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Leprechaunism syndrome

MedGen UID:
82708
Concept ID:
C0265344
Disease or Syndrome
Synonyms: Donohue syndrome; Leprechaunism
SNOMED CT: Donohue's syndrome (111307005); Leprechaunism (111307005); Leprechaunism syndrome (111307005); Donohue syndrome (111307005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): INSR (19p13.2)
 
Monarch Initiative: MONDO:0009517
OMIM®: 246200
Orphanet: ORPHA508

Disease characteristics

INSR-related severe insulin resistance syndrome (INSR-SIRS) comprises a phenotypic spectrum that is a continuum from the severe phenotype of Donohue syndrome to the milder phenotype of Rabson-Mendenhall syndrome (RMS). Donohue syndrome is characterized by severe insulin resistance (hyperinsulinemia with associated fasting hypoglycemia and postprandial hyperglycemia), severe prenatal growth restriction, postnatal growth failure, hypotonia, developmental delay, characteristic facies (proptosis, infraorbital folds, large, low-set, posteriorly rotated ears, thick vermilion of the upper and lower lips, and gingival hypertrophy), and organomegaly involving the heart, kidneys, liver, spleen, and ovaries. Death usually occurs before age one year. RMS, at the milder end of the spectrum, is characterized by severe insulin resistance that, although not as severe as that of Donohue syndrome, is nonetheless accompanied by fluctuations in blood glucose levels, diabetic ketoacidosis, and – in the second decade – microvascular complications. Findings can range from severe growth delay and intellectual disability to normal growth and development. Facial features can be milder than those of Donohue syndrome. Complications of longstanding hyperglycemia are the most common cause of death. While death usually occurs in the second decade, some affected individuals live longer. [from GeneReviews]
Authors:
Aviv Mesika  |  Aharon Klar  |  Tzipora C Falik Zaccai   view full author information

Additional description

From MedlinePlus Genetics
Donohue syndrome is a rare disorder characterized by severe insulin resistance, a condition in which the body's tissues and organs do not respond properly to the hormone insulin. Insulin normally helps regulate blood sugar levels by controlling how much sugar (in the form of glucose) is passed from the bloodstream into cells to be used as energy. Severe insulin resistance leads to problems with regulating blood glucose levels and affects the development and function of organs and tissues throughout the body.

Severe insulin resistance underlies the varied signs and symptoms of Donohue syndrome. Individuals with Donohue syndrome are unusually small starting before birth, and affected infants experience failure to thrive, which means they do not grow and gain weight at the expected rate. Additional features that become apparent soon after birth include a lack of fatty tissue under the skin (subcutaneous fat); wasting (atrophy) of muscles; excessive body hair growth (hirsutism); multiple cysts on the ovaries in females; and enlargement of the nipples, genitalia, kidneys, heart, and other organs. Most affected individuals also have a skin condition called acanthosis nigricans, in which the skin in body folds and creases becomes thick, dark, and velvety. Distinctive facial features in people with Donohue syndrome include bulging eyes, thick lips, upturned nostrils, and low-set ears. Affected individuals develop recurrent, life-threatening infections beginning in infancy.

Donohue syndrome is one of a group of related conditions described as inherited severe insulin resistance syndromes. These disorders, which also include Rabson-Mendenhall syndrome and type A insulin resistance syndrome, are considered part of a spectrum. Donohue syndrome represents the most severe end of the spectrum; most children with this condition do not survive beyond age 2.  https://medlineplus.gov/genetics/condition/donohue-syndrome

Clinical features

From HPO
Ovarian cyst
MedGen UID:
14540
Concept ID:
C0029927
Disease or Syndrome
The presence of one or more cysts of the ovary.
Clitoral hypertrophy
MedGen UID:
57848
Concept ID:
C0156394
Finding
Hypertrophy of the clitoris.
Long penis
MedGen UID:
82837
Concept ID:
C0269011
Finding
Penile length more than 2 SD above the mean for age.
Medullary nephrocalcinosis
MedGen UID:
588418
Concept ID:
C0403477
Disease or Syndrome
The deposition of calcium salts in the parenchyma of the renal medulla (innermost part of the kidney).
Labial hypertrophy
MedGen UID:
96054
Concept ID:
C0404531
Pathologic Function
Enlarged kidney
MedGen UID:
108156
Concept ID:
C0542518
Finding
An abnormal increase in the size of the kidney.
Large hands
MedGen UID:
98097
Concept ID:
C0426870
Finding
Long foot
MedGen UID:
154365
Concept ID:
C0576225
Finding
Increased back to front length of the foot.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Left ventricular hypertrophy
MedGen UID:
57442
Concept ID:
C0149721
Disease or Syndrome
Enlargement or increased size of the heart left ventricle.
Fetal growth restriction
MedGen UID:
4693
Concept ID:
C0015934
Pathologic Function
An abnormal restriction of fetal growth with fetal weight below the tenth percentile for gestational age.
Postnatal growth retardation
MedGen UID:
395343
Concept ID:
C1859778
Finding
Slow or limited growth after birth.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Abdominal distention
MedGen UID:
34
Concept ID:
C0000731
Finding
Distention of the abdomen.
Cholestasis
MedGen UID:
925
Concept ID:
C0008370
Disease or Syndrome
Impairment of bile flow due to obstruction in bile ducts.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Rectal prolapse
MedGen UID:
11151
Concept ID:
C0034888
Disease or Syndrome
Protrusion of the rectal mucous membrane through the anus.
Hepatic fibrosis
MedGen UID:
116093
Concept ID:
C0239946
Disease or Syndrome
The presence of excessive fibrous connective tissue in the liver. Fibrosis is a reparative or reactive process.
Pancreatic islet-cell hyperplasia
MedGen UID:
108598
Concept ID:
C0597167
Finding
Hyperplasia of the islets of Langerhans, i.e., of the regions of the pancreas that contain its endocrine cells.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Delayed skeletal maturation
MedGen UID:
108148
Concept ID:
C0541764
Finding
A decreased rate of skeletal maturation. Delayed skeletal maturation can be diagnosed on the basis of an estimation of the bone age from radiographs of specific bones in the human body.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Adipose tissue loss
MedGen UID:
870181
Concept ID:
C4024615
Finding
A loss of adipose tissue.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Recurrent otitis media
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Hyperglycemia
MedGen UID:
5689
Concept ID:
C0020456
Disease or Syndrome
An increased concentration of glucose in the blood.
Conjugated hyperbilirubinemia
MedGen UID:
82787
Concept ID:
C0268307
Disease or Syndrome
Abnormally high level of conjugated bilirubin in the blood.
Fasting hypoglycemia
MedGen UID:
75765
Concept ID:
C0271708
Disease or Syndrome
HYPOGLYCEMIA expressed in the postabsorptive state, after prolonged FASTING, or an overnight fast.
Recurrent hypoglycemia
MedGen UID:
335382
Concept ID:
C1846288
Finding
Recurrent episodes of decreased concentration of glucose in the blood.
Postprandial hyperglycemia
MedGen UID:
383702
Concept ID:
C1855520
Finding
An increased concentration of glucose in the blood following a meal.
Increased C-peptide level
MedGen UID:
894029
Concept ID:
C4280763
Finding
An elevated concentration of C-peptide in the circulation. Since C-peptide is secreted in equimolar amounts to insulin, this feature correlates with increased insulin secretion.
Elevated gamma-glutamyltransferase level
MedGen UID:
1370086
Concept ID:
C4476869
Finding
Increased level of the enzyme gamma-glutamyltransferase (GGT). GGT is mainly present in kidney, liver, and pancreatic cells, but small amounts are present in other tissues.
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Elfin facies
MedGen UID:
87157
Concept ID:
C0332606
Sign or Symptom
This is a description previously used to describe a facial form characterized by a short, upturned nose, wide mouth, widely spaced eyes, and full cheeks. Because of the imprecision in this definition it is preferable to describe these features precisely. This term is retained because it was often used in the past, but it should not be used for new annotations.
Gingival overgrowth
MedGen UID:
87712
Concept ID:
C0376480
Finding
Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.
Thick vermilion border
MedGen UID:
332232
Concept ID:
C1836543
Finding
Increased width of the skin of vermilion border region of upper lip.
Thick lower lip vermilion
MedGen UID:
326567
Concept ID:
C1839739
Finding
Increased thickness of the lower lip, leading to a prominent appearance of the lower lip. The height of the vermilion of the lower lip in the midline is more than 2 SD above the mean. Alternatively, an apparently increased height of the vermilion of the lower lip in the frontal view (subjective).
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Small face
MedGen UID:
343376
Concept ID:
C1855538
Finding
A face that is short and narrow.
Acanthosis nigricans
MedGen UID:
54
Concept ID:
C0000889
Disease or Syndrome
A dermatosis characterized by thickened, hyperpigmented plaques, typically on the intertriginous surfaces and neck.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Hypertrichosis
MedGen UID:
43787
Concept ID:
C0020555
Disease or Syndrome
Hypertrichosis is increased hair growth that is abnormal in quantity or location.
Hyperkeratosis
MedGen UID:
209030
Concept ID:
C0870082
Disease or Syndrome
Hyperkeratosis is thickening of the outer layer of the skin, the stratum corneum, which is composed of large, polyhedral, plate-like envelopes filled with keratin which are the dead cells that have migrated up from the stratum granulosum.
Nail dysplasia
MedGen UID:
331737
Concept ID:
C1834405
Congenital Abnormality
The presence of developmental dysplasia of the nail.
Hypermelanotic macule
MedGen UID:
375013
Concept ID:
C1842774
Finding
A hyperpigmented circumscribed area of change in normal skin color without elevation or depression of any size.
Polyhydramnios
MedGen UID:
6936
Concept ID:
C0020224
Pathologic Function
The presence of excess amniotic fluid in the uterus during pregnancy.
Hyperinsulinemia
MedGen UID:
43779
Concept ID:
C0020459
Disease or Syndrome
An increased concentration of insulin in the blood.
Precocious puberty
MedGen UID:
18752
Concept ID:
C0034013
Disease or Syndrome
The onset of secondary sexual characteristics before a normal age. Although it is difficult to define normal age ranges because of the marked variation with which puberty begins in normal children, precocious puberty can be defined as the onset of puberty before the age of 8 years in girls or 9 years in boys.
Prominent nipples
MedGen UID:
343372
Concept ID:
C1855513
Finding
Proptosis
MedGen UID:
41917
Concept ID:
C0015300
Disease or Syndrome
An eye that is protruding anterior to the plane of the face to a greater extent than is typical.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVLeprechaunism syndrome
Follow this link to review classifications for Leprechaunism syndrome in Orphanet.

Professional guidelines

PubMed

Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D
Hum Mol Genet 2002 Jun 1;11(12):1465-75. doi: 10.1093/hmg/11.12.1465. PMID: 12023989

Recent clinical studies

Clinical prediction guides

Park HS, Jin DK, Shin SM, Jang MK, Longo N, Park JW, Bae DS, Bae YS
Diabetes 2005 Nov;54(11):3175-81. doi: 10.2337/diabetes.54.11.3175. PMID: 16249442
Bier DM, Schedewie H, Larner J, Olefsky J, Rubenstein A, Fiser RH, Craig JW, Elders MJ
J Clin Endocrinol Metab 1980 Nov;51(5):988-94. doi: 10.1210/jcem-51-5-988. PMID: 6999010

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