Hepatomegaly and fatty liver disease secondary to central hypothyroidism in combination with macrosomia as initial presentation of IGSF1 deficiency syndrome.

PURPOSE: IGSF1 deficiency syndrome (immunoglobulin superfamily member 1) is considered the most common sex-linked cause of secondary congenital hypothyroidism and is characterized by a wide variety of other clinical and biochemical features, including hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Congenital central hypothyroidism is a rare disease (1:65,000 births); the detection of which may be delayed and missed by neonatal screening programs since most neonatal screening programs are based on TSH determination in dried blood spots only. Untreated hypothyroidism may cause abnormal liver biochemistry and non-alcoholic fatty liver disease. Our aim is to report a case of secondary hypothyroidism in an infant with an uncommon initial presentation. CASE PRESENTATION (METHODS/RESULTS): A 3-month-old male baby was referred to our hospital due to elevated alpha-fetoprotein levels, hypercholesterolemia, and macrosomia. Initial investigations revealed enlarged fatty liver and central hypothyroidism. Pituitary insufficiency was biochemically excluded and a pituitary MRI showed normal findings. Upon genetic analysis, a hemizygous variant NM_001170961.1:c.2422dup, p.(His808Profs*14), in IGSF1 gene was detected, establishing the diagnosis of the IGSF1 deficiency syndrome. In our patient, no other clinical findings were identified. Treatment with levothyroxine led to the remission of liver disease. CONCLUSION: Liver disease may be the initial presentation of secondary hypothyroidism in neonates and infants. Macrosomia in patients with isolated secondary central hypothyroidism is a strong indicator of IGSF1 syndrome.

Alcohol consumption before pregnancy causes detrimental fetal development and maternal metabolic disorders.

Alcohol consumption before or during pregnancy poses serious health risks to the fetus; however, the underlying mechanisms involved remain obscure. Here, we investigated whether ethanol consumption before pregnancy affects maternal or fetal health and whether pharmacological inhibition of CYP2E1, a major ethanol oxidation enzyme, by 4-methylpyrazole (4-MP) has therapeutic effects. We found that ethanol consumption (5%) 2 weeks before pregnancy resulted in a decrease in the number of viable fetuses and abnormal fetal development, and these effects were accompanied by impaired maternal glucose homeostasis and hepatic steatosis during pregnancy. Neonates of ethanol-fed mice had postnatal macrosomia and significantly decreased growth rates during the lactation period. However, treatment with 4-MP, a CYP2E1 inhibitor, markedly ameliorated the reduction in insulin action and glucose disposal responsiveness in the livers of ethanol-fed mice. Blockage of CYP2E1 significantly reduced the alteration in hepatic lipid deposition, fatty acid oxidation, mitochondrial energy status, and macrophage infiltration observed in ethanol-fed mice. Finally, there was a positive correlation between postnatal macrosomia or growth retardation and increased inflammatory responses. Collectively, our study suggests that even moderate ethanol intake may be detrimental to fetal development and may cause growth retardation through maternal metabolic disorders.

Comparative impact of pharmacological treatments for gestational diabetes on neonatal anthropometry independent of maternal glycaemic control: A systematic review and meta-analysis.

BACKGROUND: Fetal growth in gestational diabetes mellitus (GDM) is directly linked to maternal glycaemic control; however, this relationship may be altered by oral anti-hyperglycaemic agents. Unlike insulin, such drugs cross the placenta and may thus have independent effects on fetal or placental tissues. We investigated the association between GDM treatment and fetal, neonatal, and childhood growth. METHODS AND FINDINGS: PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and Cochrane databases were systematically searched (inception to 12 February 2020). Outcomes of GDM-affected pregnancies randomised to treatment with metformin, glyburide, or insulin were included. Studies including preexisting diabetes or nondiabetic women were excluded. Two reviewers independently assessed eligibility and risk of bias, with conflicts resolved by a third reviewer. Maternal outcome measures were glycaemic control, weight gain, and treatment failure. Offspring anthropometric parameters included fetal, neonatal, and childhood weight and body composition data. Thirty-three studies (n = 4,944), from geographical locations including Europe, North Africa, the Middle East, Asia, Australia/New Zealand, and the United States/Latin America, met eligibility criteria. Twenty-two studies (n = 2,801) randomised women to metformin versus insulin, 8 studies (n = 1,722) to glyburide versus insulin, and 3 studies (n = 421) to metformin versus glyburide. Eleven studies (n = 2,204) reported maternal outcomes. No differences in fasting blood glucose (FBS), random blood glucose (RBS), or glycated haemoglobin (HbA1c) were reported. No studies reported fetal growth parameters. Thirty-three studies (n = 4,733) reported birth weight. Glyburide-exposed neonates were heavier at birth (58.20 g, 95% confidence interval [CI] 10.10-106.31, p = 0.02) with increased risk of macrosomia (odds ratio [OR] 1.38, 95% CI 1.01-1.89, p = 0.04) versus neonates of insulin-treated mothers. Metformin-exposed neonates were born lighter (-73.92 g, 95% CI -114.79 to -33.06 g, p < 0.001) with reduced risk of macrosomia (OR 0.60, 95% CI 0.45-0.79, p < 0.001) than insulin-exposed neonates. Metformin-exposed neonates were born lighter (-191.73 g, 95% CI -288.01 to -94.74, p < 0.001) with a nonsignificant reduction in macrosomia risk (OR 0.32, 95% CI 0.08-1.19, I2 = 0%, p = 0.09) versus glyburide-exposed neonates. Glyburide-exposed neonates had a nonsignificant increase in total fat mass (103.2 g, 95% CI -3.91 to 210.31, p = 0.06) and increased abdominal (0.90 cm, 95% CI 0.03-1.77, p = 0.04) and chest circumferences (0.80 cm, 95% CI 0.07-1.53, p = 0.03) versus insulin-exposed neonates. Metformin-exposed neonates had decreased ponderal index (-0.13 kg/m3, 95% CI -0.26 to -0.00, p = 0.04) and reduced head (-0.21, 95% CI -0.39 to -0.03, p = 0.03) and chest circumferences (-0.34 cm, 95% CI -0.62 to -0.05, p = 0.02) versus the insulin-treated group. Metformin-exposed neonates had decreased ponderal index (-0.09 kg/m3, 95% CI -0.17 to -0.01, p = 0.03) versus glyburide-exposed neonates. Study limitations include heterogeneity in dosing, heterogeneity in GDM diagnostic criteria, and few studies reporting longitudinal growth outcomes. CONCLUSIONS: Maternal randomisation to glyburide resulted in heavier neonates with a propensity to increased adiposity versus insulin- or metformin-exposed groups. Metformin-exposed neonates were lighter with reduced lean mass versus insulin- or glyburide-exposed groups, independent of maternal glycaemic control. Oral anti-hyperglycaemics cross the placenta, so effects on fetal anthropometry could result from direct actions on the fetus and/or placenta. We highlight a need for further studies examining the effects of intrauterine exposure to antidiabetic agents on longitudinal growth, and the importance of monitoring fetal growth and maternal glycaemic control when treating GDM. This review protocol was registered with PROSPERO (CRD42019134664/CRD42018117503).

Old treatments for new genetic conditions: Sirolimus therapy in a child affected by mosaic overgrowth with fibroadipose hyperplasia.

PIK3CA-related overgrowth spectrum (PROS) are overgrowth diseases involving mesenchymal tissues caused by postzygotic variants in the PIK3CA gene. Fibro-Adipose hyperplasia or Overgrowth (FAO) belongs to PROS. We reported the beneficial effect of oral low-dose sirolimus therapy in a child affected by progressive FAO in term of stabilization of the disease, good tolerability, and easy management.

Meal related glucose monitoring is a method of diagnosing glucose intolerance in pregnancies with high probability of gestational diabetes but normal glucose tolerance by oral glucose tolerance test.

Gestational diabetes mellitus diagnosed by classical oral glucose tolerance test can result in fetal complications like macrosomia and polyhydramnios. Guidelines exist on management of patients diagnose by abnormal oral glucose tolerance test with diet modification followed by insulin. Even patients with abnormal oral glucose tolerance test maintaining apparently normal blood sugars with diet are advised insulin if there is accelerated fetal growth. But patients with normal oral glucose tolerance test can present with macrosomia and polyhydramnios. These patients are labelled as not having gestational diabetes mellitus and are followed up with repeat oral glucose tolerance test. We hypothesise that these patients may have an altered placental threshold to glucose or abnormal sensitivity of fetal tissues to glucose. Meal related glucose monitoring in these patients can identify minor abnormalities in glucose disturbance and should be treated to targets similar to physiological levels of glucose in non pregnant adults.

Atrial flutter following placement of an umbilical venous catheter.

Atrial flutter is a rare complication of the insertion of an umbilical venous catheter. We report a neonate who had an umbilical venous catheter placed within the first 24 hours of life and developed a hemodynamically stable tachyarrhythmia. The arrhythmia was successfully managed with synchronized cardioversion, with no further complications. The presentation and management are discussed. Physicians should be watchful for such potentially life-threatening complications from the placement of indwelling lines.