Pituitary Hormone Deficiency, Combined, 4

A number sign (#) is used with this entry because combined pituitary hormone deficiency-4 (CPHD4) is caused by heterozygous mutation in the LHX4 gene (602146) on chromosome 1q25.

For discussion of phenotypic and genetic heterogeneity of combined pituitary hormone deficiency, see CPHD1 (613038).

Clinical Features

Machinis et al. (2001) reported a French family in which 2 sibs, born of a consanguineous marriage, were found to have combined pituitary hormone deficiency (CPHD) involving growth hormone (GH; 139250), thyrotropin (TSH; 188540) and adrenocorticotropic hormone (ACTH; 202200). MRI imaging showed that both had small sella turcicas, persistent craniopharyngeal canals, hypoplastic anterior hypophyses with associated pointed cerebellar tonsils (Chiari malformation; 118420), and ectopic posterior hypophyses. Their mother was 148 cm tall and had a small sella turcica and a hypoplastic anterior hypophysis associated with a deformation of the cerebellar tonsils. Their maternal grandfather was 150 cm tall and had a small sella turcica.

Tajima et al. (2007) described a 16-month-old Japanese girl who presented with severe respiratory distress and hypoglycemia at birth; subsequent evaluation revealed CPHD, with deficiency of TSH, ACTH, GH, prolactin (PRL; 176760), follicle-stimulating hormone (FSH; 136530), and luteinizing hormone (LH; 152780). At age 15 months, she had short stature (-5.6 SD for a normal Japanese girl), and brain MRI demonstrated hypoplastic anterior pituitary, ectopic posterior lobe, a poorly developed sella turcica, and Chiari malformation.

Pfaeffle et al. (2008) identified 5 patients with CPHD and pituitary dysmorphology. The patients had GH deficiency and reduction in TSH, LH, FSH, or ACTH. One patient had hypoglycemia, and 2 had delayed bone age. In contrast to previously reported patients with LHX4 mutations, no cerebellar hypoplasia reminiscent of Arnold-Chiari malformation was seen.

Molecular Genetics

In 4 affected members over 3 generations of a French family with combined pituitary hormone deficiency, who displayed short stature, pituitary and cerebellar defects, and abnormalities of the sella turcica of the central skull base, Machinis et al. (2001) identified heterozygosity for a splice site mutation in the LHX4 gene (602146.0001).

In a 16-month-old Japanese girl with severe CPHD, pituitary defects, small sella turcica, and Chiari malformation, Tajima et al. (2007) identified heterozygosity for a de novo missense mutation in the LHX4 gene (602146.0005).

From a mutation screen of pituitary transcription factor genes in 253 patients from 245 pedigrees with CPHD, Pfaeffle et al. (2008) identified 3 heterozygous missense mutations in LHX4 (602146.0002-602146.0004) in 5 patients with CPHD and pituitary dysmorphology, but without cerebellar hypoplasia.

History

Ferrier and Stone (1969) described an apparently distinct form of familial pituitary insufficiency in 2 sisters, aged 10 and 11 years. The features were severe growth retardation from infancy, tendency to hypoglycemia, deficient production of growth hormone, TSH, and ACTH, marked retardation in skeletal maturation, and very small sella turcica with abnormal morphology of the petrous bone. Ozer (1974) reported a case of pituitary dwarfism with small sella turcica. Retinitis pigmentosa was an additional feature.