Abnormal liver function tests and improved survival in a child with splice mutation TARP syndrome

  1. Michael Lane 1,
  2. Nicholas M Allen 2 , 3 and
  3. Johannes Letshwiti 2
  1. 1 Paediatrics, National University of Ireland, Galway, Ireland
  2. 2 Paediatrics, Galway University Hospitals, Galway, Ireland
  3. 3 Paediatrics, University of Galway, Galway, Ireland
  1. Correspondence to Dr Johannes Letshwiti; jletshwiti@yahoo.co.uk

Publication history

Accepted:16 Mar 2023
First published:21 Mar 2023
Online issue publication:21 Mar 2023

Case reports

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Abstract

TARP (talipes equinovarus, atrial septal defect (ASD), Robin sequence, persistent left superior vena cava) syndrome is a rare X-linked disorder affecting the RBM10 gene. It was previously viewed as universally fatal in the early neonatal period, however, recent cases have shown patients surviving beyond this stage. We present a male toddler diagnosed with TARP syndrome due to a a previously unreported splicing mutation c.2295+1G>A in the RBM10 gene. At birth, he had an ASD and Robin sequence, two of the eponymous features, as well as other associated phenotypic features. During infancy, he had an extremely high alpha-fetoprotein, conjugated hyperbilirubinaemia and thrombocytopaenia, features not previously described in TARP syndrome. We discuss these findings as well as our patient’s survival past the neonatal period with special consideration to recent genotype–phenotypes correlations.

Background

TARP (talipes equinovarus, atrial septal defect (ASD), Robin sequence, persistent left superior vena cava) syndrome is a rare X-linked condition involving multiple organ systems caused by pathogenic variants in the RBM10 gene. Gorlin et al first described TARP syndrome in 1970, and RBM10 was identified as the causative gene in 2010.1 2 The RBM10 gene is involved primarily in RNA regulation both inhibiting cell proliferation and promoting apoptosis. RBM10 plays a role in cancer pathways, but has become increasingly more prominent neurodevelopmental and systemic disease with an increasing number of TARP syndrome cases reported.3 However, other than the initial 7 brothers described in 1970, only 19 cases of TARP syndrome have been published since 2010. Recent case reports have highlighted the variable phenotype seen in TARP syndrome. In all cases identified, there were severe cognitive, motor and language delays, brain malformations, airway/pulmonary abnormalities, failure to thrive (FTT) and dysmorphic features, all described as major features of the syndrome. Unfortunately, as TARP syndrome is rarely reported and neonatal mortality is high, the complete phenotypic spectrum, long-term manifestations and outcomes of affected individuals is poorly understood.4 Here, we report a case of TARP syndrome with increased alpha-fetoprotein (AFP), thrombocytopaenia and prolonged direct hyperbilirubinaemia presenting in the neonatal period and persisting into early infancy. These have not been reported previously and may represent potential features of TARP syndrome.

Case presentation

A Caucasian dichorionic-diamniotic twin male was born to non-consanguineous parents at 36 weeks gestation by emergency caesarean section due to severe intrauterine growth restriction, maternal gestational hypertension and pathological cardiotocography. His birth weight was 1.86 kg (0.4th centile), birth length was 36.5 cm (0.4th centile) and birth head circumference was 32.5 cm (25th centile). There was no family history of genetic or congenital disorders. He has five healthy male siblings.

Neonatal and early infancy period

This preterm neonate was admitted to the neonatal intensive care unit due to respiratory distress, low birth weight, hypoglycaemia (1.8 mmol/L) and central hypotonia. He was noted to have dysmorphic features including micrognathia, low-set ears, hypertelorism and a large fontanelle. He required continuous positive airway pressure from day of life (DOL) 1 to 6 and high flow nasal prongs from DOL 6 to 11. On DOL 1, he was noted to have thrombocytopaenia (76×109/L), which improved to 118×109/L by DOL 3 before falling to 28×109/L on DOL 4. He received a platelet transfusion, following which platelet count stabilised.

There was significant conjugated hyperbilirubinaemia (total 121 umol/L with direct 69 umol/L), alkaline phosphatase (425 U/L) and gamma-glutamyl transferase (483 U/L) seen at age 24 hours. Direct bilirubin peaked to 87 on DOL 16. Conjugated hyperbilirubinaemia persisted until 4 months of age without a clear alternative cause. Abdominal ultrasound did not show any liver or gallbladder abnormalities. Kidney ultrasound showed a crossed fused ectopic left kidney and an absent right kidney (figure 1). During this workup for a genetic/metabolic disorder, a markedly elevated AFP of 84 000 U/L was recorded on DOL 31. It decreased steadily to 15 000 U/L by DOL 63 and 5383 U/L at 4 months. No explanation was found for this elevated AFP.

Figure 1

Abdominal US showing elongated left kidney strongly suggestive of a crossed fused ectopic kidney. No significant renal dilation. US, ultrasound.

Investigations

Karyotyping, chromosomal microarray, TORCH screen, thyroid function tests, alpha-1 antitrypsin and extensive metabolic screen including serum amino acids, ammonia, urine organic acids, lactate and capillary gas pH were all normal. Total Very Long Chain Fatty Acids, 7-deoxycholesterol levels and transferrin isoforms sent to screen for peroxisomal disorders, Smith-Lemi-Opitz syndrome and congenital disorders of glycosylation, respectively, were all negative. The main differentials in this case, were Smith-Lemi-Opitz syndrome due to the noted congenital malformations, and Alagille syndrome due to the presence of renal malformations, atrial septal defect (ASD) and prolonged direct hyperbilirubinaemia, though the dysmorphic and neurological features noted were not typical. Other diseases with a clinical picture similar to TARP syndrome include Oral-Facial-Digital syndromes, Joubert syndrome, Ellis-van Creveld syndrome and short rib polydactyly syndromes.5

We ultimately established a diagnosis of TARP syndrome by exome sequencing which identified a novel (predicted pathogenic) de novo splicing variant/mutation (c.2295+1G>A) in RBM10. Novel mutations are common in TARP syndrome. Every non-related patient reported in the literature has had a unique mutation of the RBM10 gene. This is only the third case with a splicing mutation and the third reported de novo mutation.4 6

During the initial admission, echocardiography (ECHO) showed moderate ASD and left ventricular hypertrophy but no persistent superior left vena cava. Repeat ECHO at 2 years and 10 months was functionally normal with a ‘tiny’ residual ASD. This is an important prognostic factor as hypertrophic obstructive cardiomyopathy has been reported as ‘the potential life-limiting diagnosis for patients with TARP syndrome’.7

Course and progress from late infancy to toddler years

During infancy, our patient had multiple episodes of bronchiolitis, three of which required oxygen therapy and inpatient admission. The first episode at 4 months of age required intubation and ventilation for 1 week. He had recurrent respiratory tract infections including bronchiolitis, one of which required intubation at age 5 months. He was ultimately treated with long-term prophylactic azithromycin, bronchodilators and saline nebuliser. These infections, as well as an ongoing chronic wheeze, reflect the lung issues commonly seen in patients with TARP syndrome.4 At 8 months, home oxygen at night was commenced which significantly improved his quality of life. For the first 30 weeks, his weight and height were below the 0.4th percentile for gestational age indicative of FTT. He tolerated nasogastric feeding poorly and he was trialled on multiple formula feeds due to feeding intolerance. At 9 months, weight and height improved, increasing to the 25th centile by 14 months. A videofluoroscopy conducted at 14 months of age showed silent aspiration, delayed initiation of swallow and reduced airway closure. At this stage, he was established on puree feeds and small amounts of clear fluids. A gastrostomy tube was not indicated. Other new findings included a right inguinal hernia, bilateral myopia with peripapillary atrophy and mild hearing loss.

He had seizures from 2 months of age treated acutely with phenobarbitone and levetiracetam followed by maintenance levetiracetam. Other than one seizure at 7 months precipitated by concomitant bronchiolitis infection, he has remained seizure-free since 3 months of age and levetiracetam was stopped at 19 months. MRI Brain did not show any abnormalities and interictal EEG did not show any epileptiform activity.

The patient has global developmental delay as seen in TARP syndrome. He began to roll at 12 months old. He sat independently, crawled and had double-syllable babbling at 19 months. At 23 months, he was cruising and had five words. His developmental delay appears less severe relative to most cases of TARP syndrome.

Outcome and follow-up

The patient is alive to date and he is now in early childhood. He is walking with the support of a walker frame. He attends a special school three times a week. He is linked with the local Children’s disability network team and is under the care of the community paediatrician. He wears glasses. He has significant language delay. He wears hearing aids and had grommets inserted due to significant hearing impairment. He has no feeding issues but he does not take clear fluids due to the risk of aspiration. The child has not required hospitalisation due to respiratory infections in over a year to date.

Discussion

TARP syndrome is a rare genetic disorder with a variable and under-reported phenotype. The major clinical features include severe global development delay, brain abnormalities, FTT, neurological symptoms, respiratory abnormalities and facial dysmorphism as well multiple minor features.4 The clinical spectrum of TARP is much broader than the four historically defined cardinal features, as more cases are reported.

In our case, we noted an extremely elevated AFP, thrombocytopaenia and persistent conjugated hyperbilirubinaemia, previously not reported in TARP syndrome. Hyperbilirubinaemia was attributed to sludge gallbladder or a consequence of parenteral feeding from days 1 to 12. No anatomical, metabolic or alternative genetic pathology could be found to explain cholestasis. Elevated AFP in neonates is a debated topic due to wide variations in recommended reference intervals recorded in different studies.8 One explanation for elevated AFP may be prematurity. Each value recorded is within a proposed 10–90th percentile range. However, this is a far wider range than typically used in clinical practice and our results were far above the cut-off for suspicion of malignancy.8 Elevated AFP may also be linked to the direct hyperbilirubinaemia seen in this case explaining why it had never been mentioned before in TARP syndrome. Despite this, it would be extremely atypical to see such increased levels accounting for concomitant prematurity.9 Another consideration was malignancy due to the link between AFP and germ cell and hepatic tumours.8 Imaging showed no evidence of malignancy and no features have manifested during follow-up. These three unique features in our case may serve as future prognostic or diagnostic markers for TARP syndrome and should be highlighted and investigated in future cases.

We compare findings in this case to the major, minor and additional features according to Kumps et al 4 while factoring in the survival time of the patient (table 1). We only reported features that were explicitly reported as present or absent in previous cases. The prognosis of TARP syndrome has been an area of discussion for many years. Originally, TARP syndrome was viewed to have a 100% fatality rate during the neonatal period.2 Gripp et al described the first patient to survive past the infant period.10 Since, nine patients have been found to have survived past 18 months with the first adult identified in 2018.4 11 Our patient has survived beyond 2.5 years of age. He also has a milder phenotype compared with other patients in the literature. He is the first patient reported to have recovered from FTT without a gastrostomy and is only one of two patients not to have limb defects at birth. Additionally, compared with many other patients, he has reached a higher language and gross motor developmental level for his age.

Table 1

Characteristics of TARP syndrome using survival time as a case severity marker (where reported)

Table 1

Characteristics of TARP syndrome using survival time as a case severity marker (where reported)

It is postulated that there may be a genotype–phenotype correlation in TARP syndrome and the variable nature of the disease between cases (and specific mutations) indicate that this is likely.4 Interestingly, only two other patients had splice site mutations and both survived beyond 18 months (table 2). Additionally, only two patients have had in-frame deletions and both lived past 18 months. In contrast, all seven patients who suffered nonsense mutations died by 18 months. This may be indicative of a milder disease progression in cases with splice site, missense and in-frame deletion mutation types regardless of the specific mutation. Imagawa et al also showed that a milder phenotype occurs in missense mutations.12

Table 2

Mutations types and survival time in TARP syndrome

Mutation type Survived <18 months Survived >18 months
TARP, talipes equinovarus, atrial septal defect, Robin sequence, persistent left superior vena cava.
Splice site 0% (0/3) 100% (3/3)
Frameshift 64% (9/14) 36% (5/14)
Nonsense 100% (7/7) 0% (0/7)
Missense 0% (0/1) 100% (1/1)
Inframe deletion 0% (0/2) 100% (2/2)

Ethics statements

Patient consent for publication

Acknowledgments

The parents of the child who were keen on publication of the case in order to inform other parents and the medical community the same way they were informed by other parents.

Footnotes

  • Contributors ML wrote the manuscript. NA reviewed and edited the manuscript. JL identified the case, obtained consent, cowrote the manuscript and edited the article.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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