Combined pituitary hormone deficiency

A number of genes have been associated with combined pituitary hormone deficiency, and there are many acquired causes – including head injury, radiotherapy to the head or neck and brain surgery.

Clinical features depend on the hormones affected. Typically, short stature is one of the first presenting features. Other features can include:

• Growth hormone (GH) deficiency:
  • slow growth/short stature; and
  • increased fat distribution around the waist and face.
• Thyroid-stimulating hormone (TSH) deficiency:
  • weight gain;
  • fatigue;
  • developmental delay;
  • constipation;
  • sensitivity to cold; and
  • muscle weakness and/or aching.
• Adrenocorticotropic hormone (ACTH) deficiency:
  • fatigue;
  • low blood pressure;
  • weight loss;
  • weakness;
  • depression; and
  • nausea and/or vomiting.
• Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) deficiency:
  • delayed or absent puberty;
  • infertility;
  • lack of libido;
  • weakness; and
  • erectile dysfunction.
• Prolactin (PRL):
  • Reduced or absent lactation around childbirth.

Some patients have extra-pituitary clinical and radiological features which may include:

• Eye anomalies:
  • underdeveloped optic nerves;
  • structural defects of the iris;
  • retinopathy; and
  • microphthalmia.
• Structural brain malformations:
  • holoprosencephaly;
  • septo-optic dysplasia;
  • pituitary stalk interruption syndrome;
  • cerebellar hypoplasia;
  • Dandy–Walker cyst; and
  • corpus callosum hypoplasia.
• Ear anomalies:
  • hearing loss; and
  • hypoplastic ears.
• Other features:
  • anomalous head and neck rotation;
  • vertebral anomalies; and
  • developmental delay/learning difficulties.

MRI of the head may reveal structural anomalies of the pituitary, including:

• pituitary hypoplasia;
• thin pituitary stalk; and
• ectopic posterior pituitary.

Over 20 genes have been associated with combined pituitary hormone deficiency. Examples of those more frequently encountered include:

• PROP1: Associated with a pure pituitary phenotype. Autosomal recessive inheritance pattern. Can lead to GH, TSH, LH/FSH, ACTH and PRL deficiencies.
• POU1F1: Associated with a pure pituitary phenotype. Autosomal recessive and dominant cases have been observed. Complete TSH and GH deficiency is typically observed during childhood. FSH/LH and ACTH are typically unaffected.
• HESX1: Associated with combined pituitary deficiency and extra pituitary features. Autosomal recessive and dominant cases have been observed. Typically, GH deficiency is found in all, and other pituitary deficiencies are found in 50% of cases. Extra pituitary features can include optic nerve anomalies and corpus callosum agenesis or hypoplasia. Pituitary hypoplasia is found on MRI in most cases.
• LHX4: Associated with combined pituitary deficiency and extra pituitary features. Autosomal dominant inheritance pattern. The pituitary phenotype can range from isolated GH deficiency to complete panhypopituitarism. Extra pituitary features can include corpus callosum hypoplasia or Chiari syndrome.

It should be remembered that there are many acquired causes of multiple pituitary deficiency, including tumour, trauma, surgery or irradiation.

There are still many cases of multiple pituitary deficiency without a known cause. There may be novel genetic causes yet to be identified.

For information about testing, see Presentation: Child with multiple pituitary deficiency.

Genomic counselling regarding inheritance risks depends on the underlying genetic cause. Autosomal dominant, autosomal recessive and, rarely, X-linked causes have been reported.

Many genetic causes of combined pituitary hormone deficiency are associated with a very variable clinical presentation. Members of the same family with the same genetic variant can have very different clinical presentations. This is partly because many of the genes involved are transcription factors, which means they are responsible for controlling the expression of other downstream genes. This is especially true for the genes associated with extra pituitary signs.

Management of children with combined pituitary hormone deficiency is complex and should be delivered via a multidisciplinary team. Hormone replacement therapy offers symptomatic relief. Identification of the underlying cause determines the need and availability of further treatment.

For clinicians

• ClinicalTrials.gov
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• Medline Plus: Combined pituitary hormone deficiency
• NHS England: National Genomic Test Directory
• Web MD: Hypopituitary

References:

• Castinetti F, Reynaud R, Quentien MH and others. ‘Combined pituitary hormone deficiency: current and future status’. Journal of Endocrinological Investigation 2014: volume 38, pages 1–12. DOI: 1007/s40618-014-0141-2
• Castinetti F, Reynaud R, Saveanu A and others. ‘Mechanisms in endocrinology: an update in the genetic aetiologies of combined pituitary hormone deficiency’. European Journal of Endocrinology 2016: volume 174, issue 6, pages R239–R247. DOI: 10.1530/EJE-15-1095

For patients

• British Society for Paediatric Endrocrinology and Diabetes: Hypopituitarism (Multiple Pituitary Hormone Deficiency) leaflet (PDF, three pages)
• Child Growth Foundation
• The Pituitary Foundation