Paula and Bobby
Parents of Lillie
What is SHORT syndrome?
This rare disease is a multi-system genetic condition, meaning it affects multiple systems and organs of the body.
There are currently less than 50 cases of this rare disease recorded worldwide, to date.
The syndrome is named for its main symptoms: short stature, ocular depression, Rieger anomaly and teething delay.
Lipodystrophy, Partial, With Rieger Anomaly And Short Stature Short Stature, Hyperextensibility, Hernia, Ocular Depression, Rieger Anomaly, And Teething Delay
What gene changes cause SHORT syndrome?
Mutations in the PIK3R1 gene are responsible for causing the syndrome. It is inherited in an autosomal dominant pattern.
In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
What are the main symptoms of SHORT syndrome?
The main symptoms include a short stature, and a delay in the eruption of an individual's teeth.
The syndrome also presents with Rieger anomaly which means issues with the eyes and potentially glaucoma, hyperextensibility in the joints, the potential for intestinal hernias, as well as ocular depression or deep set eyes.
The syndrome may affect multiple organs within the body and present with multiple birth defects. Growth may be affected in the uterus and a low birth weight is to be expected.
The main facial features of the condition include a triangular face, small chin with a dimple, the loss of fat under the skin, hearing loss and abnormally placed ears.
Possible clinical traits/features:
Short stature, Opacification of the corneal stroma, Hernia of the abdominal wall, Hyperglycemia, Glaucoma, Enlarged epiphyses, Glucose intolerance, Hypoplasia of the zygomatic bone, Underdeveloped nasal alae, Hypodontia, Delayed speech and language development, Hypertelorism, Brachydactyly, Diabetes mellitus, Deeply set eye, Posterior embryotoxon, Small for gestational age, Clinodactyly of the 5th finger, Dental malocclusion, Malar flattening, Delayed eruption of teeth, Delayed skeletal maturation, Myotonia, Abnormal hair quantity, Radial deviation of finger, Premature skin wrinkling, Triangular face, Weight loss, Clinodactyly, Frontal bossing, Dimple chin, Prominent forehead, Telecanthus, Wide nasal bridge, Cataract, Aplasia/Hypoplasia of the iris, Abnormality of the immune system, Abnormality of the hip bone, Abnormal anterior chamber morphology, Birth length less than 3rd percentile, Abnormal pupil morphology, Sensorineural hearing impairment, Hand polydactyly, Prominent supraorbital ridges, Rieger anomaly
How does someone get tested for SHORT syndrome?
The initial testing for SHORT syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on SHORT syndrome
SHORT syndrome combines the features of Rieger anomaly with a characteristic facial appearance (triangular face, lack of facial fat, hypoplastic alae nasi) and short stature. Developmental milestones and cognition are normal. The syndrome is linked to heterozygous mutations in the PIK3R1 gene on chromosome 5q13.
The name is an acronym (S-short stature, H-hyperextensible joints, O-ocular depression, R-Rieger anomaly, T-teething (delayed)). The face is small and triangular with deep-set eyes. The eye signs include megalocornea, hypermetropia, and Rieger anomaly. Subcutaneous fat is diminished, and the skin may be wrinkled, which gives the appearance of premature ageing. Note that insulin resistance is a major feature. The bone age is delayed. Speech delay may be a feature.
Aarskog et al., (1983) and Bankier et al., (1995) reported dominant families where affected individuals had similar features (see Rieger anomaly-partial lipodystrophy). Sorge et al., (1996) reported a father, son and daughter with features of SHORT syndrome without lipodystrophy or diabetes. Koenig et al., (2003) reported a mother and son with the condition. There was evidence of insulin resistance in the mother.
Schwingshandl et al., (1993) and Verge et al., (1994) reported cases who were demonstrated to have insulin resistance. Their case had polycystic ovaries and late menarche.
Haan and Morris (1998) present a further case with evolution of the facial features from the neonatal period. They also describe the radiographic features, which include slender long bones with large epiphyses, short metacarpals with coned epiphyses, and Wormian bones of the skull.
Two patients reported by Reardon and Temple (2008) had nephrocalcinosis.
Mutations in PIK3R1 resulting in partial lipodystrophy have now been found. (Thauvin-Robinet et al., 2013). This is confirmed by Chudasama et al., (2013) and by Dyment et al., (2013).
Avila et al., (2016) reviewed the clinical characteristics of 40 patients with SHORT syndrome. The most frequent features included facial dysmorphism, ocular depression, lipoatrophy, short stature, IUGR, teething delay, thin, wrinkled skin with visible veins, absent hypertriglyceridemia, speech delay, insulin resistance, hyperextensibility of joints, inguinal hernia, diabetes, and anterior eye chamber abnormalities. Intellectual disability was rare.
Dysmorphic features were triangular face, prominent forehead, hypoplastic alae nasi, mild midface hypoplasia, micrognathia, large low-set ears, thin lip and downturned mouth, and progeroid-like face.
García-Morato et al., (2017) described two patients with a combination of primary immunodeficiency and SHORT syndrome caused by heterozygous splice site mutations in the same nucleotide of the PIK3R1 gene (NM_181523.2:c.1425+1G>A; c.1425+1G>T). Clinical features included poor weight gain since birth, mitral valve abnormalities, recurrent infections (upper airway, ear, gastrointestinal, skin and lacrimal ducts), and dysmorphic features resembling SHORT syndrome. One patient also had non-Hodgkin lymphoma and, later, Hodgkin lymphoma. He died at the age of 26 years.
* This information is courtesy of the L M D.
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