Arthrogryposis, renal dysfunction, cholestasis syndrome in a neonate: an uncommon association of common problems

Abstract

A male infant born out of non-consanguineous marriage to a primigravida presented to us as his third hospitalisation with ichthyotic lesions all over the body, cholestatic jaundice, multiple joint contractures and a history of recurrent sepsis. Blood and urine investigations revealed Fanconi syndrome, hypothyroidism and direct hyperbilirubinaemia with elevated liver enzymes and normal gamma glutamyl transpeptidase levels. The combination of arthrogryposis, renal dysfunction and cholestasis led to the suspicion of arthrogryposis, renal tubular dysfunction, cholestasis (ARC) syndrome, which was then proved by genetic testing. The baby was managed conservatively with respiratory support, antibiotics, multivitamins, levothyroxine and other supportive measures but succumbed to the illness on day 15 of hospitalisation. Genetic analysis using next-generation sequencing was confirmatory of a homozygous mutation in VIPAS39 gene leading to ARC syndrome type 2 in the present case. Genetic counselling was provided and prenatal testing was advised to the parents for future pregnancies.

Background

ARC Syndrome (OMIM 613404), an acronym for Arthrogryposis, Renal tubular dysfunction, and Cholestasis, is a rare autosomal recessive multisystem disorder with poor outcome. It was first described in 1973 by Lutz-Richner and Landolt et al.¹ Additional features of ARC include nephrogenic diabetes insipidus, failure to thrive, anomalies of the corpus callosum with neurodevelopmental delay, platelet dysfunction, recurrent infections, dysmorphic features, congenital heart disease, hypothyroidism, and keratitis.² Two genes, namely, VPS33B and VIPAS39, have been seen in 75% and 25% of cases, which are labelled as ARC1S and ARC2S, respectively.^{3 4}

Case presentation

A male infant presented to us with abnormal peeling of the skin over the body since day 4 of life and respiratory distress along with lethargy for the past 8 days. He was a product of non-consanguineous marriage to a primigravida in her 20s with a history of pregnancy-induced hypertension for which she was on antihypertensive medications throughout the pregnancy. He was delivered by emergency LSCS due to antepartum fetal distress and meconium-stained amniotic fluid, and required bag and mask resuscitation; he was then shifted to the mother’s side after receiving oxygen by hood for 30 min.

At 36 hours of life, the baby developed hypoglycaemia requiring neonatal intensive care unit (NICU) admission and intravenous antibiotics for 7 days. From day 4 of life, the mother noticed excessive peeling of the skin all over the body, which gradually progressed over time. Moreover, the baby was not moving his limbs freely. After discharge, the baby received oral antibiotics and topical emollients for 2 weeks. On day 15 of life, the baby was readmitted to the NICU for 8 days because of lethargy and skin peeling for which he received some intravenous antibiotics. On day 31 of life, the mother noticed respiratory distress and yellowish discolouration of the body in addition to the previous unresolved symptoms of skin peeling, reduced limb movement and lethargy. There was also poor weight gain in the baby. For the same symptoms, the baby was admitted to a local government hospital as his third hospitalisation for 5 days where he received oxygen by hood, phototherapy and intravenous antibiotics, and was referred to our hospital.

On presentation, he had ichthyotic lesions all over his body (figure 1), multiple joint contractures (figure 2) and rocker-bottom feet (figure 3) with minimal spontaneous movement of limbs. Visible jaundice was seen all over the body with bilateral intercostal and xiphoid retractions. Anterior fontanelle was at the level, and weak suck and cry were present. There was no organomegaly. The cardiovascular system appeared normal on auscultation. The stool colour was normal. Urine was highly coloured with normal output. There was no bleeding manifestation. Fundus examination was also within normal limits.

Figure 1.

Ichthyosis with arthrogryposis.

Figure 2.

Arthrogryposis of the hip, knee and ankle joints.

Figure 3.

Rocker-bottom feet.

Investigations

The blood glucose was normal on presentation and thereafter. The investigations are given in table 1. The initial sepsis screen came out to be positive. Cerebrospinal fluid (CSF) routine microscopy was suggestive of meningitis. Blood and CSF cultures were sterile. Blood gases showed hyperchloremic normal anion gap metabolic acidosis with pH ranging between 7.21 and 7.34. He also had persistent hypokalaemia, hypophosphataemia, proteinuria, with glycosuria, urine pH of 5.0 and increased urinary potassium excretion suggesting associated Fanconi syndrome. Serial kidney function tests were within normal range. Ultrasound of the abdomen was normal except for mild echogenicity in bilateral kidneys with normal size. Two-dimensional echocardiogram was normal and MRI of the brain was suggestive of mild hypoxic changes with no anatomical abnormalities. Liver function tests were suggestive of direct hyperbilirubinaemia with elevated liver enzymes with normal gamma glutamyl transpeptidase (GGT) levels. The workup for the aetiology of cholestatic jaundice was done. Urine for non-glucose-reducing substances and TORCH (toxoplasmosis, others, rubella, cytomegalovirus, herpes simplex) profile came out to be negative. However, the thyroid profile was abnormal with raised thyroid-stimulating hormone and low triiodothyronine levels (primary hypothyroidism). The association of arthrogryposis, renal dysfunction and cholestasis led to suspicion of ARC syndrome, so genetic testing using the next-generation sequencing panel was done. It was suggestive of homozygous mutation in VIPAS39 gene. This mutation was shown as likely pathological according to the American College of Medical Genetics and Genomics criteria.

Table 1.

Laboratory findings

Parameters	Units	Patient value	Reference range
Blood
Haemoglobin	g/L	71	111–141
White cell count	cells 109 /L	23	6-18
Platelet count	cells 109 /L	0.42	0.15 -0.45
Sugar	mg/dL	138
Culture	NA	Sterile
Serum
CRP	mg/L	39.9	0–6
Urea	mg/dL	85.9	10–45
Creatinine	mg/dL	0.87	0.5–1.4
Na	mmol/L	146.9	135–145
K	mmol/L	2.38	3.5–5.3
Ionic Ca	mg/dL	4	4.5–5.5
Phosphorus	mg/dL	2.08	2.5–4.5
Total bilirubin	mg/dL	12.2	0.3–1.4
Direct bilirubin	mg/dL	8.39	0–0.4
ALT	IU/L	246.1	0–45
AST	IU/L	423.4	0–40
ALP	IU/L	256.3	50–240
GGT	IU/L	109	0–114
T3	ng/dL	<0.40	0.58–1.59
T4	µg/dL	3.23	4.87–11.72
TSH	µIU/mL	11.15	0.35–4.94
CSF
Protein	mg/dL	155.1	15–45
Glucose	mg/dL	33	45–80
Total nucleated cell count	cells/mm3	30	0–5
Culture	NA (not available)	Sterile
Urine
pH	NA (not available)	5.0
Protein (dipstick method)	mg/dL	+++300
Glucose (dipstick method)	mg/dL	+++1000
Na	mmol/L	70	75–200
K	mmol/L	49.9	10–20

ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransaminase; Ca, calcium; CRP, C reactive protein; CSF, cerebrospinal fluid; GGT, gamma glutamyl transpeptidase; K, potassium; NA, not available; Na, sodium; T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.

Treatment

The patient was managed by oxygen support, tube feeding, fat-soluble vitamin supplementation along with ursodeoxycholic acid and intravenous antibiotics meropenem and linezolid. For acidosis, sodium bicarbonate supplementation was provided. Levothyroxine was started at a dose of 15 µg/kg/day. A topical emollient was applied to the skin lesions as advised by the dermatology team. The patient also received packed red blood cell transfusion on day 2 of hospitalisation.

Outcome and follow-up

Following treatment, the condition of the baby improved during the hospital stay. Oxygen support was weaned off and the baby was gradually shifted to oral feeds. However, on day 13 of hospitalisation, he developed recurrent hypoglycaemia. Glucose infusion rates were started and the baby was eventually taken on vasopressor support due to haemodynamic instability. Repeat C reactive protein was high suggestive of probable sepsis. The condition of the baby deteriorated further and despite all resuscitative efforts, he expired on day 16 of hospitalisation. The parents were counselled for prenatal testing in future pregnancy.

Discussion

Our patient presented with all three core features of ARC syndrome, namely arthrogryposis, renal dysfunction and cholestasis. Apart from the three cardinal features, various authors have reported other features in some patients such as failure to thrive, nephrogenic diabetes insipidus, neurogenic muscular atrophy (which appears to be responsible for the arthrogryposis), cerebral malformations such as corpus callosum agenesis, ichthyosis, dysmorphism such as lax skin (particularly in the neck), low-set ears, high-arched palate, cryptorchidism, hypothyroidism, congenital heart disease, diarrhoea, recurrent febrile illness, nerve deafness and abnormally large platelet without functional defect.^{5 6} Our patient presented with failure to thrive, hypothyroidism, ichthyosis and recurrent infections.

Arthrogryposis multiplex congenita is the most common diagnostic finding of ARC syndrome.⁷ It is believed to be caused by the malfunction of spinal motor neurons.⁸ The common anomalies of the musculoskeletal system in ARC syndrome are muscle atrophy, radial deviation of the wrist, dislocation of both hip joints, flexion contracture of the knee joints and calcaneovalgus. Osteopenia and pathological fractures can be observed in this syndrome owing to reduced reabsorption of phosphate ions via renal tubules and secondary to hyperparathyroidism.² Our patient had arthrogryposis involving joints of the hip, knees, ankle, shoulder, elbow and wrist. He also had muscle atrophy and rocker-bottom feet. Hip dislocation was not there in our patient.

Renal tubular manifestations are attributed to defective intracellular protein trafficking disrupting tubular epithelial polarity, which leads to defective directional absorption (endocytosis) and secretion of solutes.⁹ This can manifest as mild tubular dysfunction to global proximal tubular dysfunction (renal Fanconi syndrome). Renal tubular dysfunction may present in the first few days of life or later around the age of 2–3 months.^{10 11} Our patient had persistent hypokalaemia, hypophosphataemia, proteinuria, with glycosuria, urine pH of 5.0 and increased urinary potassium excretion suggesting associated Fanconi syndrome.

Intrahepatic cholestasis is frequently seen in patients with ARC syndrome. Direct hyperbilirubinaemia with normal GGT levels with or without abnormal liver histology is seen in these patients. Disruption in the polarity of hepatocytes leads to a reversal of the direction of flow of bile acids and other substances causing them to enter the bloodstream, hence leading to a cholestasis picture in this syndrome.^12–14 Our patient too presented with a similar pattern of liver function test. A liver biopsy usually is not required to make the diagnosis of ARC syndrome. Besides, these children are prone to bleeding, which makes the procedure riskier. Hence, a liver biopsy was not done on our patient.

The other distinguishing feature reported previously is the presence of hypothyroidism in patients with ARC syndrome, which was also seen in the present case. The underlying mechanism is still not clear. Bleeding manifestation due to abnormal platelet morphology¹⁵ as seen in various studies was not seen in our patient.

Our patient had a severe ARC phenotype manifesting renal Fanconi syndrome in addition to other clinical features. To the best of our knowledge, this is the first case report from India involving the VIPAS39 mutation. The prognosis of patients with ARC likely depends on the gene mutation type, phenotype and time of disease onset with unrevealed mechanisms, and the life span can even extend to early adulthood in milder phenotypes.

Despite ongoing research, the disease remains incurable and fatal with most children expiring before their first birthday due to recurrent infections and internal bleeding,^16–18 making a prenatal diagnosis as well as genetic counselling the cornerstone for the management of this syndrome by focusing on primary prevention of the disease.

Learning points.

• Multisystemic involvement in a sick newborn should always prompt the neonatologist to look for an underlying genetic syndrome.

• Arthrogryposis, renal tubular dysfunction, cholestasis syndrome can have myriad presentations and associations, especially concerning renal abnormalities.

• Diagnosis warrants a high index of suspicion.

• Genetic analysis remains the cornerstone for diagnosis as well as genetic counselling especially for future pregnancies.

Ethics statements

Patient consent for publication

Obtained from parent/guardian.