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. Mutations of the POU1F1 gene in the human and Pit1 in the mouse are responsible for pleiotropic deficiencies of GH, prolactin (PRL; 176760), and thyroid-stimulating hormone (TSH; see 188540), while the production of adrenocorticotrophic hormone (ACTH; see 176830), luteinizing hormone (LH; 152780), and follicle-stimulating hormone (FSH; 136530) are preserved (Wu et al., 1998). Some patients exhibit only GH deficiency, although approximately 50% of isolated GH deficiency progresses to CPHD (Gergics et al., 2021). In infancy severe growth deficiency from birth as well as distinctive facial features with prominent forehead, marked midfacial hypoplasia with depressed nasal bridge, deep-set eyes, and a short nose with anteverted nostrils and hypoplastic pituitary gland by MRI examination can be seen (Aarskog et al., 1997). Some cases present with severe mental retardation along with short stature (Radovick et al., 1992). Reviews Voss and Rosenfeld (1992) reviewed the development and differentiation of the 5 pituitary cell types: galactotropes, gonadotropes, corticotropes, thyrotropes, and somatotropes. As indicated by the mutations in PIT1 described later, combined pituitary hormone deficiency can have either autosomal dominant or autosomal recessive inheritance, depending on the part of the PIT1 molecule affected by the mutation. Some mutations have a dominant-negative effect. Genetic Heterogeneity of Combined Pituitary Hormone Deficiency CPHD2 (262600), associated with hypogonadism, is caused by mutation in the PROP1 gene (601538). CPHD3 (221750), which is associated with rigid cervical spine and variable sensorineural deafness, is caused by mutation in the LHX3 gene (600577). CPHD4 (262700) is caused by mutation in the LHX4 gene (602146). CPHD5 (see septooptic dysplasia, 182230) is caused by mutation in the HESX1 gene (601802). CPHD6 (613986) is caused by mutation in the OTX2 gene (600037). CPHD7 (618160) is caused by mutation in the RNPC3 gene (618016).

Central hypothyroidism and testicular enlargement (CHTE) is characterized by central hypothyroidism, delayed pubertal testosterone rise, adult macroorchidism, variable prolactin deficiency, and occasional transient partial GH deficiency. Some carrier females also exhibit central hypothyroidism and mild prolactin deficiency. Inter- and intrafamilial variability has been observed (summary by Joustra et al., 2016).

Nongoitrous congenital hypothyroidism-7 (CHNG7) is characterized by normal-to-low T4 and normal-to-high thyrotropin (TSH; see 188540) levels, with reduced or absent pituitary responsiveness to thyrotropin-releasing hormone (TRH; 613879). Patients may exhibit short stature, growth retardation, and delayed bone age, as well as lethargy or fatigue (Collu et al., 1997; Bonomi et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of congenital nongoitrous hypothyroidism, see 275200.

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).