Inas H. Thomas

Bone mineral density in young adult survivors of acute lymphoblastic leukemia

The purpose of the current study was to determine the prevalence of low bone mineral density (BMD) (ie, osteopenia) and identify factors associated with low BMD in young adult survivors of childhood acute lymphoblastic leukemia (ALL).

Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation

Permanent neonatal diabetes mellitus is a rare disorder known to be caused by activating mutations in KCNJ11 or ABCC8, inactivating mutations in INS, or very rarely in GCK or insulin promotor factor‐1 (IPF‐1) genes. We report a patient with permanent neonatal diabetes mellitus and severe exocrine pancreatic insufficiency. Ultrasound examination revealed pancreatic agenesis with a suggestion of a small amount of tissue in the head of the pancreas. Genetic testing revealed that the neonate had a homozygous Pro63fsX60 IPF‐1 mutation. This is the second reported case of neonatal diabetes mellitus secondary to a homozygous mutation in the IPF‐1 gene and supports the previously proposed biological role of IPF‐1 in the pancreatic development in human.

Metformin; a review of its history and future: from lilac to longevity

Metformin is a widely prescribed medication that has been used to treat children with type 2 diabetes in the United States for the past 15 years. Metformin now has a variety of clinical applications in pediatrics, and its potential clinical uses continue to expand. In addition to reviewing the current understanding of its mechanisms of action including the newly discovered effects on the gastrointestinal tract, we will also discuss current clinical uses in pediatrics, including in type 1 diabetes. Finally, we examine the existing state of monitoring for metformin efficacy and side effects and discuss prospective future clinical uses.

A cross-sectional view of the current state of treatment of youth with type 2 diabetes in the USA: enrollment data from the Pediatric Diabetes Consortium Type 2 Diabetes Registry.

To describe the clinical characteristics, treatment approaches, clinical outcomes, and co‐morbidities of youth with type 2 diabetes (T2D) enrolled in the Pediatric Diabetes Consortium (PDC) T2D Registry.

Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60

We studied the genetic and clinical features of diabetic subjects in a 5-generation Michigan-Kentucky pedigree ascertained through a proband with pancreatic agenesis and homozygous for the IPF1 mutation Pro63fsx60. Diabetic and nondiabetic family members were genotyped and phenotyped. We also carried out genetic studies to determine the history of the IPF1 mutation in the Michigan-Kentucky family and a Virginia family with the same mutation. We identified 110 individuals; 34 are currently being treated for diabetes and 10 of these are Pro63fsX60 carriers (ie, MODY4). Subjects with MODY as well as those with type 2 diabetes are characterized by obesity and hyperinsulinemia. Genetic studies suggest that the IPF1 mutation was inherited from an ancestor common to both the Michigan-Kentucky and Virginia families. MODY4 and type 2 diabetes in the Michigan-Kentucky pedigree are associated with obesity and hyperinsulinemia. Obesity and hyperinsulinemia have been observed occasionally in other subtypes of MODY, which suggests that hyperinsulinemia may be a general phenomenon when obesity occurs in MODY subjects. Hypoinsulinemia in nonobese MODY subjects seems to be caused by a functional defect in the beta cell. Genetic testing should be considered in multigenerational obese diabetic subjects, particularly when such families contain young diabetic members.

Advances in the Classification and Treatment of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a rare disorder of type 1 collagen with 13 currently identified types attributable to inherited abnormalities in type 1 collagen amount, structure, or processing. The disease is characterized by an increased susceptibility to bony fracture. In addition to the skeletal phenotype, common additional extraskeletal manifestations include blue sclerae, dentinogenesis imperfecta, vascular fragility, and hearing loss. Medical management is focused on minimizing the morbidity of fractures, pain, and bone deformities by maximizing bone health. Along with optimizing Vitamin D status and calcium intake and physical/occupational therapy, individualized surgical treatment may be indicated. Pharmacological therapy with bisphosphonate medications is now routinely utilized for moderate to severe forms and appears to have a good safety profile and bone health benefits. New therapies with other anti-resorptives as well as anabolic agents and transforming growth factor (TGF)β antibodies are in development. Other potential treatment modalities could include gene therapy or mesenchymal cell transplant. In the future, treatment choices will be further individualized in order to reduce disease morbidity and mortality.

Type 1 diabetes: a genetic Pandora's box?

In this issue of the journal, Delli et al. (1) describe the changing incidence of type 1 diabetes mellitus (T1DM) in children born in Sweden to immigrant parents, a topic of considerable scientific interest, since these changes must reflect environmental, rather than purely genetic influences. The take home message of this article (1) is that patients with T1DM born to immigrants in Sweden, a country that has a notoriously high incidence of T1DM, more frequently carry human leukocyte antigen (HLA)-DQ2 genotypes and possess glutamic acid decarboxylase 65 (GAD65) autoantibodies when compared to indigenous Swedish T1DM patients. Although this observation confirms that the effect of HLA-DQ2 is not neutral as initially thought (2), these results strongly argue that in the subset of T1DM patients described, additional genetic and/or environmental risk factors must contribute to the progression of overt disease (1). A recent genomewide association study (GWAS) and meta-analysis found over 40 loci that affect risk of T1DM (3). It is conceivable that several of those 40 loci identified by GWAS contain genes of possible functional relevance to the subgroup of T1DM individuals identified by Delli et al. (1). These loci include the region 1q32.1 which contains the potent immunoregulatory cytokine genes, IL-10, IL-19 and IL-20. The interplay between the environment and genetic disposition is unquestionably complicated. It is proposed that the incidence of T1DM is increasing, with the diagnosis occurring more in younger age children (4). Although it is acknowledged that there may be an effect due to migration, the earlier age that children with T1DM are now presenting could be related to environmental changes (4). Zung et al. noted that in Jewish Ethiopians who are genetically at risk and who immigrated from Ethiopia to Israel (an area with a high incidence of T1DM), had an increased risk of developing T1DM as they adopted their new country’s lifestyle (5). This contradicts the study by Ehehalt et al. which found that Italian immigrant children had incidence rates of T1DM that were similar to their home country and not their new country of residence, therefore reducing the importance of the environmental influence (6). The study by Delli et al. (1) expands the findings of Ehehalt’s study (6) by investigating whether multigenerational origin influenced children’s risk of developing T1DM in an area that has a high incidence of this disease. In particular, parents and grandparents were identified as either Swedish (all family members), non-Swedish or of mixed origins (some family members of Swedish descent). HLA typing and islet autoantibody testing were then performed on those younger than 18 years who were diagnosed with T1DM. At least one of the HLA genotypes, either DQ2 or DQ8, was found in 80% of these patients, a frequency significantly higher than that found in children of Swedish descent. In 85% of the patients, at least one islet autoantibody was confirmed with almost half having two or more autoantibodies. Islet autoantibodies tended to be more frequent in those of Swedish descent, although not statistically significant. When the investigators examined if specific HLA markers were associated with specific autoantibodies, they found that the HLA-DQ2 haplotype, more frequent in immigrant parents, was associated with the GAD65 antibody, whereas the HLA-DQ8 HLA haplotype, more frequent in those of Swedish descent, was associated with IA-2 autoantibodies. In those with neither DQ2 or DQ8, non-Swedish patients had increased levels of autoantibodies, which led the authors to postulate that there are other genes leading to autoimmunity (1). It is suggested that different ethnic groups have unique genetic predispositions to developing T1DM. Kawasaki et al. reported on a form of diabetes that they termed ‘fulminant’ T1DM, a subgroup of T1DM in Japanese patients, in whom there are no autoantibodies and who do not possess the known susceptibility HLA haplotypes (7). This leads us to inquire more about the patients without autoantibodies in the study by Delli et al. (1). Were their HLA haplotypes similar to expectations or did they vary from those usually associated with T1DM, suggesting that perhaps the risk of developing diabetes is not always HLA-dependent? In addition, only three autoantibodies were checked in this study, so it is possible that those without detected autoantibodies could still have distinct autoantibodies that have yet to be identified (8). The origin of the

Ectopic Cushing syndrome secondary to metastatic medullary thyroid cancer in a child with multiple endocrine neoplasia syndrome type 2B: clues to early diagnosis of the paraneoplastic syndromes

Abstract We describe a 13-year-old male with multiple endocrine neoplasia syndrome type 2B with medullary thyroid carcinoma who was diagnosed with ectopic adrenocorticotropin-dependent Cushing syndrome. This report highlights the importance of monitoring for paraneoplastic syndrome in MEN and clues to the diagnosis of this complication provided by growth patterns.

Isodicentric Y mosaicism involving a 46, XX cell line: Implications for management

Carriers of isodicentric Y (idicY) mosaicism exhibit a wide range of clinical features, including short stature, gonadal abnormalities, and external genital anomalies. However, the phenotypic spectrum for individuals carrying an idicY and a 46, XX cell line is less clearly defined. A more complete description of the phenotype related to idicY is thus essential to guide management related to pubertal development, fertility, and gonadoblastoma risk in mosaic carriers. Findings from the evaluation of twin females with an abnormal karyotype, 48, XX, +idic(Yq) x2/47, XX, +idic(Yq)/46, XX, are presented to highlight the importance of interdisciplinary care in the management of multifaceted disorders of sex development.

Unexpected ethical dilemmas in sex assignment in 46,XY DSD due to 5-alpha reductase type 2 deficiency

Sex assignment at birth remains one of the most clinically challenging and controversial topics in 46,XY disorders of sexual development (DSD). This is particularly challenging in deficiency of 5‐alpha reductase type 2 given that external genitalia are typically undervirilized at birth but typically virilize at puberty to a variable degree. Historically, most individuals with 5‐alpha reductase deficiency were raised females. However, reports that over half of patients who underwent a virilizing puberty adopted an adult male gender identity have challenged this practice. Consensus guidelines on assignment of sex of rearing at birth are equivocal or favor male assignment in the most virilized cases. While a male sex of rearing assignment may avoid lifelong hormonal therapy and/or allow the potential for fertility, female sex assignment may be more consistent with external anatomy in the most severely undervirilized cases. Herein, we describe five patients with 46,XY DSD due 5‐alpha‐reductase type 2 deficiency, all with a severe phenotype. An inter‐disciplinary DSD medical team at one of two academic centers evaluated each patient. This case series illustrates the complicated decision‐making process of assignment of sex of rearing at birth in 5‐alpha reductase type 2 deficiency and the challenges that arise when the interests of the child, parental wishes, recommendations of the medical team, and state law collide.