Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: PIK3R1
• Condition: SHORT syndrome
• Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

• PIK3R1 ⇔ 0010026 (short syndrome): Moderate Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scores

Gene Condition Pairs: PIK3R1 ⇔ 0010026 (OMIM:269880)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Morbidity due to disorders of glucose and lipid metabolism / Metabolic management (includes monitoring/treatment of hyperglycemia and hyperlipidemia)	1	3C	2C	3	9CC
Morbidity due to sensory impairment / Referral to a multidisciplinary care team, if available, and regular audiologic and ophthalmologic evaluations to optimize hearing and vision	1	2N	3C	3	9NC

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of SHORT syndrome is unknown. SHORT syndrome is very rare; with fewer than 50 cases reported in the literature. No ethnic predilection is known. [1, 2]

Clinical Features

SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deeply set eyes), Rieger anomaly, and teething delay, which reflects the most striking clinical features of the original reported cases. However, these five features are neither required to make the diagnosis nor the most specific features of SHORT syndrome. The post-natal features most consistently observed in SHORT syndrome are mild to moderate short stature; partial lipodystrophy (evident in the face, chest, and upper extremities, often sparing the buttocks and legs); and a characteristic facial gestalt (triangular face with a prominent forehead and deep-set eyes, nose with thin nasal alae and a low-hanging columella, relatively small lower face, downturned mouth, dimpled chin, and prominent ears). Generalized lipodystrophy has also been reported. Patients are sometimes described as having a progeroid appearance, thin body habitus, hands lacking subcutaneous fat, and skin with an aged translucent appearance. Other frequent features include insulin resistance and diabetes mellitus, Axenfeld-Rieger anomaly or related ocular anterior chamber dysgenesis (including glaucoma), delayed dentition and other dental issues (hypodontia, enamel hypoplasia, malocclusion, multiple dental caries), and sensorineural hearing loss. Variable clinical characteristics may include mild speech delay, hyperextensible joints, inguinal hernias, frequent minor infections in the absence of clinical immunodeficiency, nephrocalcinosis, pulmonic stenosis, ectopic kidney, ovarian cysts, advanced bone age, metabolic complications, micrognathia, heart malformations, and cataracts. [1, 2, 3, 4, 5, 6]

Natural History

Lack of subcutaneous fat may be evident in the face at birth, as the first presenting feature of partial lipodystrophy, which later becomes more readily apparent in the chest and upper extremities. The characteristic facial features of SHORT syndrome are present at birth and become increasingly apparent with age. Heart malformations (particularly pulmonary stenosis), if present, can be detected in infancy. There have been reports of lipodystrophy and nephrocalcinosis in infancy. Feeding difficulties and/or failure to thrive despite adequate caloric intake are commonly reported in early childhood. Glaucoma has been reported at or soon after birth but can also develop later. Sensorineural hearing loss has been diagnosed within the first year of life. Speech delay may develop during childhood. Mild-to-moderate short stature is usually present throughout childhood and has been observed in most adults reported to date. Insulin resistance has a highly variable age at diagnosis ranging from 7-49 years. Though insulin resistance may be evident in mid-childhood or adolescence, diabetes mellitus typically does not develop until early adulthood. Individuals with SHORT syndrome are considered to have a normal life expectancy. Male and female patients appear to be equally affected. [1, 2, 4, 5]

2. How effective are interventions for preventing harm?

Patient Management

At diagnosis, the following evaluations should be completed:
- Ophthalmological exam
- Screening for hearing loss
- Fasting glucose and insulin, with or without oral glucose tolerance test (depending on age)
- Cardiac ultrasound
- Abdominal ultrasound for renal anomalies
- Lipid blood test (triglyceride). (Tier 2) [5]

Additional tests to consider at diagnosis include:
- Measuring length and weight
- Assessing speech and language in those with evidence of developmental delay
- Dental exam
- Genetic counseling. (Tier 4) [1]

Guidelines general to lipodystrophies, but not specific to SHORT syndrome, indicate that current therapeutic options for metabolic management consist of lifestyle modifications (diet and exercise) and conventional antihyperglycemic and lipid-lowering medications. Metformin, sulfonylureas, thiazolidinediones, and insulin can be used to manage hyperglycemia, while fibrates and statins can be used to manage hypertriglyceridemia. When metabolic abnormalities associated with lipodystrophies are particularly severe, conventional treatments are likely to be inadequate at re-establishing metabolic control. Plasmapheresis may be an option to lower dangerously high triglyceride levels. Patients may require very high doses of insulin and will benefit from highly concentrated (e.g., U-500) insulin. However, very few studies were identified reporting on the effectiveness of these medications in lipodystrophies. One study of 5 nondiabetic type 2 familial partial lipodystrophy adult patients (LMNA-positive) were treated with the thiazolidinedione, rosiglitazone. Within 12 months of treatment, hip circumference significantly increased from 93.6 ± 2.78 cm to 96.2 ± 2.3 cm (p < 0.05) and there were significant reductions in fasting glucose levels, liver transaminases, and baseline and postprandial free fatty acids. However, other measures of body composition (e.g., weight, BMI) and glycemic control (e.g., insulin levels) were not improved, nor were any measures of lipid metabolism (e.g., total cholesterol, triglycerides). (Tier 2) [7, 8]

Another source that provides clinical management recommendations specific to SHORT syndrome, provides similar guidance regarding treatment with lifestyle and medication for glucose intolerance and diabetes. However, this source noted that metformin worsened insulin resistance in one case of SHORT syndrome and should be used with caution. (Tier 3) [1]

Leptin replacement therapy (LRT) (metreleptin) can be useful to manage lipodystrophy-related metabolic complications. (Tier 2) [7, 8]

No studies were identified that reported on the management of SHORT syndrome-associated lipodystrophy. However, a systematic review of 12 prospective cohort studies and clinical case series assessed the effect of LRT in 226 patients (50% males; average age: 26.5 [SD=10] years; follow-up time range: 3-100 months) with several lipodystrophy syndromes (generalized and partial; congenital and acquired) on various clinical endpoints. Meta-analyses including patients with congenital and acquired generalized lipodystrophies, and partial lipodystrophies, found that LRT decreased fasting glucose (p = 0.0001), HbA1c (p = 0.003), triglycerides (p < 0.00001), total cholesterol (p = 0.003), liver volume (p = 0.0002) and aspartate aminotransferase (p = 0.01). Other outcomes of insulin, alanine aminotransferase, and LDL and HDL cholesterol were not significantly improved. Subgroup analysis found that patients with congenital lipodystrophies (n=21) had smaller decreases in glucose, HbA1c, and triglycerides compared to those with acquired lipodystrophies (n=5). (Tier 1) [9]

Additional clinical studies on lipodystrophies (ranging from 6-86 patients predominantly diagnosed with congenital lipodystrophy, treated for 6-12 months, ranging in age from 10-68 years,) found that treatment with metreleptin was associated with markedly reduced hepatic and muscular lipid content, and improved insulin sensitivity, insulin secretion, hyperglycemia, and dyslipidemia, in part independently of reduced caloric intake. (Tier 2) [7, 8]

General guidelines for communication deficits include referral to a multidisciplinary care center, when available. A team approach that includes otolaryngologists, clinical geneticists, genetic counselors, audiologists, speech and ASL therapists, early hearing intervention and family support specialists (which may include other individuals who are deaf or hard of hearing or other parents of deaf or hard-of-hearing children), and other appropriate specialists offer optimal opportunity to provide ongoing management and support of deaf and hard-of-hearing individuals and their families as their needs change over time. (Tier 2) [10, 11, 12, 13]

Early intervention (EI) should begin as soon as possible after confirming hearing loss, regardless of age of identification or the type of hearing loss. When possible, it is recommended that intervention begin within the first year, optimally by the age of 6 months. EI comprises evaluation for amplification or sensory devices, surgical and medical evaluation, communication assessment and therapy, and access to education and support resources. The purpose of early intervention is to meet the individualized needs of the child and family, including acquisition of communication competence, social skills, emotional well-being and positive self-esteem. All children who are deaf from birth to 3 years of age and their families should have EI providers who have the qualifications, knowledge, and skills (e.g. educational strategies for infants/toddlers who are deaf), to optimize the child’s development and child/family well-being. (Tier 2) [10, 12, 14, 15]

Shorter duration of hearing loss was associated with better outcomes, as it meant upon detection of hearing loss children and families could be provided with intervention services. Eleven research studies reported on the influence of duration of hearing loss on outcomes for children with hearing loss. A wide range of speech and language measures were captured using different methodologies. Almost all studies included children who used cochlear implants. Children who had a shorter duration of hearing loss tended to do better in terms of speech and language measures compared to their peers with a longer duration of hearing loss. The impact of duration of hearing loss on other outcomes such as reading ability and play were poorly represented in the literature. The evidence indicates that a composite of interrelated constructs of a habilitation methodology contribute to optimal outcomes for children with hearing loss. (Tier 1) [16]

If the family chooses, fitting of hearing aid amplification no later than four months of age (or as soon as there is confirmation that the child is deaf or hard of hearing) is optimal, if not medically contraindicated (e.g., draining ear, local skin or ear canal condition, absent auditory nerves). The purpose of hearing aid amplification in infants who are deaf or hard of hearing is to facilitate timely and optimal auditory development as a precursor to development of spoken language. (Tier 2) [10, 12]

Age at fitting of hearing aids may influence outcomes for children who have hearing loss. Timely access to audition is likely to support the development of speech and language skills. Age at fitting of hearing aids interacts with other variables (such as age at diagnosis and commencement of intervention programs). This finding highlights the complex inter-relationship between variables and their influence on outcomes. (Tier 1) [16]

If the family’s goals for their child include development of spoken language, cochlear implants are the mainstay of treatment for most children with severe to profound hearing loss. Cochlear implants should only be considered after an assessment by a multidisciplinary team. As part of the assessment, children should also have had a valid trial of an acoustic hearing aid for at least 3 months (unless contraindicated or inappropriate). If there is failure to make expected progress with appropriately fitted amplification in those with severe to profound hearing loss, cochlear implants are indicated. Timing of the intervention remains critical, with better outcomes achieved for those receiving an implant by two years of age. Outcomes following cochlear implantation can be impacted by a number of variables that include: age at implantation, progression of hearing loss, duration of device use, cochlear morphology and cranial nerve VIII integrity, electrode placement, high qualify mapping of speech processor, parental educational level, and involvement in family centered, intensive-auditory based intervention. In general, device failure rates after successful implantation are low (less than 5% over 15 years). (Tier 2) [10, 12, 15, 17]

A child’s age at the time of cochlear implantation does influence outcomes for children who have hearing loss. The younger a child is when they receive a cochlear implant, the better the outcomes. However, there is no consensus regarding a minimum age or an optimum age for implantation. Success following implantation is dependent upon high quality intervention services. (Tier 1) [16]

Treatment of additional manifestations in individuals with SHORT syndrome is symptomatic, requires a multidisciplinary team, and include the following:
- Ocular anomalies should be treated by an ophthalmologist to decrease and stabilize ocular pressure, and preserve vision.
- Standard dental treatment, which may include crowns and dental prostheses, for dental anomalies. (Tier 4) [1, 2]

If lipodystrophic or insulin-resistant phenotypes are present, blood glucose and lipid levels should be checked carefully before first prescription of a contraceptive pill. (Tier 2) [8]

Surveillance

Recommended follow-up for individuals with SHORT syndrome includes:
- Monitor growth
- In childhood follow developmental milestones, particularly speech and language
- Fasting glucose and insulin, and HbA1C annually (potentially starting later in childhood)
- Oral glucose tolerance tests every 5 years in absence of diabetes
- In women, gynecological ultrasound to search for polycystic ovaries. (Tier 2) [5]

Regular surveillance of hearing status is recommended for all children with hearing levels that fall outside the range of normal in one or both ears. Regular assessment of progress of communication development (receptive and expressive language, speech, and auditory skills) through appropriate protocols is recommended every 6 months in the infant/toddler period and annually thereafter. (Tier 2) [10, 14]

Additional regular monitoring includes annual eye exams, including measurement of intraocular pressure. (Tier 4) [1, 2]

Circumstances to Avoid

Because growth hormone treatment could aggravate pre-existing insulin resistance and accelerate the onset of diabetes mellitus, its use in patients with SHORT syndrome should be evaluated with caution. (Tier 2) [5]

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant [1, 2, 3, 4, 5, 6]

Prevalence of Genetic Variants

The population prevalence of PIK3R1 pathogenic variants was not available.

To date, pathogenic variants in PIK3R1 have been identified in 40 affected individuals from 31 families. (Tier 3) [1]

Penetrance

The penetrance of SHORT syndrome appears complete in all individuals undergoing molecular genetic testing to date. (Tier 4) [1]

The following description of the phenotypic features associated with this condition is based on data compiled from 40 genetically confirmed affected individuals from 31 families:
- Short stature (≤-2 standard deviations): 30/38 (79%)
- Partial lipodystrophy: 31/35 (89%)
- Insulin resistance: 18/23 (78%)
- Diabetes: 11/18 (61%)
- Anterior chamber ocular defects: 6/20 (30%) (Tier 3) [1]

Glaucoma, which has been reported in at least 4 pediatric patients. (Tier 3) [1, 4]

The following phenotypes are based on a single study of 8 newly ascertained individuals and 24 previously reported patients with SHORT syndrome with causal PIK3R1 pathogenic variants (mean age at last follow-up was 21 years):
- Ocular depression (deep-set eyes): 27/27 cases (100%)
- Rieger abnormality: 13/30 cases (43%)
- Refractive errors: 12/24 (50%)
- Other abnormalities of the anterior chamber of eye: 5/16 cases (31%)
- Hyperopia, astigmatism, or myopia: 12/24 cases (50%)
- Insulin resistant diabetes with high insulin requirements: 9/14 cases (≥ 15 years) (64%)
- Deafness: 5/32 (16%) (Tier 5) [5]

In a small study of 8 patients (7 adults) genetically confirmed with SHORT in 2 unrelated families, the following laboratory values appeared to be elevated compared to BMI- and age-matched controls and reference values:
•\tFasting plasma glucose: 3 adults/7 total (43%)
•\tHbA1c: 2 adults/6 total (33%)
•\tLeptin: 1 adult/5 total (20%)
•\tTotal cholesterol: 0 adults/6 total (0%)
•\tHDL cholesterol: 1 adult/6 total (17%)
•\tLDL cholesterol: 0 adults/6 total (0%)
•\tTriglycerides: 0 adults/6 total (0%) (Tier 5) [18]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

The features of the SHORT syndrome acronym vary between patients. One case series found that only 11 of 21 patients (52%) presented at least 4 of 5 signs of this acronym. (Tier 5) [5]

Variable expression of many of the features has been observed multiple members of the same family. (Tier 3) [3, 4]

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions for SHORT syndrome include invasive and non-invasive imaging, clinical monitoring, routine blood tests, and medication. Treatment with oral sulfonylureas is associated with possible side effects of weight gain and hypoglycemia. Statins are generally well-tolerated. Adverse effects are rare even at standard doses, but include elevated liver enzymes, muscle symptoms (the most severe of which is rhabdomyolysis, which can be fatal), new onset diabetes, potential fetal teratogenicity, and impacts on sexual and physical maturation. [19, 20, 21]

Services for people who are deaf aim to improve their quality of life by maximizing their ability to communicate, using the means most appropriate for the person and their environment, and to enable the person to move safely within their environment. General risks and complications of cochlear implantation include risk of meningitis, infection, facial nerve paralysis, electrode migration and anesthesia risk; however, the overall risks of complications of screening and treatment are estimated to be small (less than 1%). Cerebral spinal fluid (CSF) outflow is another risk of cochlear implantation, particularly in patients with EVA with and without cochlear hypoplasia. Patients who experience rapid CSF outflow (known as a CSF gusher) may be at higher risk of developing postoperative otogenic meningitis. [10, 12, 15, 17]

LRT is typically administered as a subcutaneous injection once or twice daily, and treatment is lifelong. However, it appears to be well-tolerated. Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with MYALEPT and could inhibit endogenous leptin action and/or result in loss of MYALEPT efficacy. Worsening metabolic control and/or severe infection have been reported. Treatment with metreleptin is also associated with possible weight gain and hypoglycemia. [8, 9, 22]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Diagnosis of lipodystrophy is frequently challenging and may easily be confused with common central obesity, metabolic syndrome, and other metabolic disorders. (Tier 3) [7, 8]

The relatively mild clinical presentation of several of the subjects suggests that SHORT syndrome may be underdiagnosed. (Tier 3) [1, 5]

Some individuals lack the distinctive and recognizable facial features of SHORT syndrome, having a less-specific phenotype indistinguishable from many other inherited disorders with short stature and/or partial lipodystrophy. (Tier 4) [1]

Date of Search: 10.12.2020

Reference List

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