Syndromic obesity is defined as adiposity combined with dysmorphic features, organ-specific congenital anomalies, and/or developmental delay/intellectual disability. Currently, more than 79 obesity syndromes have been described [
51], of which Prader-Willi and Bardet-Biedl syndromes are most frequently reported [
3]. In addition to general weight loss measures, such as lifestyle interventions, cognitive behavioral therapy, or pharmacotherapy, there are no specific evidence-based therapies for syndromic obesity. Here, we provide an overview of the available evidence on the various bariatric procedures for the treatment of three (monogenic) obesity syndromes (see Table
1). We note that data are limited, since the use of such invasive treatments in patients with genetic obesity syndromes remains controversial, and that there is no international consensus as yet.
Prader-Willi Syndrome
In most cases, Prader-Willi syndrome (PWS) is caused by loss or disruption of the paternal copy of chromosome 15q11.2-13 and has an estimated prevalence of 1:8000–1:50,000 individuals [
52,
53]. PWS is characterized by hypotonia, feeding difficulties, and mild dysmorphic features in the neonatal period. As patients become older, a global developmental delay, neuropsychiatric and endocrine manifestations (short stature, hypogonadism, hypothyroidism, adrenal insufficiency), and more distinctive dysmorphic features can be observed. Feeding difficulties typically dissolve after the age of 9 months, and weight increases more rapidly after the age of 2. From around the age of 4 onwards, food intake increases, and excessive eating (hyperphagia) can be observed [
54,
55]. This usually results in childhood-onset morbid obesity and its associated complications (obstructive sleep apnea, diabetes mellitus type 2, and hypertension). In fact, the associated complications of their insatiable appetite and uncontrolled weight gain are the leading causes of death during adolescence or early adulthood [
56,
57].
Current obesity treatments that focus on changes in feeding behavior/diet, exercise, or hormonal replacement therapy are ineffective for long-term weight loss maintenance in the majority of patients with PWS [
58]. Although bariatric procedures, including RYGB, result in long-lasting weight reduction and remission of comorbidities in the majority of patients with obesity in the general population [
59], it remains controversial whether or not to perform this invasive therapy in patients with PWS. The pathophysiology of obesity in PWS is different from other forms of genetic obesity; the compulsive food seeking and behavioral problems in PWS are thought to interfere with lifestyle changes needed after bariatric surgery. Previously reported bariatric procedures, including intragastric balloon placement or gastric banding, did not produce favorable weight loss outcomes in patients with PWS [
60].
Today’s first-choice weight loss procedures (SG and RYGB) have been studied in one cohort of patients with PWS. SG was performed in 24 pediatric patients with molecularly confirmed PWS, and outcomes were compared with the outcomes of 72 children with obesity without PWS, who were matched for age, gender, and BMI at baseline [
61•]. Children in the study were 4.9–18.2 years old. After surgery, children with PWS lost considerable body weight, and there were no apparent differences in postoperative BMI loss between the PWS and control groups up to 3 years after sleeve gastrectomy. However, in the 4th and 5th year of follow-up, the PWS group regained weight, which resulted in a mean (±SD) BMI of 35.9 ± 12.5 kg/m
2, compared with 25.1 ± 7.0 kg/m
2 in the control group. This finding suggests that patients with PWS may be more prone to long-term weight regain, but more (complete) data are needed to confirm this trend. No short- or long-term complications were reported.
In addition to this case-control study, there are four single PWS cases reported for which outcomes of sleeve gastrectomy or biliopancreatic diversion were reported. A 25-year-old man with PWS, with a preoperative BMI of 55 kg/m
2 and impaired glucose tolerance (IGT), underwent an uncomplicated biliopancreatic diversion [
62••]. One year after surgery, his BMI had decreased to 38.5 kg/m
2 (− 30%), and his IGT had resolved. A 16-year-old adolescent with PWS and a preoperative BMI of 80.9 kg/m
2 also suffered from severe obstructive sleep apnea with nocturnal respiratory failure, hypertension, and IGT [
63••] and had a reduction in BMI to 64.6 kg/m
2 (− 20.1%) 6 months after SG. Finally, two PWS patients were reported who underwent a biliopancreatic diversion [
64•]. The first case was a 25-year-old woman with a decrease in BMI from 55.5 to 41.3 kg/m
2 after 6 months, corresponding to an excess weight loss (EWL) of 43%. The second case, an 18-year-old woman, with a preoperative BMI of 64.4 kg/m
2, showed a decrease to 53.9 kg/m
2 (− 16.3%) within 18 months after surgery. Notably, prior treatment with an intragastric balloon had failed to achieve weight loss.
Based on the available observational data, it seems that short-term bariatric surgery-induced weight loss outcomes in patients with PWS are comparable with those achieved in other patients with (non-genetic) obesity. However, these limited data do not (yet) justify the widespread application of bariatric surgery in patients with PWS, as gastric rupture and necrosis have been previously described in patients that did not even undergo bariatric surgery [
65]. Long-term outcome needs to be further studied for these patients. Intensive postoperative behavioral therapy and supervision might prevent or delay weight regain, so that bariatric surgery for patients with PWS might reduce obesity-associated morbidity and mortality.
Bardet-Biedl Syndrome
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy. BBS is characterized by severe early-onset obesity, intellectual deficit, polydactyly, renal abnormalities, and retinitis pigmentosa [
66]. Although more than 20 genes are currently known to be associated with BBS, mutations in
BBS1 and
BBS10 are identified in the majority of cases [
66,
67]. Weight loss strategies focusing on lifestyle changes and pharmacotherapy do not seem to result in sustained weight loss in affected patients [
68,
69]. Therefore, other therapies, including bariatric surgery, are being explored. During the last 5 years, two case reports of SG in patients with BBS have been published.
A 37-year-old woman with BBS who had morbid obesity underwent uncomplicated SG [
70••]. Her BMI decreased from 40.8 to 27.5 kg/m
2 (− 32.6%) within 36 months after surgery, with additional improvements in glycemic control, hypertension, and non-alcoholic fatty liver disease. Another study examined the effects of SG in adolescents, including one person who was diagnosed with BBS [
71••]. The postoperative period of the 14-year-old boy was uneventful. The intervention was associated with a total weight reduction of 28% after 12 months. His blood pressure normalized, and hypertension treatment could be discontinued.
Thus, although the available evidence on modern bariatric surgery techniques in patients with BBS is scarce, the described cases suggest that SG may be a safe and effective treatment for BBS-related obesity, although more studies are needed to support the effectiveness in the long term.
Albright Hereditary Osteodystrophy
Albright hereditary osteodystrophy (AHO) is an obesity syndrome with a broad spectrum of manifestations, including short stature, brachydactyly, and subcutaneous calcifications due to resistance to parathyroid hormone (pseudohypoparathyroidism; PHP) [
72]. AHO is caused by heterozygous inactivation of the
GNAS gene, encoding the alpha chain of the stimulatory G protein [
73]. Genomic imprinting induces a variable phenotypic expression [
74]. Maternal
GNAS inactivation results in the AHO phenotype plus resistance to other hormones, most notably thyroid-stimulating hormone [
74]. A loss of expression of
GNAS of the paternal allele results in the AHO phenotype without hormonal resistance (pseudopseudohypoparathyroidism; PPHP). To our knowledge, no data are available regarding the effects of conservative weight-loss strategies in patients with AHO. However, there is one reported case of bariatric surgery in a patient with AHO.
A 26-year-old woman with PPHP (heterozygous mutation of the paternal
GNAS gene), obesity, and type 2 diabetes underwent uncomplicated RYGB [
75]. Within the first year after surgery, her BMI decreased from 49.5 to 25.9 kg/m
2 (− 47.7%). Her body weight remained stable during the following 24 months. The effects of this weight loss on glycemic control were not discussed.