Genetic syndromes

Diabetes mellitus is an occasional feature of a range of genetic syndromes, of which Down's syndrome is the most frequently encountered in clinical practice. The more common of these are listed and briefly described in this section.


Genetic syndromes resulting in childhood-onset diabetes are rare. Analysis of a German database including 43,521 patients with early-onset diabetes identified 205 such individuals, distributed as follows: Down's syndrome (141), Turner syndrome (24), Prader-Willi syndrome (23), Friedrich's ataxia (5), Alström syndrome (5), Klinefelter syndrome (4), Bardet-Biedl syndrome (2) and Berardinelli-Seip syndrome (1).

Diabetes is related to obesity and/or insulin resistance in many of these syndromes, but islet antibodies are present in the majority of patients with Down's syndrome, Turner syndrome and Friedrich's ataxia, suggesting an immune basis for the associated diabetes [1].

Alström syndrome

Is an exceptionally rare autosomal recessive disorder with about 500 known cases world-wide. It resembles Bardet-Biedl syndrome (see below) in many respects but presents earlier. Key features are childhood obesity, blindness and deafness. Hyperinsulinaemia, early-onset type 2 diabetes and hypertriglyceridaemia are commonly present, as in the acquired metabolic syndrome seen in adults.

Berardinelli-Seip Congenital Lipodystrophy

This is an autosomal recessive condition, seen in perhaps 1 in 10 million births, in which the body is unable to lay down normal adipose tissue. The condition is characterized by hypertriglyceridaemia and ectopic deposition of fat in the liver, causing steatosis, and in the heart, causing cardiomyopathy.

Those affected appear muscular due to absence of subcutaneous fat, and have prominent jaws and orbital ridges together with large hands and feet. Insulin resistance and acanthosis nigricans are common features.

Down's Syndrome

This, the most common genetic cause of birth disorders, is due to trisomy (an additional copy) of chromosome 21, resulting in a wide range of developmental disorders. The extent of physical or mental disability may vary widely from one individual to the next.

The characteristic appearance includes short stature, a small rounded head flattened posteriorly, broadening of the neck, slanting eyes, a flattened nose, small broad hands with a single palmar crease and white (Brushfield) spots overlying the iris of the eye.

Associated defects include intellectual impairment ranging from moderate to severe, and congenital heart defects (often atrial or ventricular septal defects), which occur in up to 50% of children. Leukaemia and early onset dementia among its complications.

Autoimmune diseases including thyroid disorders, type 1 diabetes and coeliac disease are more common in Down's syndrome[2]. As compared with sporadic type 1 diabetes, there is an excess of cases presenting before the age of 3. Autoimmunity appears to be largely responsible for the excess of diabetes, but obesity and insulin resistance may also be a factor in older individuals.

Friedrich's Ataxia

Friedrich's ataxia is an autosomal recessive condition which results in nerve degeneration in the spinal cord, usually presenting before the age of 25 with muscle weakness, loss of co-ordination and a staggering gait. Scoliosis and pes cavus may be features and cardiac, auditory and visual problems can also develop. Diabetes mellitus is present in around 10% of cases, and abnormal glucose tolerance in another 20%.

Huntington's Disease

Huntington's disease is a neurodegenerative disorder, transmitted as an autosomal dominant trait, that affects muscle coordination and leads to cognitive decline and psychiatric problems. It is more common in people of Western European descent. Its characteristic feature is choreoathetoid movements but neuropsychiatric problems are also common. Symptoms may develop at any age, but most commonly between 35 and 44 years of age.

Although early reports linked Huntington's disease to diabetes, the association is in some doubt[3]. Severe acute hyperglycaemia may however provoke transient choreiform movements in diabetic individuals without Huntington's, and diabetic ketoacidosis reportedly unmasked underlying Huntington's in one Japanese patient[4].

Klinefelter's Syndrome

Klinefelter's syndrome is due to the presence of an additional X chromosome, resulting in an XXY male. This karyotype, present in between 1-2 per thousand male births, is variable in its presentation, and frequently passes unnoticed; the usual clinical presentation is with hypogonadism or infertility.

Boys are often tall with broad hips and may have less developed musculature than their peers. This is reflected in a higher truncal fat content, diminished insulin sensitivity, and an increased prevalence of the metabolic syndrome. Estimates of the prevalence of diabetes vary, but carbohydrate intolerance has been reported in up to 40%[5].

Lawrence-Moon and Bardet-Biedl Syndromes

These syndromes, formerly known as the Lawrence-Moon-Biedl (or Lawrence-Moon-Bardet-Biedl) syndrome, have more recently been subdivided into the two subtypes listed above, which may or may not form part of the same spectrum of genetic disability. Both are associated with diabetes mellitus.

The Lawrence-Moon syndrome is a rare autosomal recessive condition whose features include short stature, retinitis pigmentosa, learning and speech disabilities, ataxia and spastic paraplegia, hypogonadism, diabetes mellitus and renal problems; the latter are responsible for ~50% of deaths.

The Bardet-Biedl syndrome is associated with obesity, retinitis pigmentosa, polydactyly, hypogonadism, diabetes mellitus and renal problems. Mental retardation and spastic paraplegia are not considered features of this condition.

Myotonic Dystrophy

Myotonic dystrophy is an inherited progressive neuromuscular disorder with two main forms; type 1 typically presents in childhood and type 2 in adult life. Both forms are associated with muscle weakness and cognitive dysfunction; insulin resistance is increased in both.

A review of endocrine function in 97 patients with type 1 diabetes identified a range of mainly subclinical endocrine abnormalities, most commonly affecting calcium metabolism; early-onset type 2 diabetes was identified in 5%.

Porphyria Cutanea Tarda

This condition manifests as light sensitivity in the skin, causing blistering, hyperpigmentation and scarring of exposed areas of skin.

About 20% of cases are due to mutations in the UROD gene, which codes for a key enzyme in haem synthesis. This is transmitted as an autosomal dominant trait. The other 80% of cases are sporadic: they present without evidence of mutation in UROD. Predisposing factors include alcohol abuse, haemochromatosis (the HFE gene is also implicated), and infection with hepatitis C.

The skin condition is caused by a buildup of uroporphyrinogen under the skin. Exposure to sunlight is thought to lead to the production of reactive oxygen species resulting in the photosensitivity observed in patients with this condition. The strong association of porphyria cutanea tarda with hepatitis C infection is largely unexplained.

Chronic iron overload and inflammation of the liver appear to predispose to the development of glucose intolerance, seen in ~40% of those with this condition[6].

Prader-Willi Syndrome

This is a rare disorder in which up to 7 genes on chromosome 15 (q 11–13) are deleted or unexpressed (chromosome 15q partial deletion) on the paternal copy of the chromosome. The paternal origin of the disorder is explained by parent of origin imprinting, which silences the maternal copy of that part of the chromosome.

The reciprocal disorder is Angelman syndrome, in which the paternal sequence is silenced and abnormalities on the maternal copy are therefore expressed.

Prader-Willi syndrome presents with hypotonia, detectable at birth, and is associated with low stature, hypogonadism, low intellect and obesity linked to an insatiable craving for food. Neuropsychiatric disorders ranging from compulsive behaviour to more severe behavioural disturbance may occur.

Turner's Syndrome

Turner's syndrome is a chromosomal abnormality in which all or part of the X chromosome is missing, resulting in an XO female. The chromosome is sometimes missing in some cells but not others, a phenomenon known as mosaicism.

The condition occurs in between 1 in 2000 and one in 5000 female births. Clinical features include short stature, low hairline, low-set ears, and webbing of the neck. Gonadal dysfunction resulting in amenorrhoea and sterility is common. Other health problems include congenital heart disease, hypothyroidism, diabetes and a range of autoimmune disorders. Cognitive impairment is common.


  1. ^ Schmidt F et al. Diabetes mellitus in children and adolescents with genetic syndromes. Exp Clin Endocrinol Diabetes 2012 Mar 22 [Epub ahead of print]

  2. ^ Gillespie KM et al. Islet autoimmunity in children with Down's syndrome. Diabetes 2006;55:3185-8

  3. ^ Boesgaard TW et al. Huntington's disease does not appear to increase the risk of diabetes mellitus. J Neuroendocrinol 2009;21:770-6

  4. ^ Hashimoto K et al. Hyperglycaemic chorea-ballism or acute exacerbation of Huntington's chorea? Huntington's disease unmasked by diabetic ketoacidosis in type 1 diabetes mellitus. J Clin Endocrinol Metab 2012, June 28 [Epub ahead of print].

  5. ^ Bojesen A et al. Klinefelter's syndrome, type 2 diabetes and the metabolic syndrome: the impact of body composition. Mol Hum Reprod 2010;16:396-401

  6. ^ Munoz-Santos C et al. The association between porphyria cutanea tarda and diabetes mellitus: analysis of a long-term follow-up cohort. Br J Dermatol 2011;165:486-91


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