Limb-girdle muscular dystrophy type R2 manifesting as fetal growth restriction in a woman with two pregnancies: a case report

Introduction

Background

Limb-girdle muscular dystrophy (LGMD) refers to a group of genetic myopathies characterized by high genetic heterogeneity and phenotypic variability, with an estimated incidence of less than 1 in 100,000 (1). The main feature is weakness in the lower and upper limbs, with a typical symptom being difficulty climbing stairs (2). Some specific types may even result in respiratory and cardiac muscle involvement (3). Currently, there are no known cures or treatments available (4). In women of reproductive age, pregnancy may further exacerbate muscle weakness, heighten the risk of respiratory and cardiac complications, and increase susceptibility to obstetric adverse outcomes such as fetal growth restriction (FGR), pre-eclampsia, and intrahepatic cholestasis of pregnancy (ICP), thereby presenting significant clinical challenges (2).

Rationale and knowledge gap

LGMD has two major genetic patterns: autosomal dominant (LGMD1, accounting for 10%) and autosomal recessive (AR) (LGMD2, accounting for 90%) (4). Limb-girdle muscular dystrophy type R2 (LGMD R2) often exhibits early onset and rapid progression, with early weakness and atrophy of the pelvic and shoulder girdle muscles (5). LGMD R2 is caused by homozygous or compound heterozygous mutations in the DYSF located at 2p12-14, resulting in reduced expression or loss of function of the DYSF protein (6). Although the genetic and clinical features of LGMD R2 have been increasingly recognized, its implications for pregnancy remain largely unexplored. Reports linking LGMD R2 with adverse maternal and fetal outcomes are not published, and no clear guidance exists for clinical management.

Objective

To date, there have been no reports on the management of pregnancy in women with LGMD R2. Here, we report a case of a woman with LGMD R2 who had two pregnancies complicated by FGR. By describing the maternal complications, including FGR, preeclampsia, and ICP, as well as the progression of maternal neuromuscular symptoms, this report highlights the challenges of pregnancy management in women with LGMD R2 and underscores the need for multidisciplinary care and long-term follow-up. We present this article in accordance with the CARE reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-21/rc).

Case presentation

The woman was diagnosed with LGMD R2 at 20 years old, with a DYSF mutation (c.828-829delCG and c.2864+5G>A), which manifests as progressive limb muscle weakness. She was able to perform basic daily activities independently when she first became pregnant at age 26. Due to LGMD R2, she underwent genetic counseling before her first pregnancy, and her husband detected no pathogenic or likely pathogenic variants related to DYSF. The geneticist advised that the pregnancy could proceed normally. She took coenzyme Q10 to protect her heart before pregnancy and stopped during the preparation period. She was registered at West China Second University Hospital at 13 weeks of gestation and her fetal nuchal translucency (NT) value was measured as normal. The Down’s syndrome screening during the early and mid-stages of pregnancy was low risk. She experienced elevated transaminases in early pregnancy [alanine aminotransferase (ALT) 152 U/L, aspartate aminotransferase (AST) 133 U/L] and was advised to take the liver-protective drug ESSENTIALE by her neurologist, who suspected a possible association with LGMD R2, but the medication was not initiated. The comprehensive ultrasound at gestational age of 24⁺⁴ weeks showed good growth rate and no structural abnormalities. However, at gestational age of 29⁺⁶ weeks, the fetus was found to have growth restriction and she was admitted to the hospital 2 weeks later due to FGR [the fetal abdominal circumference below the 10^th percentile for gestational age (7)] revealed by a follow-up examination. Vital signs on admission: temperature (T), 36.4 ℃; pulse (P), 77 times/min; respiration (R), 20 times/min; blood pressure (BP), 114/68 mmHg. Physical examination: uterine height 25 cm, abdominal circumference 81 cm. During hospitalization, she was given Clexane to improve placental circulation, compounded amino acids to enhance nutrition, and underwent amniocentesis after consultation with the genetics department. However, she had recurrent nonreactive fetal non-stress test (NST) from 33⁺¹ weeks, and the fetal biophysical rating was consistently between 6–7 points several times. After admission, blood pressure increased progressively, and by gestational age of 33⁺⁶ weeks, she was diagnosed with pregnancy-induced hypertension (up to 165/102 mmHg). Two weeks after hospitalization, the uterine height was still 25 cm, the abdominal circumference was only 82 cm, and the ultrasound showed that the fetal diameter was less than the 5^th percentile of the same gestational week and oligohydramnios. Due to slow fetal growth, oligohydramnios and recurrent nonreactive fetal NST, the patient was concerned about poor fetal prognosis and requested termination of pregnancy at 34⁺¹ weeks (Table 1). When the amniocentesis results were not returned, the patient was fully informed of the risks and still opted for termination of pregnancy, so an intra-amniotic Rivanol injection was performed. The delivered infant weighed 1,448 g, which was below the 3^rd percentile for the same gestational age, and no obvious malformations were observed in appearance (Table 2). The results of amniocentesis after induction of labor showed no significant abnormalities in amniotic fluid chromosome microarray analysis and FGFR3 gene locus c.1138.

The patient conceived again 3 years later; by this time, her condition had worsened, and she required a wheelchair for mobility. The patient was registered at 15⁺¹ weeks of gestation and her fetal NT was normal, and a non-invasive DNA test showed low risk for trisomies-13, 18 and 21. Whole-exome sequencing analysis of the tissue of the previously induced fetus was performed after consultation with the genetics department, and no pathogenic or likely pathogenic variants associated with the disease phenotype were identified. The comprehensive ultrasound examination showed good fetal growth rate and no structural abnormalities. Due to a history of FGR and severe preeclampsia in the first pregnancy, aspirin 75 mg orally for prevention of preeclampsia was started after registration. During hospitalization, Clexane (enoxaparin sodium 4,000 U subcutaneously once daily) was administered from 31⁺⁶ to 35⁺¹ weeks of gestation to improve placental circulation (Table 1). At 34⁺⁵ weeks of gestation, the patient developed bilateral lower extremity edema and was admitted to the hospital at 35⁺¹ weeks when elevated blood pressure (152/94 mmHg) was detected during routine checkup. Admission vital signs: T, 36.7 ℃; P, 90 beats/min; R, 20 beats/min; BP, 133/93 mmHg. After admission, magnesium sulfate was given to relieve spasm and dexamethasone to promote fetal lung maturation. The patient was diagnosed with severe pre-eclampsia at 35⁺⁵ weeks of gestation (up to 167/110 mmHg). In second pregnancy, the patient again presented with a mild elevation of transaminases in early pregnancy (12 weeks), at the time of registration, routine laboratory tests revealed elevated liver enzymes: ALT 65 U/L (<49 U/L) and AST 57 U/L (<40 U/L). Her liver function was closely monitored during pregnancy, the transaminase levels increased progressively, reaching ALT 261 U/L and AST 227 U/L at 35⁺¹ weeks, and further rising to ALT 414 U/L, AST 332 U/L, with total bile acids (TBA) 48.7 µmol/L at 35⁺⁶ weeks, the diagnosis of severe ICP was considered after completion of exclusion tests such as Epstein-Barr virus (EBV), cytomegalovirus immunoglobulin M (IgM), hepatitis markers and hepatobiliary, pancreatic and splenic ultrasound. The patient was delivered by cesarean section at 36⁺¹ weeks due to “severe preeclampsia, severe ICP, and FGR”, and a female live baby was delivered successfully, weighing 2,180 g, less than the 10^th percentile of the same gestational week (Table 2). Intraoperatively, the patient’s abdominal wall was seen to be pale and brittle, and the operation was difficult but successful. She was discharged on the fifth postpartum day. During pregnancy, the patient’s LGMD R2 symptoms worsened. After giving birth, the patient was unable to provide proper care for the child due to the worsening of her condition (Figure 1). Now, the mother experienced mild progression of symptoms; she is currently wheelchair-dependent but can move short distances with support or assistance. Her child is in good health, now 2 years and 9 months old, with developmental milestones comparable to peers.

Figure 1 Timeline of the patient. Created in BioRender. Min D. [2025]. Available at https://BioRender.com/ch75r1r. FGR, fetal growth restriction; ICP, intrahepatic cholestasis of pregnancy; LGMD R2, limb-girdle muscular dystrophy type R2; NST, non-stress test; NT, nuchal translucency.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Key findings

This case report describes a 26-year-old woman diagnosed with LGMD R2 due to DYSF mutations, who experienced two pregnancies complicated by FGR, severe preeclampsia, and, in the second pregnancy, severe ICP. In her first pregnancy, the patient developed FGR and severe preeclampsia, leading to termination of pregnancy at 34⁺¹ weeks due to poor fetal prognosis, with the delivered infant weighing 1,448 g (below the third percentile). The second pregnancy, 3 years later, was similarly complicated by FGR and severe preeclampsia, with additional severe ICP, resulting in a cesarean delivery at 36⁺¹ weeks of a live female infant weighing 2,180 g (below the 10th percentile).

Because of the low prevalence of LGMD, there are no studies or specific guidelines on managing women with LGMD R2 during pregnancy to achieve good perinatal outcomes. However, these pregnant women still face problems related to pregnancy and delivery, so perinatal management needs to be further explored. The primary concern for women with LGMD R2 is whether their children will inherit the disease. In the study by Moore et al. (8), women with inherited neuromuscular disease may choose to terminate their pregnancy because of worsening hypotonia or concerns about the inheritance of the disease. In this case, the patient underwent termination of pregnancy at late gestation due to multiple obstetric complications when the amniocentesis results were not yet returned, but ultimately the amniotic fluid chromosome microarray analysis and FGFR3 gene locus c.1138 did not show any significant abnormalities. Even if the patient continued the pregnancy and delivered this fetus, it is still not completely certain whether the fetus had an adverse prognosis. The patient had a strong need to have a child in the second pregnancy. Although FGR with ICP and severe preeclampsia still occurred in the second pregnancy, the patient chose to have the child in combination with the results of genetic testing in the first pregnancy and the prenatal diagnosis in the current pregnancy, and the child survived the birth in good health. However, no reports directly link LGMD R2 with recurrent FGR, preeclampsia, or ICP, making this case relatively novel. The rarity of this combination of obstetric complications in the context of LGMD R2 underscores the need for further investigation into potential associations between the underlying genetic mutations, maternal disease progression, and adverse pregnancy outcomes. Although the baby weighed only 2,180 g, which is less than the 10^th percentile at the same gestational week, after 2 years of follow-up, the baby’s growth has now caught up with that of a normal-weight baby. The prognosis in this case is good and is considered to be related to the absence of the causative gene in the patient’s husband. Since LGMD R2 is AR inheritable disease, it is crucial for LGMD R2 women to complete their husband’s relevant genetic tests when preparing for pregnancy. In this case, the patient experienced a significant worsening of hypokinesia after each pregnancy (the patient complained that the rate of worsening was approximately twice the normal rate). Patients with early-onset and progressive myopathy are more likely to experience significant aggravation of symptoms during gestation compared to those with stable disease courses (9). Therefore, women with this condition should carefully consider terminating pregnancy after each conception to avoid exacerbation of the disease with multiple pregnancies.

LGMD is not an indication for cesarean delivery. Regarding the timing and mode of delivery for LGMD patients, some studies have reported that LGMD patients can deliver vaginally (10,11). Maternal and fetal comorbidities still need to be considered when deciding on the method and timing of delivery. This patient presented with FGR, severe preeclampsia, and severe ICP, so a combination of factors led to a cesarean section (12). Intraoperatively, the abdominal wall and uterine muscle tissue were seen to be pale and brittle, and the muscle tissue changes were possibly related to LGMD (13).

Strengths and limitations

The strength of our report lies in its uniqueness: to our knowledge, this is the first detailed description of a woman with LGMD R2 who experienced two consecutive pregnancies, both complicated by severe FGR and preeclampsia. This case provides rare longitudinal insights into maternal and fetal outcomes in the context of neuromuscular disease, contributing to the limited literature in this area.

As a single case report, the findings cannot be generalized to all patients with LGMD R2 owing to disease rarity and phenotypic heterogeneity. The association between LGMD R2 and ICP observed here should be interpreted with caution, as causality cannot be inferred from a single patient. Nevertheless, the observations remain clinically relevant, as they underscore potential risks and management challenges in this specific patient population. This case was analyzed retrospectively and lacks long-term follow-up of maternal neuromuscular progression, which restricts insights into the sustained impact of pregnancy. Possible mechanisms may involve placental insufficiency associated with systemic muscle dysfunction, although this remains speculative and warrants further study. The absence of comparative data with unaffected pregnancies or other LGMD subtypes limits the ability to determine whether these complications are LGMD R2-specific.

Comparison with similar research

LGMD R2 is a rare genetic muscle disease that develops with progressive loss of muscle strength in the extremities as the main clinical manifestation (14,15). It has been reported in the literature that women with hypotonia worsen after pregnancy and are unable to care for their children after delivery. These women may experience unpredictable maternal and child comorbidities or disease progression in preparation for and during pregnancy, bringing uncertainties to a woman’s fertility (2,16).

Explanations of findings

In this case, the patient presented with FGR in both pregnancies. The etiology of FGR is varied, and there is a lack of studies on LGMD R2 directly contributing to FGR (7). The patient’s low pre-pregnancy weight [body mass index (BMI)] in both pregnancies may have contributed to post-pregnancy FGR, and LGMD affects the patient’s metabolism causing her to be underweight (17), which is also a potential factor. In addition, FGR may serve as the first clinical manifestation of severe preeclampsia. Literature has revealed that females with genetic neuromuscular disorders have a higher incidence of pregnancy-induced hypertension compared to normal pregnant women (8). Reports have shown that patients with LGMD have a significantly increased risk of developing pregnancy-induced hypertension, preeclampsia, and other related complications during pregnancy (18). We found that this patient had FGR as the first clinical manifestation in both pregnancies, with FGR occurring at 29⁺⁴ and 31⁺⁶ weeks of gestation and eventually diagnosed as severe preeclampsia at 33⁺⁶ and 35⁺⁵ weeks of gestation, respectively. Pregnancy-induced hypertension in pregnant women has a complex background, especially in the case of preeclampsia-eclampsia, which exhibits heterogeneity in the etiology and pathogenesis, non-parallelism of pathological changes and clinical manifestations through multiple pathways (19). It has a multifactorial, multi-mechanism, and multi-pathway etiology syndrome. Therefore, the mechanisms and pathways by which LGMD promotes hypertension in pregnancy deserve further in-depth study. Because the patient was at high risk for preeclampsia: severe FGR in previous pregnancies and severe preeclampsia, the patient was given oral aspirin as recommended by national guidelines for the prevention of preeclampsia after registration of second pregnancy. The gestational ages at which the first symptom of FGR appeared and severe preeclampsia in the second pregnancy was diagnosed were both two weeks later than in the first pregnancy, and the degree of FGR was less than in the first pregnancy, suggesting that aspirin still has a preventive effect on preeclampsia caused by this type of disease (20). In addition, it remains worth exploring other measures to prevent or reduce disease. Most reports on pregnancy outcomes with this disease have focused on the issue of preterm birth, but the exact cause and week of gestation of preterm birth are unknown. The fetus in this case was delivered at 36⁺¹ weeks of gestation and was a late preterm infant, which was also medically preterm due to FGR, severe maternal preeclampsia and severe ICP. However, the prognosis is good for a nearly full-term preterm infant.

Implications and actions needed

The patient’s two pregnancies started with mildly elevated transaminases in early pregnancy, which the neurologist considered to be related to LGMD R2 disease (21). However, during the second pregnancy, the patient experienced pruritus along with a further increase in liver enzymes and abnormal bile acid levels in late pregnancy. The diagnosis of severe ICP was considered after completion of exclusion tests such as EBV, cytomegalovirus IgM, hepatitis markers, and hepatobiliary, pancreatic, and splenic ultrasound. The association of this disease with ICP has not been reported in the literature, and it is still worth exploring whether the occurrence of ICP is related to this disease (22).

Clinical implications

Pregnancy management in women with LGMD R2 should follow an individualized, multidisciplinary approach involving neurologists, obstetricians, cardiologists, and anesthesiologists. Preconception evaluation of neuromuscular, cardiac, and respiratory function, together with genetic counseling, is essential for risk stratification and delivery planning. During pregnancy, close maternal-fetal surveillance and guideline-based prevention of preeclampsia (e.g., low-dose aspirin) are recommended. The use of low-molecular-weight heparin (LMWH) may be considered on a case-by-case basis when placental insufficiency is suspected. Such coordinated care may help reduce complications and improve outcomes for both mother and child in this rare condition.

Conclusions

Patients with LGMD R2 are more difficult to diagnose until they are symptomatic. When symptoms appear, the disease deteriorates with age, making the timing of pregnancy very important. Pregnancy is recommended during the early, stable stage of the disease. Up to now, there are no specific guidelines or expert consensus on the management of LGMD patients before, during and after pregnancy. Combined with our patient and literature review, these patients need to be evaluated by a neurologist before pregnancy and followed regularly during pregnancy. Patients should undergo genetic counseling before pregnancy preparation and improve husband-related examinations. During pregnancy, regular obstetric monitoring and strengthened guardianship are essential, with special attention to complications such as hypertensive disorders and FGR, and preventive measures such as low-dose aspirin may be beneficial. Through integrated multidisciplinary management before, during, and after pregnancy, a good maternal and child outcome can be expected.

Acknowledgments

We sincerely appreciate the valuable information provided by the patient and thank her for her contribution to scientific research.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-21/rc

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-21/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-21/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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