Congenital generalized lipodystrophy type 4 due to a novel PTRF/CAVIN1 pathogenic variant in a child: effects of metreleptin substitution.

OBJECTIVES: Congenital generalized lipodystrophies (CGLs) are a heterogeneous group of rare autosomal recessive disorders characterized by near/total absence of body fat. Pathogenic variants in polymerase-I and transcript release factor gene (PTRF), or CAVIN1, is responsible for CGL4. In addition to generalized fat loss, patients with CGL4 were reported to suffer from myopathy, malignant cardiac arrhythmias, gastrointestinal disorders, and skeletal abnormalities. Here we describe the phenotype of a child with CGL4 due to a rare, novel pathogenic variant in the PTRF/CAVIN1 gene and the long-term effects of metreleptin substitution on comorbidities. CASE PRESENTATION: We describe a now 20-year-old female patient. At the age of 14-years, she was referred to the University Clinic because of uncontrolled diabetes with an HbA1c of 9.3%, requiring 2.4 IU insulin/kg total-body-weight to normalize blood glucose, hepatomegaly, and hypertriglyceridemia of 515 mg/dL. Additionally, she was suffering from malignant cardiac arrhythmia, myopathy, and hyperCKemia. In light of these clinical findings, she was diagnosed with CGL due to a rare, novel variant in the PTRF gene, and was started on metreleptin, a synthetic analog of human leptin. After the initiation of metreleptin treatment, insulin therapy could be stopped and improvement of sonographically assessed liver size was observed, even though serum liver function test stayed mildly elevated. Furthermore, a noticeable improvement of the serum triglyceride levels was also seen. Medical care and regular follow-up visits are being carried out by a multi-disciplinary team. CONCLUSIONS: Although CGL4 is rare, due to its life-threatening comorbidities and the opportunity for an early intervention, it is important that the clinicians should recognise these patients.

[Innovative medical care concepts for adolescents with severe obesity]. / Innovative medizinische Betreuungskonzepte für Jugendliche mit extremer Adipositas.

There is no convincing, science-based treatment or care concept for adolescents with severe obesity in Germany or other countries. The affected young people have an increased risk of numerous somatic comorbidities (e.g. type 2 diabetes mellitus, orthopaedic disorders and sleep apnoea syndrome), mental disorders (e.g. depression and anxiety disorders, social phobia and self-harming behaviour), as well as social isolation (e.g. avoidance of school and unemployment), which develops due to functional impairments and stigmatisation. Despite the negative effects of severe obesity in adolescence, these young people are medically difficult to reach and treat. Only a small percentage of patients actively seek treatment.Aware of these difficulties, the German multi-centre Youth with Extreme Obesity (YES) Study (funded by the German Ministry of Education and Science; 01 GI 1120 A and B) was carried out between 2012 and 2019 with the aim of improving care concepts for this neglected group of young people. In our article, we show possible supply routes. These consist of accompanying the adolescents and treating their comorbidities, sustainable lifestyle interventions in a protected environment and treatment for weight reduction through bariatric surgery. The overriding goals for patients are an increase in self-esteem, early diagnosis and treatment of secondary diseases and integration into the training and labour market.