Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.

INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.

Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family.

INSR-related severe syndromic insulin resistance comprises a phenotypic spectrum that is a continuum from the severe phenotype Donohue syndrome (DS) (also known as leprechaunism) to the milder phenotype Rabson-Mendenhall syndrome (RMS). DS at the severe end of the spectrum is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction and postnatal growth failure, hypotonia and developmental delay, characteristic facies, and organomegaly involving heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS at the milder end of the spectrum is characterized by severe insulin resistance that, although not as severe as that of DS, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of DS. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer.

Insulin (INS; 176730) is produced posttranslationally from its precursor molecule, proinsulin, by site-directed proteolysis in beta-cell granules. Conversion involves cleavage at pairs of basic residues that link both the insulin A and B chains to C-peptide. Human proinsulin conversion has a preferred sequential route, such that cleavage at the B-chain/C-peptide junction occurs first, producing des-31,32 split proinsulin as the major conversion intermediate. Under normal circumstances, proinsulin conversion is largely completed before secretion, and low plasma levels of intact proinsulin and conversion intermediates are found. Structural abnormalities in the proinsulin molecule can impair conversion, leading to the accumulation of proinsulin-like material in the circulation. Such defects show an autosomal dominant mode of inheritance and are the main cause of familial hyperproinsulinemia (summary by Warren-Perry et al., 1997).

Familial partial lipodystrophy (FPLD) is a metabolic disorder characterized by abnormal subcutaneous adipose tissue distribution beginning in late childhood or early adult life. Affected individuals gradually lose fat from the upper and lower extremities and the gluteal and truncal regions, resulting in a muscular appearance with prominent superficial veins. In some patients, adipose tissue accumulates on the face and neck, causing a double chin, fat neck, or cushingoid appearance. Metabolic abnormalities include insulin-resistant diabetes mellitus with acanthosis nigricans and hypertriglyceridemia; hirsutism and menstrual abnormalities occur infrequently. Familial partial lipodystrophy may also be referred to as lipoatrophic diabetes mellitus, but the essential feature is loss of subcutaneous fat (review by Garg, 2004). The disorder may be misdiagnosed as Cushing disease (see 219080) (Kobberling and Dunnigan, 1986; Garg, 2004). Genetic Heterogeneity of Familial Partial Lipodystrophy Familial partial lipodystrophy is a clinically and genetically heterogeneous disorder. Types 1 and 2 were originally described as clinical subtypes: type 1 (FPLD1; 608600), characterized by loss of subcutaneous fat confined to the limbs (Kobberling et al., 1975), and FPLD2, characterized by loss of subcutaneous fat from the limbs and trunk (Dunnigan et al., 1974; Kobberling and Dunnigan, 1986). No genetic basis for FPLD1 has yet been delineated. FPLD3 (604367) is caused by mutation in the PPARG gene (601487) on chromosome 3p25; FPLD4 (613877) is caused by mutation in the PLIN1 gene (170290) on chromosome 15q26; FPLD5 (615238) is caused by mutation in the CIDEC gene (612120) on chromosome 3p25; FPLD6 (615980) is caused by mutation in the LIPE gene (151750) on chromosome 19q13; FPLD7 (606721) is caused by mutation in the CAV1 gene (601047) on chromosome 7q31; FPLD8 (620679), caused by mutation in the ADRA2A gene (104210) on chromosome 10q25; and FPLD9 (620683), caused by mutation in the PLAAT3 gene (613867) on chromosome 11q12.

A rare familial partial lipodystrophy with characteristics of adult onset of distal lipoatrophy with gluteofemoral fat loss, as well as increased fat accumulation in the face and trunk and visceral adiposity. Additional manifestations include diabetes mellitus, atherogenic dyslipidemia, eyelid xanthelasma, arterial hypertension, cardiovascular disease, hepatic steatosis, acanthosis nigricans on axilla and neck, hirsutism, and muscular hypertrophy of the lower limbs. Caused by heterozygous mutation in the PPARG gene on chromosome 3p25.

Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.

Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.

Mandibuloacral dysplasia with type B lipodystrophy (MADB) is a rare autosomal recessive disorder characterized by postnatal growth retardation, craniofacial anomalies such as mandibular hypoplasia, skeletal anomalies such as progressive osteolysis of the terminal phalanges and clavicles, and skin changes such as mottled hyperpigmentation and atrophy. The lipodystrophy is characterized by generalized loss of subcutaneous fat involving the face, trunk, and extremities. Some patients have a progeroid appearance. Metabolic complications associated with insulin resistance have been reported (Schrander-Stumpel et al., 1992; summary by Simha et al., 2003). For a general phenotypic description of lipodystrophy associated with mandibuloacral dysplasia, see MADA (248370).

The severity of congenital hyperinsulinism varies widely among affected individuals, even among members of the same family. About 60 percent of infants with this condition experience a hypoglycemic episode within the first month of life. Other affected children develop hypoglycemia by early childhood. Unlike typical episodes of hypoglycemia, which occur most often after periods without food (fasting) or after exercising, episodes of hypoglycemia in people with congenital hyperinsulinism can also occur after eating.\n\nCongenital hyperinsulinism is a condition that causes individuals to have abnormally high levels of insulin. Insulin is a hormone that helps control levels of blood glucose, also called blood sugar. People with this condition have frequent episodes of low blood glucose (hypoglycemia). In infants and young children, these episodes are characterized by a lack of energy (lethargy), irritability, or difficulty feeding. Repeated episodes of low blood glucose increase the risk for serious complications such as breathing difficulties, seizures, intellectual disability, vision loss, brain damage, and coma.

Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

Estrogen resistance (ESTRR) is characterized by absence of puberty with elevated estradiol and gonadotropic hormones, as well as markedly delayed bone maturation. Female patients show absent breast development, small uterus, and enlarged multicystic ovaries; male patients may show small testes (Bernard et al., 2017). Some patients exhibit continued growth into adulthood (Smith et al., 1994).

Patients with biallelic mutations in the ADCY3 gene show hyperphagia within the first 2 years of life and develop severe obesity. Other features include hyposmia or anosmia, and some patients exhibit mild to moderate intellectual disability (Saeed et al., 2018).

Obesity due to mutation in the MC4R gene is the most common cause of monogenic obesity. Patients have early-onset severe obesity and hyperphagia (Farooqi et al., 2003).

Mandibuloacral dysplasia with type A lipodystrophy (MADA) is an autosomal recessive disorder characterized by growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, and pigmentary skin changes. The lipodystrophy is characterized by a marked acral loss of fatty tissue with normal or increased fatty tissue in the neck and trunk. Some patients may show progeroid features. Metabolic complications can arise due to insulin resistance and diabetes (Young et al., 1971; Simha and Garg, 2002; summary by Garavelli et al., 2009). See also MAD type B (MADB; 608612), which is caused by mutation in the ZMPSTE24 gene (606480).

BDV syndrome (BDVS) is an autosomal recessive disorder characterized by early-onset profound obesity, hyperphagia, and moderately impaired intellectual development accompanied by infantile hypotonia and other endocrine disorders including hypogonadotropic hypogonadism, hypothyroidism, and insulin resistance (summary by Bosch et al., 2021).

Atelis syndrome-2 (ATELS2) is an autosomal recessive disorder characterized by poor overall growth with microcephaly and short stature, dysmorphic facial features, and congenital cardiac defects. Additional more variable features may include hematologic abnormalities, variable ocular abnormalities, motor delay, and anxiety. Patient cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy (Grange et al., 2022). See also ATELS1 (620184), caused by mutation in the SLF2 gene (610348). For a discussion of genetic heterogeneity of MVA, see MVA1 (257300).

Obesity and hypopigmentation (OBHP) is characterized by early-onset severe obesity and hypopigmentation of the skin. Some affected individuals have red hair, and some experience increased appetite and exhibit reduced energy expenditure (Kempf et al., 2022).

Familial hyperinsulinemic hypoglycemia-8 (HHF8) is an autosomal recessive disorder characterized by protein-related hypoglycemia and persistent mild hyperammonemia (summary by Shahroor et al., 2022). For a phenotypic description and a discussion of genetic heterogeneity of familial hyperinsulinemic hypoglycemia, see HHF1 (256450).

Congenital generalized lipodystrophy type 5 (CGL5) is an autosomal recessive metabolic disorder characterized by childhood onset of lipodystrophy, severe nonalcoholic fatty liver disease, dyslipidemia, hypertriglyceridemia, low HDL, and insulin-resistant diabetes mellitus. Affected individuals also have short stature (Payne et al., 2014). For a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).

Familial partial lipodystrophy type 9 (FPLD9) is an autosomal recessive metabolic disorder characterized by the loss of adipose tissue resulting in a lean appearance with muscular hypertrophy, usually most apparent in the limbs and trunk. Some patients have more generalized lipoatrophy, whereas others have abnormal fat accumulation in the face and neck regions and show cushingoid or acromegalic facial features. The disorder is associated with insulin-resistant diabetes mellitus, dyslipidemia, low HDL, and hepatic steatosis. Symptom onset is usually in the first decade. Females tend to have hirsutism and polycystic ovary syndrome, whereas males have gynecomastia. Most patients also have neurologic involvement, including demyelinating polyneuropathy (in most) and delayed development with intellectual disability (in about half) (Schuermans et al., 2023). For a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.