Hyposomatotropism Clinical Presentation

Updated: Oct 30, 2015
  • Author: Sunil Kumar Sinha, MD; Chief Editor: Stephen Kemp, MD, PhD  more...
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Presentation

History

Congenital hyposomatotropism

  • Infants with congenital growth hormone (GH) deficiency (GHD) are typically born with a length and weight between the 5th and 10th percentiles for their gestational age. A family history of short stature or parental consanguinity may suggest a genetic etiology.

  • A recent study compared fetal an neonatal growth curves in detecting growth restriction. [4]

  • Newborns with congenital hypopituitarism (defined as deficiencies of all anterior pituitary hormones) often present with midline craniofacial abnormalities (eg, single central maxillary incisor, cleft lip or palate, optic hypoplasia), hypoglycemia, blindness, micropenis, and hyperbilirubinemia.

  • Hypoglycemia can be profound and clinically resembles congenital hyperinsulinism in patients with GHD or, especially, hypopituitarism. Hypoglycemia results from the lack of counterregulatory hormones important for glucose homeostasis; these include GH, corticotropin, and thyroid-stimulating hormone. Although not usually considered a source for hypoglycemia, thyroid hormone may stimulate gluconeogenesis and increase insulin clearance. This mechanism could account for the hyperinsulinemic hypoglycemia observed in a small number of patients with congenital hypothyroidism.

  • The combination of microcephalus, cryptorchidism, and hypoplasia of the scrotum can occur with coexistent GHD and gonadotropin deficiencies. Testosterone bioactivity plays an essential role in the differentiation and development of the male genitalia. During the first trimester, GH modulates fetal testosterone production, perhaps by regulating placental chorionic gonadotropins. During the second and third trimesters, testosterone production appears to be independent of GH and relies on fetal pituitary gonadotropins.

  • Liver disease has been associated with neonatal hypopituitarism. Hypothyroidism is a well-recognized cause of neonatal jaundice, typically an indirect hyperbilirubinemia. The current theory regarding conjugated hyperbilirubinemia is based on the relationship of GH to bile acid synthesis. GH stimulates the synthesis of bile acids, which are major determinants for the induction of canalicular bile secretion. Cholestasis associated with congenital hypopituitarism resolves with hormonal replacement.

  • Neonatal hypoglycemia, persistent cholestatic jaundice, or hypogonadism in a male patient should immediately suggest the possibility of GHD. Neonatal hypopituitarism is potentially fatal if untreated.

Acquired hyposomatotropism

  • Acquired GHD can have multiple sources (see Causes).

  • By the age of 6-12 months, infants with GHD clearly demonstrate an abnormally low growth velocity. Skeletal proportions remain normal, but skeletal age is delayed, often to less than 60% of the infant's chronologic age. Delay in dental eruption may precede this finding. Characteristic facies in patients with GHD result from retarded growth of the facial bones. Closure of the fontanelles is often delayed and results in frontal bossing and hydrocephalus. The nasal bridge may be markedly underdeveloped, and the orbits may be shallow; these alterations result in disproportionate cephalofacial relationships.

  • The weight-to-height ratio tends to be increased, just as the ratio of fat to lean muscle is elevated the absence of the effect of GH on the peripheral tissues. Decreased development of lean muscle results in poor muscular tone during infancy and early childhood; this sometimes leads to gross motor delays. Hair growth is sparse, and nails are thin and grow slowly. Laryngeal hypoplasia results in continuation of the prepubescent voice in boys with GHD.

  • Puberty may be delayed by 3-7 years despite normal gonadotropin release. This is likely related to the delay in skeletal age. For reasons that remain incompletely understood, skeletal development must be of a certain age (at least 9 y for girls and 10 y for boys) for puberty to ensue. Despite this delay, sexual function and fertility are normal in people with GHD. Although micropenis may occur during infancy in the congenital form of GHD, the penis is normal for the person's body size during adulthood.

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Physical

Findings in patients with congenital or acquired hyposomatotropism are summarized below.

Congenital hyposomatotropism

  • Normal length at birth

  • Midline defects

  • Cleft lip

  • Cleft palate

  • Blindness

  • Single central maxillary incisor

  • Hypogonadotropic hypogonadism

  • Jaundice

  • Icterus

  • Hepatosplenomegaly

  • Hypoglycemia

  • Shaking

  • Irritability

  • Lethargy

  • Hypotonia

  • Diaphoresis

  • Tachycardia

  • Pallor

  • Seizures

Acquired hyposomatotropism

  • Short stature

  • Characteristic facies

    • Frontal bossing

    • Flattened nasal bridge

    • Forehead prominence

Other findings

  • Delayed dental eruption and exfoliation

  • Delayed bone age

  • Increased weight-to-height ratio

  • Poor muscle tone (motor delay may result)

  • Laryngeal hypoplasia

  • Poor hair and nail growth

  • Delayed puberty

  • Normal genitalia

  • Normal skeletal proportions

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Causes

Hypothalamic regulatory peptides: Decreased or abnormal production of any of the regulatory peptides discussed above, or their respective receptors, may result in GHD.

Genetic abnormalities of GH production

  • A great deal has been learned about the genetic causes of hypopituitarism. By 1979, many families with isolated GHD or diminished production of GH and one or more additional pituitary hormones had been described. The development of a complementary DNA probe for the pit-hGH gene permitted scientists to recognize GH gene deletions in 1981 and placental GH and chorionic somatotropin gene deletions in 1982. The power of polymerase chain reaction (PCR) amplification and DNA sequencing subsequently revealed mutations and small deletions affecting GH in other families with isolated GHD.

  • The path to understanding the mechanisms that underlie multiple pituitary hormone deficiency was less straightforward than that regarding single genetic defects. Solutions emerged with the discovery of transcriptional activation factors that direct embryonic development of the anterior pituitary. This story began with the discovery in 1988 of a homeobox protein, called Pit-1, that binds to sequences in the promoter for the GH gene. The story continued with the recognition of many other pituitary and hypothalamic factors that orchestrated pituitary development; 3 main transcriptional factors have been implicated as causes of multiple pituitary hormone deficiency in humans. In chronologic order of their association with human disease, they are Pit-1, PROP1, and HESX1.

  • The PIT1 gene, located on chromosome 3, is a member of a large family of transcription factor genes responsible for the development and function of somatotrophs and of other neuroendocrine cells of the adenohypophysis. At least 7 point mutations of the PIT1 gene have been associated with hypopituitarism in Dutch, American, Japanese, and Tunisian families.

  • In 1992, Tatsumi et al described the first human example of pituitary hormone deficiency due to a PIT1 mutation. [5] Two sisters born to parents who were second cousins had profound neonatal hypothyroidism without elevated levels of thyroid-stimulating hormone. One died from aspiration pneumonia at the age of 2 months. The surviving sister also had deficiencies of GH and prolactin. Multiple recessive and dominant types of PIT1 mutations have been recognized over the years. Sporadic cases have also been reported.

  • The first examples of PROP1 mutations in humans with pituitary hormone deficiencies were reported in early 1998. In humans, the hormonal phenotype involves deficiencies of luteinizing hormone, follicle-stimulating hormone, prolactin, thyroid-stimulating hormone, and GH. Mutations recognized to date involve the paired-like DNA-binding domain encoded by exons 2 and 3 and demonstrate autosomal recessive inheritance.

  • The HESX1 gene plays an important role in the development of the optic nerves and the anterior pituitary gland. The human gene is located on chromosome 3p21.2. Dattani et al identified the first human patients with a mutation in HESX1 after 135 patients with pituitary disorders were screened. [6]

Developmental malformations: Developmental malformations commonly associated with GHD include anencephaly, holoprosencephaly, and septooptic dysplasia (de Morsier syndrome). Septooptic dysplasia, in its complete form, combines hypothalamic insufficiency with hypoplasia (or absence) of the optic chiasm, optic nerves, septum pellucidum, and corpus callosum. Consider this diagnosis in any child with growth failure and impaired vision, especially in one with accompanying nystagmus. HESX1 mutations have been associated with septooptic dysplasia.

Trauma, infections, tumors, and cranial irradiation

  • Trauma, infections, sarcoidosis, tumors, and cranial irradiation of the hypothalamus, pituitary stalk, or anterior pituitary may also result in isolated GHD or anterior hypopituitarism.

  • GHD is most commonly associated with breech delivery, prolonged labor, placental abruption, and other complicated deliveries.

  • Hypothalamic tumors or pituitary tumors (eg, craniopharyngioma, glioma) are major causes of hypothalamic-pituitary insufficiency.

  • In rare cases, metastasis from extracranial carcinomas (eg, histiocytosis, germ cell tumor) lead to hypopituitarism.

  • Craniopharyngiomas and histiocytosis X are major etiologies of pituitary insufficiency. Craniopharyngiomas arise from remnants of the Rathke pouch, which is a diverticulum arising from the roof of the embryologic oral cavity and which gives rise to the anterior pituitary.

  • Most patients present in mid childhood with symptoms of increased intracranial pressure, such as headaches, vomiting, visual field deficits, and oculomotor abnormalities. Short stature often coexists, but this is usually not the first complaint. Most children with craniopharyngiomas have growth failure at the time of presentation. Because of this association, any child in whom GHD is diagnosed should undergo MRI to exclude a brain tumor before the start of GH therapy.

  • Irradiation-induced hypothalamic-pituitary dysfunction is dose related. Low-dose irradiation usually results in isolated GHD, whereas high doses most often result in multiple hormonal deficiencies. One study group reported that 2-5 years after irradiation, 100% of children receiving doses of at least 3000 cGy to the hypothalamic-pituitary axis over 3 weeks had subnormal GH responses to provocative testing. Hypothalamic irradiation also damages the growth plate cartilage and is associated with an increased incidence of precocious puberty (advanced bone age and premature epiphyseal fusion); both of these processes compound the effect on linear growth.

Developmental abnormalities of the pituitary: Congenital absence or hypoplasia of the pituitary has also been identified. Common findings on MRI include an ectopic neurohypophysis, an absent infundibulum, a small adenohypophysis, and absence of the usual high signal intensity (bright spot) in the posterior pituitary as seen on T1-weighted MRIs.

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