Hormone Research in Paediatrics最新文献

Introduction: The testicular regression syndrome (TRS) is a form of differences of sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress. The clinical phenotype of TRS often overlaps with that of partial gonadal dysgenesis (PGD). Previous studies have demonstrated a causal association between TRS/PGD and heterozygous missense variants of DHX37.

Methods: We enrolled 11 Japanese 46,XY individuals (from 10 families) with TRS/PGD who exhibited undetected or hypoplastic testes, Müllerian duct regression, and low serum testosterone or anti-Müllerian hormone levels. The subjects underwent targeted sequencing of 36 known causative genes for DSD, PCR-based Sanger sequencing of DHX37, or whole exome sequencing.

Results: Previously described pathogenic variants or novel nonsense variants (SRY, NR5A1, and DMRT1) were observed in four out of 10 families. Additionally, we identified two heterozygous rare variants of DHX37 in four families: a previously reported pathogenic variant (c.923G>A, p.Arg308Gln) in three and a novel likely pathogenic variant (c.1882A>C, p.Thr628Pro) in one. The external genitalia of patients with the DHX37 variants varied from female-type to male-type without micropenis. Eighty percent of Japanese patients with TRS/PGD had monogenic disorders including DHX37 variant being the most commonly identified (40%). The external or internal genital phenotype of TRS/PGD overlaps between DHX37 variant carriers and others.

Conclusions: DHX37 variant is one of common genetic causes in Japanese patients with TRS/PGD without Müllerian derivatives. Genetic test is helpful in detecting DHX37-related TRS/PGD, because of the phenotypic diversity of the external genitalia in this disorder.

Background: Short stature is one of the most common reasons for referral to a pediatric endocrinologist, that can be due to multitude of conditions, including an ever-growing list of genetic etiologies. Despite the numerous different causes, options for medical therapy remain quite limited, with the primary medication available being recombinant human growth hormone (rhGH). A second option is recombinant insulin-like growth factor 1 (rIGF-1) in select patients with severe primary IGF-1 deficiency. Alternative strategies to increase height have been attempted such as delaying the onset of puberty with a gonadotropin releasing hormone agonist or delaying epiphyseal fusion with an aromatase inhibitor. However, these options focus on increasing the duration of growth as opposed to directly stimulating growth at the growth plate.

Summary: Novel approaches to growth promotion have recently been developed, including analogs of C-type natriuretic peptide (CNP). The purpose of this study is to review the function of CNP and its potential use in different conditions.

Key messages: • Alterations in the CNP/FGFR3 pathway can lead to multiple defined genetic causes of short stature. • The CNP pathway has become the focus for treatment of children with short stature that suffer from such genetic conditions, with promising outcomes.

Introduction Aldosterone synthase deficiency is a rare autosomal recessive disease characterized by vomiting, dehydration, salt wasting, life-threatening hyperkalemia in infancy, followed by failure to thrive. It results from pathogenic variants in CYP11B2. Case Presentation A boy, born in Montreal to Lebanese parents who are first cousins, was referred at nine days of life for severe dehydration. A diagnosis of primary adrenal insufficiency was made, and treatment was started with fludrocortisone and hydrocortisone. Exome sequencing revealed a homozygous variant p.(Asn201Asp)(N201D). In silico, this variant was considered benign, but in vitro functional expression studies established it caused the severe aldosterone deficiency. It ended the diagnostic odyssey and allowed to safely stop hydrocortisone replacement. Conclusion If a gene variant co-segregates with a phenotype, in vitro functional studies are required even if in silico studies are negative.

Background: In the last 15 years, the care provided for individuals born with differences of sex development (DSD) has evolved, with a strong emphasis on interdisciplinary approaches. However, these developments have not convinced some stakeholders to embrace the current model of care. This care model has also paid insufficient attention to socio-cultural differences and global inequalities.

Summary: This article is an opinion statement, resulting from in-depth discussions and reflection among clinicians, patients, and family support organizations based in the US and Europe, where we seek areas of common ground and try to identify opportunities to further develop resources. The product of these conversations is summarized in 10 panels. The corresponding sections provide additional discussion on some of the panel items.

Key messages: Participants identified areas of agreement and gained a deeper understanding of the reasons behind disagreements on certain matters and identified the necessary steps to foster future consensus. We offer preliminary recommendations for guiding clinical management and resource allocation. By promoting a broader consensus, we aim to enhance the quality of care and well-being for individuals of all ages who have a DSD.

Background: Skeletal dysplasias encompass a group of genetic conditions associated with cartilaginous and bone tissue abnormalities, exhibiting a variable phenotype depending on the involved genes and mechanisms. Differential diagnosis is challenging as there are many skeletal dysplasias with similar phenotypes.

Summary: In this review, we describe the physiology of skeletal development and the classification of skeletal dysplasias, followed by a practical approach to the workup of a child with suspected skeletal dysplasia. Diagnosis requires clinical, laboratory, and radiological evaluation to differentiate potential conditions in the patient. Genotyping has emerged as a confirmatory tool in many cases, enabling personalized treatment through a multidisciplinary approach and assessment of associated comorbidities.

Key messages: As skeletal dysplasias often present with short stature, proportionate or disproportionate, the pediatric endocrinologist plays a crucial role in initial investigative and diagnostic guidance. Identifying the critical clinical manifestations, conducting appropriate initial screening tests, and referring for multidisciplinary follow-up contribute to expeditious diagnosis and family support.

Introduction: Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Loss of function mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene causes X-linked central hypothyroidism and represent the most common genetic cause of central hypothyroidism. In addition to central hypothyroidism, some patients with IGSF1 deficiency have hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Here, we describe a case-series of three patients with central hypothyroidism caused by two novel IGSF1mutations.

Case presentation: Three males (including two siblings) were diagnosed with central hypothyroidism between 0.06 - 1.5 years of age. Additional features included hypoprolactinemia, normal cortisol and growth hormone - insulin like growth factor 1 axis, high body mass index, birth weight greater than 0 SDS and isolated speech delay. Genetic testing identified two novel IGSF1 mutations [(c.1829G>A, p.W610* and c.3692G>A, p.(Cys123Tyr)]. Both variants have not been reported in the gnoMAD database (~90,000 individuals) and are predicted deleterious.

Conclusions: Loss of function mutations in IGSF1 represent the most common genetic cause of central hypothyroidism Detailed phenotyping of IGSF1 deficiency from extensive case series have led to formulation of recommendations for clinical management of these patients. We have highlighted the potential adverse consequences of delayed treatment of CCH (speech delay).

Introduction: Menarche is the last stage of pubertal development, which coincides with the completion of longitudinal growth. As a consequence of the lack of national and up-to-date data related to post-menarcheal (PM) growth, the aim of our work was to evaluate post menarcheal growth in a group of contemporary healthy Chilean girls followed, prospectively, until 4 years post-menarche.

Methods: This study was nested within the GOCS cohort, in a prospective fashion. The girls were followed yearly after menarche for at least four years. We modeled each girl growth using a Super Imposition by Translation and Rotation (SITAR) model.

Results: A total of 534 girls were evaluated prospectively, 399 girls had height measured two years after menarche, 421 after three years, and 364 of 534 had height measured at four year post menarche. Expected height gained PM, in the complete study group was 6.6 ± 2.5 cm. We observed that the largest gain in height occurred after the first year PM (3.8 1.5 cm). According to the age of menarche, the group with earlier menarche (< 11 years old ) had a greater height gain in cm after four years PM ( 8.2± 3.2 cm ) and the smallest gain was among girls with menarche at an age older than 13 yr (4.4±1.6) ( p<0.001). Age at menarche was significantly associated with all post menarche growth patterns (size, timing and intensity), indicating that girls with older age at menarche grew taller, later and slower than girls with younger age at menarche. Adjusting PM growth pattern by BMI maintained all these association. Applying the SITAR model specifically , girls experiencing menarche after the age of 13 years exhibited slower growth , occurring slightly earlier and with less intensity when adjusted by BMI at menarche .

Conclusion: In a national and updated dataset we observed that girls grew until 4 years post menarche an average of 6.6 ± 2.5 cm., with greatest gain occurring in the first year PM , (3.8 ± 1.5 cm). Age at menarche was associated with menarche growth patterns.

Introduction: Agranulocytosis is a rare, but serious complication of methimazole (MMI) use for Graves' disease (GD). Treatment requires discontinuation of MMI, and the use of propylthiouracil (PTU) is also contraindicated. Few reports exist about the optimal alternative treatment regimens for the management of thyrotoxicosis in these medically complex patients in the pediatric population.

Case report: We report prolonged saturated solution of potassium Iodide (SSKI) use (29 days) in a 17-year-old female with GD and MMI-induced agranulocytosis, who presented with septic shock. Her treatment course also included beta-blockade, cholestyramine, and granulocyte colony stimulating factor. We performed a review of the literature on the use of SSKI in the management of thyrotoxicosis, as well as best practices from the view of endocrinology, infectious disease, hematology, surgery, and intensivists, for the evaluation and management of MMI-induced agranulocytosis.

Discussion: The management of MMI-induced agranulocytosis and associated sequelae require subspecialty input and intensive evaluation and monitoring. Alternative treatments to manage hyperthyroidism and control symptoms of thyrotoxicosis during agranulocytosis are a bridge to definitive therapy, and include beta-blockade, SSKI, cholestyramine, steroids, lithium, and plasmapheresis.