Donohue syndrome

Definition

Donohue syndrome, also formerly called leprechaunism, is a genetic disorder caused by mutations in the insulin receptor gene . W. L. Donohue first described this rare syndrome in 1948.

Description

Donohue syndrome is a disorder that causes low birth weight, unusual facial features, and failure to thrive in infants. Donohue syndrome is associated with the over-development of the pancreas, a gland located near the stomach. It is also considered to be the most insulin resistant form of diabetes.

Donohue syndrome results from a mutation of the insulin receptor gene which prevents insulin in the blood from being processed. Therefore, even before birth, the fetus exhibits "insulin resistance" and has high levels of unprocessed insulin in the blood. Insulin is one of two hormones secreted by the pancreas to control blood sugar (glucose) levels. Donohue syndrome is known as a progressive endocrine disorder because it relates to the growth and functions of the endocrine system, the collection of glands and organs that deliver hormones via the bloodstream.

Hormones are chemicals released by the body to control cellular function (metabolism) and maintain equilibrium (homeostasis). These hormones are released either by the endocrine system or by the exocrine system. The endocrine system consists of ductless glands that secrete hormones into the bloodstream. These hormones then travel through the blood to the parts of the body where they are required. The exocrine system consists of ducted glands that release their hormones via ducts directly to the site where they are needed. The pancreas is both an endocrine and an exocrine gland. As part of the endocrine system, the pancreas acts as the original producer of estrogen and other sex hormones in fetuses of both sexes. It also regulates blood sugar through its production of the hormones insulin and glucagon. The pancreas releases insulin in response to high levels of glucose in the blood. Glucagon is released when glucose levels in the blood are low. These two hormones act in direct opposition to each other (antagonistically) to maintain proper blood sugar levels. As an exocrine gland, the pancreas secretes digestive enzymes directly into the small intestine.

In an attempt to compensate for the high blood insulin level, the pancreas overproduces glucagon as well as the female hormone estrogen and other related (estrogenic) hormones. As excess estrogen and related hormones are produced, they affect the development of the external and internal sex organs (genitalia) of the growing baby.

Insulin mediates the baby's growth in the womb through the addition of muscle and fat. A genetic link between fetal insulin resistance and low birthweight has been suggested. Without the proper processing of insulin, the fetus will not gain weight as fast as expected. Therefore, the effects of Donohue syndrome tend to become visible during the seventh month of development when the fetus either stops growing entirely or shows a noticeable slowdown in size and weight gain. This lack of growth is further evident at birth in affected infants, who demonstrate extreme thinness (emaciation), difficulty gaining weight, a failure to thrive, and delayed maturation of the skeletal structure.

Genetic profile

Donohue syndrome is a non-sex-linked (autosomal) recessive disorder. In 1988, Donohue syndrome was identified as the first insulin receptor gene mutation directly related to a human disease. The gene responsible for the appearance of Donohue syndrome is the insulin receptor gene located at 19p13.2. Over 40 distinct mutations of this gene have been identified. Besides Donohue syndrome, other types of non-insulin-dependent (Type II) diabetes mellitus (NIDDM) can result from mutations of this gene, including Rabson-Mendenhall syndrome and type A insulin resistance.

Demographics

Donohue syndrome occurs in approximately one out of every four million live births. As in all recessive genetic disorders , both parents must carry the gene mutation in order for their child to have the disorder. Therefore, Donohue syndrome has been observed in cases where the parents are related by blood (consanguineous). Parents with one child affected by Donohue syndrome have a 25% likelihood that their next child will also be affected with the disease.

Signs and symptoms

Infants born with Donohue syndrome have characteristic facial features that have been said to exhibit "elfin" or leprechaun-like qualities, such as: a smallish head with large, poorly developed and low-set ears; a flat nasal ridge with flared nostrils, thick lips, a greatly exaggerated mouth width, and widely spaced eyes. They will be very thin and have low blood sugar (hypoglycemia) due to their inability to gain nutrition through insulin processing. They will exhibit delayed bone growth and maturation, and difficulty in gaining weight and developing (failure to thrive).

Donohue syndrome patients are prone to persistent and recurrent infections. Delayed bone growth not only leads to skeletal abnormalities, it also leads to a compromised immune system. Many of the chemicals used by the body to fight infection are produced in the marrow of the bones. When bone maturation is delayed, these chemicals are not produced in sufficient quantities to fight off or prevent infection.

At birth, affected individuals can also have an enlarged chest, with possible breast development, excessive hairiness (hirsutism), as well as overdeveloped external sex organs, because of increased estrogen production caused by an overactive pancreas. As an additional side effect of the increased sex hormones released in Donohue syndrome, these individuals often have extremely large hands and feet relative to their non-affected peer group. As the result of a lack of insulin, the infant is likely to have a relatively small amount of muscle mass, very little fat, and a distended abdomen (due to malnutrition). Additional symptoms of Donohue syndrome include pachyderma, or elephant skin, in which there is excess skin production causing large, loose folds; and abnormal coloration (pigmentation) of the skin. These individuals are also quite susceptible to both umbilical and inguinal hernias.

In addition to the defect in the insulin receptor gene, Donohue syndrome is associated with problems in the epidermal growth factor receptor, which controls growth of the skin. An abnormal functioning of the epidermal growth factor receptor has been identified in three unrelated individuals affected with Donohue syndrome. This suggests that the probable cause of leprechaunism is more than just the insulin receptor. These observations may help explain the physical symptom of pachyderma in those affected with Donohue syndrome. It has also been suggested that the high concentrations of insulin close to the cell membranes lead to receptor activity at these locations. This lowered growth hormone activity, in turn, causes slowed cellular growth which leads to systemic growth failure in affected patients.

Diagnosis

In families with a history of the disease, diagnosis in utero before birth of the fetus is possible through molecular DNA analysis of tissue samples from the chorionic villi, which are cells found in the placenta. After birth, the diagnosis of Donohue syndrome is usually made based on the blood tests that show severe insulin resistance coupled with hypoglycemia. The presence of several of the physical symptoms listed above in addition to positive results in a test for severe insulin resistance, such as an insulin receptor defect test or a fasting hypoglycemia test, is usually sufficient for a diagnosis of Donohue syndrome. The diagnosis of Donohue syndrome may be confirmed by observed cellular (histologic) changes in the ovaries, pancreas, and breast that are not normal for the age of the patient.

Treatment and management

Genetic counseling of parents with a Donohue syndrome affected child may help prevent the conception of additional children affected with this genetic disorder. After birth, affected infants may require treatment for malnutrition as well as insulin resistant diabetes. Patients with a demonstrated residual insulin receptor function may survive past infancy. In these cases, the treatment regimen must certainly include on-going insulin resistant diabetes care and dietetic counseling to assist with weight gain. It may also be necessary to administer growth hormone therapy to certain patients to spur growth, but this is only indicated in those individuals who show signs of functioning growth hormone receptors and no signs of higher than normal resistance to growth hormone.

The revolutionary impact of recombinant DNA technology, whereby scientists can mass produce genetic material for use in medicine, has made possible another treatment method which involves the introduction of recombinant human insulin-like growth factor 1 (rhIGF-1) into the body. A case study has been reported of a female affected with Donohue syndrome and low levels of insulin-like growth factor 1 (IGF-1), which is indicative of a higher than normal resistance to growth hormone.

Examination of the patient's fibroblasts showed normal binding of IGF-1 and normal functioning of these fibroblasts in response to IGF-1. Fibroblasts are connective tissue cells that accomplish growth in humans by differentiating into chondroblasts, collagenoblasts, and osteoblasts, all of which are the precursor cells necessary to produce bone growth in humans. This case report indicates that if enough IGF-1 could get to the fibroblasts in the patient's body, there is every reason to believe that these fibroblasts would function normally and mature into the precursor cells needed for bone growth. This finding made the patient an ideal candidate for rhIGF-1 treatments.

The long- and short-term effects on growth patterns and glucose metabolism in the patient were studied after the treatment with recombinant human insulin-like growth factor 1 (rhIGF-1). The rhIGF-1 that was not immediately utilized by the patient was rapidly destroyed in the cellular conditions produced by Donohue syndrome. Therefore, to maintain the desired levels of rhIGF-1 in the blood, the patient received rhIGF-1 both in injection form prior to every meal and via a continuous subcutaneous infusion method similar to that used to continuously pump insulin for some patients with diabetes. Recombinant human IGF-1 was administered to this patient over a period of six years with an observation of normal blood glucose levels and a return to normal growth patterns. Moreover, the treatment did not cause negative side effects. The results of this case study offer a promising new treatment for certain individuals affected with Donohue syndrome. As of 2001, other clinical studies of treatments with rhIGF-1 are in progress.

Prognosis

Individuals born with Donohue syndrome generally die in infancy from either malnutrition or recurrent and persistent infection. All individuals affected with Donohue syndrome that survive past infancy have severe mental retardation and profound motor skill impairment. Survival into childhood is thought to be due to some remaining insulin receptor function and the ability of extremely high insulin concentrations to transmit signals through alternate pathways.

Resources

PERIODICALS

Desbois-Mouthon, C., et al. "Molecular analysis of the insulin receptor gene for prenatal diagnosis of leprechaunism in two families." Prenatal Diagnosis (July 1997): 657–63.

Hattersley, A. "The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease." Lancet (May 1999): 1789–92.

Nakae, J., et al. "Long-term effect of recombinant human insulin-like growth factor I on metabolic and growth control in a patient with leprechaunism." Journal of Clinical Endocrinology and Metabolism (February 1998): 542–9.

Psiachou, H., et al. "Leprechaunism and homozygous nonsense mutation in the insulin receptor gene." Lancet (October 1993): 924.

Reddy, S., D. Muller-Wieland, K. Kriaciunas, C. Kahn. "Molecular defects in the insulin receptor in patients with leprechaunism and in their parents." Journal of Laboratory and Clinical Medicine (August 1989): 1359–65.

ORGANIZATIONS

Children Living with Inherited Metabolic Diseases. The Quadrangle, Crewe Hall, Weston Rd., Crewe, Cheshire, CW1-6UR. UK 127 025 0221. Fax: 0870-7700-327. <http://www.climb.org.uk>.

National Center for Biotechnology Information. National Library of Medicine, Building 38A, Room 8N805, Bethesda, MD 20894. (301) 496-2475. <http://www.ncbi.nlm.nih.gov>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

WEBSITES

"Leprechaunism." National Organization for Rare Disorders, Inc. http://www.stepstn.com/cgi-win/nord.exe?proc=GetDocument&rectype=0&recnum=387. (05 February 2001).

OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?246200>. (05 February 2001).

Paul A. Johnson