation study. Results The only difference found concerns the parents' score results for children aged 8-12, which showed physical health and emotional dimension scores significantly higher (86.16±9.86 vs.68.90±23.02 p=0.004, 69.17±14.14 vs. 65.82±19.24 p=0.004), while psychosocial health's score and total scale score were significantly lower than the control group (59.99±9.90 vs. 69.34±14.07 p=0.047, 73.11±4.65 vs.78.86±16.61 p=0.017). Conclusion HRQoL scores are not negatively affected by NC-CAH in most group ages, with the exception of the parents' reports on HRQoL for children aged 8-12. Further studies with a greater number of patients are needed to determine the impact of this chronic disease on the HRQoL of children.

Liver dysfunction and hypoglycaemia as presentations of hypopituitarism in a child.

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Papillary thyroid carcinoma in a 7-year-old boy presenting with a goitre without microcalcifications and enlarged cervical lymph nodes.

The most frequent type of thyroid malignancy in children is papillary thyroid carcinoma (PTC), which usually presents as a thyroid nodule, but may also present as a diffuse infiltration with microcalcifications. Herein, we report the case of an uncommon presentation of a PTC in a 7-year-old boy. The child was referred for a goiter with cervical lymphadenopathies. Ultrasonography showed a hypervascularised goiter without microcalcifications but with numerous bilateral cervical nodular formations. A lymph node biopsy revealed metastatic thyroid cancer, hence a total thyroidectomy and complete neck dissection were performed. Histopathology confirmed a PTC. Ablative 131I, 30 mCi was performed 4 months postsurgery. At the end of this treatment, a metastatic lung nodule was identified. Since then, another three ablative 131I treatments have been administered. Thyroid cancers presenting as a diffuse infiltration without microcalcifications are rare. In the presence of lymphadenopathies, thyroid cancer needs to be suspected, even without microcalcifications.

Wolfram syndrome: Portuguese research.

INTRODUCTION: Wolfram syndrome (WFS) is a neurological and endocrinological degenerative disorder, also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy, and Deafness) syndrome. It is an autosomal recessive disorder, mostly involving the Wolfram syndrome 1 gene (WFS1). The phenotypic pleiomorphism, rarity, and molecular complexity complicate the follow-up of these patients. MATERIAL AND METHODS: We aimed to describe the clinical characteristics and the follow-up of 11 patients with this disorder. We retrospectively analysed all WFS patients diagnosed between 1990 and 2020 in the Centro Hospitalar São João, a tertiary hospital in Northern Portugal. RESULTS: Eleven patients were included. Four patients had all 4 components of DIDMOAD. The presentation was diabetes mellitus (DM) in 9 patients, optic atrophy (OA) in another patient, and diabetes insipidus (DI) in another one. The median age of DM and OA diagnosis was 6 and 14 years, respectively. Nine patients had diabetes mellitus, and the other 2 patients had impaired glucose tolerance. All patients had OA. Four patients presented DI, all of them diagnosed in adolescence. Four patients had hearing impairment, 5 had urological abnormalities, 5 had neurological disorders, and 8 had psychiatry disorders. Eight patients had a broad spectrum of recessive mutations in WFS1. CONCLUSION: The information obtained in this study can facilitate further research in an attempt to improve prevention strategies for this devastating disease.

Clinicopathological features of neonatal subcutaneous fat necrosis and its implications.

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Autonomous functioning thyroid nodule - a rare paediatric diagnosis.

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Neonatal presentation of growth hormone deficiency in CHARGE syndrome: the benefit of early treatment on long-term growth

SUMMARY CHARGE syndrome is a complex disorder involving multiple congenital anomalies and is caused by heterozygous mutations in the CHD7 gene. Growth retardation is a characteristic finding and about 10% of cases present growth hormone (GH) deficiency. GH treatment of short stature in CHARGE syndrome has shown some benefit, but normal height is rarely attained. We report a girl with CHARGE syndrome due to a de novo frameshift mutation in the CHD7 gene (c.2509_2512delCATT), in whom recurrent hypoglycaemia led to the diagnosis of GH deficiency in the second month of life. Early initiation of treatment with recombinant GH resulted in normal growth over ten years of follow-up. This case is the youngest reported CHARGE patient to be diagnosed and treated for GH deficiency and demonstrates that GH deficiency in CHARGE syndrome may manifest early in life through hypoglycaemia, before growth retardation is noted, and can be successfully treated with recombinant GH.

Symptomatic hypoglycemia in a child with common variable immunodeficiency: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome.

Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a rare condition characterized by symptomatic ACTH deficiency and primary hypogammaglobulinemia, caused by pathogenic variants of the nuclear factor kappa-B subunit 2 (NF-κB2) gene. We report the case of a 9-yr-old boy diagnosed with common variable immunodeficiency at the age of 3, who is under monthly intravenous immunoglobulin. The patient was admitted twice to the pediatric emergency service at the age of 9 due to symptomatic hypoglycemic events. During the hypoglycemic crisis, serum cortisol was low (< 0.1 µg/dL), ACTH level was inappropriately low (4.4 ng/L) and the ACTH stimulation test failed to raise the blood cortisol level. Pituitary magnetic resonance imaging showed a hypoplastic pituitary. Other pituitary deficiencies, primary hyperinsulinism and other metabolic diseases were excluded. He started hydrocortisone replacement treatment while maintaining immunoglobulin substitution and he remains asymptomatic. Molecular analysis revealed the heterozygous nonsense pathogenic variant, c.2557C>T (Arg853Ter) in the NF-κB2 gene. Thus, symptomatic hypoglycemia in a child with primary immunodeficiency should raise the suspicion of DAVID syndrome, prompting NF-κB2 molecular analysis, to allow timely and appropriated therapy and genetic counseling.

Neonatal diabetes - same disease, same gene, different outcomes.

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Neonatal presentation of growth hormone deficiency in CHARGE syndrome: the benefit of early treatment on long-term growth.

CHARGE syndrome is a complex disorder involving multiple congenital anomalies and is caused by heterozygous mutations in the CHD7 gene. Growth retardation is a characteristic finding and about 10% of cases present growth hormone (GH) deficiency. GH treatment of short stature in CHARGE syndrome has shown some benefit, but normal height is rarely attained. We report a girl with CHARGE syndrome due to a de novo frameshift mutation in the CHD7 gene (c.2509_2512delCATT), in whom recurrent hypoglycaemia led to the diagnosis of GH deficiency in the second month of life. Early initiation of treatment with recombinant GH resulted in normal growth over ten years of follow-up. This case is the youngest reported CHARGE patient to be diagnosed and treated for GH deficiency and demonstrates that GH deficiency in CHARGE syndrome may manifest early in life through hypoglycaemia, before growth retardation is noted, and can be successfully treated with recombinant GH.