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.

AIP familial isolated pituitary adenoma (AIP-FIPA) is defined as the presence of an AIP germline pathogenic variant in an individual with a pituitary adenoma (regardless of family history). The most commonly occurring pituitary adenomas in this disorder are growth hormone-secreting adenomas (somatotropinoma), followed by prolactin-secreting adenomas (prolactinoma), growth hormone and prolactin co-secreting adenomas (somatomammotropinoma), and nonfunctioning pituitary adenomas (NFPA). Rarely TSH-secreting adenomas (thyrotropinomas) are observed. Clinical findings result from excess hormone secretion, lack of hormone secretion, and/or mass effects (e.g., headaches, visual field loss). Within the same family, pituitary adenomas can be of the same or different type. Age of onset in AIP-FIPA is usually in the second or third decade.

The Cabezas type of X-linked syndromic intellectual developmental disorder is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor (Cabezas et al., 2000).

Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by Beales et al., 1999). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014). Genetic Heterogeneity of Bardet-Biedl Syndrome BBS2 (615981) is caused by mutation in a gene on 16q13 (606151); BBS3 (600151), by mutation in the ARL6 gene on 3q11 (608845); BBS4 (615982), by mutation in a gene on 15q22 (600374); BBS5 (615983), by mutation in a gene on 2q31 (603650); BBS6 (605231), by mutation in the MKKS gene on 20p12 (604896); BBS7 (615984), by mutation in a gene on 4q27 (607590); BBS8 (615985), by mutation in the TTC8 gene on 14q32 (608132); BBS9 (615986), by mutation in a gene on 7p14 (607968); BBS10 (615987), by mutation in a gene on 12q21 (610148); BBS11 (615988), by mutation in the TRIM32 gene on 9q33 (602290); BBS12 (615989), by mutation in a gene on 4q27 (610683); BBS13 (615990), by mutation in the MKS1 gene (609883) on 17q23; BBS14 (615991), by mutation in the CEP290 gene (610142) on 12q21, BBS15 (615992), by mutation in the WDPCP gene (613580) on 2p15; BBS16 (615993), by mutation in the SDCCAG8 gene (613524) on 1q43; BBS17 (615994), by mutation in the LZTFL1 gene (606568) on 3p21; BBS18 (615995), by mutation in the BBIP1 gene (613605) on 10q25; BBS19 (615996), by mutation in the IFT27 gene (615870) on 22q12; BBS20 (619471), by mutation in the IFT172 gene (607386) on 9p21; BBS21 (617406), by mutation in the CFAP418 gene (614477) on 8q22; and BBS22 (617119), by mutation in the IFT74 gene (608040) on 9p21. The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Although BBS had originally been thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001). Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation.

Chromosome Xq27.3-q28 duplication syndrome is an X-linked recessive neurodevelopmental disorder characterized by mild mental retardation, mild facial dysmorphism, short stature, and primary testicular failure manifest as high-pitched voice, sparse body hair, abdominal obesity, and small testes. Female carriers may have short stature and premature ovarian failure (summary by Rio et al., 2010).

Any metabolic syndrome in which the cause of the disease is a mutation in the DYRK1B gene.

ACTH-independent macronodular adrenal hyperplasia-2 is an autosomal dominant tumor susceptibility with syndromic incomplete penetrance, as a second hit to the ARMC5 gene is required to develop macronodular hyperplasia (Assie et al., 2013).

Familial partial lipodystrophy type 6 (FPLD6) is characterized by abnormal subcutaneous fat distribution, with variable excess accumulation of fat in the face, neck, shoulders, axillae, back, abdomen, and pubic region, and reduction in subcutaneous fat of the lower extremities. Progressive adult-onset myopathy is seen in some patients, and there is variable association with diabetes, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and hepatic steatosis (Zolotov et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

A clustering of abdominal obesity, high triglycerides, low levels of high density lipoprotein cholesterol (HDLC), high blood pressure, and elevated fasting glucose levels is sometimes called metabolic syndrome X (Reaven, 1988) or abdominal obesity-metabolic syndrome (Bjorntorp, 1991). The syndrome may affect nearly 1 in 4 U.S. adults and is considered a veritable epidemic (Ford et al., 2002). It is a major risk factor for both diabetes mellitus (see 125853 and Haffner et al., 1992) and cardiovascular disease (Isomaa et al., 2001). The etiology is complex, determined by the interplay of both genetic and environmental factors. The prevalence varies substantially among ethnic groups, with the highest rates in Mexican American women (Park et al., 2003). Other factors influencing the metabolic syndrome include age, smoking, alcohol, diet, and physical inactivity. Genetic Heterogeneity of Abdominal Obesity-Metabolic Syndrome AOMS2 (605572) has been mapped to chromosome 17p12. AOMS3 (615812) is caused by mutation in the DYRK1B gene (604556) on chromosome 19q13. AOMS4 (618620) is caused by mutation in the CELA2A gene (609443) on chromosome 1p36.

Combined pituitary hormone deficiency (CPHD) in man denotes impaired production of growth hormone (GH; 139250) and one or more of the other 5 anterior pituitary hormones. Some patients exhibit only GH deficiency, although approximately 50% of isolated GH deficiency progresses to CPHD (Gergics et al., 2021). Individuals with CPHD7 have been reported with isolated GH deficiency as well as combined deficiencies including thyroid-stimulating hormone (TSH; see 188540) and/or prolactin (PRL; 176760). In addition to severe postnatal short stature, patients exhibit delayed bone age and hypoplasia of the anterior pituitary, as well as distinctive facial dysmorphisms including frontal bossing and depressed nasal bridge (Argente et al., 2014; Verberne et al., 2020; Yamada et al., 2021). For general phenotypic information and a discussion of genetic heterogeneity of CPHD, see 613038.

Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD) is an X-linked recessive phenotype characterized by global developmental delay with hypotonia, delayed speech, and mildly delayed walking associated with somatic marfanoid features, including tall stature, long fingers, and mildly dysmorphic facies. Some patients may have cardiac defects, such as mitral valve regurgitation, as well as other anomalies related to connective tissue defects, such as scoliosis (summary by Fiordaliso et al., 2019).

Growth restriction, hypoplastic kidneys, alopecia, and distinctive facies (GKAF) is characterized by microcephaly, congenital alopecia, distinctive craniofacial features, severe congenital sensorineural hearing loss, global developmental delay, hydrocephalus, hypoplastic kidneys with renal insufficiency, genital hypoplasia, and early mortality (Ito et al., 2018).