A Genotyped Case of Townes–Brocks Syndrome with Absent Pulmonary Valve Syndrome from Turkey

Abstract

Townes–Brocks syndrome (TBS) is a rare syndrome characterized by triad of anal, ear, and thumb anomalies. Further malformations/anomalies include congenital heart diseases, foot malformations, sensorineural and/or conductive hearing impairment, genitourinary malformations, and anomalies of eye and nervous system. Definitive diagnosis for TBS is confirmed by molecular analysis for mutations in the SALL1 gene. Only one known case of TBS with absent pulmonary valve syndrome (APVS) has been previously described to our knowledge. Here, we report a newborn diagnosed with TBS with APVS and tetralogy of Fallot (TOF) who was found to carry the most common pathogenic SALL1 gene mutation c.826C > T (p.R276X), with its surgical repair and postoperative follow-up. To our knowledge, this is the first genotyped case of TBS from Turkey to date. TBS should be suspected in the presence of ear, anal, and thumb malformations in a neonate. If a patient with TBS and TOF-APVS needs preoperative ventilation within the first months of life, this implies prolonged postoperative intubation and increased risk of mortality.

Introduction

Townes and Brocks first described in 1972 a malformation syndrome, now known as Townes–Brocks syndrome (TBS, OMIM #104780), characterized by anal, hand, foot, and ear abnormalities. ¹

Background

The estimated prevalence of TBS in the general population is approximately 1 in 250,000 live births. ² TBS is inherited in an autosomal dominant manner and results from mutations of the developmental gene spalt-like transcription factor 1 ( SALL1 ). ³ The proportion of cases caused by de novo pathogenic variants is estimated at 50%. Each child of an individual with TBS caused by a SALL1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. ⁴ Bozal-Basterra et al ⁵ proposed that TBS is a potential ciliopathy-like disorder with symptoms caused by truncated SALL1 interfering with the normal function of cilia and/or centrosomal-related proteins.

Clinical Manifestation

TBS is a rare inherited malformation syndrome characterized by triad of anal, ear, and thumb anomalies. Other anomalies such as renal impairment with or without structural abnormalities, congenital heart diseases, foot malformations, genitourinary malformations, and sensorineural and/or conductive hearing impairment may occur. Rare eye anomalies can include iris coloboma, microphthalmia, and cataract. Central nervous system anomalies such as Duane's anomaly, Arnold–Chiari malformation type 1, intellectual disability, and behavioral problems can be detected. Growth retardation may also occur. ^{2 3 4} Absent pulmonary valve syndrome (APVS) is a rare form of congenital heart diseases, which is present in 3 of 10,000 live births. It leads to hypoplastic pulmonary valve frequently with the dilatation of the pulmonary artery and its branches. Most of APVS cases are related with tetralogy of Fallot (TOF) and the incidence of APVS is 3 to 6% in patients diagnosed with TOF. ⁶

Diagnosis

The diagnosis of TBS is made by evaluating the following major and minor criteria. Major criteria include imperforate anus or anal stenosis, dysplastic ears (overfolded superior helices, microtia), and typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius. Minor criteria include sensorineural and/or conductive hearing impairment, foot malformations (syndactyly, overlapping toes, missing toes, pes planus, club foot, fused metatarsals), renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease. It is sufficient to have three major criteria for the diagnosis of TBS. If only two major criteria are present, the occurrence of minor criteria without radius hypoplasia or cleft lip/palate further support the diagnosis. ^{4 5 7} Definitive diagnosis for TBS is confirmed by molecular analysis for mutations in the SALL1 gene. The most common pathogenic variant is c.826C > T (p.Arg276Ter) and this mutation causes a severe phenotype in all known instances. ^{4 5 8} The diagnosis of APVS-TOF is made by echocardiography showing dilated pulmonary arteries and TOF. ⁹

Management

Anal anomalies may require emergency surgery. Early treatment should be initiated for significant hearing loss. Thumb malformations may require surgery such as removal of additional thumbs. Congenital renal anomalies and impaired renal function may require closed monitoring, hemodialysis, or kidney transplantation. Surgery or medical treatment should be considered for congenital heart defects. Respiratory support may be administered for pulmonary impairment caused by heart defects. ^{3 8 9 10 11}

Prognosis

The prognosis of the disease varies depending on the body part affected and the severity of symptoms. Generally, the prognosis is good if anal atresia is treated early. In the presence of heart and kidney involvement, the prognosis may be poor and there may be increased risk of mortality. ^{3 4 11}

Case Report

A singleton, female infant born to a 26-year-old mother from her second pregnancy via planned, repeated caesarean section at 39 weeks of gestation was admitted to the neonatal intensive care unit due to TOF, which was diagnosed antenatally. Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. On admission, her weight was 2,810 g (10–50th percentile), the length was 49 cm (10–50th percentile), and the head circumference was 36 cm (50–90th percentile). She was born to nonconsanguineous parents. On physical examination, imperforate anus with rectoperineal fistula, microcephaly, satyr's ear, and mildly protruding dysplastic ears with overfolding of superior helices were detected ( Fig. 1 ). She had preaxial polydactyly on the right hand and triphalangeal thumb on the left hand, confirmed by X-ray examination ( Fig. 2 ). The left foot had talipes equinovarus deformity. She had a grade 3/6 pansystolic murmur on cardiac auscultation at the mesocardiac region. Ophthalmological examination was normal. An echocardiographic examination revealed APVS-TOF and dilated pulmonary arteries. Cranial ultrasonography was unremarkable. Abdominal ultrasonography showed increased echogenicity of the renal parenchyma and mildly pelvicalyceal dilatation in both kidneys. Serum creatinine level was 1.22 mg/dL at the third day of life and 1.11 mg/dL at the fourth day of life (normal range for serum creatinine level: 0.4–0.9 mg/dL). Thyroid profile and ultrasonography were normal. The brainstem evoked response audiometry test revealed bilateral sensorineural hearing loss.

Fig. 1.

( A ) Satyr's ear with overfolding of superior helices. ( B ) Mildly protruding dysplastic right ear.

Fig. 2.

( A ) Triphalangeal thumb on the left hand and ( B ) preaxial polydactyly on the right hand. X-ray examination of the hands showing ( C ) triphalangeal thumb on the left and ( D ) preaxial polydactyly on the right.

The patient presented clonic seizure in right upper and right lower limbs on the 45th day of life. Levetiracetam was initiated. Control cranial ultrasonography was normal. Electroencephalography could not be performed due to the poor clinical condition of the patient.

In light of all these findings, the patient was clinically diagnosed with TBS. As a result of the SALL1 whole gene sequence analysis, a previously defined c.826 C > T pathogenic mutation was also detected. The detected point mutation was confirmed by Sanger analysis. It was observed that the detected change was reported as pathogenic in various in-silico databases. The diagnosis was finalized because the detected mutation was previously observed in a large number of TBS patients in more than one ethnic group. An ultrasound of the mother showed bilateral multicystic dysplastic kidney. Her father and 6-year-old brother were unaffected. Pedigree of the family is shown in Fig. 3 .

Fig. 3.

Pedigree of the family. Arrow indicates the proband.

The patient was intubated due to respiratory distress and she was placed on mechanical ventilation on the 60th day of life. A chest X-ray showed cardiomegaly. Computed tomography of the chest demonstrated enlarged right and left pulmonary arteries causing severe bilateral bronchial compression ( Fig. 4 ).

Fig. 4.

( A ) Axial computed tomography image of the chest showing enlarged right and left pulmonary arteries. ( B ) Flexible bronchoscopy showing severe compression of bilateral bronchi at the level of carina. ( C ) Intraoperative photograph showing aneurysmal enlarged right pulmonary artery. RPA, right pulmonary artery.

The infant underwent surgical repair of TOF-APVS and dilated pulmonary arteries on the 85th day of life. Under general anesthesia, flexible bronchoscopy was performed. Severe compression of bilateral bronchi at the level of carina was observed ( Fig. 4 ). After sternotomy, agenesia of thymus and presence of aneurysmal huge pulmonary arteries were detected ( Fig. 4 ). The operation was completed under moderate hypothermia using cardiopulmonary bypass. Cardiac arrest was ensured by HTK (histidine-tryptophan-ketoglutarate) crystalloid solution (Custodiol). Malalignment ventricular septal defect was closed with Dacron patch using transatrial approach. Meanwhile, a part of the infundibular septal muscle was transected. Mean pulmonary artery was incised toward both branch pulmonary arteries. Bilateral branch pulmonary arteries were constricted by extracting the anterior portion and closing primarily. Finally, bovine jugular vein conduit in 12-mm diameter (Contegra) was sutured between pulmonary bifurcation and right ventricular outflow tract. Postoperatively, low-dose inotropic medication was applicated for 48 hours. Patient could not be extubated until postoperative day 29 due to high ventilation pressures under mechanical ventilation. Due to extended intubation period, tracheotomy was performed. However, the patient could not be extubated during the follow-up in the intensive care unit and she died at the 6th month of life due to pneumonia and sepsis.

This research was managed in accordance with the Declaration of Helsinki. The patient's parents gave their informed consent for the molecular genetic analysis of the patient and the publication of the patient data and photos.

Discussion

Since our patient had three major criteria and most of the minor criteria, the diagnosis of TBS was made clinically. Definitive diagnosis of TBS in our patient was made as a result of the SALL1 mutation analysis, and a previously defined c.826 C > T pathogenic mutation was detected. To our knowledge, this is the first genotyped case of TBS from Turkey to date.

In patients with TBS, congenital heart defects may be seen in 50% of patients with the common R276X mutation and 12 to 25% of patients with other SALL1 mutations. These heart defects include atrial septal defect, ventricular septal defect, TOF, truncus arteriosus, pulmonary valve atresia, and persistent ductus arteriosus. ^{3 4 8 12} R276X mutation is the only SALL1 mutation known to be associated with TOF. APVS is a rare congenital anomaly that occurs in 3 to 6% of patients with TOF. ¹³ APVS leads to pulmonary regurgitation and aneurysmal dilatation of the pulmonary arteries, which results in compression of the tracheobronchial tree and thus significant respiratory compromise. ¹⁴ Patients who present with respiratory symptoms within the first 3 months of life typically need surgery to correct abnormalities of TOF and to resolve the airway compression by revision of the enlarged pulmonary arteries. ¹⁵ The need of preoperative ventilation for respiratory distress means severe airway compression by the aneurysm of the pulmonary arteries. The requirement of preoperative ventilation implies prolonged postoperative intubation and increased risk of mortality. ⁹ This patient confirms that there is a high correlation between requirement of preoperative ventilation and mortality. Previously, only one case of TBS that was accompanied by APSV was described. ¹² In this case, we detected TOF-APVS and dilated pulmonary arteries causing bilateral bronchial compression. We attributed the need of early surgery and prolonged postoperative intubation to the requirement of preoperative mechanical ventilation due to severe respiratory distress. We considered that this heart defect might be associated with R276X mutation.

Genitourinary anomalies such as renal agenesis, renal hypoplasia, polycystic kidneys, dysplastic kidneys, posterior urethral valves, vesicoureteral reflux, and meatal stenosis may be observed in patients with TBS, as well as functional impairment of kidney with or without structural abnormalities (42% of individuals). ^{4 10 11} In the present case, we detected increased renal parenchymal echogenicity and mildly pelvicalyceal dilatation in both the kidneys. Transient renal functional impairment occurred within the first 4 days of life.

Brain neurons are particularly sensitive to SALL1 mutations. ¹⁶ Therefore, central nervous system abnormalities such as intellectual disability (∼10%), mental retardation, behavioral problems, cranial nerve palsy, and hypoplasia of corpus callosum may be observed in patients with TBS. ^{4 12 17} Botzenhart et al ¹⁷ reported a child with TBS who suffered from seizures. Our patient had clonic seizure, although imaging of her central nervous system was normal.

Clinical ideas about the disease can be obtained with hand and wrist radiography such as pseudoepiphyses of the second metacarpal, fusion of triquetrum and hamate, and absent triquetrum and navicular bones. In our patient, radiographs were taken for hand and wrist bone, but since no ossification had occurred, clinically supportive findings were not obtained from this area. ^{4 7 16}

Features of TBS can overlap with other genetic syndromes. Goldenhar's syndrome usually presents with incomplete development of the nose, soft palate, lip, and mandible, but usually no upper limb or anal malformations and no overlapping toes. Okihiro's syndrome has Duane's anomaly and radial ray defects, but rarely hearing loss and renal anomalies. Vertebral anomalies, anal atresia, cardiovascular anomalies, tracheoesophageal fistula, renal and/or radial anomalies, limb defects( VACTERL) association may present with vertebral abnormalities and tracheoesophageal fistula without ear anomalies or deafness; however, severe vertebral defects and tracheoesophageal fistula are not observed in TBS patients. Branchiootorenal syndrome is characterized by dysplastic ears, hearing loss, or genitourinary malformations, but no thumb or anal anomalies. ^{3 4 18}

Conclusion

TBS should be suspected in the presence of ear, anal, and thumb malformations in a neonate. Further investigations should be performed for hearing loss and cardiac and genitourinary system anomalies, and finally genetic testing should be done to confirm the diagnosis. If a patient with TBS and TOF-APVS needs preoperative ventilation within the first months of life, this implies prolonged postoperative intubation and increased risk of mortality.

Funding Statement

Funding R. B. acknowledges funding by grants BFU2017–84653-P (MINECO/FEDER, EU), SEV-2016–0644 (Severo Ochoa Excellence Program), 765445-EU (UbiCODE Program), and SAF2017–90900-REDT (UBIRed Program).