Table 1 Clinical characteristics of classical monogenic/syndromic obesity.

LEP (leptin)

Yes/yes

Autosomal recessive

Frequent childhood infections, high childhood mortality, hypogonadotropic hypogonadism, hypothyroidism, thyroid dysfunction, immune dysfunction

Cognitive impairment, slow learning, socialization difficulty, high school dropout rate

LEPR (leptin receptor)

Yes/yes

Autosomal recessive

Frequent infections, childhood mortality, hypogonadotropic hypogonadism, hypothyroidism, immune dysfunction, hyperleptinemia

Cognitive impairment, slow learning, socialization difficulty, high school dropout rate

MC4R (melanocortin 4 receptor)

Yes/yes

Co-dominant

Hyperinsulinemia, accelerated linear growth,

Mild learning difficulties and behavioral issues, mood disorder, disruptive behavior

POMC (proopiomelanocortin)

Yes/yes

Autosomal recessive

ACTH deficiency, altered pigmentation (Red hair, fair skin), hypogonadotropic hypogonadism.

Behavioral abnormalities, possible neurological symptoms, possible decreased pain sensation

PCSK1 (proprotein convertase subtilisin/Kexin Type 1)

Yes/yes

Autosomal recessive

Hypocortisolism, hypogonadotropic hypogonadism, hyperinsulinemia, malabsorptive diarrhea and other gastrointestinal issues (constipation).

Neurological and developmental issues

MRAP2 (melanocortin 2 Receptor accessory protein 2)

Yes/yes

Autosomal dominant

Altered adrenal funsion, insulin resistance, dyslipidemia

NA

SH2B1 (SH2B adaptor protein 1)

Yes/yes

Autosomal dominant

Insulin resistance, dyslipidemia

Impulsivity and attention deficits, emotional dysregulation

SIM1 (single-minded family BHLH transcription factor 1)

Yes/yes

Autosomal dominant

Altered growth hormone axis, hyperinsulinemia

Behavioral anomalies, cognitive impairment, developmental anomalies

KSR2 (kinase suppressor of Ras 2)

Yes/yes

Autosomal dominant

Insulin resistance

Learning difficulties

P4HTM (prolyl 4-hydroxylase, transmembrane

Yes/yes

Autosomal recessive

Connective tissue abnormalities, hypotonia (muscle weakness)

behavioral or cognitive features, developmental delay, seizures

ADCY3 (adenylate cyclase 3)

Yes/yes

Autosomal recessive

Anosmia, respiratory complications

Moderate intellectual disability, neurological or neurodevelopmental issues

ASIP (agouti-signaling protein)

Yes/yes

Autosomal recessive

Hyperphagia, hyperinsulinemia, overgrowth, hypopigmentation

GNAS (guanine nucleotide binding protein (G Protein), Alpha stimulating activity polypeptide 1)

Yes/yes

Autosomal dominant with imprinting (can vary among different GNAS-related disorders)

Pseudohypoparathyroidism, short stature, round face, subcutaneous calcifications, brachydactyly

Cognitive impairment, development delay, affected motor skills and coordination, seizures

ALMS1 (Alstrom Syndrome)

Yes/yes

Autosomal recessive

Rod-cone dystrophy, hearing impairment, hypogonadotropic hypogonadism, hypothyroidism, growth hormone deficiency

Developmental delays, intellectual disability or learning difficulties

BBS1-BBS20 (Bardet-Biedl Syndrome)

Yes/yes

Autosomal recessive

Craniofacial dysmorphism, Polydactyly, hypogonadotropic hypogonadism, genital abnormalities, structural and functional renal abnormalities.

Developmental and cognitive impairments, developmental delay, behavioral problems and poor coordination and balance

VPS13B (Cohen Syndrome)

Yes/yes

Autosomal recessive

Retinal dystrophy, progressive myopia, retinochoroidal dystrophy, short stature, delayed puberty.

Developmental delay, intellectual disability, microcephaly, characteristic facial features

PWS (Prader-Willi Syndrome)

Yes/yes

Autosomal dominant with imprinting

Growth hormone deficiency, hypogonadism

Cognitive impairment, intellectual disability, behavioral issues (temper outbursts, stubbornness, and compulsive behaviors), sleep disorders, motor milestones delayed