Hereditary leiomyomatosis and RCC

Overview

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a rare genetic condition that significantly increases an individual's risk of developing tumours in the skin, uterus, and kidneys [PMID:33651114]. These growths can be benign (non-cancerous) or malignant (cancerous). The condition is inherited, meaning it can be passed down through families. While the specific manifestations can vary among affected individuals, the presence of multiple skin leiomyomas is a common feature. Recognition of HLRCC is crucial for early detection and management of potential associated cancers, particularly kidney cancer.

HLRCC is considered a cancer predisposition syndrome, which means individuals with this condition have a higher likelihood of developing certain types of cancer compared to the general population. The most significant concern in HLRCC is the elevated risk of a specific and often aggressive form of kidney cancer, known as type 2 papillary renal cell carcinoma [PMID:33651114]. Understanding HLRCC helps healthcare professionals provide appropriate screening and preventative care, aiming to improve outcomes for affected individuals.

Symptoms & clinical features

The clinical features of HLRCC can vary significantly between individuals, even within the same family. One of the most common and often earliest signs is the development of cutaneous leiomyomas, which are benign growths of smooth muscle cells in the skin. These typically appear as firm, reddish-brown bumps that may be painful or sensitive to touch, especially when exposed to cold or pressure [PMID:33651114]. They can appear anywhere on the body but are frequently found on the torso and limbs.

For women, uterine leiomyomas, also known as uterine fibroids, are another common feature. These benign growths in the womb can lead to symptoms such as heavy menstrual bleeding, pelvic pain, and pressure symptoms. Women with HLRCC often develop uterine fibroids at a younger age and may experience more numerous and larger fibroids compared to women in the general population. The most serious manifestation of HLRCC is an increased risk of developing renal cell carcinoma (RCC), specifically an aggressive type known as type 2 papillary RCC. This kidney cancer can present with symptoms such as blood in the urine, flank pain, or a palpable mass, though it may also be discovered incidentally during imaging for other reasons.

Video: Is cancer in your genes?

Affected organs

HLRCC primarily affects three main organ systems: the skin, the uterus (in women), and the kidneys. In the skin, benign smooth muscle growths called leiomyomas are characteristic. These skin lesions can be isolated or occur in clusters and may cause discomfort or pain.

In women, the uterus is commonly affected by leiomyomas, also known as fibroids. These are benign growths that originate from the smooth muscle of the uterine wall. While common in the general population, women with HLRCC often experience earlier onset, increased number, and larger size of these fibroids, potentially leading to significant gynaecological symptoms. The kidneys are the organ of most significant clinical concern due to the increased risk of developing type 2 papillary renal cell carcinoma. This specific type of kidney cancer associated with HLRCC tends to be aggressive and can metastasise (spread) at an earlier stage than other kidney cancers.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

HLRCC is a rare condition, though its exact prevalence is not well established. The severity of HLRCC can vary widely, even within the same family. Some individuals may only develop skin lesions, while others may experience significant uterine fibroid burden and develop kidney cancer. Individuals with HLRCC have an increased lifetime risk of developing renal cell carcinoma [PMID:33651114]. This kidney cancer tends to be aggressive, often presenting at an earlier age compared to sporadic kidney cancers.

The age of onset for skin leiomyomas can be variable, sometimes appearing in early adulthood. Uterine fibroids also tend to develop at a younger age in women with HLRCC. Due to the potential for aggressive kidney cancer, individuals with an HLRCC diagnosis require regular, specialised surveillance. The severity of HLRCC is largely determined by the development and progression of kidney cancer, making early detection critical for improved prognosis.

Genetic causes

HLRCC is caused by pathogenic (disease-causing) variants in the FH gene (fumarate hydratase). The FH gene provides instructions for making the enzyme fumarate hydratase, which plays a critical role in the Krebs cycle (also known as the citric acid cycle) [PMID:33651114]. The Krebs cycle is a fundamental process in cells that generates energy from food.

Fumarate hydratase converts fumarate to malate, an important step in cellular metabolism and energy production. When the FH gene has a pathogenic variant, the fumarate hydratase enzyme may not function correctly or may be produced in insufficient amounts. This leads to an accumulation of fumarate within cells, which is thought to trigger abnormal cell growth and proliferation, ultimately increasing the risk of tumour formation in affected organs [PMID:33651114]. The exact mechanisms by which fumarate accumulation leads to tumour development are still an area of active research.

• FH
  fumarate hydratase
  The FH gene provides instructions for producing the fumarate hydratase enzyme, which is vital for cellular energy metabolism and plays a role in various inherited conditions, including certain cancer predisposition syndromes.

Inheritance pattern

HLRCC is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered FH gene from a parent to develop the condition. If a parent has HLRCC, there is a 50% chance with each pregnancy that their child will inherit the pathogenic FH variant and thus the condition, regardless of the child's sex.

Individuals who inherit the pathogenic FH variant will have an increased risk of developing the associated features of HLRCC. However, the specific symptoms and their severity can vary greatly, even among family members who carry the same genetic variant. This is known as variable expressivity. Individuals with HLRCC can also pass the condition on to their children, meaning it can affect multiple generations within a family.

Subtypes & variants

This page covers Hereditary leiomyomatosis and RCC as a single condition. Several distinct variants and clinical subtypes are recognised in the literature - they share the underlying biology and broad management approach, but differ in severity, age of onset, or causative gene:

• Cutaneous-only presentation OMIM 150800

  Some FH carriers manifest only with cutaneous and uterine leiomyomas without developing renal cell cancer. Surveillance recommendations are unchanged - renal monitoring is recommended for all carriers regardless of cutaneous presentation.

Diagnosis & testing

The diagnosis of HLRCC is typically suspected based on clinical features, such as the presence of multiple cutaneous leiomyomas, early-onset or numerous uterine fibroids, or a diagnosis of type 2 papillary renal cell carcinoma. A family history of similar conditions or specific tumour types can also raise suspicion. Once HLRCC is suspected, genetic testing is used to confirm the diagnosis.

Genetic testing for HLRCC involves analysing the FH gene for pathogenic variants. This is usually performed on a blood sample. In the UK, genetic testing for suspected HLRCC is available through the NHS Genomic Medicine Service (GMS) as part of national genomic testing pathways. Referrals for genetic testing are typically made by a clinical geneticist, oncologist, or other specialist familiar with cancer predisposition syndromes. The relevant NHS National Genomic Test Directory R-code for hereditary leiomyomatosis and renal cell carcinoma is R157.

Management & lifestyle

Management of HLRCC focuses on surveillance for early detection of associated tumours and appropriate treatment when identified. For kidney cancer, regular imaging, such as MRI scans, is typically recommended to screen for renal lesions [PMID:33651114]. If kidney tumours are detected, active surveillance, partial nephrectomy (removal of part of the kidney), or other surgical approaches may be considered, depending on the size and characteristics of the tumour.

For cutaneous leiomyomas, treatment is usually aimed at symptom relief, which can include topical treatments for pain or surgical removal if they are particularly bothersome. For uterine fibroids, management may involve medication to control symptoms, or surgical options such as myomectomy (removal of fibroids) or hysterectomy (removal of the uterus), especially if fibroids are large, numerous, or causing significant symptoms. Individuals diagnosed with HLRCC should be managed by a multidisciplinary team of specialists, including clinical geneticists, oncologists, urologists, and gynaecologists, within the NHS framework. Genetic counselling is also an important component of care, providing information and support to affected individuals and their families.

UK care pathway

In the UK, individuals suspected of having HLRCC are typically referred to a clinical genetics service. This service provides expert assessment, genetic counselling, and access to genomic testing through the NHS Genomic Medicine Service (GMS). The GMS utilises a National Genomic Test Directory, which specifies the genetic tests available for various conditions, including HLRCC. The relevant R-code for HLRCC testing is R157.

Following a diagnosis, individuals with HLRCC will be counselled on the implications for themselves and their family members. A personalised surveillance and management plan will be developed, often involving multidisciplinary teams across various NHS trusts. Genetic counsellors play a vital role in explaining the inheritance pattern, discussing reproductive options, and providing psychological support.

Related conditions

Several conditions can have overlapping features with HLRCC, making accurate diagnosis important. For instance, sporadic uterine fibroids are very common in women, but when they appear at a young age or are numerous, HLRCC should be considered. Similarly, other hereditary kidney cancer syndromes, such as von Hippel-Lindau (VHL) disease or Birt-Hogg-Dubé syndrome, can also present with kidney tumours, although the specific types of renal cell carcinoma and associated features differ.

Distinguishing HLRCC from these conditions relies on a careful assessment of the full clinical picture, including the presence of cutaneous leiomyomas, the specific histology of any kidney tumours, and family history. Genetic testing is usually definitive in differentiating HLRCC from other conditions with similar presentations.

Frequently asked questions