A number sign (#) is used with this entry because of evidence that combined pituitary hormone deficiency-3 (CPHD3) is caused by homozygous mutation in the LHX3 gene (601538) on chromosome 9q34.

Combined pituitary hormone deficiency-3 (CPHD3) is an autosomal recessive disorder characterized by hypopituitarism with structural anterior pituitary defects and cervical abnormalities with or without restricted neck rotation. Some patients have sensorineural hearing loss (summary by Rajab et al., 2008).

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

Winkelmann et al. (1972) described 2 sisters with inner ear deafness and asexual ateleiotic dwarfism. Deficiency of growth hormone and gonadotropin was demonstrated by radioimmunoassay. The parents were not known to be related.

Netchine et al. (2000) reported 2 unrelated consanguineous families with CPHD in which affected members exhibited severe growth retardation and deficiency of all but 1 of the anterior pituitary hormones, including growth hormone (GH; 139250), thyrotropin (TSH; see 188540), prolactin (PRL; 176760), luteinizing hormone (LH; see 152780), and follicle-stimulating hormone (FSH; see 136530); levels of adrenocorticotrophic hormone (ACTH; see 176830) were normal. Affected individuals also had elevated and anteverted shoulders leading to the clinical appearance of a stubby neck associated with a severe restriction of rotation of the cervical spine, preventing dissociation of head and trunk movements. Cervical x-rays did not reveal any vertebral malformation, and magnetic resonance imaging (MRI) showed the abnormal steepness of the cervical spine but normal soft tissue structures, without evidence of muscle fibrosis or atrophy. Electromyelograms in 2 patients did not reveal any signs of denervation or myopathic changes. In both families, all other members tested had normal neck rotation. Two affected individuals from 1 family had severe anterior pituitary hypoplasia by MRI, whereas the affected individual from the other family had an enlarged anterior pituitary by MRI at age 19 years that was not documented on a computer-assisted tomography (CT) scan performed 10 years earlier.

Bhangoo et al. (2006) studied a 6.75-year-old boy, born of consanguineous parents, who had CPHD associated with rigid cervical spine causing limited head rotation. The child had presented shortly after birth with cyanosis, feeding difficulty, persistent jaundice, micropenis, and poor weight gain and growth rate. Laboratory data, including an undetectable TSH, low free T4, low IGF-I and IGF binding protein-3, prolactin deficiency, and LH and FSH deficiency, were consistent with hypopituitarism. MRI revealed an apparently structurally normal cervical spine and a post-contrast hypointense lesion in the anterior pituitary consistent with microadenoma; pituitary volume was calculated to be 570.15 cubic millimeters, more than twice the normal mean. On school assessment, the boy was diagnosed with mental retardation resulting in severe speech delay. Neurologic exam revealed mild hypotonia and immature prehensile skills. EMG findings were suggestive of an anterior horn cell disease process; nerve conduction studies were normal. The clinically unaffected parents had normal anterior pituitary hormone panels.

Rajab et al. (2008) described 3 sibs from a consanguineous Middle Eastern family who exhibited an unusual phenotype of panhypopituitarism with severe anterior pituitary hypoplasia, skeletal abnormalities including short neck with limited neck rotation and lumbar kyphosis and/or lordosis, hyperextensible joints and hyperelastic skin, deep palmar and plantar creases, hypoplastic nails, and dental caries. The 3 sibs also had mild (30 dB) sensorineural hearing loss bilaterally. Rajab et al. (2008) subsequently ascertained an unrelated boy, born of consanguineous parents, with a very similar phenotype: he had CPHD diagnosed in infancy with anterior pituitary hypoplasia on MRI, and later developed the appearance of skeletal dysplasia with a short neck, stiff back, and thoracic kyphosis; audiologic assessment revealed profound (96 dB) sensorineural hearing loss bilaterally. A presumptive diagnosis of ACTH deficiency was made in the first family based on clinical phenotype as well as low random cortisol concentrations; ACTH stimulation performed in the proband of the second family unequivocally established a diagnosis of ACTH deficiency.

Rajab et al. (2008) reevaluated 3 affected individuals from the families previously described by Netchine et al. (2000), and found moderate (60 dB) and mild (30 dB) sensorineural hearing loss in 2 patients from 1 family; the single patient from the second family, who was extremely mentally retarded, was diagnosed to be completely deaf on the basis of the absence of any acoustic evoked potential (AEP).

Rajab et al. (2008) performed homozygosity mapping in members of a family with CPHD, cervical rigidity, and sensorineural deafness, and identified 3 significant regions of shared homozygosity in the 3 affected individuals. Two of the regions contained no candidate genes of interest, but the locus on 9q34-qter encompassed the transcription factor LHX3, in which mutations had previously been associated with CPHD.

The transmission pattern of CPHD3 in the families reported by Netchine et al. (2000) was consistent with autosomal recessive inheritance.

Using a candidate-gene approach based on mouse studies involving the LHX3 gene (see 600577 and Sheng et al., 1996), Netchine et al. (2000) screened the LHX3 gene in affected members of 2 unrelated consanguineous families with CPHD involving all of the anterior pituitary hormones except ACTH, who also displayed rigidity of the cervical spine and in whom mutation in the PROP1 gene (601538) had been excluded, and identified homozygosity for a nonsense mutation (600577.0001) and an intragenic deletion (600577.0002), respectively. The data were considered consistent with the known involvement of LHX3 in the development of all anterior pituitary cell types except corticotropes, and of extrapituitary structures as well.

In a 6.75-year-old boy with CPHD and rigid cervical spine, Bhangoo et al. (2006) identified homozygosity for a 1-bp deletion mutation in the LHX3 gene (600577.0003).

Pfaeffle et al. (2007) analyzed the LHX3 gene in 366 patients from 342 families with pituitary insufficiency and identified mutations in 7 affected individuals (1.9%) from 4 CPHD families (600577.0004-600577.0007, respectively). None of the 48 patients with isolated GH deficiency had an LHX3 mutation. The authors concluded that LHX3 mutations are a rare cause of CPHD and involve deficiencies of GH, PRL, TSH, and LH/FSH in all cases. Whereas most patients have a severe hormone deficiency manifesting after birth, milder forms can be observed. Pfaeffle et al. (2007) noted that limited neck rotation is not a universal feature in these patients, since it was not present in 3 sibs with CPHD who had a nonsense mutation in LHX3 (600577.0007).

Rajab et al. (2008) sequenced the LHX3 gene in 4 patients from 2 unrelated consanguineous families, who presented with early-onset hypopituitarism with neonatal hypoglycemia, short neck with limited rotation, and mild sensorineural hearing loss, and identified homozygosity for a large intragenic deletion (600577.0008) and a nonsense mutation (600577.0009), respectively. Noting that sensorineural hearing loss was found upon reexamination of 3 of the mutation-positive patients studied by Netchine et al. (2000) and that ACTH deficiency was unequivocally confirmed in 1 of their own patients, Rajab et al. (2008) stated that the phenotypic spectrum associated with LHX3 mutations should be extended to encompass these features. Regarding the skin laxity and skeletal abnormalities seen in the 3 affected members of their family with the large deletion, Rajab et al. (2008) suggested that a second recessive mutation might be segregating in that family.