From genomic imbalances associated with developmental abnormalities of the female genital tract to the molecular mechanisms underpinning endometriosis and uterine leiomyomatosis, new technologies have allowed the exploration of the genetic contribution and mapping the molecular pathways underpinning common and rare gynaecological conditions.
While some of these conditions have historically been considered sporadic, recent research has demonstrated their potentially heritable nature linked to single genes or copy number variants. The phenotypic variability including non-penetrance indicates their multifactorial, complex aetiology encompassing genetic, epigenetic and environmental influences.
Although genetic tests are not routinely conducted in gynaecological practice, there is an increasing body of evidence suggesting that, in appropriate cases, molecular investigations such as array CGH analysis may be an important part of the diagnostic algorithm. The subtlety of clinical features, especially in the context of syndromic diagnoses, requires the practitioner to become familiar with those conditions and the approach to diagnostic investigations.
This chapter combines the recent research output related to gynaecological disorders with a clinical genetics approach aiming to highlight the multisystem character of some of these conditions, their implications for management, reproductive risks and options, and the importance of genetic counselling.
Introduction
This text concerns gynaecological disorders associated with genetic variations that follow the Mendelian pattern of inheritance. Most conditions discussed here are associated with heterozygous gene variants which often exert their phenotypic effects variably, in conjunction with other genetic, epigenetic and environmental factors.
Extensive research of the genetic jigsaw underpinning health and disease has led to the identification of numerous genes associated with both common and exceedingly rare disorders. Next-generation sequencing (NGS) technology has transformed the laborious process of gene discovery into a sophisticated, high-throughput, robotic approach. With powerful bioinformatics support, the progress in molecular genetics has accelerated rapidly over the last decade, allowing its implementation into mainstream clinical practice.
Our understanding of the molecular pathways associated with the development and health of the female reproductive system has enfolded at a slower pace than in other areas of medicine. There are several reasons for this. First, abnormalities of the female genital tract may be associated with infertility, making it difficult to study familial cases. Second, the clinical variability, reduced penetrance and multitude of genes linked to the physiology and pathology of the female reproductive system have made it difficult to identify suitable cohorts that can be used to map new genes. Nevertheless, NGS has allowed us to overcome many of the difficulties concerning the study of sporadic or genetically heterogeneous conditions.
Unlike other areas of clinical practice, genetic tests are not frequent, or critical diagnostic investigations in gynaecological practice. However, a genetic or syndromic diagnosis may have important ramifications for the individuals and families if the condition is associated with involvement of other systems, require active management or imply a significant offspring risk. In addition, understanding the pathways that lead to conditions such as endometriosis and uterine leiomyomatosis paves the way for designing new, more effective treatment modalities. This chapter aims to elucidate the current knowledge of the genetics of gynaecological conditions, some of which are commonly observed in clinical practice.
General considerations
Most conditions discussed in this chapter are associated with heterozygous loss of function gene variants. They may be sporadic, de novo or inherited as autosomal dominant traits. The key attributes of autosomal dominant genes are their variable expression and reduced penetrance. Variable expression implies that the condition manifests with a different degree of severity in different individuals even when they share the same genetic variation. The probability of any features of the condition manifesting in carriers of pathogenic variants indicates the penetrance. If the presence of a pathogenic gene variant is compatible with completely normal phenotype, then that gene has reduced penetrance.
With very few exceptions, variability in expression and penetrance are features common to all autosomal dominant genes. Although the mechanisms behind this are not fully understood, they most likely result from the interplay between other genes on the same or different pathways, epigenetic factors and the environment.
Fewer conditions caused by autosomal recessive genes are presented in this chapter. These are mostly rare syndromic disorders, in which the abnormality of the female genital tract is one of the aspects of a multisystem disorder. In some cases, the abnormalities of the female genital tract may be under-recognised as the diagnosis is often established early in childhood when screening for these anomalies is not performed, or under-recognised because the severity of some conditions means that the affected individuals usually do not have children.
General considerations
Most conditions discussed in this chapter are associated with heterozygous loss of function gene variants. They may be sporadic, de novo or inherited as autosomal dominant traits. The key attributes of autosomal dominant genes are their variable expression and reduced penetrance. Variable expression implies that the condition manifests with a different degree of severity in different individuals even when they share the same genetic variation. The probability of any features of the condition manifesting in carriers of pathogenic variants indicates the penetrance. If the presence of a pathogenic gene variant is compatible with completely normal phenotype, then that gene has reduced penetrance.
With very few exceptions, variability in expression and penetrance are features common to all autosomal dominant genes. Although the mechanisms behind this are not fully understood, they most likely result from the interplay between other genes on the same or different pathways, epigenetic factors and the environment.
Fewer conditions caused by autosomal recessive genes are presented in this chapter. These are mostly rare syndromic disorders, in which the abnormality of the female genital tract is one of the aspects of a multisystem disorder. In some cases, the abnormalities of the female genital tract may be under-recognised as the diagnosis is often established early in childhood when screening for these anomalies is not performed, or under-recognised because the severity of some conditions means that the affected individuals usually do not have children.
Female Genital Tract Malformations
Sporadic (multifactorial) Female Genital Tract Malformations (FGTM)
The transformation of the Müllerian ducts into the female genital tract during embryonic development is the result of an orchestrated interaction of a multitude of genes and molecular pathways. Disruption of any of these in a 46XX embryo may lead to structural abnormalities of the female genital tract, including the fallopian tubes, uterus, cervix and the proximal part of the vagina, usually with preservation of ovarian anatomy and function.
Complete agenesis of the uterus and proximal vagina, known as Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, affects approximately 1 in 4500–5000 newborn girls. Isolated, MRKH type 1 accounts for 44% of cases. MRKH type 2 is associated with renal and/or skeletal anomalies and is observed in 56% of patients . Unilateral renal agenesis and/or renal ectopia are the most common malformation observed in 40–60% of MRKH type 2 patients. MURCS syndrome (Müllerian duct aplasia-renal agenesis-cervical somite dysplasia) represents the most severe end of the spectrum and encompasses both skeletal and renal anomalies, which affects approximately 16% of MRKH type 2 patients .
MRKH type 1 and MRKH type 2 very rarely occur in multiple family members, which suggests that a single, highly penetrant gene is an unlikely cause. This is further supported by the observation that the recurrence of MRKH in the biological offspring of affected women conceived by assisted reproductive technology, is extremely rare. Conversely, the relatively high prevalence of the condition in the general population would be in keeping with the polygenic/multifactorial model, thus linking the aetiology to the aggregate effect of variants in several genes, with the epigenetic and environmental factors as likely modifiers of the phenotype.
MRKH has also been reported in sporadic conditions, such as Goldenhaar syndrome and VATER/VACTERL association. Goldenhaar syndrome, also known as oculo-auriculo-vertebral syndrome (OAVS), is associated with ear abnormalities (microtia and anotia), hearing loss, epibulbar dermoid and fusion of cervical vertebral bodies. Occasional patients have congenital heart defects. Most patients with Goldenhaar syndrome are sporadic cases. Very rarely, this phenotype is associated with identifiable single gene or genomic rearrangement, for example, 22q11.2 deletion.
VATER/VACTERL association (Vertebral segmentation defect – Anal atresia – Cardiac abnormality – Tracheoesophageal fistula/Oesophageal atresia – Renal dysplasia – Limb abnormality) is a highly variable, sporadic condition of unknown, probably polygenic, aetiology. Familial cases are exceptionally rare. The limb abnormality usually concerns the radial ray. The presence of three of the key features is required for clinical diagnosis, which is usually made in the neonatal period. The incidence and type of female genital tract abnormalities in this condition is not known.
Copy number variants
Copy number variants (CNVs) are small, 100–3000 kb, chromosomal deletions and duplications, which are invisible under the standard cytogenetic resolution and often referred to as microdeletions or microduplications. They can be identified by comparative genomics hybridisation array (array CGH) analysis, a test which has replaced standard chromosome analysis. Often requested by paediatricians investigating a child with motor or cognitive delay, array CGH is a test that adult physicians and gynaecologists rarely consider in their routine practice.
Some CNVs recur in populations at low frequencies. The recurrence of these rearrangements is facilitated by the genomic architecture, which predisposes to unequal exchange in meiosis leading to a deletion in one allele and duplication in the other. Recurrent CNVs are recognised as distinct syndromes, some of which, such as 22q11.2 deletion, have been described as clinical entities long before their genetic basis was known. CNVs may be inherited from a carrier parent in an autosomal dominant fashion or arise as de novo in the gamete.
Studies have revealed enrichment for some CNVs in cohorts of patients with female genital tract abnormalities. They give rise to a variable clinical presentation. This variability can be observed between unrelated individuals and among members of a family who share the same genomic rearrangement. In some cases, completely unaffected individuals have also been identified, usually after a CNV has been found in one of their children who was, most likely, investigated for reasons unrelated to genital tract abnormalities.
CNVs are identified in up to 20% of individuals with FGTM. Nik-Zainal reported 14% prevalence of CNVs in a cohort of patients with isolated and syndromic Müllerian aplasia. However, only 10% of patients with isolated Müllerian aplasia harboured a CNV compared to 20% of patients with syndromic FGTM constellation .
Although identifying a CNV in an otherwise healthy woman with FGTM is unlikely to have an impact on her gynaecological management, a genetic diagnosis may inform about the extent of clinical phenotype and reproductive risk, and may be potentially relevant to other family members. Therefore, it is prudent to consider array CGH testing in appropriate patients and provide genetic counselling.
16p11.2 deletion syndrome
16p11.2 deletion syndrome is one of the most common CNVs in the general population, with an estimated prevalence of 3 in 10,000 women. The commonly deleted, 593-kb region, harbours 16 genes and gives rise to a non-specific clinical phenotype consisting of a variable combination of learning difficulties, expressive language delay, autism spectrum disorder and epilepsy. Approximately 80% of patients experience psychiatric problems and 25% suffer from seizures. Mild dysmorphic facial features, including large head circumference, have been described, but these are subtle, non-specific and difficult to discern even to a trained eye.
IQ scores range from normal/average to mild intellectual disability. Careful analysis reveals that even when the IQ scores were within the normal range, they were still approximately two standard deviations lower on the full-scale intelligence quotient than expected for the family. These individuals typically have other developmental issues, such as expressive language delay and behavioural problems .
Nik-Zainal reported a 6% prevalence of 16p11.2 deletion in a cohort of individuals with Müllerian aplasia. The prevalence was lower (5%) in non-syndromic than in syndromic cases (8%). Congenital heart disease was reported in 6% of cases. Other structural abnormalities were rare. Obesity was a major co-morbidity, which was already present in 50% of patients by 7 years of age and in 75% of adults. In a cohort of patients with morbid obesity defined as BMI ≥ 40, 0.7% were carriers of 16p11.2 deletion .
Most adult patients are identified through cascade screening or thorough investigations for neurodevelopmental or psychiatric concerns. Provision of genetic counselling is part of the best clinical practice; prenatal diagnosis is discouraged, given the variability of the condition and the fact that it does not preclude normal development and health.
17q12 deletion syndrome
Typically, this deletion removes approximately 1.2–1.8 MB of genetic material from the long arm of chromosome 17 containing about 19 genes, including HNF1B ( TCF2 ). Deletions and inactivation of mutations in HNF1B are associated with renal cysts and diabetes syndrome. Approximately 30% of patients inherit this syndrome from a carrier parent.
Patients with 17q12 deletion syndrome present with a variable combination of congenital abnormalities of the kidneys and urinary tract (CAKUT) and/or tubulointerstitial disease, maturity-onset diabetes of the young type 5 (MODY5) and neurodevelopmental and/or neuropsychiatric disorders. Dysmorphic facial features are reported in virtually all deletion carriers. Often subtle, these are described as high forehead, frontal bossing, depressed nasal bridge, deep-set eyes and down slanting palpebral fissures.
Multicystic kidneys and other structural abnormalities of the renal tract occur in up to 85% of deletion carriers. A proportion of patients develop chronic renal failure, and 15% of these will progress to end-stage disease requiring a kidney transplant . MODY5 affects approximately 40%, with an average age of onset 25 years (range 10–50 years) . The risk of diabetes increases after a kidney transplant.
The neurodevelopmental profile comprises mild to moderate intellectual disability and autism spectrum disorder, which are reported in over 50% of deletion carriers. Psychiatric disorders including schizophrenia are more prevalent among deletion carriers compared to controls, although the incidence is uncertain due to studies’ ascertainment bias towards the younger age group.
Genital anomalies are reported in 25–50% of deletion carriers. Müllerian aplasia is frequent, although the true incidence is not known because of the lack of systematic searches for these anomalies. Chen et al. reported an 18.2% prevalence of FGTM in a cohort of 99 women whose DNA harboured an HNF1B gene deletion or point mutation. Conversely, Oram et al. found HNF1B gene deletions or mutations in 18% of women with both Müllerian aplasia and renal abnormalities, but no genetic abnormalities were identified in the cohort of patients with Müllerian aplasia and structurally and functionally normal renal tract. The mean detection rate of deletions and mutations in HNF1B among patients with CAKUT is 19% (5%–31%) .
The complexity and variability of the clinical phenotype and the management implications, due to the risk of renal disease or diabetes, make the diagnosis of this condition important for the proband and members of the family at risk. Referral for genetic counselling is strongly recommended.
22q11.2 deletion/duplication and 22q11.2 distal deletion syndrome
The standard 3-MB deletion from 22q11.2, often referred to as the DiGeorge syndrome or Velocardiofacial syndrome, is a common microdeletion syndrome that affects approximately 1 in 2000 individuals. The distal and smaller, 1.5-MB, 22q11.2 deletion is much less frequent and gives rise to a similar although milder clinical picture than that associated with the standard deletion. Despite their proximity, the two deletions very rarely molecularly overlap, with only a handful of cases reported in the literature. Although the breakpoints distinguish the critical intervals for the cytogenetic subtypes, this does not translate into phenotypic predictability. In general, the severity is likely to be milder with the smaller and distal 22q11.2 deletion.
Despite the molecular distance and size difference, 22q11.2 deletions have many clinical aspects in common. Cleft lip and/or palate and congenital heart disease, including ventricular septal defect, Tetralogy of Fallot, persistent ductus arteriosus, bicuspid aortic valve and laterality defect, are key features, albeit more often associated with the standard deletion. Distinct facial gestalt is often recognisable in childhood, such as mild ptosis, broad nasal bridge, open mouth appearance and retrognathia. Many of these characteristics remain in adulthood, as well as a nasal intonation of speech secondary to palatopharyngeal incompetence, even in the absence of cleft palate.
Virtually, all patients have specific learning difficulties, particularly in the areas of abstract thinking, with an average IQ score of 70. About a half perform within the normal range, although below the IQ score expected for the family. There is some evidence to suggest intellectual decline with age; however, more longitudinal studies are required to distil the natural history of the condition. The risk of mental illness is increased by 25 times that of the average population, including schizophrenia and bipolar disease .
Del 22q11.2 is reported in 8% of patients with MURCS type 2 , while about a third have a structurally abnormal renal system. In a review of paediatric patients with 22q11.2 deletion of both sexes, genitourinary malformations were identified in up to 45%. However, these abnormalities were mostly observed in male infants. The incidence of female genital tract abnormalities may, therefore, be underestimated.
22q11.2 duplication syndrome has been reported in only one patient with MURCS . However, this too may be under-reported, as the phenotype of this microduplication is, although similar to 22q11.2 deletion, usually milder.
Carriers of 22q11.2 deletion/duplication have 50% chance of passing the rearrangement to their offspring. Familial cases are not uncommon, and some adults may be diagnosed after a diagnosis in their child was established. Genetic counselling is strongly recommended, together with careful antenatal ultrasound imaging of pregnancies at risk, including fetal echocardiogram.
Cat eye syndrome (22p trisomy/tertrasomy)
Cat eye syndrome (CES) is a rare chromosomal rearrangement comprising a duplication or triplication of the short arm of chromosome 22 (22p) and an adjacent small amount of the proximal part of the long arm of chromosome 22 (22q). It often presents as supernumerary chromosome composed of 22q11 inversion/duplication containing two centromeres. Less frequently, the excess chromosome material is interstitial within chromosome 22.
Often sporadic, this rearrangement tends to result in a mosaic pattern and may escape detection in DNA from peripheral lymphocytes. Analysis of DNA extracted from solid tissue such as skin may confirm the diagnosis. Rare families have been reported in the literature, in whom several individuals presented with mosaic CES. Although, on balance, the offspring risk in the case of parental mosaicism is usually small, in rare cases, it may be up to 50%.
The key clinical features are iris/retinal/choroid coloboma, congenital heart disease, typically total anomalous pulmonary venous return, and structural renal anomalies including renal agenesis. Biliary atresia, anal atresia and intestinal malrotation have been reported infrequently. Patients may have subtle dysmorphic features, such as down-slanting palpebral fissures, micro/retrognathia, low set ears and pre-auricular tags or pits. Cognitive functions are usually intact or mildly reduced compared to unaffected siblings.
Genital anomalies affect both sexes. In females, they range from hypoplastic to absent uterus and atretic vagina. The severity of FGTM does not correlate with the overall severity of the clinical picture. These may be isolated or associated with additional anomalies, similar to MKRH type 2.
Single gene disorders
Abnormalities of the female genital tract comprise part of the phenotype in several syndromic Mendelian disorders. Most of these conditions occur due to de novo heterozygous variants and demonstrate significant variability of severity including non-penetrance.
Hand–foot–genital syndrome
Key features: genital and limb abnormalities
FGTA: Uterus, cervix and vagina duplication/septation
Gene: Heterozygous HOXA13 or HOXD13
Hand–foot–genital syndrome (HFGS) is caused by heterozygous variants in HOXA13 or HOXD13 . HOX genes encode a highly conserved family of transcription factors, which are crucial for patterning during embryogenesis, and comprise 4 groups (A–D) and 39 genes. Only HOXA13 and HOXD13 have been associated with genitourinary abnormalities .
HFGS is characterised by limb and genital tract anomalies. Typically, patients have short, broad thumbs and short fifth finger clinodactyly. Halluces are also short, broad or even absent. Hand/foot X-rays reveal shortening of the first metacarpal/metatarsal bone, trapezium–scaphoid fusion in the wrist and cuneiform–navicular fusion in the foot .
Genital tract abnormalities include duplication of the uterus, cervix and vagina. The severity is variable and the penetrance reduced, in contrast with the skeletal phenotype, which is considered fully penetrant and usually involves both the upper and lower limbs symmetrically.
Variants in HOXA13 and HOXD13 are inherited in an autosomal dominant fashion and give rise to variable clinical severity. HOXA13 mutations are associated with hypospadias in males. Exploring the family history, including male relatives, may be helpful when considering genetic investigations, segregation analysis and ascertainment of variant pathogenicity.
Renal cysts and diabetes syndrome
Key features: Renal cysts, early-onset diabetes mellitus
FGTA: Müllerian duct aplasia
Gene: Heterozygous HNFB1
Approximately 50% of patients harbour a whole gene deletion as part of the contiguous 17q12 deletion syndrome. The latter, as discussed earlier in this chapter, is usually diagnosed by array CGH analysis. When no genomic imbalance is identified, gene sequencing with dosage analysis, which searches for intragenic deletions and duplications, confirms the diagnosis. The phenotype associated with variants confined to HNF1B involves only the renal system and diabetes (MODY5). In contrast, virtually all 17q12 deletion syndrome patients have a degree of learning difficulties and dysmorphic features, the severity of which is determined by the adjacent genes and correlates to the deletion size.
Townes–Brocks syndrome
Key features: anal atresia, dysplastic ears, limb abnormalities
FGTA: Vaginal aplasia, rectovaginal fistula, bifid uterus
Gene: Heterozygous SALL1
The triad of ear, anal and thumb abnormalities should raise the suspicion of Townes–Brocks syndrome (TBS), which is caused by heterozygous mutations in the SALL1 gene. Over 80% of patients are born with imperforate anus and have dysplastic ears. Conductive, sensorineural or mixed hearing loss is observed in nearly two-thirds, and limb abnormalities, including duplicated, tri-phalangeal or hypoplastic thumbs, syndactyly or absence of toes and club foot, are reported in more than 90% of cases.
Structural renal abnormalities, such as multicystic dysplastic kidneys, renal hypoplasia and vesicoureteric reflux, affect nearly half of patients, including end-stage renal failure even in the presence of structurally normal kidneys. Congenital heart disease is reported in approximately 25% of TBS patients. Learning difficulties are rare, and affect only about 10% of TBS patients.
Up to a third of patients in a cohort of males and females have genital anomalies. Bifid uterus and vaginal aplasia have been reported in females; however, the true incidence of female genital tract abnormalities remains unclear because of the ascertainment bias mostly related to the age at diagnosis, when screening for these anomalies is not performed. A systematic review would help ascertain their frequency and phenotypic spectrum.
In about a half of patients, the SALL1 variants occur de novo . The majority are non-sense or frame-shift and likely exert a dominant negative effect. Whole gene deletions usually present with a much milder phenotype .
Familial cases demonstrate a significant degree of variability in severity. Careful examination of seemingly unaffected carrier relatives may reveal subtle clinical signs, thereby suggesting that the gene is almost fully penetrant. The 50% risk and the unpredictable severity in offspring highlight the need for genetic counselling and careful prenatal imaging to diagnose recurrence.
McKusick–Kaufman syndrome
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Key features: cystic pelvic mass, polydactyly, congenital heart disease
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FGTA: hydrometrocolpos, rectovaginal/vesicovaginal fistula
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Gene: bi-allelic MKKS
McKusick–Kaufman syndrome (MKKS) is a rare autosomal recessive disorder that mostly affects individuals in the Amish community. The earliest presentation is in infancy, with a cystic pelvic mass formed by the accumulation of secretions in the obstructed female genital tract. The obstruction arises because of a transverse vaginal membrane, vaginal stenosis or atresia and may be associated with a rectovaginal or vesico-vaginal fistula. Additional features include mesoaxial or postaxial polydactyly and/or syndactyly and congenital heart disease, as well as Hirschsprung disease and anal atresia. The intellect is usually intact.
MKKS is allelic with Bardet–Biedel syndrome 6 (BBS6), a condition associated with retinal dystrophy, obesity, post-axial polydactyly, urogenital anomalies, including hydrometrocolpos, and learning difficulties. The absence of learning and visual impairment and later obesity differentiates these two conditions clinically. It has been postulated that BBS6 and MKKS are effectively the same conditions and that the phenotypic differences are secondary to the specific MKKS variants. Clinical or electrodiagnostic evidence of retinal dysfunction clarifies the phenotype. Therefore, clarification of the specific diagnosis may not be possible until late teens or early twenties, when the distinguishing features are likely to occur.
Both conditions require multidisciplinary management. Parents of affected individuals have a 25% recurrence risk for future children. Affected females from the Amish population are at increased risk of having affected offspring, given the higher prevalence of heterozygous carriers in this population. Prenatal ultrasound imaging provides some assistance; however, accurate diagnosis relies on genetic testing.
Mullerian aplasia and hyperandrogenism
Key features: primary amenorrhoea, hyperandrogenism, hirsutism
FGTA: absent/rudimentary vagina and/or uterus
Gene: heterozygous WNT4
WNT4 is a signalling molecule involved in Müllerian duct development and androgen synthesis in the ovary. The WNT gene family is crucial for early embryonic development, patterning and symmetry. WNT4 was the first gene identified in association with MRKH. There is some evidence that other WNT genes may contribute to female genital tract development in a polygenic fashion.
Hyperandrogenism in association with dysplastic/aplastic Müllerian duct derivatives and normal ovaries in a 46XX patient should raise the suspicion of WNT4 involvement. A small number of cases have been reported in the literature, and some have had congenital heart disease and/or renal tract abnormalities.
Synonymous, heterozygous WNT4 variants have been identified in individuals with MRKH, suggesting that they may exert their effect by aberrant splicing, however, further studies are necessary to validate this hypothesis. Such variants probably act concomitantly with other genetic and environmental factors in a multifactorial fashion. Variants in WNT7 , WNT9B and WNT5 , as well as in TBX6 and LHX1 , most likely operate in a similar manner. Functional analysis is required to test this hypothesis .
Bi-allelic WNT4 variants cause a rare autosomal recessive disorder, SERKAL syndrome (Sex reversal with dysgenesis of kidneys, adrenals and lungs). All reported cases in the literature have been in fetuses after termination of pregnancy for congenital malformations; no live born children have been reported to date .
Popliteal pterygium syndrome
Key features: cleft lip/palate, lower lip pits, syndactyly, talipes, ankyloblepharon, popliteal pterygium
FGTA: hypoplastic uterus and/or vagina, hypoplastic labia majora
Gene: heterozygous IRF6
Popliteal pterygium syndrome (PPS) is a rare condition, which is on the severe end of the spectrum of IRF6 -related disorders. The mildest phenotype presents as isolated cleft lip and/or palate, and the association of cleft lip/palate and lip pits defines the Van der Woude syndrome (VWS).
In addition to syndactyly of fingers and toes and popliteal pterygium, PPS is characterised by genital anomalies, including hypoplasia of the labia majora, vagina and uterus. The most severe cases present with ankyloblepharon and syngnathia.
The clinical picture in familial cases tends to be consistent, although the severity can vary. VWS-associated mutations are spread throughout the gene, unlike those associated with PPS. However, both VWS and PPS have occasionally been reported in the same family.
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