Role of genetic investigation in the diagnosis of short stature in a cohort of Italian children.

BACKGROUND: Short stature (SS) is defined as height more than 2 standard deviations below the mean for age and sex. Hypothyroidism, celiac disease, growth hormone deficiency, hormonal abnormalities, and genetic conditions are among its causes. A wide range of conditions often due to largely unknown genetic variants can elude conventional diagnostic workup. AIM: We used next-generation sequencing (NGS) to better understand the etiology of SS in a cohort of Italian children. PATIENTS AND METHODS: The study sample was 125 children with SS of unknown origin referred to our Institute between 2015 and 2021. All had undergone complete auxological and hormonal investigations to exclude common causes of SS. Genetic analysis was performed using a NGS panel of 104 genes. Clinical data were reviewed to clarify the pathogenicity of the variants detected. RESULTS: In this cohort, 43 potentially causing variants were identified in 38 children. A syndromic genetic condition was diagnosed in 7: Noonan syndrome in 3, Leri-Weill syndrome in 3, and hypochondroplasia in 1. Moreover, 8 benign variants and other 37 like benign variants were found. In 88 children, 179 variants of uncertain significance (VUS) were identified. No variant was found in 16 children. CONCLUSION: Genetic analysis is a useful tool in the diagnostic workup of patients with SS, in adapting management and treatment, and in identifying syndromes with mild atypical clinical features. The role of VUS should not be underestimated, particularly when multiple VUS with possible mutual worsening effects are present in the same child.

Growth hormone and early treatment.

Growth hormone (GH) treatment is approved by the US Food and Drug Administration (FDA) not only for GH deficiency (GHD) but also for other childhood growth disorders with growth failure and/or short stature. GHD is the most frequent endocrine disorder presenting with short stature in childhood. During neonatal period, metabolic effects due to congenital GHD require a prompt replacement therapy to avoid possible life-threatening complications. In childhood and adolescence, growth impairment is the most evident effect of GHD and early treatment has the aim of restore normal growth and to reach normal adult height. We reassume in this review the conditions causing GHD and the diagnostic challenge to reach an early diagnosis, and an early treatment, necessary to obtain the best results. Finally, we summarize results obtained in clinical studies about pediatric patients with GHD treated at an early age, in which a marked early catch-up growth and a normalization of adult height were obtained.

Genotype in the diagnosis of 21-hydroxylase deficiency: who should undergo CYP21A2 analysis?

AIMS: to confirm the diagnosis of 21-hydroxylase deficiency (21-OHD) by the analysis of CYP21A2 gene in infants with clinical and/or biochemical features of 21-OHD in order to clarify which patients to submit to genetic analysis; to analyze the genotype-phenotype concordance in these infants. SUBJECTS AND METHODS: We studied 25 children with clinical and/or biochemical features of 21-OHD. All of them and their parents were submitted to genetic analysis of CYP21A2. Patients were classified in 3 groups according to mutations' severity: severe (group A), moderate (group B) or mild (group C). RESULTS: CYP21A2 gene mutations were found in 17 children. Whereas all infants of groups A and B presented a classical form of 21- OHD, children of group C had a non-classical form of 21-OHD. Four infants resulted heterozygotes and 4 children were wildtype. A girl clinically presenting a non-classical form of 21-OHD resulted compound heterozygote with one of the mutations not described in literature (R25W) and whose residual enzymatic activity is not already known. All affected children presented a 17-OHP level after ACTH stimulation greater than 100 nmol/l. We found an optimal concordance between 17-OHP levels after ACTH test and genotype. CONCLUSIONS: CYP21A2 analysis permitted to confirm the diagnosis of 21-OHD in 68% of our children. To improve this percentage we suggest to perform the CYP21A2 analysis only when 17-OHP after ACTH test is greater than 100 nmol/l. Moreover, we found an optimal genotype-phenotype concordance in the 21-OHD patients.

Serum inhibin B levels before and after varicocelectomy in early adolescence.

BACKGROUND: Whereas no clear relationship has been observed between varicocelectomy and serum inhibin B levels in men, in adolescents comparison between inhibin B levels before and after varicocelectomy is lacking. AIM: To evaluate the effect of varicocele surgical treatment on inhibin B levels in adolescents at the beginning of puberty compared to a group of healthy adolescents. SUBJECTS AND METHODS: We studied 28 adolescents in Tanner 2 pubertal stage with a grade III left-sided varicocele (patients) compared to 13 age and pubertal stage-matched healthy adolescents (controls). All patients underwent blood tests to determine serum inhibin B levels before and 6 months after varicocelectomy by Palomo procedure. For comparison we investigated inhibin B levels in controls and repeated this test 6 months later. Testicular ultrasound was performed for patients only. RESULTS: Baseline inhibin B concentrations of patients and controls were 109.90 ± 40.26 and 109.33 ± 38.34 pg/ml, respectively. No significant changes were observed in patients' inhibin B concentrations after varicocelectomy (116.00 ± 42.65 pg/ml), or in controls during the 6 months' follow-up (99.12 ± 30.09 pg/ml). Doppler examination after treatment shows a complete resolution of varicocele in all the patients without alterations in testicular parenchyma. CONCLUSIONS: Varicocelectomy performed on adolescents at T2 pubertal stage might be useful to avoid alteration in inhibin B production and consequently in testicular function. Further studies are necessary to confirm the prognostic value of inhibin B levels and the benefit of early varicocelectomy in preserving the fertility of these adolescents.

Hypovitaminosis D and nocturnal hypertension in obese children: an interesting link.

In adults, low levels of vitamin D are associated with hypertension. The aim of this study was to evaluate the relationship between 24-h blood pressure (BP) patterns and vitamin D levels in obese children. We recorded anthropometric parameters, took blood samples for 25-hydroxivitamin D measurements and monitored ambulatory BP (ABP) in 32 obese children (male/female: 21/11, age 7-16 years). Subjects in the lower tertiles had higher homeostasis model assessment of insulin resistance, nighttime systolic and diastolic ABP, nighttime systolic and diastolic ABP load, 24-h ABP index and nighttime systolic and diastolic ABP index than those in the higher tertile. Vitamin D correlated negatively with 24-h and nighttime systolic ABP, 24-h systolic ABP load, nighttime systolic and diastolic ABP load, 24-h systolic ABP index and nighttime systolic ABP index. The percentage of subjects with pathological 24-h systolic BP (SBP) load, nighttime SBP load, nighttime diastolic BP (DBP) load, nighttime SBP index and nighttime DBP index increased progressively as the vitamin deficiency categories increased (χ(2)=10.26, P<0.05; χ(2)=16.34, P<0.01; χ(2)=10.23, P<0.05; χ(2)=10.38 and χ(2)=10.06, P <0.01). Low levels of vitamin D in obese children were associated with a higher BP burden, especially at night.

[Influence of thyroid morphology on psychomotor development in patients with congenital hypothyroidism during 8 year follow-up]. / Influenza della morfologia tiroidea sullo sviluppo psicomotorio di bambini affetti da ipotiroidismo congenito durante 8 anni di follow-up.

AIM: The aim of this paper was to evaluate the impact of thyroid morphology on auxological and neuropsychological development in children affected by congenital hypothyroidism (CH), treated with levothyroxine, up to 8 years of age. METHODS: Fifty-three children affected by CH divided into 3 groups on the basis of thyroid morphology determined at birth: patients with athyreosis (N=17), with ectopic gland (N=23), with in situ thyroid (N=13). The developmental quotient (DQ) was evaluated by the Brunet-Lezine test up to 3 years, and intelligent quotient (IQ) by the Terman-Merril test after 3 years of age. RESULTS: DQs at one year in athyreotic patients are lower (P<0,05) as compared to those determined in patients with other thyroid morphology. Later on these patients still showed lower DQ and IQ values than in other groups, although statistically not significant. CONCLUSION: Thyroid morphology seems to be fundamental in psychomotor development, in fact patients with athyreosis show a transient impairment at one year of age. This difference could be transient or to have repercussions on adult. Individualization of the starting dose of levothyroxine on the basis of thyroid morphology, could be useful.