Matthew-Wood Syndrome in Monochorionic, Diamnionic Twins

Abstract

Matthew-Wood syndrome represents a rare genetic disorder characterized by diaphragmatic defects, pulmonary hypoplasia, micro- or anophthalmia, and cardiac defects. Most cases are lethal with very few infants living beyond a few years of life. Siblings with this diagnosis have been reported but never twins. In this article, we provided a review and discussion of this syndrome following its presentation in monochorionic, diamnionic twin females.

Introduction

Matthew-Wood syndrome (MWS) or syndromic microphthalmia-12 or 9 or pulmonary hypoplasia, diaphragmatic hernia, anophthalmia, cardiac (PDAC) defect represents an extremely rare, genetic disorder characterized by diaphragmatic defects, pulmonary hypoplasia, micro- or anophthalmia, growth retardation, and cardiac defects. Various pathogenic variants have been associated with this disorder. ¹ There have been reported cases of siblings with this syndrome but never of twins. We reported a case of monochorionic, diamnionic twin females that demonstrated clinical features consistent with this syndrome and were later found to have a likely pathogenic variant in the RARB gene. To our knowledge, this is the first reported case of twins diagnosed with this rare genetic syndrome.

Background

MWS is a rare, genetic disorder with epidemiological data noting only a handful of reported cases. The combination of diaphragmatic defects, pulmonary agenesis, microphthalmia or anophthalmia, and growth retardation should alert the clinician of this diagnosis. ² Two cases thus far have showcased siblings: one with two siblings ² and one with three siblings. ³ However, no case reports to date have included twins.

Clinical Manifestations

The cardinal features of this syndrome include pulmonary agenesis, microphthalmia, diaphragmatic defects, and intrauterine growth retardation. ² Prior reported cases of this syndrome describe anophthalmia, microphthalmia, and intellectual disability in 80 to 99% of cases with cardiovascular abnormalities and diaphragmatic hernias seen in 30 to 79%. ² However, not all the reported cases associated with MWS describe all the associated anomalies occurring together. Case reports have demonstrated findings ranging from unilateral or bilateral anophthalmia with associated hypoplasia of either the right, left, or both lungs or none at all. ⁴ Most, but not all, had some form of diaphragmatic defect with over half having associated cardiac anomalies. Pulmonary vascular abnormalities were not persistently present, and de novo variants were most likely indicated as the cause.

A brief overview of the various features that can be encompassed within the spectrum of MWS is summarized in Table 1 and compared with the cases that we observed. Including our two cases, there are 15 cases with a male: female ratio of 1.1:1.

Table 1. Clinical characteristics of Matthew-Wood syndrome: current case report vs reported cases ^{3 4 5 6 7 8} .

Characteristic (# of cases where present; if applicable)	Current cases (2)	Reported cases (13)
Gender	Female (2)	Male (8) and female (5)
Dysmorphic facial features	Frontal bossing, flat nasal bridge, low set ears, and high-arched palate.	Wide nasal bridge, low set ears, recessed orbits, barely opened palpebral fissures, narrow nose, short upper lip, micrognathia, brachycephaly, short prominent maxilla, broad nasal root, fused eyelids, cleft soft palate, and narrow palpebral fissures.
Ocular manifestations	Bilateral anophthalmia	Bilateral anophthalmia, bilateral microphthalmia, and left microphthalmia
Pulmonary manifestations	Pulmonary hypoplasia with persistent pulmonary hypertension	Pulmonary hypoplasia, pulmonary agenesis, abnormal lung lobations, bilateral unilobular lungs, and normal lung structure and function
Diaphragmatic defects	Right-sided diaphragmatic hernia (1) Left-sided diaphragmatic hernia (1)	Left diaphragmatic eventration (3) Right-sided eventration (1) Left-sided diaphragmatic hernia (1) Right-sided diaphragmatic hernia (2) Bilateral hernia (1) Hypoplastic diaphragm a (1)
Congenital heart disease	Hypoplasia of the left ventricle, mitral regurgitation, dextroposition, and hypoplasia of the right pulmonary artery.	Patent ductus arteriosus, atrial septal defect, single ventricle with hypoplastic left atrium, absent ductus arteriosus, overriding aorta, ventricular septal defect, hypoplastic left atrium, enlarged pulmonary trunk, hypoplastic right ventricle and tricuspid valve, pulmonary valve atresia, bicuspid aortic valve, absent ductus arteriosus, small pulmonary veins, coarctation of the aorta, and abnormal branching of the pulmonary arteries.
Other abnormalities	Right-sided hydronephrosis, bilateral perilobar nephroblastomatosis, bile ductular proliferation with cholestasis, and extramedullary hematopoiesis.	Left renal pelviectasis, subarachnoid hemorrhages intraventricular hemorrhages, hypoplastic spleen, bicornate and hypoplastic uterus, right and left kidney agenesis, malrotation of the bowel, accessory spleens, ambiguous genitalia, micropenis, hypoplastic bifid scrotum, inguinal hernias, severe subglottic laryngeal stenosis, ureter atresia, and ectopic pancreas.

^aNot reported in four cases.

Diagnosis

Genetic causes of this syndrome have been most commonly found to be due to pathogenic variants in both the STRA6 and RARB genes, both recessive, and recessive and dominant in nature, respectively. However, these mutations are not necessary for the syndrome to occur. ⁴

Management

Care of infants with MWS consists of routine management of diaphragmatic defects and congenital heart disease. Evaluation by a pediatric ophthalmologist should occur during the neonatal period. Survival depends on the degree of pulmonary hypertension, pulmonary hypoplasia, and whether the cardiac defect is amenable to surgery.

Prognosis

Most cases reported with this syndrome have been fatal with very few infants living beyond the first year of life. One report described an infant with dysmorphic features, anophthalmia, and cardiac defects surviving until 14 years, ⁵ while another reported an infant with bilateral microphthalmia and left diaphragmatic hernia surviving until 9.5 years. ³ Infants surviving beyond the first year of life have a very high risk for significant intellectual disabilities.

Case Presentation

The infants were identical, female monochorionic, diamnionic twins born at 34 ^3/7 weeks via emergent cesarean section under general anesthesia. The mother had presented with premature labor with premature rupture of membranes with twin B being transverse. They were born to a gravida 4, para 4 mother with negative serologies although unknown group B strep status. Prenatally, both twins were diagnosed with diaphragmatic abnormalities, echogenic bowel, and orbital malformations with twin B having polyhydramnios. Twin A was felt to have a diaphragmatic eventration, while twin B was felt to have a diaphragmatic hernia with a lung-to-head ratio of 1.25:1.5. Cell-free DNA testing was felt to be low risk, and fetal echocardiograms did not demonstrate any obvious structural heart disease. Birth weight for twin A was 1.760 kg (12.3%), length 44 cm (41.7%), and head circumference 30.0 cm (24.8%); twin B weighed 1.750 kg (11.9%) with a length of 40.0 cm (4.2%) and head circumference of 30.5 cm (36.7%).

Both twins were immediately intubated after delivery due to concerns for diaphragmatic hernias as noted prenatally. APGARS were 4 and 8 for twin A and 7 and 8 for twin B, at 1 and 5 minutes, respectively. The twins were taken to the neonatal intensive care unit where further evaluations and care were performed.

Radiologic imaging of the twins confirmed diaphragmatic hernias (twin A on the right and twin B on the left). Physical examination of the twins demonstrated frontal bossing with flat nasal bridges, low set ears, high-arched palates, suspected anophthalmia, and clenched hands.

Both infants had symptoms of respiratory distress syndrome and were given one dose of surfactant as well as placed on high-frequency oscillatory ventilation prior to surgery. Cardiac evaluations demonstrated elevated pulmonary pressures in both infants with stretched patent foramen ovales. Twin A had mild hypoplasia of the left ventricle and moderate tricuspid regurgitation, while twin B had dextroposition, elevated pulmonary pressures with mild hypoplasia of the left ventricle, and moderate hypoplasia of the right pulmonary artery. Abdominal ultrasound demonstrated right-sided hydronephrosis for twin A and left-sided hydronephrosis for twin B. Ophthalmologic examinations demonstrated bilateral anophthalmia for both twins.

Due to the constellation of findings, concerns were raised for MWS with clinical genetic evaluations and testing performed shortly after birth. Chromosome and microarray testing demonstrated normal 46 XX females, but further genetic testing proved positive for the aforementioned syndrome with a novel pathogenic variant noted.

Despite concerns for a suspected genetic syndrome, the parents desired surgical repair of the diaphragmatic hernias to provide them with the best opportunity for life. The infants were taken to surgery at 1 week of life for repairs of suspected diaphragmatic hernias. Twin A was found to have a large defect on the right with a moderately sized diaphragm anteriorly, but no diaphragm posteriorly. Twin B was found to have no diaphragm on the left.

Despite surgical repair of the diaphragmatic hernias, the infants remained on aggressive ventilation support raising concerns for significant pulmonary hypoplasia and persistent pulmonary hypertension. Their condition did not improve, and support was withdrawn on 29th day of life with both infants expiring shortly after the removal of support.

The blood sample for NewbornDx Advanced Sequencing Evaluation that was sent to Athena Diagnostics for twin B (only one sample was sent due to the twins being identical) demonstrated a likely pathogenic de novo variant (c.881C > T; p.Gly294Val) in the RARB gene consistent with a diagnosis of microphthalmia syndrome 12 (MIM;615524), MWS. These findings were discussed with the family prior to the removal of support.

Autopsies were performed, and twin A was found to have bilateral anophthalmia, repaired right-sided diaphragmatic hernia with normally positioned lungs and no lobar division of the left lung, hypoplastic lungs with vascular congestion and focal areas of dilated lymphatics, mild left ventricular hypoplasia, patent foramen ovale, patent ductus arteriosus, bilateral perilobar nephroblastomatosis, bile ductular proliferation with moderate cholestasis, increased portal vein profiles, and normal locations of the uterus, bladder, and kidneys. Twin B was found to have bilateral anophthalmia, left-sided diaphragmatic hernia with normally positioned lungs with an incomplete division of the lobes bilaterally, hypoplastic lungs, mild left ventricular hyperplasia, patent foramen ovale, patent ductus arteriosus, extramedullary hematopoiesis with mild ductular proliferation, cholestasis, and normal positioning of the bladder and kidneys.

Discussion

Many conditions may be considered in the differential diagnosis of diaphragmatic hernia, microphthalmia/anophthalmia, and pulmonary hypoplasia whether in combination or isolation. With regard to the twins presented, the combination of dysmorphic facial features, diaphragmatic hernias, pulmonary hypoplasia, anophthalmia, and cardiovascular abnormalities strongly suggested a diagnosis of microphthalmia syndromic type 9 or 12, PDAC, or MWS. The cardinal features of this syndrome have been characterized by pulmonary agenesis, microphthalmia, diaphragmatic defects, and intrauterine growth retardation. ²

Prior reported cases of this syndrome describe anophthalmia, microphthalmia, and intellectual disability in 80 to 99% of cases with cardiovascular abnormalities and diaphragmatic hernias seen in 30 to 79% of the cases. ² However, not all the reported cases associated with MWS describe all the associated anomalies occurring together. Few case reports have demonstrated anything from unilateral and bilateral anophthalmia with associated hypoplasia of either the right, left, or both lungs or none at all. ⁴ Most, but not all, had some form of diaphragmatic defect with over half having associated cardiac anomalies. Pulmonary vascular abnormalities were not persistently present, and de novo variants were most likely indicated as the cause.

We reported the first set of twins noted to have dysmorphic features, anophthalmia, diaphragmatic hernias, hypoplastic lungs, cardiac abnormalities, and pulmonary vasculature congestion with focal areas of dilated lymphatics. All the main features of the syndrome were present with next-generation sequencing in proband and parents revealing the causative pathogenic variant to be a de novo missense substitution in the RARB gene. Parents were counseled that recurrence risk in future pregnancies would likely be low, less than 1%, but not zero, because of a small residual risk of gonadal mosaicism.

We presented this case of twins with MWS to highlight the first case of twins with this genetic diagnosis and to educate clinicians to be aware of this syndrome in infants with diaphragmatic defects and microphthalmia or anophthalmia. Thus far disruptions in two genes have been identified that result in PDAC: STRA6 and RARB. The STRA6 variants are biallelic in nature resulting in autosomal recessive inheritance. Inheritance in the RARB gene has been shown to be more complex. It can be inherited as autosomal recessive with biallelic pathogenic variants. However, clinically indistinguishable PDAC has also been shown to be caused by de novo heterozygous changes in a single, recurrent nucleotide, indicating a new autosomal dominant mutation. Srour et al pursued functional studies to demonstrate that the biallelic RARB variants resulted in the loss of function, whereas the de novo heterozygous change increased transcription several folds, suggesting a gain-of-function dominant negative effect. ⁶ It is possible that other, yet unidentified, genes also contribute to the PDAC phenotype, as some patients have been found to be negative for variants in both STRA6 and RARB. Genomic sequencing of both patients and parents will not only aid in refining the diagnosis but will also facilitate the determination of recurrence risk for future siblings. If parentally inherited homozygous or compound heterozygous pathogenic variants are found in the RARB or STRA6 gene s , then recurrence risk is 25% for each future pregnancy, compatible with an autosomal recessive condition. However, if a single de novo pathogenic change is found in the RARB gene, as in the case of these presumed monozygotic twins, then recurrence risk drops to less than 1%. Sending parental samples along with the neonates in next-generation sequencing techniques including genomic sequencing can also improve the diagnostic rate and facilitate rapid turnaround time. This will serve to guide families and providers in making management decisions for this complex condition.

Conclusion

In this article, we presented the first case of MWS in identical monochorionic, diamnionic twins. Both infants demonstrated clinical features consistent with this syndrome, and genetic testing confirmed the diagnosis. These cases highlight the severity of the syndrome and how confirming a diagnosis early in the neonatal period may assist with prognosis and clinical management, especially when surgery is required.