Short Syndrome

Clinical characteristics.

SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deeply set eyes), Rieger anomaly, and teething delay. It is now recognized that the features most consistently observed in SHORT syndrome are mild intrauterine growth restriction (IUGR); mild to moderate short stature; partial lipodystrophy (evident in the face, and later in the chest and upper extremities, often sparing the buttocks and legs); and a characteristic facial gestalt. Insulin resistance may be evident in mid-childhood or adolescence, although diabetes mellitus typically does not develop until early adulthood. Other frequent features include Axenfeld-Rieger anomaly or related ocular anterior chamber dysgenesis, delayed dentition and other dental issues, and sensorineural hearing loss.

Diagnosis/testing.

The diagnosis of SHORT syndrome is established in a proband with compatible clinical features (with emphasis on the facial gestalt) and a heterozygous pathogenic variant in PIK3R1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Glaucoma: reduce and stabilize intraocular pressure and to preserve vision. Sensorineural hearing loss: use of hearing aids. Dental anomalies: standard treatment; may include crowns and dental prostheses. Glucose intolerance and diabetes mellitus: to be followed by an endocrine specialist.

Surveillance: Regular monitoring of growth including height, weight, and body mass index. For all individuals with and without apparent anterior chamber anomaly: routine eye examinations to include measurement of intraocular pressure. Hearing assessment every two to three years. Screening for insulin resistance by oral glucose tolerance test every five years in the absence of diabetes. Annual screening lab tests for diabetes mellitus beginning after age ten years.

Agents/circumstances to avoid: Administration of human growth hormone as it may exacerbate insulin resistance. One individual with SHORT syndrome had worsening insulin resistance when treated with metformin; additional study is needed to determine the effects of this drug.

Pregnancy management: If present, diabetes mellitus is managed as appropriate.

Genetic counseling.

SHORT syndrome is inherited in an autosomal dominant manner. The proportion of individuals with SHORT syndrome caused by a de novo pathogenic variant is unknown but appears to be significant. Each child of an individual with SHORT syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.

Suggestive Findings

SHORT syndrome should be suspected in individuals with some combination of the following findings:

• Intrauterine growth restriction
• Short stature
• Partial lipodystrophy
• Characteristic facial gestalt (see Figure 1). The face has a triangular appearance. The forehead is broad and the eyes are deep-set. The nose has a narrow tip and thin nasal alae. The columella is low-hanging. The middle and lower thirds of the face are relatively small. The corners of the mouth are downturned and the chin can be dimpled. The ears are often prominent but not low-set or posteriorly rotated.
• Axenfeld-Rieger anomaly or related anterior chamber ocular anomalies
• Delayed dentition
• Insulin resistance / diabetes mellitus

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Figure 1.

Facial features of SHORT syndrome. The face has a triangular appearance with a prominent forehead and deep-set eyes. The nose has characteristic thin nasal alae and a low-hanging columella. The corners of the mouth can be downturned and the chin can be (more...)

No formal diagnostic criteria have been published for SHORT syndrome; however, to date the presence of characteristic facial features is highly predictive for identifying a heterozygous PIK3R1 pathogenic variant.

Establishing the Diagnosis

The diagnosis of SHORT syndrome is established in a proband with compatible clinical features (with emphasis on the facial gestalt) and a heterozygous pathogenic variant in PIK3R1 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive and recognizable facial features of SHORT syndrome described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a less-specific phenotype indistinguishable from many other inherited disorders with short stature and/or partial lipodystrophy are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, a pathogenic variant in PIK3R1 has been identified in 40 affected individuals from 31 families [Avila et al 2016, Huang-Doran et al 2016, Klatka et al 2017, Hamaguchi et al 2018]. The following description of the phenotypic features associated with this condition is based on these reports.

Intrauterine growth restriction (IUGR). Infants with SHORT syndrome are usually born at or slightly before term and typically exhibit mild IUGR [Lipson et al 1989].

Short stature. Feeding difficulties and/or failure to thrive despite adequate caloric intake are commonly reported in young children.

• Mild-to-moderate short stature is usually present throughout childhood. Bone age may or may not be delayed. Other skeletal changes include gracile diaphyses and large and coned-shaped epiphyses [Haan & Morris 1998].
• Mild short stature has been seen in most adults reported to date. Adult height in males with a molecularly confirmed diagnosis of SHORT syndrome was between 155 and 163 cm and in females between 143 and 160 cm [Chudasama et al 2013, Dyment et al 2013, Thauvin-Robinet et al 2013].

Partial lipodystrophy. Partial lipodystrophy is very common in SHORT syndrome [Koenig et al 2003]. Lack of subcutaneous fat is evident in the face and later becomes more readily apparent in the chest and upper extremities. Although the buttocks and legs are often spared, localized regions of lipoatrophy at the elbows and buttocks have been reported [Aarskog et al 1983, Koenig et al 2003]. The hands also lack subcutaneous fat, and the skin has an aged, translucent appearance.

The body habitus is described as thin. All four adult males reported to date with a molecularly confirmed diagnosis had a body mass index (BMI) below 18.5 (range 13.5-17.9); four of eight adult females also had a BMI below 18.5 (range 15.1-22.5) [Chudasama et al 2013, Dyment et al 2013, Thauvin-Robinet et al 2013].

Characteristic facial gestalt. The characteristic facial features of SHORT syndrome – sometimes described as having an "aged" or "progeroid" appearance [Koenig et al 2003] – are present at birth and become increasingly apparent with age. Head shape is normal and occipital-frontal circumference is proportionate with other growth parameters. The vasculature of the scalp is prominent. The forehead is broad, palpebral fissures are deep-set, and alae nasi are thin with a low-hanging columella. The chin is small and can be dimpled. (See Figure 1.)

Insulin resistance / diabetes mellitus. Although insulin resistance may be evident in mid-childhood or adolescence, diabetes mellitus typically does not develop until early adulthood [Aarskog et al 1983, Schwingshandl et al 1993].

Axenfeld-Rieger anomaly or related anterior chamber ocular anomalies – also referred to as anterior chamber dysgenesis – have been reported in the majority of individuals with SHORT syndrome. Glaucoma, which has been reported in at least one individual at birth [Brodsky et al 1996], can also develop later [Bankier et al 1995]. Glaucoma is thought to be the result of poorly developed aqueous humor drainage structures of the anterior chamber of the eye.

The majority of individuals with a PIK3R1 pathogenic variant have at least some ocular involvement including myopia, hyperopia, and/or astigmatism, and half have Rieger anomaly or related anterior chamber defects [Chudasama et al 2013, Dyment et al 2013, Thauvin-Robinet et al 2013, Schroeder et al 2014].

Delayed dentition. Delayed dentition is common in individuals with a molecularly confirmed diagnosis of SHORT syndrome. Other dental issues include hypodontia, enamel hypoplasia, and malocclusion. Multiple dental caries have also been reported [Koenig et al 2003].

Other

• Sensorineural hearing loss of 80-90 dB has been diagnosed within the first year of life. Among individuals with a molecularly confirmed diagnosis of SHORT syndrome, six have been reported with hearing loss [Avila et al 2016].
• While cognition is not affected in SHORT syndrome, some affected children have mild speech delay.
• Some, but not all, affected individuals exhibit hyperextensible joints and/or inguinal hernias.
• Although there does not appear to be an increased risk for life-threatening infections or evidence of clinical immunodeficiency, there have been reports of a nonspecific history of frequent infections [Koenig et al 2003].
• Nephrocalcinosis has been reported in a mother-son pair with a molecularly confirmed diagnosis [Reardon & Temple 2008]. Nephrocalcinosis was identified incidentally in the son at age two months (on an abdominal US examination performed for follow up of anorectal atresia); the nephrocalcinosis was stable when reassessed at age two years. The mother also developed nephrocalcinosis as an adult.
• Pulmonic stenosis and ectopic kidney have also been reported [Koenig et al 2003, Schroeder et al 2014, Bárcena et al 2014].
• Fertility is generally preserved in SHORT syndrome; ovarian cysts are commonly reported in affected females.

Genotype-Phenotype Correlations

To date no clear genotype-phenotype correlation is evident; however, pathogenic variants appear to cluster in the C-terminal SH2 domain of PIK3R1.

The recurrent missense pathogenic variant c.1945C>T has been identified in 22 of 31 families with SHORT syndrome. While individuals with this specific variant usually have typical SHORT syndrome, to date the numbers are too small to determine whether the phenotype observed with this pathogenic variant differs from that observed with other pathogenic variants.

Penetrance

The penetrance of SHORT syndrome appears complete in all individuals undergoing molecular genetic testing to date: all simplex cases (i.e., a single occurrence in a family) with parents available for testing have had a de novo PIK3R1 pathogenic variant, and all familial cases have inherited the pathogenic variant from an affected parent.

Nomenclature

Since it was first described in the early 1970s, what appears to be SHORT syndrome has been described by different terms, including:

• Low-birthweight Rieger syndrome
• Autosomal partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes *
• Absent iris stroma, narrow body build, and small facial bones *

* Individuals with the latter two disorders have subsequently been demonstrated to have a PIK3R1 pathogenic variant and SHORT syndrome.

Prevalence

SHORT syndrome is very rare; fewer than 50 cases have been reported in the literature.

No ethnic predilection is known.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SHORT syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance