In Singapore, a rare disease is defined as a condition that affects fewer than one in 2,000 people. Persons with rare diseases are typically identified during the mother’s pregnancy following screening or testing, or at birth due to the presence of congenital anomalies.

In some cases, a rare disease may be late-onset, with symptoms only presenting gradually from early childhood, school-going age or even as late as adulthood. Hence, these cases may remain undetected for a long time.

Two such conditions are 22q11.2 deletion syndrome (22q11.2DS) and Neurofibromatosis Type 1 (NF1) which, while classified as rare, have a noticeable prevalence in the Singapore population.

Early detection during a routine developmental follow-up session can help patients. With a referral for tertiary assessment, patients can receive timely diagnosis and support to optimise their quality of life.

General practitioners (GPs) can help to play an active role in looking out for tell-tale signs of 22q11.2DS and NF1.

What is 22q11.2 deletion syndrome (22q11.2DS)?​
​Individuals with 22q11.2DS (also including velocardiofacial syndrome (VCFS) and DiGeorge Syndrome) are born without a small part of chromosome 22, known as 22q11.2, resulting in the loss of an estimated 40 to 60 genes.   This genetic disorder occurs in one in 6,000 persons, and can affect many parts of the body, including the heart, immune system and development.	​ Photo credit: SingHealth
​Clinical presentation
​Individuals can present with a combination of the following symptoms, which may gradually appear over a number of years, with varying degrees of severity:
​Congenital heart defects	Particularly conotruncal defects, such as: Ventricular septal defect: A hole between the lower chambers of the heart Tetralogy of Fallot: A combination of four abnormal heart structures Interrupted aortic arch: Incomplete formation of the aorta, the large blood vessel that carries blood from the heart to the rest of the body Truncus arteriosus: One large vessel, instead of two, leading out of the heart
​Palatal abnormalities	Velopharyngeal insufficiency: Incomplete closure of the seal between the oral and nasal cavities Submucous cleft palate: Lack of or incorrect positioning of muscles in the tissue covering the soft palate Bifid uvula: A forked or split uvula Cleft palate: A gap in the roof of the mouth Hypernasal speech and dysphagia
​Hearing loss	Sensorineural and/or conductive
​Craniofacial features	​Hooded eyelids Ear anomalies such as low set ears Prominent nasal bridge Bulbous nose Micrognathia: Where the chin is underdeveloped Asymmetric crying facies: Where the face appears symmetric at rest but asymmetric during crying due to abnormalities in muscle development Craniosynostosis: Misshapen skull due to premature fusion of joints between the bone plates
​Immune deficiency	Frequent infections Thymic hypoplasia: Underdeveloped or involuted thymus, which leads to reduced T-cells
​Hypoparathyroidism and hypocalcaemia	Hypoparathyroidism: Smaller-than-normal parathyroid glands (located in the neck which regulate the calcium level in the body) Hypocalcaemia: Low calcium levels
​Developmental delay and/or learning difficulties	Learning difficulties such as delays in speech development Behavioural issues such as attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder Greater risk of depression, schizophrenia and anxiety disorders later in life​
​Common prenatal findings	Aberrant Right Subclavian Artery (ARSA) Congenital heart disease
​Testing for 22q11.2DS
​Screening test during pregnancy: Non-invasive prenatal testing (NIPT) Diagnostic tests: Chromosome microarray analysis (CMA) Karyotype + FISH (Fluorescence in Situ Hybridisation)
​Benefits of timely diagnosis and management
Genetic counselling on prevalence, etiology, detection, variability, interventions and family planning, with a genetic counsellor or geneticist. Condition-specific anticipatory management such as early intervention therapies for developmental delays, vitamin supplementation, surgery or treatment for infections due to immune deficiencies.
​Resources
SingHealth brochure about 22q11.2DS 22q11.2 Deletion Syndrome - GeneReviews® - NCBI Bookshelf (nih.gov) 22 q – Detect. Know. Grow. 22q Support Groups Links | 22q Family Foundation​

What is Neurofibromatosis Type 1 (NF1)?
​NF1 is caused by a fault in the tumour suppressor NF1 gene, which produces a protein that blocks the development of tumours and cancer.   About one in 3,000 people are born with NF1. The condition can affect the brain, spinal cord, nerves and skin, resulting in skin changes and the growth of tumours along the nerves.   The median life expectancy of people with NF1 is at least eight years lower than that of the general population. They are almost 10 times more likely to develop cancer during their lifetime in comparison to the general population.	​ Photo credit: SingHealth
​Clinical features
Symptoms may gradually appear over a number of years, with varying degrees of severity. An individual may be diagnosed with NF1 if they sent with two or more of the following symptoms:​
​Six or more café-au-lait spots	Flat, coffee-coloured patches on the skin > 5mm in diameter in young children or >15mm in diameter after puberty​
​Freckling around the armpits or groins	Cluster of many small freckles (spots) may appear on the skin at these areas​
​Two or more neurofibromas, or one plexiform neurofibroma	Neurofibromas: Pea-sized bumps that grow on the nerve tissue or under the skin; these may appear just before puberty and increase in number throughout life Plexiform neurofibroma: Larger and deeper tumours around the nerves; these may not be seen or felt, and can be present from early childhood​
​Eye manifestations	Optic pathway glioma: A tumour along the main nerve of the eye that is responsible for sight Two or more Lisch nodules: Tiny tan clumps of pigments within the iris of the eyes that do not affect vision​
​Skeletal changes	Enlargement or malformation of bones in the skeletal system, such as scoliosis, tibial dysplasia (curved lower leg bone) or sphenoid dysplasia (abnormally shaped bone around the eye)​
​Family history	A family member who has been diagnosed with NF1​
​Developmental and behavioural issues	Learning difficulties Behavioural issues such as attention-deficit/hyperactivity disorder (ADHD) ​
​Hypertension	High blood pressure​
​Benefits of timely diagnosis and management
​Long-term integrated care by a multidisciplinary team consisting of genetics, dermatology, neurology, orthopaedic surgery, oncology, ophthalmology and surgical specialties.   Genetic counselling to anticipate the manifestation of skin changes from an early age, to support the child’s psychological well-being and also guide them in future family planning decisions.   The NF1 Clinic at KK Women’s and Children’s Hospital (KKH) is Singapore’s first such dedicated clinic for children. Launched in April 2023, and jointly led by the Genetics Service and Department of Dermatology, the team seeks to improve the care of NF1 patients with comorbidities and provide cross-disciplinary care.
​Resources
​SingHealth brochure about Neurofibromatosis Type 1 Video interview with a KKH patient diagnosed with NF1

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​Dr Nikki Fong, Consultant, Genetics Service, KKH Dr Nikki Fong cares for children with rare diseases. She closely manages patients with Neurofibromatosis Type 1 (NF1), and is involved in maintaining the NF1 registry in Singapore. An active researcher, Dr Fong is pursuing a study into ‘Expanding newborn screening for treatable inherited disorders by using targeted genetic analysis’, which has obtained a grant from the SingHealth Duke-NUS Paediatrics Academic Clinical Programme’s Tan Cheng Lim Research & Education Fund. Dr Fong is also actively involved in medical education as a Clinical Assistant Professor with the Duke-NUS Medical School. Dr Fong obtained her Bachelor of Medicine and Bachelor of Surgery (MBBS) from the National University of Singapore’s Yong Loo Lin School of Medicine in 2013 and completed her paediatric residency at KKH in 2019.

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​Lim Jiin Ying, Principal Genetic Counsellor, Genetics Service, KKH Lim Jiin Ying has strong interest in genetic counselling and genomic medicine. Apart from clinical interests in paediatric and general genetics, Jiin Ying is also a biocurator in the Syndromic Disorders Gene Curation Expert Panel under Clinical Genome Resource (ClinGen), a United States of America (USA) National Institutes of Health (NIH)-funded resource since 2017. Actively involved in research and teaching, Jiin Ying is a trainer for Genetics Education for Healthcare Professionals Workshop jointly developed by KKH Genetics Service and the SingHealth Duke-NUS Institute of Precision Medicine (PRISM), and supported by SingHealth Academy. She is also the Module lead for the Executive Certificate Programme in Clinical Genomics. Jiin Ying graduated from the University of Melbourne with Bachelor of Science: Double Major in Biochemistry & Molecular Biology and Genetics in 2009 and Master of Genetic Counselling in 2011.