Alternative titles; symbols
SNOMEDCT: 32390006; ICD10CM: E23.0; ICD9CM: 253.2; ORPHA: 90695, 95494; DO: 9406;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q35.3 | Pituitary hormone deficiency, combined, 2 | 262600 | Autosomal recessive | 3 | PROP1 | 601538 |
A number sign (#) is used with this entry because combined pituitary hormone deficiency-2 (CPHD2) is caused by homozygous or compound heterozygous mutation in the PROP1 gene (601538) on chromosome 5q35.
For discussion of phenotypic and genetic heterogeneity of combined pituitary hormone deficiency, see CPHD1 (613038).
Panhypopituitary dwarfism is not excessively rare, there probably being 7,000 to 10,000 cases in the United States. Many cases are due to craniopharyngioma and other nongenetic causes. The form inherited as an autosomal recessive is probably rare. (See also the rare X-linked form (312000).) Multiple cases in multiple sibships observed among the Hutterites, a religious isolate in the United States and Canada, indicate the recessive inheritance of panhypopituitarism (McKusick and Rimoin, 1967). McArthur et al. (1985) studied the natural history of the Hutterite panhypopituitarism. The patients showed sequential loss of anterior pituitary tropic hormones. Three untreated sibs developed deficiency of growth hormone (GH; 139250) and gonadotropin (see 118850) in the first decade of life, with subsequent loss of thyroid-stimulating hormone (TSH; see 188540) function, and finally development of ACTH deficiency (210400) in the third decade. In a second family, deficiency of GH, gonadotropins, and TSH were evident in the first decade. Southern blot analysis showed no abnormality of growth hormone genes; linkage studies excluded close linkage to HLA.
Hanhart (1925, 1953) studied familial cases of dwarfism in the inbred population of certain areas of Switzerland and on the island of Veglia (Krk) in the Adriatic. Krzisnik et al. (1999) studied 6 affected patients on Krk. Clinical examination revealed dwarfism, obesity, dry wrinkled skin, and lack of sexual development. Hormonal investigations showed absence of growth hormone, unresponsive to growth hormone-releasing hormone (GHRH; 139190), absence of luteinizing hormone (LH; 118850) and follicle-stimulating hormone (FSH; 136530), unresponsive to gonadotropin-releasing hormone (GnRH; 152760), and absence of thyrotropin-stimulating hormone, unresponsive to thyrotropin-releasing hormone (TRH; 613879). None of the patients were deficient in ACTH. In a follow-up study of patients from Krk, Krzisnik et al. (2010) found that despite their long-lasting hormonal deficiencies, the patients live as long as 87 to 91 years, longer than the mean (71.1 to 79.1) reported for the Croatian population.
The nature of most panhypopituitarism as a congenital malformation with little indication of a mendelian basis is supported by the observation by Rosenfield et al. (1967) of 16-year-old identical twins, one normal and one with panhypopituitarism.
Kirchhoff et al. (1954) described 3 sibs with dwarfism who may have had panhypopituitarism, the oldest being almost 18 years old. Selye (1947) pictured 3 brothers, aged 25, 22, and 11 years, with panhypopituitarism. The cases described by Schmolck (1907) may have been of the panhypopituitary type. Bailey et al. (1967) reported 2 families with a total of 5 affected. In one, the parents were first cousins.
Steiner and Boggs (1965) described brother and sister, offspring of first-cousin parents, with congenital absence of the pituitary, leading to hypothyroidism, hypoadrenalism, and hypogonadism. A third sib was probably also affected and died, presumably of hypoglycemia, in the newborn period. The sella turcica was normal in size. The disorder reported by Sadeghi-Nejad and Senior (1974) may be the same or an allelic disorder. A male newborn developed hypoglycemic convulsions. Diagnostic studies showed evidence of deficiency of thyrotropin, growth hormone, and prolactin (176760). The child thrived on replacement therapy. A female sib died in the first day of life with similar clinical findings and at autopsy showed absence of the anterior pituitary and atrophic adrenal glands.
Pinto et al. (1997) noted that the finding of 'pituitary stalk interruption syndrome' (PSIS) by MRI is a clinical marker of permanent growth hormone deficiency. Some patients with PSIS have isolated GHD, whereas some have other pituitary hormone deficiencies. In a comparison of 16 patients with PSIS and isolated GHD with 35 patients with PSIS and other pituitary deficiencies, Pinto et al. (1997) concluded that most patients with GHD associated with multiple anterior pituitary abnormalities and PSIS had features suggestive of an antenatal origin.
Fluck et al. (1998) followed 2 apparently unrelated consanguineous CPHD families (12 individuals total), with 5 affected individuals (3 males and 2 females), for more than 2 decades. The authors noted that there was variability in the phenotype, even among these patients who all carried the same mutation (R120C; 601538.0001). The age at diagnosis, ranging from 9 months to 8 years of age, was dependent on the severity of symptoms. Although in 1 patient TSH deficiency was the first symptom of the disorder, all patients exhibited severe growth retardation and failure to thrive, which was primarily (4 individuals) caused by GH deficiency. The secretion of the pituitary-derived hormones GH, PRL, TSH, LH, and FSH declined gradually with age, following a different pattern in each individual; therefore, the deficiencies developed over a variable period of time. All 5 patients entered puberty spontaneously, and the 2 females also experienced menarche before replacement therapy was necessary.
Mendonca et al. (1999) studied 2 unrelated females with CPHD: patient 1 presented at 8.8 years with severe short stature, slightly enlarged sella turcica by x-ray, and a diffusely enlarged pituitary gland with hyperintense enhanced signal on T1 weighted image at coronal and sagittal views on magnetic resonance imaging (MRI). MRI repeated at age 15 years revealed a marked reduction of pituitary height. Patient 2 presented at 27 years with short stature, no pubertal development, normal sella turcica, and a pituitary gland of reduced size and normal intensity on MRI. Both patients had normal pituitary stalks and normally located neurohypophyses. Both had deficiencies of GH, TSH, PRL, LH, and FSH. Patient 1 had normal cortisol secretion at 8.8 years but by 16.6 years had developed partial cortisol deficiency, whereas patient 2 maintained normal cortisol secretion at 28.4 years. The authors concluded that a large sella turcica and an enlarged pituitary anterior lobe with hyperintense enhanced T1 signal on MRI suggests PROP1 deficiency; that pituitary morphology can change during follow-up of patients with PROP1 mutations; and that hormonal deficiencies associated with PROP1 mutations can include the adrenal axis.
Rosenbloom et al. (1999) investigated a large Dominican kindred with PROP1 deficiency presenting as CPHD, the largest such family reported to that time. Eight patients, aged 17 to 40 years, in 2 sibships with possibly related mothers but no parental consanguinity, had marked short stature and were sexually immature. Affected individuals had similarities to and significant differences from patients with insulin-like growth factor (IGF1; 147440) deficiency due to GH receptor (GHR; 600946) deficiency (see Laron syndrome, 262500), who have normal thyroid function and sexual maturation. The differences from patients with GHR deficiency included normal hand and foot length in 7 of 8 patients, normal arm span with relatively long legs, and persistence of extremely low levels of IGF1 into adulthood; similarities included the degree of growth failure, frequent but not uniform increased body weight for height or body mass index, and the presence of limited elbow extensibility and blue sclerae in 6 of 8 patients. While 3 patients had markedly increased sella turcica area for height age and bone age, the degree of sellar enlargement was variable in these 2 sibships.
Congenital hypoplasia of the anterior pituitary gland is the most common MRI finding in patients with PROP1 mutations. Riepe et al. (2001) studied 2 brothers with CPDH prospectively for almost 12 years with respect to variations in pituitary size. Both showed combined pituitary hormone deficiency of GH, TSH, PRL, and the gonadotropins FSH and LH, as is typical for PROP1 deficiency; retesting at ages 12 and 15 years, respectively, revealed developing insufficiency of ACTH and cortisol secretory capacity as well in both patients. Computerized tomography (CT) revealed an enlarged pituitary in the older brother at 3.5 years of age. Repeated MRI after 12 years showed a constant hypoplasia of the anterior pituitary lobe. Similarly, MRI of the younger brother showed a constant enlargement of the anterior pituitary gland until age 10 years. At the age of 11 years, the anterior pituitary was hypoplastic. The authors concluded that early pituitary enlargement may be the typical course in such patients in whom pituitary surgery is not indicated.
Reynaud et al. (2004) reported the natural history of hypopituitarism in a large Tunisian kindred including 29 subjects from the same consanguineous family. The index case was a 9-year-old girl with severe growth retardation due to complete GH deficiency and partial corticotroph, lactotroph, and thyrotroph deficiencies. MRI showed a hyperplastic anterior pituitary. Thirteen of the 28 relatives examined had hypopituitarism. In the 14 patients, previously untreated, height was -5.7 +/- 1.7 SD score, and puberty was spontaneously initiated in only 2 females. Complete GH deficiency was found in all 12 patients investigated, of whom 11 had thyrotroph deficiency; 8 of 10 investigated had corticotroph deficiency.
To analyze the prevalence of adrenal insufficiency in patients with PROP1 defects and to characterize the temporal pattern of anterior pituitary failure, Bottner et al. (2004) performed a retrospective longitudinal analysis of 9 patients with PROP1 mutations who were under medical supervision. All patients initially presented with growth failure at a mean age of 4.9 +/- 0.8 years. They were first diagnosed with GH and TSH deficiency, and replacement therapy was instituted at 6.1 +/- 1.1 and 6.8 +/- 1.2 years, respectively. All 7 patients who reached pubertal age required sex hormone substitution at 15.0 +/- 0.7 yr. Repeated functional testing of the anterior pituitary axes revealed a progressive decline with age in peak levels of GH, TSH, prolactin, and LH/FSH. All patients developed at least partial adrenal insufficiency with a gradual decline of the function of the pituitary adrenal axis and eventually required substitution with hydrocortisone at a mean age of 18.4 +/- 3.5 years. The authors concluded that anterior pituitary function in patients with PROP1 mutations deteriorates progressively and includes adrenal insufficiency as a feature of this condition, which has important clinical relevance in childhood and adolescence.
Voutetakis et al. (2004) used long-term MRI findings to characterize the morphologic abnormalities of the pituitary gland in 15 patients with CPHD caused by PROP1 gene mutations. Small pituitary gland was detected in 7 patients (25.2 +/- 14.4 years of age), normal pituitary size in 3 patients (10.2 +/- 5.8 years of age), and pituitary enlargement in 5 patients (6.5 +/- 2.7 years of age). The pituitary enlargement consisted of a nonenhancing mass lesion interposed between the normally enhancing anterior lobe and the neurohypophysis. The pituitary stalk was displaced anteriorly, whereas the neurohypophysis was orthotopic, displaying a normal signal. Spontaneous regression of the mass lesion with normalization of the pituitary stalk position was observed in 3 patients. The authors concluded that while a small pituitary gland is usually observed in older subjects, a significant number of young patients with PROP1 gene mutations demonstrate pituitary enlargement with subsequent regression.
In affected members of 4 CPHD families, who showed deficiency of growth hormone (GH; 139250), prolactin (PRL; 176760), thyrotropin (TSH; see 188540), luteinizing hormone (LH; see 152780), and follicle-stimulating hormone (FSH; see 136530), but normal levels of adrenocorticotrophic hormone (ACTH; see 176830), Wu et al. (1998) identified homozygosity or compound heterozygosity for inactivating mutations of the PROP1 gene (601538.0001-601538.0003, respectively). In contrast to individuals with CPHD1 (613038), who have mutations in the human homolog of the mouse Pit1 gene, POU1F1 (173110), those with PROP1 mutations cannot produce LH or FSH at a sufficient level and do not enter puberty spontaneously. These results identified a major cause of combined pituitary hormone deficiency in humans and suggested a direct or indirect role for PROP1 in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes, and caudomedial thyrotropes.
In 5 affected individuals from 2 apparently unrelated consanguineous CPHD families, Fluck et al. (1998) identified homozygosity for the R120C mutation in the PROP1 gene (601538.0001). The authors noted that there was variability in age of onset and severity of symptoms, even among these patients with the same mutation.
In 2 individuals with panhypopituitarism from the isolated community on the Island of Krk, Krzisnik et al. (1999) identified homozygosity for a frameshift mutation in the PROP1 gene (601538.0014).
PROP1 deficiency should be considered as a potential cause of all familial cases of CPHD. In 10 independently ascertained CPHD kindreds, Cogan et al. (1998) found that 55% (11 of 20) of the PROP1 alleles were 301delAG (602538.0002).
Fofanova et al. (1998) analyzed the POU1F1 (173110) and PROP1 genes in 14 Russian children with CPHD, 7 unrelated and 7 from 4 families, who had complete GH and complete or partial PRL and TSH deficiencies. A missense mutation in POU1F1 was identified in 1 patient, and 8 other patients were found to be homozygous or compound heterozygous for 2 different deletions in the PROP1 gene, 149delGA (601538.0004) and 296delGA (601538.0005), respectively. All parents were of normal stature and each was heterozygous for a wildtype allele and 1 of the deletions, respectively.
In 2 unrelated females with CPHD involving GH, TSH, PRL, LH, and FSH, 1 of whom also had partial cortisol deficiency, Mendonca et al. (1999) identified homozygosity for a 2-bp deletion in the PROP1 gene (601538.0002).
In 8 patients from a large Dominican CPHD kindred, Rosenbloom et al. (1999) identified homozygosity for the 296delGA mutation in the PROP1 gene.
In 10 CPHD patients from a large Brazilian kindred, 9 of whom were born of consanguineous marriages, Pernasetti et al. (2000) identified homozygosity for a 2-bp deletion in the PROP1 gene (301delAG; 601538.0002). All affected patients presented complete absence of puberty and low GH, PRL, TSH, LH, and FSH associated with severe hypoplasia of the pituitary gland, as seen by MRI. The authors observed ACTH/cortisol insufficiency in 5 of 6 of the older patients and in 1 11-year-old patient, and suggested that the phenotype of this mutation includes late-onset adrenal insufficiency.
Agarwal et al. (2000) analyzed the PROP1 gene in a large consanguineous Indian pedigree with CPHD and identified homozygosity for a 13-bp deletion in affected individuals, predicted to generate a null allele (601538.0007). Severe cortisol deficiency was observed in 2 patients in this family, suggesting a role for PROP1 in the differentiation and/or maintenance of corticotroph cells in the mature anterior pituitary.
Vallette-Kasic et al. (2001) screened the PROP1 gene in 23 CPHD patients and identified homozygosity or compound heterozygosity for 4 different mutations in 9 patients from 8 unrelated families. All mutations were located in exon 2 and affected only 2 different sites (see 601538.0005 and 601538.0009-601538.0011). All of the patients were born to unaffected parents, and consanguinity was documented in 2 patients. They had complete GH, LH-FSH, and TSH deficiencies, and normal basal levels of PRL with blunted PRL response to TRH; delayed ACTH deficiency was diagnosed in 4 patients. All had complete hypogonadotrophic hypogonadism and none entered puberty spontaneously. MRI showed a hypoplastic anterior pituitary 7 patients and in 2 patients, there was initial hyperplasia with subsequent hypoplasia on a later study; 2 patients also showed an enlarged sella turcica. Vallette-Kasic et al. (2001) stated that, in keeping with previous reports, they found no correlation between phenotype and genotype.
In 2 brothers with CPHD who both had early hyperplasia and later hypoplasia of the anterior pituitary by MRI, Riepe et al. (2001) identified compound heterozygosity for inactivating mutations in the PROP1 gene, 301delAG and 150delA (601538.0008).
The panhypopituitarism in the Hutterite cases reported by McKusick and Rimoin (1967) were shown to be due to the common 2-bp deletion (301-302delAG) in the PROP1 gene (601538.0002) (Mosely et al., 2002).
Reynaud et al. (2004) studied 3 brothers with CPHD from a consanguineous family of Tunisian descent. The brothers had been referred for cryptorchidism and/or delayed puberty, and initial investigations revealed hypogonadotropic hypogonadism. One of the patients had psychomotor retardation, intracranial hypertension, and minor renal malformations. The brothers reached normal adult height and developed GH and TSH deficiencies after age 30. Reynaud et al. (2004) identified homozygosity for a nonsense mutation in the PROP1 gene (W194X; 601538.0010) in the affected brothers, and concluded that PROP1 mutations should be considered among the genetic causes of initially isolated hypogonadotropic hypogonadism.
Inactivating mutations in PROP1 perturb ontogenesis of pituitary gonadotropes, somatotropes, lactotropes, and thyrotropes. These developmental defects result in deficiencies of PRL, LH, FSH, GH, or TSH.
Individuals with PROP1 mutations that cause GH and TSH deficiencies respond to GH and thyroid hormone replacement. Those with PROP1 mutations that cannot produce luteinizing or follicle-stimulating hormone at a sufficient level may not enter puberty spontaneously which may require gonadotropin replacement. Some older affected individuals have been reported to develop adrenal insufficiency in their third to fifth decades due to ACTH deficiency (202200) (Fluck et al., 1998).
Lee et al. (2004) reported 3 adult sibs, aged 18 to 25 years, with short stature, hypothyroidism, and lack of pubertal maturation, who were homozygous for the 301delAG PROP1 deletion (601538.0002). They treated them in adulthood with GH for 4 to 5 years and thyroid replacement before sex steroid replacement therapy. Despite delay in treatment and fairly advanced bone age, all responded to these therapies with a dramatic increase in linear growth. The authors concluded the substantial linear growth in adult sibs with a PROP1 mutation illustrates that despite an advanced bone age, linear growth potential remains in adulthood in the setting of sex steroid deficiency.
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