Pituitary Hormone Deficiency, Combined, 1

A number sign (#) is used with this entry because combined pituitary hormone deficiency-1 (CPHD1) is caused by homozygous or compound heterozygous mutation in the POU1F1 gene (173110) on chromosome 3p11.

Description

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). 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).

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).

Clinical Features

Wit et al. (1989) described 2 unrelated Dutch families in which 4 of 10 children presented with total pituitary growth hormone (GH; 139250) and prolactin (PRL; 176760) deficiency and a partial thyrotropin (TSH; see 188540) deficiency. The GH gene was intact in 'family I.' The pituitaries were normal by MRI. All children responded well to GH and L-thyroxine therapy. Baseline plasma somatostatin and its peak response to arginine infusion were elevated in the 2 affected sibs in 'family I,' and they had a milder TSH deficiency than the 2 affected sibs in 'family II;' plasma insulin showed a poor response to arginine infusion. Wit et al. (1989) suggested that this hereditary combination of pituitary deficiencies was due to deficiency of a common positive transcription factor.

Tatsumi et al. (1992) reported 2 sisters, born of consanguineous parents, who had cretinism due to deficiency of thyrotropin, growth hormone, and prolactin. Both patients showed typical clinical features of cretinism, such as puffy face and saddle nose, hoarse voice, and myxedema. The younger sister died of aspiration pneumonia 2 months after birth. The parents and 5 brothers were unaffected.

Radovick et al. (1992) studied a patient with a deficiency of GH, PRL, and TSH, previously reported by Rogol and Kahn (1976), who had severe mental retardation and short stature. The patient's mother was of normal stature and had normal pituitary hormone levels; other family members were unavailable for study.

Okamoto et al. (1994) described a Japanese girl who had prolonged neonatal jaundice, severely retarded postnatal growth, and protruding forehead with retracted nasal bridge. Hormone evaluation revealed complete deficiency of PRL and GH, with decreased TSH. Her serum cortisol level was normal and she had no symptoms associated with adrenal insufficiency. The anterior pituitary was normal in size by MRI. An older brother, who also had severe neonatal jaundice, died of hypoplastic left heart syndrome at 10 days of age; no endocrinologic evaluation or postmortem examination was done. There was also an unaffected older sister.

De Zegher et al. (1995) reported a mother-infant pair with CPHD. Growth failure was noted in the mother from early infancy, and she was more than 7 standard deviations below the normal mean at 7 years of age; pulmonary valve stenosis was also noted. She was hypothyroid with a good response to thyroid therapy, and initiation of GH therapy was followed by catch-up growth. Spontaneous puberty occurred at age 15 years and menarche at 17 years. Low prolactin levels were found. A final height of 149.5 cm (-2.1 SD) was reached at age 19 years; 7 molars had not developed. MRI showed hypoplasia of the anterior pituitary; the pituitary stalk and the intrasellar neurohypophysis were normal. She became pregnant at age 29 years; ultrasound examinations after 33 weeks showed fetal femoral growth retardation and polyhydramnios was present in increasing amounts after 35 weeks. The fetus was delivered by cesarean section at 38 weeks. Preoperatively the mother was found to be severely hypothyroid; prolactin concentrations were undetectable in the mother's serum after delivery and lactogenesis failed. At birth, the infant girl was hypotonic with a widely open sagittal suture, depressed nasal bridge, enlarged tongue, and scalp and thoracic edema as well as ascites. Correction of severe neonatal hypotension necessitated prolonged administration of dopamine and/or dobutamine; the ductus arteriosus failed to close despite cyclooxygenase inhibitor therapy, and was surgically transected on day 10. Despite thyroid replacement therapy and recombinant human GH administration, neurologic development of the infant was impaired. At 1 year of age, the infant had a normal size but was hypotonic, had severe strabismus, and presented a 'chaotic behavior,' with short attention span and poor visual and auditory contact.

Pellegrini-Bouiller et al. (1996) studied 4 sibs with CPHD, born of consanguineous unaffected parents, who had complete GH deficiency diagnosed in early childhood and later developed hypothyroidism and were found to have undetectable PRL levels. MRI in 1 of the sibs showed a hypoplastic pituitary.

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.

Clinical Management

Individuals with POU1F1 mutations that cause GH and TSH deficiencies respond to GH and thyroid hormone replacement (Wit et al., 1989).

Molecular Genetics

Noting that a combined pituitary hormone deficiency (CPHD) in 2 strains of mice, Snell dwarf and dwarf Jackson, was caused by mutation in the Pit1 gene, Tatsumi et al. (1992) analyzed the PIT1 gene (POU1F1; 173110) in a female patient with CPHD and identified homozygosity for a nonsense mutation (R172X; 173110.0001). The mutation was found in heterozygosity in her unaffected consanguineous parents.

In a patient with CPHD, previously reported by Rogol and Kahn (1976), Radovick et al. (1992) identified a heterozygous missense mutation in the PIT1 gene (R271W; 173110.0002) that was not found in the unaffected mother. Functional analysis demonstrated that the mutant protein bound DNA normally, but acted as a dominant inhibitor of the action of the gene in the pituitary.

In 3 unrelated Japanese children with CPHD, Ohta et al. (1992) identified 2 different missense mutations in heterozygous state in the PIT1 gene (173110.0002 and 173110.0004, respectively) and 1 in homozygous state (173110.0005). Ohta et al. (1992) suggested that mutant PIT1 proteins may act as dominant-negative mutants or recessive mutants depending on the location of the mutation, and as a result, hormonal kinetics and the formation of the anterior pituitary are affected.

Pfaffle et al. (1992) analyzed the PIT1 gene in 2 unrelated Dutch families segregating apparently autosomal recessive CPHD, previously reported by Wit et al. (1989), and identified a homozygous missense mutation in the PIT1 gene (A158P; 173110.0003) in affected members of 'family II,' whereas affected members of 'family I' were compound heterozygous for A158P and a maternally inherited deletion of the PIT1 gene.

In a Japanese girl with CPHD involving PRL, GH, and TSH, Okamoto et al. (1994) identified heterozygosity for the R271W mutation in the PIT1 gene. Her unaffected father and paternal grandmother and 2 aunts also carried the mutation, as did an older brother who had died at 10 days of age of hypoplastic left heart syndrome. RT-PCR analysis in peripheral lymphocytes revealed monoallelic expression of the normal allele in the father and grandmother and a skewed pattern of biallelic expression in the proband, suggesting epigenetic control of expression of the PIT1 gene.

In a mother and infant with CPHD, de Zegher et al. (1995) identified heterozygosity for the R271W mutation in the PIT1 gene. At birth, serum T4 was undetectable in mother and infant, and the newborn presented with a striking delay of respiratory, cardiovascular, neurologic, and bone maturation. De Zegher et al. (1995) concluded that fetomaternal PIT1 deficiency resulted in unmitigated fetal hypothyroidism, unmasking thyroid hormone as a potent endogenous drive of fetal maturation and revealing placental transfer of maternal T4 as a rescue mechanism for infants with congenital hypothyroidism that prevents fetal and neonatal symptoms of thyroid deficiency and safeguards developmental potential.

In a patient with combined deficiency of TSH, GH, and PRL, Irie et al. (1995) identified homozygosity for a nonsense mutation in the PIT1 gene (173110.0006); the unaffected parents were heterozygous for the mutation.

In 4 sibs with CPHD, born of unaffected consanguineous parents, Pellegrini-Bouiller et al. (1996) identified homozygosity for a missense mutation in the PIT1 gene (F135C; 173110.0007); their healthy mother was heterozygous for the mutation, indicating recessive inheritance. Vallette-Kasic et al. (2001) analyzed the functional effects of the F135C mutation and demonstrated that the mutant had decreased transactivation capacity on the PRL, GH, and PIT1 genes; structural modeling indicated that interaction with other transcription factors might be prevented.

Aarskog et al. (1997) reported a Norwegian patient with the R271W mutation and found reports of 9 other cases in different populations, suggesting that codon 271 in exon 6 is a 'hotspot' for PIT1 mutations.

Pernasetti et al. (1998) analyzed the PIT1 gene in 3 reportedly unrelated consanguineous Saudi Arabian families in which there was a total of 7 children who were deficient in GH, PRL, and TSH, with an empty sella turcica on CT scan. Homozygosity for a missense mutation (P239S; 173110.0008) was identified in all affected individuals; the unaffected parents were heterozygous for the mutation.

Hendriks-Stegeman et al. (2001) reported an Indian boy who was found to be hypothyroid on neonatal screening after arrival in The Netherlands at 4 months of age. He showed typical signs of congenital hypothyroidism, including low nasal bridge, macroglossia, facial myxedema, and wide open fontanels, and also exhibited generalized hypotonia, slight peripheral myxedema, constipation, and hypothermia. He was subsequently found to have undetectable PRL and GH and a hypoplastic anterior pituitary by MRI, and analysis of the POU1F1 (formerly 'PIT1') gene revealed compound heterozygosity for a 1-bp deletion and a missense mutation (173110.0009 and 173110.0010, respectively). The phenotypically normal mother, who had a normal hormonal profile, was heterozygous for the missense mutation, indicating that it was unlikely to have a dominant-negative effect; the unaffected father was heterozygous for the deletion. Hendriks-Stegeman et al. (2001) stated that the majority of patients with a POU1F1 defect present with growth failure, whereas less than half present with hypothyroidism as the first clinical manifestation.

Hashimoto et al. (2003) studied a 15-year-old Italian girl with a history of neonatal jaundice and failure to thrive, who had presented at 2 months of age with signs of hypothyroidism, including large tongue, myxedema, umbilical hernia, jaundice, and widely open anterior and posterior fontanels. TRH stimulation revealed undetectable basal and stimulated TSH and PRL levels, whereas cortisol and ACTH levels were normal; peak GH responses to arginine, glucagon, and GHRH were extremely low. CT scan revealed hypoplasia of the anterior pituitary gland, which was confirmed by MRI at age 7 years. Analysis of the POU1F1 gene revealed homozygosity for a nonsense mutation (K145X; 173110.0011). Her parents, who were heterozygous for K145X, both showed evidence of mild endocrine dysfunction, with low normal TSH and PRL levels; in addition, the mother had hypogalactorrhea and had difficulties with breast feeding. Hashimoto et al. (2003) concluded that 2 normal copies of the POU1F1 gene appear necessary for full POU1F1 gene function.

Turton et al. (2005) screened the POU1F1 gene in 80 patients with CPHD, 48 with isolated GH deficiency, and 1 with isolated TSH deficiency, and identified mutations in 10 (7.8%) of the 129 patients (see 173110.0002 and 173110.0012-173110.0014). All but 1 of the mutation-positive individuals had profound GH, TSH, and PRL deficiency: at age 20.5 years, 1 patient continued to have a free T4 in the normal range without hormone replacement therapy. Of 8 patients in whom MRI scans had been performed, 7 had a hypoplastic anterior pituitary and 1 had a normal-appearing pituitary gland. Citing the variable age of onset of TSH deficiency (9 years to 15 years) in the sibs described by Pellegrini-Bouiller et al. (1996), Turton et al. (2005) suggested that the phenotype associated with POU1F1 mutations may be variable, with occasional preservation of TSH secretion.

Dattani (2005) reviewed the genetic causes and phenotypic features of IGHD and combined pituitary hormone deficiency (CPHD). The author noted that hormone abnormalities may evolve over time, necessitating frequent reevaluation, and that establishing the genotype can aid in management.

In a 20-year-old Japanese man who was diagnosed with CPHD in infancy, with undetectable serum basal levels of GH, PRL, and TSH and a hypoplastic anterior pituitary on MRI, Miyata et al. (2006) identified homozygosity for a novel missense mutation in the POU1F1 gene (S179R; 173110.0015). His mother was heterozygous for the S179R allele; his father did not participate in the study.

Heterogeneity

Sloop et al. (2000) studied 7 children with CPHD and 2 with isolated GH deficiency, all of whom displayed abnormal pituitary gland development with ectopic posterior lobe location and frequently hypoplastic anterior lobes by magnetic resonance imaging. Noting that embryonic development of the pituitary requires the coordinated expression of specific transcription factors, and that mutations of the PIT1 and PROP1 transcription factors are responsible for CPHD in some patients with normally positioned posterior pituitaries, the authors hypothesized that mutations in 1 or both of the 2 human LHX3 isoforms might be responsible for posterior pituitary ectopia associated with anterior pituitary hypopituitarism. Comprehensive molecular analysis of the LHX3 isoforms was performed to test this hypothesis, but no loss-of-function mutations in the LHX3 gene were detected. In addition, analysis of PROP1 did not reveal mutations that might cause this phenotype. The authors concluded that the abnormal processes leading to the development of CPHD or GH deficiency associated with posterior pituitary ectopia are not a result of aberrant LHX3 or PROP1 function, but may be caused by defects at other gene loci.