Mitochondrial trifunctional protein (MTP) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiencies have been a part of the Slovenian newborn screening (NBS) program since 2018. We describe a case of early lethal presentation of MTPD/LCHADD in a term newborn. The girl was born after an uneventful pregnancy and delivery, and she was discharged home at the age of 3 days, appearing well. At the age of 4 days, she was found without signs of life. Resuscitation was not successful. The NBS test performed using tandem mass spectrometry (MS/MS) showed a positive screen for MTPD/LCHADD. Genetic analysis performed on a dried blood spot (DBS) sample identified two heterozygous variants in the HADHA gene: a nucleotide duplication introducing a premature termination codon (p.Arg205Ter) and a nucleotide substitution (p.Glu510Gln). Post-mortem studies showed massive macro-vesicular fat accumulation in the liver and, to a smaller extent, in the heart, consistent with MTPD/LCHADD. A neonatal acute cardiac presentation resulting in demise was suspected. We conducted a systematic literature review of early neonatal deaths within 14 days postpartum attributed to confirmed fatty acid oxidation disorders (FAODs), which are estimated to account for 5% of sudden infant deaths. We discuss the pitfalls of the NBS for MTPD/LCHADD.

The distinctive effects of maintaining the upper- (0–2) versus lower-normal (−2–0) range of IGF-1 SDS in adult growth hormone deficiency (AGHD) remain understudied. We conducted a cross-sectional study on 31 patients with AGHD receiving growth hormone replacement therapy (GHRT) with daily GH for >5 years, with a 2-year mean IGF-1 SDS ranging between −2 and +2. Patients were categorized into the upper- or lower-normal range IGF-1 SDS groups according to their 2-year mean. Associations of clinical characteristics, anthropometric parameters, laboratory tests, and vascular markers of subclinical atherosclerosis with the 2-year IGF-1 SDS range and 5-year mean IGF-1 SDS were explored. Long-term maintenance of upper-normal IGF-1 SDSs was more common in men and in patients with a longer duration of GHRT. Patients with tumor-related AGHD had a lower 5-year mean IGF-1 SDS. Long-term maintenance of IGF-1 SDS in the upper-normal range was associated with lower high-sensitivity C-reactive protein (hs-CRP) levels (median (25–75% range): 0.8 (0.6–1.1) vs. 1.8 (0.8–4.6); p = 0.005). Moreover, a negative correlation was identified between a hs-CRP and the 5-year mean IGF-1 SDS. The association between the upper-normal IGF-1 SDS range and lower body fat percentage lost significance after adjusting for sex, due to the higher proportion of male patients in the upper-normal IGF-1 SDS group. In conclusion, long-term maintenance of upper-normal IGF-1 SDSs was associated with male sex and reduced low-grade inflammation. Randomized controlled studies are needed to evaluate the long-term and sex-specific effects of targeting the upper- vs. lower-normal IGF-1 range in AGHD.

Background: Patients with adult growth hormone deficiency (AGHD) show accelerated atherosclerosis. While growth hormone replacement therapy (GHRT) may help mitigate this process, the mechanisms driving atherosclerosis progression in GHRT-treated patients with AGHD remain unclear. Methods: Thirty-one patients with AGHD on daily GHRT for ≥5 years were assessed in this crosssectional study. Carotid intima-media thickness (cIMT) was evaluated by ultrasound. Reactive hyperemia index (RHI) was measured using peripheral arterial tonometry. Associations between vascular measures and clinical, pituitary, treatment, body composition, and laboratory parameters were evaluated. Results: cIMT correlated with body mass index (r=0.584, p=0.001) and visceral adipose tissue area (r=0.791, p<0.001), while demonstrating nominally significant associations with triglyceride levels, insulin resistance index, smoking history, and arterial hypertension. Neither the current nor the 5-year mean insulin-like growth factor 1 standard deviation score directly correlated with vascular parameters. Median cIMT was higher in adult-onset compared with child-onset AGHD (0.70 vs. 0.58 mm; p=0.020), while median RHI was lower in genetic than structural etiology (1.58 vs. 2.18; p=0.010); however, both associations were nominally significant. Discussion: Several of the identified cardiovascular risk factors associated with cIMT are unlikely to be sufficiently controlled through GHRT. Pituitary disease characteristics may play a role in atherogenesis; however, the subgroups defined by disease onset timing and etiology were small and not fully comparable. Conclusion: In long-term GHRT-treated patients, cIMT is linked to well-established cardiovascular risk factors rather than features of the pituitary disorder and its management, highlighting the need for targeted cardiovascular risk management alongside GHRT in AGHD.