What Is Lamb-Shaffer Syndrome

Overview

Lamb-Shaffer syndrome (LAMSHF) is a rare genetic disorder that was discovered in 2012 by Dr. Lisa Shaffer and Dr. Alan Lamb.¹ Often, children with LAMSHF have symptoms that present similarly to those of a child with an autism spectrum disorder. While the syndrome is not associated with a decreased life expectancy, it can have implications for a person’s ability to live independently. The disorder can cause intellectual and developmental delays and can cause mild changes in facial features.² To date, according to the official LAMSHF charity page there are currently only around 500 people diagnosed with LAMSHF syndrome in the world, underscoring just how rare this disorder is.³

Causes of lamb-shaffer syndrome

LAMSHF syndrome is a genetic disorder and it occurs because of a mutation in a gene called SOX5. The gene is located on the short arm of the 12^th chromosome and is typically associated with the regulation of embryonic development controlling white matter nerve cells in the brain.⁴ The white matter of your brain is responsible for transmitting, processing and sending nerve signals up and down the spinal cord.

LAMSHF can occur when one of the two copies of this gene undergoes a damaging change. This means that people without LAMSHF have two normally functioning and healthy copies of the SOX5 gene. 

While the syndrome has genetic origins, it is unlikely that someone will inherit the disorder. LAMSHF is an autosomal dominant disorder, meaning it is caused by a single copy of the mutated gene. It equally affects people assigned male at birth (AMAB) and people assigned female at birth (AFAB). Anyone affected by LAMSHF has a 50% chance of passing the disorder down to their children.⁵

A recent study examining 34 families of someone affected by LAMSHF showed that only 3% of the cases were inherited from an affected parent.⁶ This means that in most instances, LAMSHF is a de novo occurrence whereby the condition results from a newly occurring mutation – this same study found 74% of the cases to be occurring de novo.⁶

Signs and symptoms of lamb-shaffer syndrome

The first signs of LAMSHF will relate to the developmental delays generated by the condition. The most common developmental delays include global developmental delay, intellectual delay, and deficits in speech and language. Some people with LAMSHF can also experience seizures; however, this is quite uncommon.⁷

• Global developmental delay means that children take longer to reach development milestones than other children their age. This can encompass a range of developmental delays including but not limited to learning to talk and walk, various motor skills and interacting with others both socially and emotionally⁸
• Intellectual delay is commonly used to describe people who have developmental delays in cognitive functioning, which can affect practical, social and conceptual skills. It affects a person's ability to function at their expected age-appropriate level in daily life; these symptoms manifest as delays in language, social skills and self-care⁹
• Speech and language delays: some of the most well-researched case studies of people with LAMSHF note severe expressive language delays and poor early speech development.^4,10 This means that children have difficulties putting words together into sentences or phrases and will not be able to say or understand simple words (such as ‘mama/dada’ and ‘no/stop’) by 18 months of age.¹¹

As well as developmental delays, numerous skeletal and facial changes have been associated with LAMSHF:

Abnormalities in the head, neck and eyes including:

• Crowded teeth
• Bulbous nose 
• Wide or low nasal bridge 
• Facial asymmetry 
• Myopia (near-sightedness) 
• Cross-eyed 
• Optic nerve atrophy - vision is dim, and field of vision is reduced. 
• Low-set ears

Abnormalities of the limbs and musculoskeletal system including: 

• Fingers that curve to one side (clinodactyly)
• Long fingers 
• Long big toe/overlapping toes 
• frontal bossing - unusually large or prominent forehead 
• Decreased muscle tone anywhere on the body 
• Scoliosis - twisted or curved spine⁵

Management and treatment for lamb-shaffer syndrome

There are currently no specific treatments for LAMSHF, but there are management interventions that focus on helping people improve their quality of life. The syndrome can look very different from individual to individual because people with LAMSHF can have varying capacities to function independently. Some options to consider include: 

• Individualised education programmes (IEPs): children in the UK are entitled to IEPs if they have any emotional, behavioural, cognitive, speech, language, communication, sensory or physical difficulties. The programmes are designed to give children extra support where needed and can be offered within the general school environment¹²
• Speech therapy: speech and language therapist professionals can provide therapy to children/adults who need it to improve communication, assist with language development, and help children improve strength and control of speech muscles in order to speak correctly¹³
• Physical therapy: paediatric physiotherapists can work with children to improve strength and endurance through the development of motor skills to achieve functional independence.¹⁴ As well as this, there is also physiotherapy for ophthalmology that involves eye exercises to improve visual difficulties, particularly myopia¹⁵
• Neurological evaluations: these are typically done to assess cognition, cranial nerves (nerves in the head), motor functions, sensory functions, gait abnormalities and reflexes. This can be a useful tool in determining the individual's neurological functioning¹⁶
• Orthopaedic evaluations: orthopaedic surgeons carry out these evaluations to determine the most appropriate treatment for musculoskeletal conditions and can be useful for LAMSHF patients who present with spinal issues such as scoliosis.¹⁷

Additionally, the official webpage for LAMSHF offers a number of different links to groups offering support to the individuals and their families through their community:

• This link provided by the Lamb-Shaffer Syndrome Organization is a form for a global register of people with LAMSHF  so that a newly diagnosed child can be added. The register enables accurate patient information to be given to the organisation so that they are updated about the syndrome.
• This link is for a Facebook support group for parents and primary caregivers looking after someone who has been newly diagnosed with LAMSHF. 

Since it can be isolating dealing with such a rare genetic disorder, joining support groups can help provide empathic, helpful support and comfort for people close to someone with LAMSHF through speaking in confidence and sharing experiences with people in the same circumstances.

Diagnosis

The diagnosis of LAMSHF is carried out using genetic screening tools. Healthcare providers can recommend this testing for children if they have any of the developmental delays and musculoskeletal abnormalities previously discussed. The diagnosis can be confirmed by using microarray analysis or sequencing (see below) of the SOX5 gene.¹⁸

• Microarray analysis: a sample is used to compare the suspected LAMSHF patient sample with an unmutated control sample to find the mutated chromosome pieces, which are often not able to be detected with a microscope.

• There are a few different techniques for sequencing SOX5:
  • Genome sequencing: is used to determine the order of the chemical building blocks of the DNA molecule. This can tell scientists more information about the genetic material in that particular DNA segment  
  • Exome sequencing: is similar to genome sequencing, but it only uses specific coding regions of the genome. This allows scientists to focus on specific genes that can affect the disorder, such as SOX5. 

FAQs

Can lamb-shaffer syndrome be prevented?

LAMSHF cannot be prevented as such. The syndrome is not typically screened for during pregnancy unless the birthing parent is already an identified carrier of the SOX5 gene mutation or has LAMSHF themselves.

Genetic counselling is readily available to help inform prospective parents on how the condition can affect the family. Healthcare providers can use personal and family health history to help evaluate how likely it is that your child will have a genetic condition. They can help you decide if you should seek genetic testing and also help you understand the risks and options associated with your child inheriting a rare genetic disease.

Genetic testing is free with the NHS in the UK if you have a referral from a doctor or hospital specialist, and you may even be offered genetic counselling with the NHS. The genetic tests use the child’s blood or saliva samples to diagnose this rare health condition. 

How common is lamb-shaffer syndrome?

Experts are not certain exactly how many cases of LAMSHF exist to date. Numerous medical journals give varying estimates; however, the official LAMSHF charity page details that there are only around 500 people diagnosed with the syndrome in the world. 

Who is at risk of lamb-shaffer syndrome?

People assigned male at birth (AMAB) and people assigned female at birth (AFAB) can both be equally affected by the syndrome, and most cases are acquired from newly occurring (de novo) mutations of the SOX5 gene. However, in the case that a parent has LAMSHF syndrome, there is a 50% chance that the parent will have a child who is also affected by a mutation in one of their two SOX5 gene copies.⁶

When should I see a doctor?

If you or a family member already know of a SOX5 mutation, you can seek genetic counselling. This counselling can help you determine if you should get a genetic testing referral from your doctor to determine if your child has the syndrome. If your child is exhibiting any of the symptoms above, it is worth consulting a healthcare provider where differential diagnoses can be considered because there are a variety of developmental disorders that involve intellectual disabilities and/or morphological issues. 

Summary

In conclusion, Lamb-Shaffer syndrome is a rare genetic neurodevelopmental disorder that was first discovered in 2012. Symptoms can cause developmental delays, intellectual disabilities, and facial and skeletal abnormalities. 

The syndrome is the consequence of a mutation in the SOX5 gene and typically occurs as a de novo (new) mutation but has been seen to be inherited in some cases. 

While there is no specific treatment for LAMSHF, there is no evidence to suggest it results in a reduced lifespan and there are many resources available to improve the quality of life of affected individuals. 

Support groups and resources can also provide empathic assistance and comfort for affected individuals and their families. 

Genetic counselling and testing can also help prospective parents to understand the risks associated with the syndrome and their available options. 

LAMSHF remains an exceedingly rare condition, with around 500 reported cases worldwide. Anyone experiencing symptoms or with a family history of the syndrome should seek medical advice and consider genetic counselling in order to receive the proper informed guidance and support needed.