Apert syndrome is characterized by the presence of multisuture craniosynostosis, midface retrusion, and syndactyly of the hands with fusion of the second through fourth nails. Almost all affected individuals have coronal craniosynostosis, and a majority also have involvement of the sagittal and lambdoid sutures. The midface in Apert syndrome is underdeveloped as well as retruded; a subset of affected individuals have cleft palate. The hand in Apert syndrome always includes fusion of the middle three digits; the thumb and fifth finger are sometimes also involved. Feeding issues, dental abnormalities, hearing loss, hyperhidrosis, and progressive synostosis of multiple bones (skull, hands, feet, carpus, tarsus, and cervical vertebrae) are also common. Multilevel airway obstruction may be present and can be due to narrowing of the nasal passages, tongue-based airway obstruction, and/or tracheal anomalies. Nonprogressive ventriculomegaly is present in a majority of individuals, with a small subset having true hydrocephalus. Most individuals with Apert syndrome have normal intelligence or mild intellectual disability; moderate-to-severe intellectual disability has been reported in some individuals. A minority of affected individuals have structural cardiac abnormalities, true gastrointestinal malformations, and anomalies of the genitourinary tract.

Individuals with 22q11.2 deletion syndrome (22q11.2DS) can present with a wide range of features that are highly variable, even within families. The major clinical manifestations of 22q11.2DS include congenital heart disease, particularly conotruncal malformations (ventricular septal defect, tetralogy of Fallot, interrupted aortic arch, and truncus arteriosus), palatal abnormalities (velopharyngeal incompetence, submucosal cleft palate, bifid uvula, and cleft palate), immune deficiency, characteristic facial features, and learning difficulties. Hearing loss can be sensorineural and/or conductive. Laryngotracheoesophageal, gastrointestinal, ophthalmologic, central nervous system, skeletal, and genitourinary anomalies also occur. Psychiatric illness and autoimmune disorders are more common in individuals with 22q11.2DS.

Aspartylglucosaminuria (AGU) is a severe autosomal recessive lysosomal storage disorder that involves the central nervous system and causes skeletal abnormalities as well as connective tissue lesions. The most characteristic feature is progressive mental retardation. The disorder is caused by deficient activity of the lysosomal enzyme glycosylasparaginase, which results in body fluid and tissue accumulation of a series of glycoasparagines, i.e., glycoconjugates with an aspartylglucosamine moiety at the reducing end. AGU belongs to the group of disorders commonly referred to as the Finnish disease heritage (summary by Mononen et al., 1993 and Arvio and Arvio, 2002).

X-linked lymphoproliferative disease (XLP) has two recognizable subtypes, XLP1 and XLP2. XLP1 is characterized predominantly by one of three commonly recognized phenotypes: Inappropriate immune response to Epstein-Barr virus (EBV) infection leading to hemophagocytic lymphohistiocytosis (HLH) or severe mononucleosis. Dysgammaglobulinemia. Lymphoproliferative disease (malignant lymphoma). XLP2 is most often characterized by HLH (often associated with EBV), dysgammaglobulinemia, and inflammatory bowel disease. HLH resulting from EBV infection is associated with an unregulated and exaggerated immune response with widespread proliferation of cytotoxic T cells, EBV-infected B cells, and macrophages. Dysgammaglobulinemia is typically hypogammaglobulinemia of one or more immunoglobulin subclasses. The malignant lymphomas are typically B-cell lymphomas, non-Hodgkin type, often extranodal, and in particular involving the intestine.

The primary characteristics of the Frank-ter Haar syndrome (FTHS) are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by Maas et al., 2004). Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (Wilson et al., 2014).

A rare pleiotropic auto-inflammatory disorder of childhood, primarily affecting the joints and skin. The first affected family contained ten affected members from three generations and manifested variable expression of a pauciarticular, nonaxial, arthritis that began in childhood; pyoderma gangrenosum; and severe cystic acne in adolescence and beyond. Recurrent sterile arthritis usually occurs after minor trauma, but can also occur spontaneously. PAPA syndrome is a self-limiting disease, but it can lead to severe joint destruction. The gene responsible for the syndrome is the proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1).

Autosomal dominant primary hypertrophic osteoarthropathy (PHOAD) is characterized by 3 major features: digital clubbing, periostosis, and pachydermia. Patients may also experience joint swelling and pain, and some have reported gastrointestinal symptoms, including watery diarrhea. Males are more commonly affected, and more severely affected, than females (Lee et al., 2016; Xu et al., 2021). Touraine et al. (1935) recognized pachydermoperiostosis (PDP) as a familial disorder with 3 presentations or forms: a complete form with periostosis and pachydermia, an incomplete form without pachydermia, and a forme fruste with pachydermia and minimal skeletal changes. Genetic Heterogeneity Autosomal recessive forms of PHO have been reported (see 259100), including PHOAR2E (614441), which is also caused by mutation in the SLCO2A1 gene.

Müllerian aplasia and hyperandrogenism is a condition that affects the reproductive system in females. This condition is caused by abnormal development of the Müllerian ducts, which are structures in the embryo that develop into the uterus, fallopian tubes, cervix, and the upper part of the vagina. Individuals with Müllerian aplasia and hyperandrogenism typically have an underdeveloped or absent uterus and may also have abnormalities of other reproductive organs. Women with this condition have normal female external genitalia, and they develop breasts and pubic hair normally at puberty; however, they do not begin menstruation by age 16 (primary amenorrhea) and will likely never have a menstrual period. Affected women are unable to have children (infertile).\n\nWomen with Müllerian aplasia and hyperandrogenism have higher-than-normal levels of male sex hormones called androgens in their blood (hyperandrogenism), which can cause acne and excessive facial hair (facial hirsutism). Kidney abnormalities may be present in some affected individuals.

This form of brachyolmia, here designated brachyolmia type 4, is characterized by short-trunk stature with normal intelligence and facies. The radiographic features include rectangular vertebral bodies with irregular endplates and narrow intervertebral discs, precocious calcification of rib cartilages, short femoral neck, mildly shortened metacarpals, and mild epiphyseal and metaphyseal changes of the tubular bones (summary by Miyake et al., 2012).

PHOAR2-enteropathy syndrome (PHOAR2E) is characterized by primary hypertrophic osteoarthropathy (PHO) and/or chronic nonspecific ulcers (CNSU) of the small intestine. The cardinal features of PHO are digital clubbing, pachydermia, and periostosis; other manifestations include swelling and pain of the large joints, hyperhidrosis, seborrhea, and acne. CNSU often presents with chronic unexplained anemia and abdominal pain, and patients may exhibit edema due to hypoalbuminemia. Radiologic imaging or endoscopy shows multiple small ulcers, predominantly in the ileum, although the stomach, duodenum, and jejunum are often involved. PHO is more frequent and more severe in male patients, who often also report watery diarrhea, whereas CNSU is more often diagnosed in female patients, who may also show features of PHO such as digital clubbing or arthralgias and swelling of the joints. The same mutations in the SLCO2A1 gene have been reported in patients presenting with either diagnosis, and presumed sex-related modifiers of the manifestations of disease or other genotype/phenotype correlates have yet to be elucidated (Li et al., 2017; Umeno et al., 2018; Hong et al., 2022; Kimball et al., 2024). For a discussion of genetic heterogeneity of PHO, see PHOAR1 (259100).

Cortisone reductase deficiency (CRD) results from a failure to regenerate the active glucocorticoid cortisol from cortisone via the enzyme 11-beta-hydroxysteroid dehydrogenase (HSD11B1; 600713). The oxoreductase activity of 11-beta-HSD requires the NADPH-regenerating enzyme hexose-6-phosphate dehydrogenase (H6PD; 138090) within the endoplasmic reticulum. Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting in midlife with hirsutism, oligomenorrhea, and infertility. Biochemically, CRD is diagnosed through the assessment of urinary cortisol and cortisone metabolites and consists of measuring the tetrahydrocortisol (THF) plus 5-alpha-THF/tetrahydrocortisone (THE) ratio, which in CRD patients is typically less than 0.1 (reference range, 0.7 to 1.2) (summary by Lavery et al., 2008). Genetic Heterogeneity of Cortisone Reductase Deficiency CORTRD2 (614662) is caused by mutation in the HSD11B1 gene (600713) on chromosome 1q32.

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).

Cushing syndrome is a clinical designation for the systemic signs and symptoms arising from excess cortisol production. Affected individuals typically show hypertension, impaired glucose tolerance, central obesity, osteoporosis, and sometimes depression. Corticotropin-independent Cushing syndrome results from autonomous cortisol production by the adrenal glands, often associated with adrenocortical tumors. Adrenocortical tumors are most common in adult females (summary by Cao et al., 2014; Sato et al., 2014).