Hypogonadotropic hypogonadism presenting with arhinia: a case report

INTRODUCTION: Arhinia, congenital absence of the nose, is a rare malformation. We present the third reported case of arhinia accompanied by hypogonadism and demonstrate that this is due to gonadotropin deficiency. CASE PRESENTATION: A 13-year-old Caucasian boy with congenital arhinia presented for evaluation of delayed puberty and micropenis. We examined genes known to be associated with hypogonadotropic hypogonadism for mutations and performed a chromosomal microarray to assess copy number variation. CONCLUSION: No mutations in KAL1, FGFR1, PROK2, PROKR2, FGF8, CHD7 and GnRHR were identified in our patient and there were no copy number variations observed that would explain the phenotype. Though studies are limited in such patients, we suggest that hypogonadotropic hypogonadism is associated with arhinia and that the two entities likely result from a common genetic cause that affects early nasal development and gonadotropin-releasing hormone neuron formation or migration

Medullary thyroid cancer in a 9-week-old infant with familial MEN 2B: Implications for timing of prophylactic thyroidectomy

BACKGROUND: Patients with Multiple Endocrine Neoplasia type 2 (MEN 2) are at high risk of developing aggressive medullary thyroid carcinoma (MTC) in childhood, with the highest risk in those with MEN type 2B (of whom >95% have an M918T RET proto-oncogene mutation). Metastatic MTC has been reported as young as 3 months of age. Current guidelines recommend prophylactic thyroidectomy within the first year of life for MEN 2B. PATIENT FINDINGS: We report a 9-week-old infant with MTC due to familial MEN 2B. A full-term male infant, born to a mother with known MEN 2B and metastatic MTC, had an M918T RET proto-oncogene mutation confirmed at 4 weeks of age. He underwent prophylactic total thyroidectomy at 9 weeks of age. Pathology showed a focal calcitonin-positive nodule (2.5 mm), consistent with microscopic MTC. SUMMARY: This case highlights the importance of early prophylactic thyroidectomy in MEN 2B. Although current guidelines recommend surgery up to a year of life, MTC may occur in the first few weeks of life, raising the question of how early we should intervene. In this report, we discuss the risks, benefits and barriers to performing earlier thyroidectomy, soon after the first month of life, and make suggestions to facilitate timely intervention. Prenatal anticipatory surgical scheduling could be considered in familial MEN 2B. Multidisciplinary collaboration between adult and pediatric specialists is key to the optimal management of the infant at risk

Primary Caregivers of Children Affected by Disorders of Sex Development: Mental Health and Caregiver Characteristics in the Context of Genital Ambiguity and Genitoplasty

Purpose. To determine the relationship between having a child with a DSD including ambiguous external genitalia, as well as the decision of whether or not to have early genitoplasty for that child, on the mental health and parenting characteristics of caregivers. Materials and Methods. Caregivers were recruited from centers that specialize in DSD medicine and completed the Beck Depression Inventory 2nd Edition (BDI-2), Beck Anxiety Index (BAI), Parent Protection Scale (PPS), Child Vulnerability Scale (CVS) and Parenting Stress Index/Short Form (PSI/SF). Results and Conclusions. Sixty-eight caregivers provided informed consent and completed the study. Among female caregivers whose children never received genitoplasty, greater parenting stress was reported (F(1, 40) = 5.08, p = .03). For male caregivers, those whose children received genitoplasty within the first year of life reported more overprotective parenting and parenting stress than those whose children received genitoplasty later than 12 months of age (F(1, 13) = 6.16, p = 0.28); F(1, 15) = 6.70, p = .021), respectively)

Proteolytic cleavage of insulin-like growth factor binding protein 4 (IGFBP-4). Localization of cleavage site to non-homologous region of native IGFBP-4

Insulin-like growth factor binding protein 4 (IGFBP-4) is a 24-kDa protein that binds insulin-like growth factor 1 (IGF-1) and IGF-2 with high affinity and inhibits IGF action in vitro. We recently described a protease produced by the B104 neuronal cell line that cleaves IGFBP-4, yielding an approximate 16-kDa immunoreactive protein that binds IGFs with reduced affinity. We analyzed fragments produced by exposing pure IGFBP-4 to the protease to determine potential cleavage sites. Electrospray mass spectrometry and amino acid sequencing indicated the 16-kDa fragment spanned the NH2 terminus of native IGFBP-4 through Lys-120. There was evidence for an additional proteolytic fragment beginning at amino acid 132 and continuing to the COOH terminus. Proteolysis could be blocked by a synthetic peptide that spanned amino acids 117-126 but not by peptides that contained flanking sequences 111-120 or 125-135. Mutagenesis was used to alter the basic residue at position 120. The expressed mutant IGFBP-4 (K120A) was relatively resistant to cleavage, strongly suggesting that residues 120-121 represent the cleavage site. This region of IGFBP-4 is not homologous with other IGFBPs, explaining the apparent specificity of the protease for IGFBP-4. The 16-kDa IGFBP-4 fragment no longer inhibited IGF-1-stimulated thymidine uptake in vitro, suggesting that proteolytic processing of IGFBP-4 may have important functional consequences in vivo

Adult and Near-Adult Height in Patients with Severe Insulin-Like Growth Factor-I Deficiency after Long-Term Therapy with Recombinant Human Insulin-Like Growth Factor-I

BACKGROUND: Treatment with recombinant human insulin-like growth factor-I (IGF-I) stimulates linear growth in children with severe IGF-I deficiency (IGFD). AIMS: To evaluate the efficacy and safety of treatment with IGF-I in patients with severe IGFD treated until adult or near-adult height. METHODS: Twenty-one children with severe IGFD were treated until adult or near-adult height under a predominantly open-label design. All patients were naive to IGF-I. Recombinant human IGF-I was administered subcutaneously in doses between 60 and 120 µg/kg twice daily. Nine patients received additional therapy with gonadotropin- releasing hormone (GnRH) analog for a mean period of 2.9 ± 1.8 years. RESULTS: Mean duration of treatment was 10.0 years. Mean height velocity increased from 3.1 cm/year prior to treatment to 7.4 cm/year during the first year of treatment. Height velocities during the subsequent years were lower, but remained above baseline for up to 12 years. Cumulative mean Δ height SD score at (near) adult height was +2. The observed mean gain in height was 13.4 cm more than had been expected without treatment. The adult height achieved by the patients also treated with GnRH analog was not different from those who received IGF-I therapy alone. There were no new safety signals identified in these patients, a subset of those previously reported. CONCLUSION: Long-term therapy with IGF-I improves adult height of patients with severe IGFD. Most patients did not bring their heights into the normal adult range

cAMP and PMA enhance the effects of IGF-I in the proliferation of endometrial adenocarcinoma cell line HEC-1-A by acting at the G 1 phase of the cell cycle

The present study was undertaken to determine whether endometrial cancer cell line HEC-1-A differ from nontransformed cells, in that the cAMP and protein kinase C pathways may enhance IGF-I effects in mitogenesis by acting at the G 1 phase of the cell cycle instead of G 0 . Immunofluorescence staining of HEC-1-A cells using the proliferating cell nuclear antigen (PCNA) monoclonal antibody and flow cytometric analysis determined that HEC-1-A cells do not enter the G 0 phase of the cell cycle when incubated in a serum-free medium. Approximately 51% of the cells were in G 1 , 12% were in S and 37% in G 2 phase of the cell cycle prior to treatment. Forskolin and phorbol-12-myristate 13-acetate (PMA) were used to stimulate cAMP production and protein kinase C activity, respectively. IGF-I, forskolin and PMA each increased ( P <0.01) [ 3 H]-thymidine incorporation in a dose and time dependent manner. The interaction of forskolin and PMA with IGF-I was then determined. Cells preincubated with forskolin or PMA followed by incubation with IFG-I incorporated significantly more ( P <0.01) [ 3 H]-thymidine into DNA than controls or any treatment alone. It is concluded that forskolin and, to a lesser extent, PMA exert their effect at the G 1 phase of the cycle to enhance IGF-I effects in cell proliferation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75013/1/j.1365-2184.1995.tb00061.x.pd

International Consensus Guideline on Small for Gestational Age (SGA): Etiology and Management from Infancy to Early Adulthood

: This International Consensus Guideline was developed by experts in the field of SGA of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Besides, it presents long-term consequences of SGA birth and new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, and the metabolic and cardiovascular health of young adults born SGA after cessation of childhood-GH-treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardio-metabolic health profile in adulthood. Children born SGA with persistent short stature &lt; -2.5 SDS at age 2 years or &lt; -2 SDS at age of 3-4 years, should be referred for diagnostic work-up. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033-0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3-4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle

Proceedings from the Turner Resource Network symposium: The crossroads of health care research and health care delivery

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals. The inaugural “Turner Resource Network (TRN) Symposium” brought together individuals with Turner syndrome and their families, advocacy group leaders, clinicians, basic scientists, physician-scientists, trainees and other stakeholders with interest in the well-being of individuals and families living with the condition. The goal of this symposium was to establish a structure for a TRN that will be a patient-powered organization involving those living with Turner syndrome, their families, clinicians, and scientists. The TRN will identify basic and clinical questions that might be answered with registries, clinical trials, or through bench research to promote and advocate for best practices and improved care for individuals with Turner syndrome. The symposium concluded with the consensus that two rationales justify the creation of a TRN: 1. inadequate attention has been paid to the health and psychosocial issues facing girls and women who live with Turner syndrome; 2. investigations into the susceptibility to common disorders such as cardiovascular or autoimmune diseases caused by sex chromosome deficiencies will increase understanding of disease susceptibilities in the general population.Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant 1R13HD079209-01)March of Dimes Birth Defects FoundationAmerican Heart AssociationNational Institutes of Health (U.S.) Office of Women's HealthLeaping Butterfly MinistryTurner Syndrome Society of the United State

Diagnosis and management of Silver–Russell syndrome: first international consensus statement

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver–Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood