Failure to Thrive, Jaundice, and Polyuria in Early Infancy: Common Presentation with an Uncommon Lethal Etiology

Abstract

A 5-month-old female infant from a consanguineous Indian Muslim family presented with polyuria, polydipsia, failure to thrive, impaired renal function, and neonatal hepatitis of unknown cause at 1 month of age. Clinical exome testing revealed renal–hepatic–pancreatic dysplasia caused by homozygous c. 1985 + 5G > A pathogenic variations in NPHP3 . Our case illustrates delay in confirmatory diagnosis of such rare disorders in our region due to the lack of suspicion and unawareness of the availability of genetic testing even when there are no cost constraints.

Introduction

We are hereby presenting a case of renal–hepatic–pancreatic dysplasia (RHPD) or Ivemark syndrome. This is a very rare genetic disorder first described in 1959 in two siblings by Ivemark et al. ¹ Ivemark syndrome has been classified into two types based on the gene involved: type 1 ( NPHP3 on chromosome 3q22) and type 2 ( NEK8 on chromosome 17q11). Our patient has type 1 RHPD due to pathogenic variants in NPHP3 . NPHP3 gene is associated with three distinct phenotypes: type 1 RHPD caused by homozygous or compound heterozygous pathogenic variants, a milder presentation as nephronophthisis 3 due to hypomorphic pathogenic variants, and a Meckel syndrome 7 presentation. ² We describe here a severe type 1 RHPD presentation caused by homozygous pathogenic variants in NPHP3 .

Case Report and Presentation

A 5-month-old female infant presented to our pediatric nephrology clinic for polyuria, polydipsia, failure to thrive, and mildly raised serum potassium levels. The child was born full term with a birth weight of 3.5 kg and had no antenatal concerns. She had mild jaundice in the first week of life but was otherwise asymptomatic for the first few days after birth. After about 1 month of age, she developed progressively increasing inadequate feeding, lethargy, intermittent clay-colored stool, and increasing pallor. She was initially seen and admitted to the liver institute in New Delhi for failure to thrive and moderate-to-severe dehydration. She had jaundice with mildly raised unconjugated bilirubin and liver enzymes with hypothyroidism. During her stay for a month in the hospital, all blood evaluation for possible etiologies were negative and liver biopsy was nonspecific (reviewed reports suggested chronic sclerosing cholangitis, portal and periportal fibrosis). She was discharged from the hospital after some improvement in the icterus with the diagnosis of idiopathic neonatal cholestasis and hypothyroidism. The patient was then seen for polyuria in our pediatric nephrology clinic at 5 month of age. Her weight was 4.1 kg (25th percentile) and length was 54 cm (75th percentile). Her vital signs were as follows: pulse rate of 154/minute, respiration of 36/minute, and blood pressure of 120/70 mm Hg (>95th percentiles) on repeated readings. She looked alert with mild-to-moderate dehydration, depressed anterior fontanelle, and mild pallor but no cyanosis, edema, facial dysmorphism, seizures, cataract, or apparent hearing defect. Developmentally, social smile was present, but she had no head control. Abdomen examination revealed mild distension and hepatomegaly with ill-defined margins and smooth surface. No abnormality was noted on chest, cardiac, and nervous systemic examination. Investigations suggested the following: urea level of 70 mg/dl, creatinine level of 1 mg/dl, sodium level of 134 mmol/L, potassium level of 6.2 mmol/L, albumin level of 3.9 g/dL, serum chloride level of 120 mmol/L, bicarbonate level of 14 mmol/L, aspartate and alanine aminotransferase levels of 60 and 72 U/L, respectively, serum bilirubin and level of 1.4 mg/dL. Urine routine and microscopy examination revealed nil protein and red blood cells and no hypercalciuria. Ultrasonography revealed normal size bilateral echogenic kidney and mild hepatomegaly. High-resolution scan later suggested a few bilateral renal subcortical cysts. During admission, urine output noted was 5.2 L/day (52.8 mL/kg/h). It was noted that she was taking a high volume of oral rehydration solution (ORS) containing sodium and potassium for polydipsia, which was changed to potassium-free fluid in addition to other conservative management such as antihypertensive medications and calcium supplements. Possibilities of infantile onset nephronophthisis, polycystic kidney, and variant of renal tubular acidosis were considered as the differential diagnosis, and blood samples of the child and parents were sent for genetic analysis. Clinical exome sequencing analysis revealed a homozygous mutation in the NPHP3 gene on chromosome 3 (c.1985 + 5G > A). This pathogenic mutation resulted in the skipping of exon 13. Hence, the diagnosis of RHPD type 1 was made. Parents were counseled in detail for the disease prognosis and risk of inheritance.

Progressive worsening of renal function and clinical deterioration was noted over a period of 2 months, requiring peritoneal dialysis (PD), but no significant improvement was seen and, unfortunately, the patient passed away.

Discussion and Conclusion

RHPD type 1 is characterized by renal dysplasia in the form of glomerular cortical cysts and primitive collecting ducts, hepatic dysgenesis with enlarged portal areas and perilobular fibrosis, and pancreatic involvement. ³ This is a rare autosomal recessive disorder, with few case reports since the first case description in 1959 by Ivemark et al. In our case, NPHP3 mutation c.1985 + 5G > A–substitution was identified by clinical exom sequencing, which leads to a premature termination of translation. It has been reported before in an 8-year-old girl of a Vietnamese family with a similar phenotype, who received combined kidney–liver transplant at the age of 4 years. ⁴ Unfortunately, our patient did not survive on PD. High fetal and neonatal mortality and morbidity have been reported in previous reports ( Table 1 ). ^{4 5 6 7 8 9 10} Apart from the renal–hepatic–pancreatic triad, other associated morbidities reported are insulin-dependent diabetes, situs inversus, polydactyly, tapetoretinal degeneration, brain cysts, and anencephaly. ^{13 14 15 16} Nervous system abnormalities are more common in Meckel–Gruber's syndrome 7 and nephronophthisis presentations.

Table 1. RHPD type 1 reporting year, survival, and pathogenic mutations.

Year: after first report	Age and survival	Pathogenic NPHP3 mutations reported
1976: males 5	24 h
1978: brother and sister 6	Died within 24 h
1987: 5 unrelated 7	3 died within 1 mo, 2 in infancy
1988: premature males 8	Few minutes after birth
1995: 2 males 9	Both died shortly after birth
1996: 2 Swiss brothers 10	1 died immediately, second had renal failure at 13 mo—combined kidney liver transplant at 3.9 y—survival	c.3373C > T c.273delC
1996: 2 brothers 11	Died shortly after birth (Spanish)
2007: 2 siblings, males 12	1 abortion, second for 2 h
2007; 2 unrelated males 13	Stillborn	c.1817G > A
2008: 4 families—African (male), Turkey (female), Swiss (male), Vietnamese (female) 4	Perinatal, 45 d, 17 and 8 y who got combined liver–kidney transplant at 3 and 4 y, respectively.	c.3340C > T c.1729C > T c.2918G > A
2010: 2 siblings (female, male) 14	1 abortion, second for 24 h
2013: 5 siblings 15	3 term and 2 survived for 15 and 58 d, respectively, and 2 abortions	c.1985 + 5G > A
2019: first-born girl 16	1 mo/not mentioned	c.2694-2_2694–1delAG

Abbreviation: RHPD, renal–hepatic–pancreatic dysplasia.

In conclusion, here we highlight the need of early diagnosis to initiate management such as transplantation. Awareness of genetic etiology of this condition is needed for timely diagnosis.

Funding Statement

Funding None.